INTRODUCTION:

The study on the individualization of pharmacotherapy has been carried out aiming at further improvement of pharmacotherapy. The individualization of pharmacotherapy has been performed mainly by monitoring drug concentrations; however, pharmacogenetic approach such as genetic diagnosis has become a very attractive field by the rapid progress of molecular biology. Consequently, the dosage adjustment has been based on the interindividual differences of drug pharmacokinetics. However, intraindividual variability as well as interindividual variability should be considered to aim at further improvement of rational pharmacotherapy, because many drugs vary in potency and or toxicity associated with the rhythmicity of biochemical, physiological and behavioral processes^1–3.Theoretically, it has been argued that drug administration at certain times of the day should improve the outcome of pharmacotherapy. This has been accepted by the medical community and/or described in interview form for the treatment of nocturnal asthma, allergic rhinitis, arthritis, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease; however, many drugs are still given without regard to the time of day.

Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chrono-pharmacotherapy.

In contrast, several drugs cause alterations in the 24 hr rhythms of biochemical, physiological and behavioral processes⁶ .The alteration of rhythmicity is sometimes associated with therapeutic effects. This review introduces the concept of chronopharmaceutics to bridge the gap between the existing concept of chronobiology, chronopharmacology, chronopharmacokinetics, chronotherapeutics, and chronotoxicology. This review addresses the theoretical and formal basis of this emerging sub-discipline, reviews chronopharmaceutical technologies, and provide examples of formulations under development or on the market.

Chronotherapy:

The knowledge of 24 hr rhythm in the risk of disease plus evidence of 24 hr rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy). One approach to increase the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. The chronotherapy of a medication may be accomplished by the appropriate timing of conventionally formulated tablets and capsules, and a special drug delivery system to synchronize drug concentrations to rhythms in disease activity. Chronotherapy is especially relevant in the following cases. The risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. The therapeutic-to-toxicity ratio of a medication varies predictably according to chronobiological determinants as exemplified by antitumor medications. The pharmacokinetics and pharmacodynamics of a medication vary depending on biological rhythms. The goal of pharmacotherapy is hormonal substitution to mimic the rhythmic variation of hormone levels in healthy individuals. Also on the horizon are drugs to fix broken biological clocks, Perhaps a factor in all illness in the opinion of some physicians.⁴

Chronopharmaceutics:

Chronopharmaceutics: Definition and Concept:

To introduce the concept of chronopharmaceutics, it is important to define the concepts of chronobiology and pharmaceutics. Chronobiology is the study of biological rhythms and their mechanisms. Biological rhythms are defined by a number of characteristics ⁵. The term ‘‘circadian’’ was coined by Franz Halberg from the Latin circa, meaning about, and dies, meaning day ⁶. Oscillations of shorter duration are termed ‘‘ultradian’’ (more than one cycle per 24 h). Oscillations that are longer than 24 h are ‘‘infradian’’ (less than one cycle per 24 h) rhythms. Ultradian, circadian, and infradian rhythms coexist at all levels of biologic organization⁶. Pharmaceutics is an area of biomedical and pharmaceutical sciences that deals with the design and evaluation of pharmaceutical dosage forms (or drug delivery systems) to assure their safety, effectiveness, quality and reliability. Traditionally, drug delivery has meant getting a simple chemical absorbed predictably from the gut or from the site of injection. A second-generation drug delivery goal has been the perfection of continuous, constant rate (zero-order) delivery of bioactive agents. However, living organisms are not ‘‘zero-order’’ in their requirement or response to drugs. They are predictable resonating dynamic systems, which require different amounts of drug at predictably different times within the circadian cycle in order to maximize desired and minimize undesired drug effects ⁷. Based on the previous definitions, chronopharmaceutics is a branch of pharmaceutics devoted to the design and evaluation of drug delivery systems that release a bioactive agent at a rhythm that ideally matches the biological requirement of a given disease therapy. Ideally, chronopharmaceutical drug delivery systems (ChrDDS) should embody time-controlled and site-specific drug delivery systems ⁸. Advantages are safer, more effective and reliable therapeutic effect taking into account advances in chronobiology and chronopharmacology, system biology ⁹and nanomedicine For example, it has recently been demonstrated that it is possible to perform a continuous label-free detection of two cardiac biomarker proteins (creatin kinase and myoglobin) using an array of microfabricated cantilevers functionalized with covalently anchored anti-creatin kinase and anti-myoglobin antibodies by antigen–antibody molecular recognition¹⁰.Clinical applications of such nanotechnological approach lie in the field of early and rapid diagnosis and even design of ChrDDS against acute myocardial infarction. Evidence suggests that an ideal ChrDDS should: (i) be non-toxic within approved limits of use, (ii) have a real-time and specific triggering biomarker for a given disease state, (iii) 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), (iv) be biocompatible and biodegradable, especially for parenteral administration, (v) be easy to manufacture at economic cost, and (vi) be easy to administer in to patients in order to enhance compliance to dosage regimen. To our knowledge such ideal ChrDDS is not yet available on the market. The majority of these features may be found at the interface of chronobiology, chronopharmacology, system biology and nanomedicine.

