Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery?

Journal of Controlled Release 98 (2004) 337 – 353 www.elsevier.com/locate/jconrel

Review

Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery? Bi-Botti C. Youan * Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo 1300, Coulter, TX 79106, USA Received 9 February 2004; accepted 25 May 2004 Available online 17 July 2004

Abstract Due to advances in chronobiology, chronopharmacology, and global market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. The last decade has witnessed the emergence of ChrDDS against several diseases. The increasing research interest surrounding ChrDDS may lead to the creation of a new subdiscipline in pharmaceutics known as chronopharmaceutics. This review introduces the concept of chronopharmaceutics, addresses theoretical/formal approaches to this sub-discipline, underscores potential disease-targets, revisits existing technologies and examples of ChrDDS. Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as system biology and nanomedicine. Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy in the future. D 2004 Elsevier B.V. All rights reserved. Keywords: Chronopharmaceutics; Chronopharmacology; Chronotherapeutics; Drug Delivery; Technologies

Contents

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Introduction to chronopharmaceutics . . . . . . . . . . . . . . . . 1.1. Chronopharmaceutics: definition and concept . . . . . . . 1.2. Theoretical and formal approaches to chronopharmaceutics 1.2.1. Modeling cardiovascular diseases . . . . . . . . .

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Abbreviations: API, active pharmaceutical ingredient; ChrDDS, chronopharmaceutical drug delivery system; CODAS, chronotherapeutic drug oral absorption system; COER, controlled onset extended release; 3DP, three dimensional printing; ET, erodible tablets; HMG-CoA, 3hydroxy-3methyl-glutaryl-coenzyme A; MW, molecular weight; m.p., melting point; NA, noradrenaline; NDDS, novel drug delivery system; NSAID, non-steroidal, anti-inflammatory drug; SCN, suprachiasmatic nucleus. * Tel.: +1-806-356-4015x236; fax: +1-806-356-4034. E-mail address: [email protected] (B.-B.C. Youan). 0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2004.05.015

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1.2.2. Modeling cancer chemotherapy . . . . . . . . . . 1.2.3. Modeling glucose insulin interaction . . . . . . . . 1.2.4. Modeling other diseases . . . . . . . . . . . . . . 2. New global trends in drug discovery and development . . . . . . . 3. Diseases with established oscillatory rhythm in their pathogenesis . 3.1. Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Duodenal ulcer . . . . . . . . . . . . . . . . . . . . . . . 3.4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Cardiovascular diseases . . . . . . . . . . . . . . . . . . . 3.7. Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . 3.8. Neurological disorders. . . . . . . . . . . . . . . . . . . . 4. Examples of chronopharmaceutical technologies . . . . . . . . . . 4.1. CONTINR technology . . . . . . . . . . . . . . . . . . . 4.2. Physico-chemical modification of the API . . . . . . . . . 4.3. OROSR technology . . . . . . . . . . . . . . . . . . . . . 4.4. CODASR technology . . . . . . . . . . . . . . . . . . . . 4.5. CEFORMR technology . . . . . . . . . . . . . . . . . . . 4.6. DIFFUCAPSR technology . . . . . . . . . . . . . . . . . 4.7. Chronomodulating infusion pumps . . . . . . . . . . . . . 4.8. TIMERxR technology . . . . . . . . . . . . . . . . . . . . 4.9. Three-dimensional printingR . . . . . . . . . . . . . . . . 4.10. Other Controlled-release erodible polymers . . . . . . . . 4.11. Controlled-release microchip . . . . . . . . . . . . . . . . 5. Examples of chronopharmaceutical drug delivery systems . . . . . 6. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction to chronopharmaceutics Daily rhythms in plants and animals have been observed since early times. As early as the fourth century BC, Alexander the Great’s scribe Androsthenes noted that the leaves of certain trees opened during the day and closed at night showing a clear rhythmicity. In 1729, the French astronomer Jean Jacques d’Ortous deMairan conducted the first known experiment on biological rhythms [1]. Since then, it has been proven that insects use photoperiodic information to bring their growth and dormant periods into harmony with seasons [2]. Circadian rhythms of behavior in mammals are known to be robust and precise [3,4]. A recent review on developmental timing underlined the importance of chronobiologic processes [5]. The effectiveness and toxicity of many drugs vary

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depending on the relationship between the dosing schedule and the 24-h rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24h rhythms leading to illness and altered homeostatic regulation. The alteration of biological rhythm is a new concept of adverse effects. It has been demonstrated that the latter can be minimized by optimizing the dosing schedule [6]. A large body of literature exists demonstrating the rationale behind chronotherapy [7 –28]. However, much of drug delivery research over the past decades has focused on constant drug release rate. So, why are the majority of drug delivery systems designed with little emphasis on proven oscillatory phenomena? The bottleneck may be in drug delivery limitations. Chronopharmaceutics should address these new challenges in drug delivery. This review introduces

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the concept of chronopharmaceutics to bridge the gap between the existing concept of chronobiology [29,30], chronopharmacology [31 – 35], chronopharmacokinetics [36,37], chronotherapeutics [38 – 43], and chronotoxicology [7,8] previously defined in the literature. To achieve this goal with the latest informations, relevant peer-reviewed articles, United States patents, specific pharmaceutical company websites and the US Food and Drug Administration (FDA) electronic orange book have been consulted. 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. 1.1. 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 [7]. The term ‘‘circadian’’ was coined by Franz Halberg from the Latin circa, meaning about, and dies, meaning day [28]. 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 organization [7]. 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 (Fig. 1). 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 [30]. Based on the previous

Fig. 1. Key steps to be well-integrated for successful ChrDDS design and evaluation.

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 [44]. Advantages are safer, more effective and reliable therapeutic effect taking into account advances in chronobiology and chronopharmacology, system biology [45] and nanomedicine [46]. 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 recognition [47]. 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

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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. 1.2. Theoretical and formal approaches to chronopharmaceutics When treating human diseases, the overall goal is to cure or manage the disease while minimizing the negative impact of side effects associated with therapy. In this respect, chronopharmaceutics will be a clinically relevant and reliable discipline if pharmaceutical scientists could delineate a formal and systematic approach to design and evaluate drug delivery system that matches the biological requirement. The key component for the success of ChrDDS design for the treatment of diseases is the elucidation of control-relevant models for drug delivery [48]. A control-relevant model is that one that has: (i) predictive capability in terms of the process input –output behavior; and (ii) utility in performing on-line calculations for control or optimization purposes. Because of the complexity of identified biological oscillators, two physical descriptors have been discussed to illustrate the mathematical description of such system: the linear mass-spring oscillator and the non-linear, electrical oscillator described by van der Pol [49]. The latter provides a simple example of an oscillator in which the variation of one parameter alters the system from being relatively insensitive to noise to one that is very sensitive [49]. A general introduction to the mathematics of biological oscillators can be found in the monograph by Pavlidis [50]. A number of modeling approaches are available in the broad area of hemodynamic variable regulation, cancer chemotherapy, and glucose concentration control [48]. The advantages and disadvantages of some of the modeling approaches can be found elsewhere [48] and are beyond the scope of this manuscript. The modeling of some major dis-

eases to illustrate basic principles are presented below. 1.2.1. Modeling cardiovascular diseases Modeling works on blood pressure (BP) control available in the literature includes empirical tuning of controllers using linear models [51,52], nonlinear approaches [53,54], and formulation of a finite number of multiple linear models [55,56]. An alternative to either the empirical or fundamental modeling approaches for BP control is the construct of fuzzy set theory models and the corresponding rule-based controllers [57,58]. Moreover, the two following harmonic regression equations for the frequency of onset of myocardial infarction according to plasma creatine kinase MB (CK-MB) activity were suggested by Muller et al. [59]:   dnmi 2p  t ¼ 29:3  6:74cos 24 dt     2p  t 4p  t þ 5:03sin þ 0:78cos 24 24   4p  t  3:55sin ð1Þ 24 where dnmi/dt is the number of myocardial infarctions per hour and t is the time of day in hours. This two-harmonic equation demonstrated an improved fit to the CK-MB data compared to the singleharmonic-regression [59]. 1.2.2. Modeling cancer chemotherapy The modeling approaches to cancer chemotherapy can be classified into two major groups: lumped parameter models (e.g. Gompertz model) and cellcycle models [60,61]. Some oncology groups use the Gompertz model to describe tumor growth, but allow for more complicated tumors, behavior heterogeneity, and spatial variations within tumor, different tumor types, cellular, micro- and macro-environments, and many other factors through statistical techniques and Monte Carlo simulations [48]. Cell-cycle models describe cancer tumor behavior based on the number of cells in a given phase of the cell cycle [60,61]: resting phase (G0), RNA and protein synthesis (G1), DNA synthesis (S), construction of mitotic apparatus