Diseases With Established Oscillatory Rhythm In Their Pathogenesis:

The diseases currently targeted for chronopharmaceutical formulations are those for which there are enough scientific backgrounds to justify ChrDDS compared to the conventional drug administration approach. These include: asthma, arthritis, duodenal ulcer, cancer, diabetes, cardiovascular diseases (e.g. hypertension and acute myocardial infarction), hypercholesterolemia, and ulcer and neurological disorderes.The rationale for chronotherapy for each of these diseases will be briefly reviewed below. Interested readers may find a comprehensive coverage of the topics in several excellent reviews and references provided .^{7, 11}

Asthma:

The chronotherapy of asthma has been extensively studied ^12-13. The role of circadian rhythms in the pathogenesis and treatment of asthma indicates that airway resistance increases progressively at night in asthmatic patients ¹⁵. Circadian changes are seen in normal lung function, which reaches a low point in the early morning hours. This dip is particularly pronounced in people with asthma. Because bronchoconstriction and exacerbation of symptoms vary in a circadian fashion, asthma is well suited for chronotherapy ¹⁴. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline, and B2-agonists .¹⁵

Arthritis:

The chronobiology, chronopharmacology and chronotherapeutics of pain have been extensively reviewed ¹⁵. For instance, there is a circadian rhythm in the plasma concentration of c-reactive protein ¹⁶ and interleukin-6 ¹⁷of patients with rheumatoid arthritis. Increasingly, the arthritides have shown statistically quantifiable rhythmic parameters. Included in the latter group are joint pain and joint size. In addition, a number of drugs used to treat rheumatic diseases have varying therapeutic and toxic effects based on the time of day of administration .Patients with osteoarthritis tend to have less pain in the morning and more at night; while those with rheumatoid arthritis, have pain that usually peaks in the morning and decreases throughout the day. Chronotherapy or all forms of arthritis using NSAIDs such as ibuprofen should be timed to ensure that the highest blood levels of the drug coincide with peak pain. For osteoarthritis sufferers, the optimal time for a nonsteroidal anti-inflammatory drug such as ibuprofen would be around noon or mid-afternoon. The same drug would be more effective for people with rheumatoid arthritis when taken after the evening meal. The exact dose would depend on the severity of the patient’s pain and his or her individual physiology.

Duodenal ulcer:

Many of the functions of the gastrointestinal tract are subject to circadian rhythms: gastric acid secretion is highest at night ¹⁸, while gastric and small bowel motility and gastric emptying are all slower at night. These biorhythms have important implications in the pharmacokinetics of orally administered drugs. At nighttime, when gastric motility and emptying are slower, drug disintegration, dissolution, and absorption may be slower. In peptic ulcer patients, gastric acid secretion is highest during the night. Suppression of nocturnal acid is an important factor in duodenal ulcer healing. Therefore, for active duodenal ulcer, once daily at bedtime is the recommended dosage regimen for H2 antagonists ¹⁹. Theoretical problems associated with a sustained or profound decrease of 24-h intragastric acidity include the threat of enteric infection and infestation, potential bacterial overgrowth with possible N-nitrosamine formation, and drug-induced hypergastrinaemia. In light of these potential problems, for the management of simple peptic ulceration, it appears sensible to use the minimum intervention required. Bedtime H2-receptor blockade is one such regimen ²⁰.