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(G); and mitosis (M). Each cell-cycle is governed by its own differential equation [61]. XG0 ¼ ðTG0 þ dG0 ÞXG0 ðtÞ þ 2rTM XM ðtÞ

ð2Þ

XG1 ¼ ðTG1 þ dG1 ÞXG1 ðtÞ þ 2ð1  rÞTM XM ðtÞ

ð3Þ

Xs ¼ ðTS þ dS ÞXS ðtÞ þ TG1 XG1 ðtÞ

ð4Þ

XG2 ¼ ðTG2 þ dG2 ÞXG2 ðtÞ þ TS XS ðtÞ

ð5Þ

XM ¼ ðTM þ dM ÞXM ðtÞ þ TG2 XG2 ðtÞ

ð6Þ

Here the number of cells in a particular stage is given by Xi, the transition rate between stages is Ti, the death rate for cells in a particular stage is di, and of the cells that undergo mitosis, r enter the resting stage, and (1  r) return to the RNA/protein synthesis stage. The model formulation assumes that each stage is subdivided into only one compartment. Goldbete and Claude [62] also discussed the implications of modeling studies to improve the temporal patterning of drug administration. They showed the importance of time-patterned signals in physiology focused on the insights provided by a modeling approach using examples of pulsatile intercellular communication. They also showed that time-patterned treatments of cancer involve two distinct lines of research: clinical trials (e.g. circadian chronomodulation of anticancer drugs) and theoretical studies (e.g. resonance phenomenon with the cell-cycle length). 1.2.3. Modeling glucose insulin interaction Since the early modeling results of Bolie [63], a wide variety of models (low order structured [64] to physiological-based model [65]) have been used to capture the glucose and insulin dynamics in diabetic patients. A typical example of low order is the minimal model developed by Bergman et al. [64]. Given by the following equations: dGðtÞ ¼ ðP1  X ðtÞÞGðtÞ  P1 Gb dt

ð7Þ

dX ðtÞ ¼ P2 X ðtÞ þ P3 IðtÞ dt

ð8Þ

dIðtÞ ¼ EðtÞ  nIðtÞ dt

ð9Þ

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This three-state model describes plasma glucose G(t), dynamics based on plasma insulin, I(t), and insulin concentration in a remote compartment, X(t). Insulin is assumed to be delivered only through exogenous means, E(t), and the parameters, Pi and n, are characterized to individual patients. The basal glucose concentration is given by Gb. A physiologically-based compartmental model of glucose and insulin dynamics treated glucose and insulin separately, with coupling through metabolic effects utilizing threshold functions [48]. 1.2.4. Modeling other diseases In the literature, there are several attempts of theoretical and formal approaches to several other diseases such as rheumatoid arthritis [66], epilepsy [67] ulcer [68], and glaucoma [69]. One issue that complicates biomedical control and modeling problems, perhaps more than chemical process control, is the significant inter- and intrapatient variability observed [48]. Ideally, technology-driven and hypothesis-driven research and development in chronopharmaceutics will start with the selection of appropriate biochemical marker of clinical significance and the creation of a model representing the rhythmic phenomenon following the steps illustrated in Fig. 1. A general approach to model and analyze circadian pharmacodynamics is based on cosinor rhythmometric methods. In this respect, for example cosine functions (e.g. Eq. (10)) have been used by several researchers in the literature [13,16,25,70 – 72]. f ðtÞ ¼ M þ Acosðxt þ /Þ þ ei