Cancer:

Human and animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully selected times that take advantage of tumor cell cycles while less toxic to normal tissue ²¹. The rhythmic circadian changes in tumor blood flow and cancer growth are relevant both when tumors are small and growing most rapidly and when they are larger and growing more slowly. The blood flow to tumors and tumor growth rate are each up to threefold greater during each daily activity phase of the circadian cycle than during the daily rest phase ²². Clinical studies testing whether circadian chemotherapy timing meaningfully affects drug toxicity patterns and severity, maximum tolerated dose, average dose intensity, tumor response quality and frequency and the survival of patients with cancer, have been indicated since the pioneer work of Haus et al.²¹ on leukemic mice. The chronotherapy concept offers further promise for improving current cancer-treatment options, as well as for optimizing the development of new anticancer or supportive agents .²²

Diabetes:

There circadian variations of glucose and insulin in diabetes have been extensively studied and their clinical importance in case of insulin substitution in type 1 diabetes has been previously discussed ^23-25. The goal of insulin therapy is to mimic the normal physiologic pattern of endogenous insulin secretion in healthy individuals, with continuous basal secretion as well as meal-stimulated secretion. Providing basal insulin exogenously to patients with diabetes inhibits hepatic glucose production ²⁵. Exogenous administration of mealtime doses promotes peripheral glucose uptake (i.e. it prevents postprandial increases in blood glucose concentration) as well as reducing hepatic glucose release ³⁵.

Cardiovascular diseases:

Several functions (e.g. BP, heart rate, stroke volume, cardiac output, blood flow) of the cardiovascular system are subject to circadian rhythms. For instance, capillary resistance and vascular reactivity are higher in the morning and decrease later in the day. Platelet aggregability is increased and fibrinolytic activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood ²⁶. It was postulated that modification of these circadian triggers by pharmacologic agents may lead to the prevention of adverse cardiac events ²⁷. Cardiac events also occur with a circadian pattern. Numerous studies have shown an increase in the incidence of early-morning myocardial infarction, sudden cardiac death, stroke, and episodes of ischemia ²⁸. The circadian pattern of BP has been well documented ²⁹. BP is at its lowest during the sleep cycle and rises steeply during the early morning awakening period. Most patients with essential hypertension have a similar circadian rhythm of BP as do normotensive persons, although hypertensive patients have an upward shift in the profile ³⁰.

Hypercholesterolemia:

Diverse directions of circadian changes in lipid fractions in patients and normal subjects may contribute to alteration in the rhythmicity of other metabolisms and in the blood coagulation system, thus leading to various complications ³¹. A circadian rhythm occurs during hepatic cholesterol synthesis ³². However, this rhythm varies according to individuals. Indeed, there is a large variation in plasma mevalonate concentrations between individuals. Therefore cholesterol synthesis is generally higher during the night than during daylight, and diurnal synthesis may represent up to 30%–40% of daily cholesterol synthesis. Many individuals display a paradoxical synthesis, with an inverted diurnal cholesterol synthesis. It seems therefore that cholesterol is synthesized during the night as well as during daylight; however the maximal production occurs early in the morning, i.e. 12 h after the last meal ³³. Studies with HMG CoA reductase inhibitors have suggested that evening dosing was more effective than morning dosing ³⁴.

Neurological disorders:

As an integrative discipline in physiology and medical research, chronobiology renders possible the discovery of new regulation processes regarding the central mechanisms of epilepsy. Chronophysiology investigations considered at a rhythmometric level of resolution suggest several heuristic perspectives regarding (i), the central pathophysiology of epilepsy and (ii) the behavioral classification of convulsive events. Such circadian studies also show that chronobiology raises some working hypotheses in psychophysiology and permits the development of new theoretical concepts in the field of neurological science ³⁵. It is also well known that the brain area with the highest concentration in noradrenergic nerve terminals and noradrenaline (NA) have a circadian rhythm in their content of NA ³⁶. Moreover, it has been shown that the human sleep, its duration and organization depend on its circadian phase ³⁷. A breakthrough chronopharmaceutical formulation against insomnia that plagues many people would be one that addresses the entire oscillatory cycle of human sleeping process.

Chrono-Drug Delivery System (cHR-DDS):

The effectiveness and toxicity of many drugs vary depending on the 24 hr rhythms of biochemical, physiological and behavioral processes. Also, several drugs can cause alterations to the 24 hr rhythms leading to illness and altered homeostatic regulation. The alteration of biological rhythm is a new concept of adverse effects. It can be minimized by optimizing the dosing schedule.³⁸.Many researches demonstrate the rationale behind chronotherapy³⁹ however, drug delivery research has focused on a constant drug release rate. The reason why the majority of DDS is designed without emphasis on proven oscillatory phenomena may be in drug delivery limitations. Advances in chronobiology and global market constraints change the traditional goal of pharmaceutics such as a constant drug release rate.

Drug Delivery Technologies For Chronotherapy:

Pharmaceutical formulations are characteristic of particular delivery system. Delivery systems are based on the general approach differentiating on the route of administration and their application via temporal and spatial mode which finally lead to systemic circulation. Drug delivery systems based on various technologies have been developed for chronotherapy. They are summarized further ³⁹

1 .CONTIN® technology:

In this technology, molecular coordination complexes are found 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, preferable as a melt. This technology has enabled the development of tablet forms of sustained release aminophylline, theophylline, morphine and other drugs. This technology is characterized by providing for closer control over the amount of drug released into blood stream there by reducing the number of doses which in turn lower the side effects ⁴⁰.

2. Physico-chemical modification of the API:

In this strategy, a proprietary method is used to modify the physicochemical properties (e.g. solubility, partition coefficient, membrane permeability, etc.) of the API to achieve the chronopharmaceutical objective. 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. The different chemical structures of different H2-receptor antagonists (e.g. cimetidine, ranitidine, famotidine and nizatidine) do not alter the drugs clinical efficacies as much as they determine interactions with other drugs and change the side effect profile. Other physico-chemical strategies to chronopharmaceutical drug delivery may include selection of the salt forms (e.g. divalent rather than monovalent salts of weakly acidic drugs), chirality, and control of particle size (micronization). This strategy has resulted in the actual use of these drugs as ChrDDS against hypercholesterolemia and ulcer ^{41, 43...}

3. OROS® technology:

OROS® technology uses an osmotic mechanism to provide pre-programmed, controlled drug delivery to the gastrointestinal tract. The dosage form comprises a wall that defines a compartment. The active drug is housed in a reservoir, surrounded by a semi-permeable membrane/wall (e.g. cellulose esters, cellulose ethers and cellulose ester–ethers) and formulated into a tablet. This technology, especially the OROS® Delayed Push– Pull System, also known as controlled onset extended release (COER) was used to design Covera-HSR, a novel anti-hypertensive 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 ^44-46.

4. CODAS® technology:

The Chronotherapeutic Oral Drug Absorption System (CODAS®) is a multiparticulate system which is designed for bedtime drug dosing, incorporating a 4–5 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. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of verapamil. The CODAS®-verapamil extended release capsules (Verelan® PM) as ChrDDS actually provided enhanced BP reduction during the morning period when compared with other time intervals of the 24-h dosing period ^47,48.

5. CEFORM® technology:

CEFORM® technology allows the production of uniformly sized and shaped microspheres of pharmaceutical compounds. This ChrDDS approach is based on ‘‘melt-spinning’’, 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 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 ⁴⁹.

6. DIFFUCAPS® technology:

DIFFUCAPS® technology comprise 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 3–5 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 film-forming formulation and preferably a water-soluble film forming composition (e.g. hydroxypropyl methylcellulose, 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 concentration–time 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 ⁵⁰.