ð10Þ

In such a model, f(t) may be the pharmacodynamic/ pharmacodynamic (PK/PD) factor that is time (t) dependant. The parameters M is the mesor (midline, value about which oscillation occurs), A the amplitude (half the difference between the highest and lowest values), x the angular frequency (radian/unit time, is inversely proportional to the period, s = 2p/x), with 2p representing a complete cycle), / the acrophase (timing of high point, in degrees =  //N F 2kp/x, k being a natural number such as 0, 1, 2, etc.) and ei is the residuals. s is the period is time interval between two successive maxima. The cycle duration (and hence x) is given, on the basis of either prior

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knowledge or a reasonable assumption. The remaining parameters are to be estimated [70,71]. These types of regressions may be useful means to formally evaluate the PK/PD data analysis in the context of ChrDDS.

2. New global trends in drug discovery and development In this century, the pharmaceutical industry is caught between pressure to keep prices down and the increasing cost of successful drug discovery and development. The average cost and time for the development of a new chemical entity are much higher (approximately $500 million and 10 – 12 years) than those required to develop a novel drug delivery system (NDDS or ChrDSS) ($20 –$50 million and 3 –4 years) [73]. In the form of an NDDS or ChrDDS, an existing drug molecule can ‘‘get a new life’’, thereby increasing its market value and competitiveness and extending patent life [73]. According to IMS Health [74], retail growth for major generics markets (1999 –2004) was forecasted to reach 13% in 2005. Of the leading 35 molecules worldwide in US dollars terms, 13 will lose their patent protection over the next 5 years. Major patents will expire during this period in all major therapy classes: central nervous system (anti-depressants), cardiovascular system (ACE Inhibitors), alimentary tract (proton pump inhibitors), and respiratory system (antihistamines). It is important to point out most of the diseases targeted by these drugs have been shown to have a chronobiological pattern in their pathogenesis. The key issues impacting the generic growth, especially in Europe, include: economic growth, cost-containment reinforcement including reference price cuts and stringent reimbursement conditions, governmental promotion of rational prescribing (generic interchangeability), emphasis on cost-effectiveness and integrated care, and encouraged used of generics (mandatory substitution and prescribing guidelines) [74]. In addition to scientific evidence demonstrating the usefulness of ChrDSS, these market constraints (cost, patent expiration and political pressure) are the key driving forces for the pharmaceutical industry to consider chronopharmaceutical formulations in order to maintain competitiveness.

3. 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 [7,8,30,75]. 3.1. Asthma The chronotherapy of asthma has been extensively studied [76 – 78]. The role of circadian rhythms in the pathogenesis and treatment of asthma indicates that airway resistance increases progressively at night in asthmatic patients [77]. 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 [79]. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline, and B2-agonists [76,77]. 3.2. Arthritis The chronobiology, chronopharmacology and chronotherapeutics of pain have been extensively reviewed [32]. For instance, there is a circadian rhythm in the plasma concentration of c-reactive protein [80] and interleukin-6 [81] of 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 [66]. Patients with osteoarthritis tend to have less pain in the morning and more at night; while those with

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rheumatoid arthritis, have pain that usually peaks in the morning and decreases throughout the day. Chronotherapy for 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. 3.3. Duodenal ulcer Many of the functions of the gastrointestinal tract are subject to circadian rhythms: gastric acid secretion is highest at night [82,83], 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 [35]. 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 an H2 antagonists [83,84]. 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 [68]. 3.4. 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 [9– 27,30,41,75,85,86]. The rhythmic circadian changes in tumor blood flow and cancer growth are relevant both when tumors are small and

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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 [87]. 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. [85] 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 [86]. 3.5. 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 have been previously discussed [88 – 93]. 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 [94]. 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 [94]. 3.6. 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 [38,95 –97]. It was postulated that modification of these circadian triggers by pharmacologic agents may lead to the prevention of adverse cardiac events [97,98]. Cardiac events also occur with a circadian pattern. Numerous studies have shown an increase in the incidence of early-morning

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myocardial infarction, sudden cardiac death, stroke, and episodes of ischemia [98]. The circadian pattern of BP has been well documented [99,100]. 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 [100].

ence [67,107]. 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 [108]. Moreover, it has been shown that the human sleep, its duration and organization depend on its circadian phase [109]. A breakthrough chronopharmaceutical formulation against insomnia that plagues many people would be one that addresses the entire oscillatory cycle of human sleeping process.