7. Chronomodulating infusion pumps:

Externally and internally controlled systems across a range of technologies including pre-programmed systems as well as systems that are sensitive to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation have been used. Till now infusion pumps as chronomodulators for drug delivery application include the Melodie®, programmable Synchromed® , Panomat® V5 infusion and the Rhythmic® pumps. The portable pumps are usually characterized by a light weigh (300–500 g) for easy portability and precision in drug delivery. Doses adjustments are made by the patient (within ranges established by the physician) using radiotelemetry and an electronic device that is held over the pump. These pumps have been effectively used in the chronotherapy of several diseases such as cancer and diabetes^51.52.

8. TIMERx® technology:

TIMERx® technology (hydrophilic system) combines primarily xanthan and locust bean gums mixed with dextrose. Drug release is controlled by the rate of water penetration from the gastrointestinal tract into the TIMER®R gum matrix, which expands to form a gel and subsequently releases the active drug substance. A chronotherapeutic version of this technology platform is being tested in clinical trial with a bioactive agent known as AD 121 against rheumatoid arthritis. Potential application of this technology is the development of an oral, CR opioid analgesic oxymorphone ^53,
54.

9. Three-dimensional printing®:

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 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 pulses of about 4 h. This technology is the basis of the TheriForm® technology ⁵⁵.

10. Other CR erodible polymers:

Erodible polymers have been designed in different forms (e.g. tablets, capsules, microparticles) for ChrDDS applications. For example, Ross et al. reported the development of a chronopharmaceuticals capsule drug delivery system which contained the drug formulation sealed inside the insoluble capsule body by an erodible tablet (ET) that is composed of an insoluble (e.g. dibasic calcium phosphate) and gel-forming (e.g. hydroxypropyl methyl cellulose) excipient. Programmable pulsatile release was achieved from a capsule device over a 2–12-h period, consistent with the demands of chronopharmaceutic drug delivery. Guar gum-based matrix tablets represent a simple and economical alternative to existing drug sustained release dosage forms. Recently, various polymers like Eudragit® polymers have been used in combination with biodegradable polymers to control the release of heparin for potential chronotherapeutic application against thrombosis and hypertension. Overall by careful selection and combination of polymeric drug carrier of different erosion/degradation kinetic, or by manipulating the interaction energy between the drug and the polymer, it may be possible to control the release of a drug at a rate that matches the requirement of the biological rhythm of a given disease state^56,57.

11. Controlled-release microchip:

An alternative method to achieve pulsatile or chronopharmaceutical drug release involves using microfabrication technology. Santini et al. reported 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 microreservoirs filled with chemicals in solid, liquid or gel form. 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 ^{58, 59}.

Chronothearpeutics:

A list of other chronotherapies that are now in use in clinical medicine are given as follows ⁶⁰,

· Once-daily and alternate-day morning corticosteroids dosing minimizes risk of adrenal suppression and other side effects.

· Bedtime corticosteroid dosing controls excessive hormone secretion in congenital adrenal hyperplasia.

· Asymmetrical morning high and late-afternoon low-dose corticosteroid substitution chronotherapy for Addison’s disease best corrects fatigue and abnormal circadian time structure.

· Evening ingestion of certain HMG-CoA reductase antagonist medications optimizes cholesterol-lowering effect.

· Nitroglycerin transdermal patch medication worn during the portion of the 24 h to protect against angina when risk is greatest and removed in time to avoid sensitization to medication.

· Evening H2-receptor antagonist ingestion best controls nocturnal peptic ulcer and gastroesophageal reflux disease.

· Evening NSAID treatment optimizes attenuation of morning symptoms of rheumatoid arthritis; midday and/or afternoon NSAID treatment best for osteoarthritis that is typically worse in evening.

· Bedtime ADH analogue dosing helps to alleviate nocturnal bedwetting in children and nocturia in adults.

· Bedtime (but not morning) aspirin dosing best for preventing pregnancy-induced hypertension and preeclampsia.

· Evening theophylline chronotherapy (Uniphyl), producing highest drug concentration in sleep, optimizes control of nocturnal asthma and COPD.

· Evening verapamil chronotherapy (Verelan PM and Covera-HS) achieves more complete 24-h BP control than once-a-day conventional constant-release medications.

· Timed melatonin and bright-light chronotherapies enhance speed of adjustment to alteration of the sleep–wake routine after rapid transmeridian displacement by airplane or rotation between day and night shifts.

· Timed bright-light chronotherapy is effective for seasonal affective disorder (SAD), premenstrual dysphoric disorder (PMDD), and circadian rhythm sleep disorders (advanced and delayed sleep phase syndromes and non–24-h sleep–wake cycle disorder).

· Luteal phase (commencing 6 to 14 days before menses) therapy of premenstrual dysphoric disorder (PMDD) using alprazolam, clomipramine, citalopram, fluoxetine, or sertraline.

Infusion of cancer medications in synchrony with circadian rhythms minimizes drug-induced toxicity, aenabling more aggressive treatment.

Thunbergia alata Bojer popularly known as Black Eyed Susan Vine belongs to family Acanthaceae is nearly neither aggressive nor hardy; the flowers look very striking due to the dark center and will be covered in bloom most of the year, excepting the depths of winter ⁶.

REFERENCES:

1. D. Horter, J. B. Dressman, Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract, Adv. Drug Deliv. Rev. 46 (2001) 75–87.

2. E. A. Stein, M. H. Davidson, A. S. Dobs, H. Schrott, C. A. Dujovne, H. Bays, S.R. Weiss, M. R. Melino, M. E. Mitchel, Y. B. Mitchel, Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin US Study Group, Am. J. Cardiol. 82 (1998) 311–316.

3. The Meck Index, 13th ed., Merck & Co., Whitehouse Station, NJ, 2001.

4. R. Mahley, T. Bersot, Drug therapy for hypercholesterolemia and dyslipidemia, in: J. Hardman, L. Limbird, A. Gilman (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, 2001, pp. 971– 1002.

5. W. Hoogerwerf, P. Pasricha, Agents used for control of gastric acidity and treatment of peptic ulcers and gastroesophageal reflux disease, in: J. Hardman, L. Limbird, A. Gilman (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, 2001, pp. 1005–1020.

6. W. B. White, D. V. Mehrotra, H. R. Black, T. D. Fakouhi, Effects of controlled-onset extended-release verapamil on nocturnal blood pressure (dippers versus nondippers). COER-Verapamil Study Group, Am. J. Cardiol. 80 (1997) 469–474.

7. L. M. Prisant, J. G. Devane, J. Butler, A steady-state evaluation of the bioavailability of chronotherapeutic oral drug absorption system verapamil PM after nighttime dosing versus immediate-acting verapamil dosed every 8 h, Am. J. Ther. 7 (2000) 345–351

8. D. H. Smith, J. M. Neutel, M. A. Weber, A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning, Am. J. Hypertens. 14 (2001) 14–19.

9. B. L. Carter, Optimizing delivery systems to tailor pharmacotherapy to cardiovascular circadian events, Am. J. Health Syst. Pharm. 55 (1998) S17– S23.

10. R. Verma, G. Sanjay, Current status of drug delivery technologies and future directions, Pharm. Technol. 25 (2001) 1–14.

11. www.elan.com

12. M. A. Weber, L. M. Prisant, H. R. Black, F. H. Messerli, Treatment of Elderly Hypertensive Patients With a Delayed-Release Verapamil Formulation in a Community-Based Trial, Am J Geriatr Cardiol. 13 (2004) 131–136.

13. www.biovail.com

14. www.eurand.com

15. S. Sershen, J. West, Implantable, polymeric systems for modulated drug delivery, Adv. Drug Deliv. Rev. 54 (2002) 1225–1235.