3.7. 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 [101]. A circadian rhythm occurs during hepatic cholesterol synthesis [102,103]. 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 [104]. Studies with HMG CoA reductase inhibitors have suggested that evening dosing was more effective than morning dosing [105,106]. 3.8. 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 sci-

4. Examples of chronopharmaceutical technologies Currently key technologies in chronopharmaceutics includes: CONTINR, physico-chemical modification of the active pharmaceutical ingredient (API), OROSR, CODASR, CEFORMR, DIFFUCAPSR, chronomodulating infusion pumps, TIMERxR, threedimensional printing, controlled-release (CR) erodible polymer and CR microchip strategies. Readers may find advantages and disadvantages of each technology depending on their specific needs on the website of each developer/marketer website before selection. Informations on FDA approval status and dosage formed were compiled from the FDA electronic orange book [110]. We will focus on the principle and application of each of these technologies. 4.1. CONTINR technology 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 (semipermeable matrixes) which may be varied [111]. 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 bronchoconstriction in the morning.

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Patients demonstrated improved pulmonary function in the morning compared with use of twice-daily theophylline when once-daily UniphylR was administered in the evening. Thus, evening administration of once-daily theophylline may block the morning dip in lung function commonly seen [112]. 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 [76,78]. 4.2. 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. The rationale for such approach is based on the published work demonstrating that solubility and permeability are critical factors governing drug bioavailability [113]. Typical examples of the use of this strategy in chronotherapy are those of antihyperlipidemic statins (HMG-CoA reductase inhibitors) [105,114] and antiulcerative agents (histamine H2 receptor-antagonists) [83,84,115]. Basically, the introduction a methyl group in the chemical structure of lovastatin (C24H36O5, 404.54 MW) leads to the production of simvastatin (C25H38O5, 418.56 MW). Such modifications change the melting point (m.p.) of these compounds from 174.5 to 135– 138 jC for lovastatin and simvastatin, respectively [116]. Based on the work of Yalkowsky et al. [117], it is now established that molecular weight and m.p. of compounds are related to their solubility. In fact, water solubility data for lovastatin is unavailable, but that of simvastatin is 0.03 mg/ ml [116]. 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 [118]. In the case of H2-receptor antagonist, for example, by basically introducing oxygen and two additional

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sulfur atoms in the formula of cimetidine (C10H16N6S, 252.35 MW, m.p. = 141 –143 jC), one obtains famotidine (C8H15N7O2S3, 337.45 MW, m.p. = 163 –164 jC). Based on the previous reasoning, these modifications induce dramatic reduction in the water solubility data to approximately 1.14 – 0.1% (w/v) for cimetidine and famotidine, respectively [116]. Therefore, the duration of action of these two compounds varied from 6 to 12 h, for cimetidine and famotidine, respectively [119]. 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 sideeffect profile [119]. 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 as underscored in Section 3 (above). 4.3. OROSR technology OROSR technology [120] 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. The tablet is divided into two layers, an active drug layer and a layer of osmotically active agents (e.g. poly(ethylene oxide)) comprising means for changing from a non-dispensable viscosity to a dispensable viscosity when contacted by fluid that enters the dosage form. 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 predetermined rate. This creates a ‘pump’ effect that pushes the active drug through a hole in the tablet. This technology, especially the OROSR Delayed Push – Pullk System, also known as controlled onset extended release (COER) was used to design CoveraHSR, a novel anti-hypertensive product. It actually enabled delayed, overnight release of verapamil to

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help prevent the potentially dangerous surge in BP that can occur in the early morning [39,40,121]. 4.4. CODASR technology The Chronotherapeutic Oral Drug Absorption System (CODASR) [122] is a multiparticular 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 releasecontrolling 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 [123]. The rate of release is essentially independent of pH, posture and food. The nighttime 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 [124]. 4.5. CEFORMR technology The CEFORMR technology [125] 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 obtained are almost perfectly spherical, having a diameter that is typically 150 –180 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 [73].