16. F. Levi, R. Zidani, J. L. Misset, Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy, Lancet 350 (1997) 681–686.

17. S. T. Tzannis, W. J. Hrushesky, P. A. Wood, T. M. Przybycien,Irreversible inactivation of interleukin 2 in a pump-based delivery environment, Proc. Natl. Acad. Sci. USA 93 (1996) 5460–5465.

18. www.penwest.com

19. J. N Staniforth, A. Baichwal, TIMERx^®: novel polysaccharide composites for controlled/programmed release of drugs in the gastrointestinal tract R Exp. Opin. Drug Del. 2 (2005) 587-595.

20. A. Baichwal, D. A. Neville, Culturing innovation and enhancing medications using oral drug delivery, Drug Delivery Tech article 6

21. W. E. Katstra, R. D. Palazzolo, C. W. Rowe, B. Giritlioglu, P. Teung, M. J. Cima, Oral dosage forms fabricated by three dimensional printing, J. Control. Release. 66 (2000) 1–9.

22. C. W. Rowe, W. E. Katstra, R. D. Palazzolo, B. Giritlioglu, P. Teung, M. J. Cima, Multimechanism oral dosage forms fabricated by three dimensional printing, J. Control. Release. 66 (2000) 11–17.

23. A. C. Ross, R. J. MacRae, M. Walther, H. N. Stevens, Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion, J. Pharm. Pharmacol. 52 (2000) 903–909.

24. S. A. Altaf, K. Yu, J. Parasrampuria, D. R. Friend, Guar gum based sustained release diltiazem, Pharm. Res. 15 (1998) 1196–1201.

25. R. Bodmeier, X. Guo, R. E. Sarabia, P. F. Skultety, The influence of buffer species and strength on diltiazem HCl release from beads coated with the aqueous cationic polymer dispersions, Eudragit RS, RL 30D, Pharm. Res. 13 (1996) 52–56.

26. J. T. Santini Jr., M. J. Cima, R. Langer, A controlled-release microchip, Nature 397 (1999) 335–338.

27. A. C. Richards Grayson, I. S. Choi, B. M. Tyler, P. P. Wang, H. Brem, M. J. Cima, R. Langer, Multi-pulse drug delivery from a resorbable polymeric microchip device, Nat. Mater. 2 (2003) 767–772.

28. J. L. West, N. J. Halas, Engineered nanomaterials for biophotonics applications: improving sensing, imaging, and therapeutics, Annu. Rev. Biomed. Eng. 5 (2003) 285–292.

29. D. L. Wise, Handbook of Pharmaceutical Controlled Release Technology, 2000, Marcel Dekker, Inc.

30. Cherng-ju Kim, Advanced pharmaceutics Physicochemical Principles, 2004, CRC Press LLC.

31. Supercritical fluid technology for drug product development , 2004, Marcel Dekker.

32. Understanding drug release and absorption mechanisms a physical and mathematical approach, 2006, Taylor & Francis Group, LLC.

33. F. Uchegbu, A. G. Schätzlein, Polymers in drug delivery, 2006, Taylor & Francis Group, LLC.

34. M. C. Rogge, D.R. Taft, Preclinical drug development, 2005, Taylor & Francis Group, LLC.

35. V. V. Ranade, M. A. Hollinger, Drug delivery systems Second Edition,CRC Press.

36. E. Touitou, B. W. Barry, Enhancement in Drug Delivery, 2006, CRC press.

37. S. S. Davis, A. F. Stockwell, M. J. Taylor, J. G. Hardy, D. R. Whalley, C. G. Wilson, H. Bechgaard, F. N. Christensen, The effect of density on the gastric emptying of single- and multiple-unit dosage forms, Pharm. Res. 3 (1986) 208–213.

38. R. Gröning, G. Heun, Oral dosage forms with controlled gastrointestinal transit. Drug Dev. Ind. Pharm. 10 (1984) 527–539.

39. B. N. Singh,K. H. Kim, Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention, J. Control. Release. 63 (2000) 235–259.

40. A. Streubel, J. Siepmann, R. Bodmeier,Drug delivery to the upper small intestine window using gastroretentive technologies, Cur. Opinion Pharmacol.6 (2006) 501-508

41. S. Sangekar, W. A. Vadino, I. Chaudry, A. Parr, R. Beihn,G. Digenis, Evaluation of the effect of food and specific gravity of tablets on gastric retention time, Int. J. Pharm. 35 (1987) 187–191.

42. B. N. Singh, Effects of food on clinical pharmacokinetics, Clin. Pharmacokinet 37 (1999) 213–255

43. P. L. Bardonnet, V. Faivre, W. J. Pugh, J.C. Piffaretti, F.Falson,Gastroretentive dosage forms: Overview and special case of Helicobacter pylori, J. Control Release. 111 (2006)1-18.

44. S. S. Davis, Formulation strategies for absorption windows, Drug Disc. Today, 10 (2005) 249-257.

45. L. Whitehead, J. T. Fell, J. H. Collett, H. L. Sharma, A. M. Smith, Floating dosage forms: an in vivo study demonstrating prolonged gastric retention, J. Control Release. 55 (1998)3-12.

46. B. Y. Choi, H. J. Park, S. J. Hwang, J. B. Park, Preparation of alginate beads for floating drug delivery system: effects of CO₂ gas-forming agents, Int. J. Pharm. 239 (2002)81-91.

47. I.Krögel, R. Bodmeier, Floating or pulsatile drug delivery systems based on coated effervescent cores, Int. J. Pharm.187 (1999) 175-184.

48. S. Y. Hou, V. E. Cowles, B. Berner, Gastric retentive dosage forms: a review, Crit. Rev. Ther. Drug Carrier Syst. 20 (2003) 459–497.

49. L. H. Reddy,R. S. Murthy, Floating dosage systems in drug delivery, Crit. Rev. Ther. Drug Carrier Syst. 19 (2002) 553–585.

50. F. C. Hampson, A. Farndale, V. Strugala, J. Sykes, I.G. Jolliffe, P. W. Dettmar Alginate rafts and their characterization, Int. J. Pharm. 294 (2005) 137-147.

51. F. A. Johnson, D. Q. M. Craig, A. D. Mercer, S. Chauhan, The effects of alginate molecular structure and formulation variables on the physical characteristics of alginate raft systems, Int. J. Pharm.159 (1997) 35-42.

52. S. V. Mandlekar, S. S. Marathe, P. V. Devarajan, A novel raft-forming antacid suspension using a natural dietary fibre, Int. J. Pharm.148 (1997) 117-121.

53. N. Washington, C. Washington, C. G. Wilson, S. S. Davis, The effect of inclusion of aluminium hydroxide in alginate-containing raft-forming antacids, Int. J. Pharm. 28(1986)139-143.

54. P. Sher, G. Ingavle, S. Ponrathnam, A. P. Pawar, Low density porous carrier based conceptual drug delivery system,Micro.Meso.Mater.102 (2007) 290-298.

55. P. Sher, G. Ingavle, S. Ponrathnam, A. P. Pawar, Low density porous carrier: Drug adsorption and release study by response surface methodology using different solvents, Int. J. Pharm.331 (2007) 72-83.

56. S. Sharma, A. Pawar, Low density multiparticulate system for pulsatile release of meloxicam, Int. J. Pharm. 313(2006)150-158.

57. J. T. Santini Jr., M. J. Cima, R. Langer, A controlled-release microchip, Nature 397 (1999) 335–338.

58. A. C. Richards Grayson, I. S. Choi, B. M. Tyler, P. P. Wang, H. Brem, M. J. Cima, R. Langer, Multi-pulse drug delivery from a resorbable polymeric microchip device, Nat. Mater. 2 (2003) 767–772.

59. J. L. West, N. J. Halas, Engineered nanomaterials for biophotonics applications: improving sensing, imaging, and therapeutics, Annu. Rev. Biomed. Eng. 5 (2003) 285–292.

60. M. H. Smolensky, E. Haus, Circadian rhythms and clinical medicine with applications to hypertension, Am. J. Hypertension. 14 (2001) 280S–290S.

Received on 06.12.2008 Modified on 02.02.2009

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 58-64