4.6. DIFFUCAPSR technology In the DIFFUCAPSR technology [126], a unit dosage form, such as a capsule for delivering drugs into the body in a circadian release fashion, is comprising 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. hydroxypropylmethylcellulose, polyvinylpyrrolidone) 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 [110]. 4.7. 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 reviewed in detail elsewhere [127]. To our knowledge infusion pumps on the market that have been referred to as chronomodulating for drug delivery application include the MelodieR [24], programmable SynchromedR [22], PanomatR V5 infusion [128], and the RhythmicR pumps. The portable pumps are usually characterized by a light weigh (300 –500 g) for easy portability and precision in drug delivery. For example portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the

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tablet by varying the proportion of the gums, together with the third component, the tablet coating and the tablet manufacturing process. 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 [131].

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 [24]. In case of insulin therapy, implantable infusion pumps containing a reservoir of insulin may be surgically placed within the subcutaneous tissue of the abdomen in the left upper or lower quadrant (above or below the belt). A catheter leads from the pump through the muscle layers into the peritoneal cavity, where it floats freely, and insulin delivery is by the intraperitoneal route. The insulin reservoir is refilled once a month or every 3 months at a physician’s office by inserting a needle through the skin into the pump (a local anesthetic is first used) [129]. 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. Their advantages include the fact that the peritoneum provides a large, well-vascularized surface area, and absorption is faster by this route than after subcutaneous injection (better insulin gradient), improved glycemic control and a reduction in the frequency of hypoglycemic episodes. Possible drawbacks of this approach include eventual formation of fibrous tissue pocket and local skin erosion. Cathether blocade which can reduce insulin delivery, are the most common problems with implantable pumps [129]. However, these pumps have been effectively used in the chronotherapy of several diseases such as cancer and diabetes [24,129].

Three dimensional printingR (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 [132]. 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 pulses of about 4 h [133]. This technology is the basis of the TheriFormR technology [134]. The latter is a microfabrication process that works a manner very similar to an ‘‘ink-jet’’ printer. It is a fully integrated computer-aided development and manufacturing process. Products may be designed on a computer screen as three-dimensional models before actual implementation of their preparation process. This versatile technology may found potential application in chronopharmaceutics in the future.

4.8. TIMERxR technology

4.10. Other CR erodible polymers

The TIMERxR technology (hydrophilic system) [130] 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

Erodible polymers have been designed in different forms (e.g. tablets, capsules, microparticles) for ChrDDS applications. For example, Ross et al. [135] reported the development of a chronopharmaceutical capsule drug delivery system. The drug formulation is 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. hydroxypropylmethylcellulos) excipient. The time-delayed release of a model drug

4.9. Three-dimensional printingR

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(propranolol HCl) was investigated by dissolution testing. Both composition and weight of ET influence the time of drug release rate. Programmable pulsatile release has been achieved from a capsule device over a 2– 12-h period, consistent with the demands of chronopharmaceutic drug delivery [135]. Guar gum-based matrix tablets represent a simple and economical alternative to existing drug sustained release dosage forms [136]. EudragitR RL and RS 30D are pseudolatexes based on cationic copolymers stabilized with quaternary ammonium groups. Anionic buffer species and not the pH had a significant effect on the hydration and hence on the drug release from beads coated with these cationic polymers [137]. Recently, such polymers have been used in combination with biodegradable polymers to control the release of heparin for potential chronotherapeutic application against thrombosis and hypertension [138,139]. The rationale for chronotherapy against thrombosis is based on evidences that blood coagulability follows a circadian cycle [96]. An excellent review of pulsatile drug-delivery system involving erodible polymers has been made by Bussemer et al. [44]. 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.

4.11. Controlled-release microchip An alternative method to achieve pulsatile or chronopharmaceutical drug release involves using microfabrication technology. Santini et al. [140] 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. Initially the authors 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 radiolabelled dextran, human growth hormone or heparin in vitro [141]. 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.

5. Examples of Chronopharmaceutical drug delivery systems A major objective of chronopharmaceutics is to deliver the drug in higher concentrations during the

Table 1 Examples of ChrDDS on the market FDA approval date

API

Propriatory name; dosage form

Proprietary chronopharmaceutical technology [ref.]

Indications/rationale for chronotherapy [ref.]

Sept. 01, 1982

Theophylline

CONTINR [111]

Oct. 15, 1986

Famotidine

UniphylR; extended release tablets PepcidR; tablets

Dec. 23, 1991

Simvastatin

ZocorR; Tablets

Feb. 26, 1996

Verapamil HCl

Nov. 25, 1998

Verapamil HCl

CODASR [122]

Feb. 06, 2003

Diltiazem HCl verapamil HCl Propranolol HCl verapamil HCl

Covera-HSR; extended release tablets VerelanRPM; extended release capsules CardizemR LA; extended release tablets InnoPranR XL extended release capsules

Asthma/increased bronchoconstriction in morning [76,78] Ulcer/increased gastric acid secretion in evening [35,82] Hypercholesterolemia/increased cholesterol synthesis overnight [103,104] Hypertension/increased BP in early morning [59,97,99] Hypertension (cf. above)

CEFORMR [125]

Hypertension (cf. above)

DIFFUCAPSR [126]

Hypertension (cf. above)

Mar. 12, 2003

Physico-chemical modification of API [115] Physico-chemical modification of API [114] OROSR [120]

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time of greatest need and in lesser concentrations when the need is less to minimize unnecessary sideeffects. Table 1 gives examples of ChrDDS on the market. These include compounds such as theophylline (UniphylR), famotidine (PepcidR), simvastatin (ZocorR), COER-verapamil (Covera-HSR, VerelanR PM), diltiazem (CardizemR LA) and propranolol (InnoPranR XL). Their approval dates, proprietary name and technology, indications and rationale for chronotherapy in each case are underlined. The selected dosage forms are claimed by the marketer/ developer as exhibiting chronotherapeutic effects. Most data were compiled from FDA electronic orange book [110], specific product package inserts and United States patents and specific pharmaceutical company websites.

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chromes) [4] that may be potential target for efficient chronopharmaceutical drug development. Because we are moving smaller in drug discovery and development [142], engineered nanomaterials for biophotonics applications [143] may also be used to develop optically controlled ChrDDS. The overall success of chronopharmaceutics will depend on the successful integration of knowledge from future advances in development timing, system biology and nanomedicine. The selection of the appropriate chronopharmaceutical technology should take into considerations the application range (e.g. targeted drugs of different physico-chemical properties), the ease of manufacturing, the cost-effectiveness, and the flexibility in the pharmacokinetic profile.

Acknowledgements 6. Conclusion and perspectives This review demonstrates that there are both experimental and theoretical backgrounds, and market constraints as basis for the clinical relevance of chronopharmaceutics as an emerging approach to drug delivery. Chronopharmaceutics will certainly improve patient outcome and optimize disease management in the future. The major drawbacks of existing oral ChrDDS on the market are that they rely on human action to trigger the drug administration for example on daily basis. Ideal ChrDDS should be self regulating, when taken any time of the day and should take environmental factors in account (e.g. awake– sleep, light – dark, activity –rest status). For example, the human body is comprised of molecules, hence the availability of molecular nanotechnology that facilitate self-regulation of ChrDDS based on body immune system and disease state will permit dramatic progress in human medical services. Moreover, the circadian clock of the suprachiasmatic nucleus (SCN) is thought to drive daily rhythms of behavior by secreting factors that act locally within the hypothalamus. Epidermal growth factor receptors signaling have been implicated in the daily control of locomotor activity, and neural circuit in the hypothalamus that likely mediates the regulation of behavior both by the SCN and the retina have been identified [3]. Clearly, mammals possess a retinally based light-detection system that has component (e.g. melanopsin, crypto-

This work was financially supported by the administration of Texas Tech University Health Sciences Center School of Pharmacy (TTUHSC SOP). Helpful discussions during this manuscript with Professor Quentin Smith (Chair, Department of Pharmaceutical Sciences, TTUHSC SOP) and Dr. Michael Veronin (Assistant Professor of Pharmaceutical Sciences at TTUHSC SOP) are appreciated.

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