Pharmaceutical Development and Technology, 2009; 14(6): 602–612

R E V I E W A R T I C L E

Drug delivery technologies for chronotherapeutic applications

Zaheeda Khan, Viness Pillay, Yahya E. Choonara, and Lisa C. du Toit

Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, South Africa

Address for Correspondence: Prof. Viness Pillay, PhD, Pharmacy and Pharmacology, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193 South Africa. E-mail: viness.pillay@wits.ac.za

(Received 7 November 2008; revised 6 February 2009; accepted 25 March 2009)

Introduction

During the 1700s Jean-Jacques d’Ortous de Mairan was the first researcher to take note of the 24-hour patterns occurring in the movement of a plant. Since then, research has been conducted to prove the presence of the 24-hour cycle. The 24-hour cycle that occurs in physiological proc-esses of all human beings is termed the circadian rhythm. Related biological rhythms include the ultradian (length of hours, minutes or seconds), infradian (length of days or months), circatrigantan (the female menstrual cycle) and circannual rhythms (seasonal variation).[1,2] The term circadian rhythm was first coined by Halberg and Stephens in 1959 and literally means “ about-a-day”.[1,3] Thereafter, it was found that the human biological clock is coordinated by the suprachiasmatic nucleus located at the base of the hypothalamus.[4] The suprachiasmatic nucleus is a paired nucleus situated above the optic nerve. Light that passes through the retina conducts impulses to the retino-hypothalamic tract that in turn

regulates nine genes that create 24-hour variations in cellular physiological processes.[1,5,6] The suprachias-matic nucleus inherently possesses a pacemaker which produces endogenous electrical activity thus allowing variations in the suprachiasmatic nucleus to occur in the absence of external stimuli.[1] The biological rhythms generated play a role in controlling biological functions that include the autonomic nervous system, endocrine system and immune system.[3] The circadian clock essentially comprises three components: An input path-way (photoreceptors and projections of retinal ganglion cells), circadian pacemakers that generate the circadian signal and an output pathway that couples the pacemak-ers to effector systems manifesting into circadian physi-ology and behavior.[7,8] The circadian clock behaves like a multifunctional timer in order to regulate homeostatic systems within the human body.[8] Circadian rhythms govern nearly all functions in the body, including sleep and activity, hormone levels, appetite and those func-tions responsible for pharmacokinetic parameters.[8–10]

ISSN 1083-7450 print/ISSN 1097-9867 online © 2009 Informa UK LtdDOI: 10.3109/10837450902922736

AbstractIt has been proven that the body follows a 24-hour cycle called a circadian rhythm. This cycle is coordinated by the suprachiasmatic nucleus and controls nearly all bodily functions including those related to drug delivery. Knowledge of the body’s circadian rhythm leads to an improved understanding of diseases and their treatment, known as chronotherapy, such that synchronizing drug application in accordance with the natural rhythm of the body leads to improved disease management and a greater patient therapeu-tic outcome. Chronotherapeutic diseases include asthma, cardiovascular diseases, glaucoma, rheumatoid arthritis and cancers. In order to treat these diseases numerous chronotherapeutic drug delivery systems have been developed, such that drug is released in the period when it is most needed. This review paper attempts to concisely explicate the role of circadian rhythms in various disease states and furthermore describes the various oral drug delivery technologies that have been employed for the treatment of chron-otherapeutic diseases.

Keywords: Chronotherapy; circadian rhythm; chronopharmaceutical; pulsatile drug delivery; polymers; rate-modulated drug delivery

http://www.informahealthcare.com/phd

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Drug delivery technologies for chronotherapeutic applications 603

Furthermore, hormones such as cortisol, rennin, growth hormone and aldosterone also display daily fluctua-tions.[10] The secretion of growth hormone peaks dur-ing sleep, with aldosterone and cortisol levels typically peaking during the morning.[11] A list of hormones and biological functions that are known to follow a circadian rhythm are highlighted in Table 1.

A thorough knowledge of the circadian clock helps in understanding the 24-hour biological clock as well as the pathophysiology and symptoms of disease. In addi-tion, the pharmacokinetics and pharmacodynamics of various drugs can be further understood. Information on the circadian rhythms and their influence on disease states may assist formulation scientists in developing innovative approaches for drug delivery and other treat-ment modalities.

The role of circadian rhythms in disease

Diseases that follow the daily biological rhythms are known as chronotherapeutic disorders. The symptoms of these disorders are exacerbated or more prominent at certain times during the day. The biological systems known to follow a circadian rhythm are described hereunder.

The cardiovascular system

Several functions of the cardiovascular system such as the heart rate, stroke volume, fibrinolytic activity,

platelet aggregability, cardiac output and blood flow follow a circadian rhythm.[10,12,14] In addition, the blood pressure and heart rate in both normotensive and hypertensive patients are higher during the morning hours (06:00–12:00 h) than any other time of the day due to a decrease in sympathetic output occurring at night while the individual is asleep.[14–18] Upon wak-ing, the systolic blood pressure rises rapidly by 20–25 mmHg and diastolic blood pressure by 10–15 mmHg.[1,19] Ghergel et al.[1] represented the extent of the drop in blood pressure during the night in the region of 10–20%. It is further described that approximately two thirds of the world’s population present with a blood pressure drop of this magnitude during the night and they are known as dippers. The remaining one third present with a blood pressure drop of < 10% and are known as non-dippers. These factors, in conjunction with the pro-longed exposure to a higher blood pressure level seen in non-dippers, contributes to an increase in cardiovascu-lar diseases such as myocardial infarctions, angina and strokes during the early hours of the morning.[13,15,17,20] Douglas[17] reported that there is a 40% higher risk of a heart attack, a 29% increased risk of cardiac death and a 49% increased risk of stroke between 06:00 and 12:00 h in the morning. Conversely, vasospasms in Prinzmetal angina and congestive heart failure symptoms are com-mon during sleep.[13,20,21] Furthermore, the diagnosis of hypertension is based on the assessment of blood pressure when a patient presents at the doctor during the daytime. However, blood pressure fluctuates dur-ing the day. Thus a single measurement during the day is not representative of the systolic and diastolic blood pressure throughout the day. The use of 24-hour blood pressure ambulatory monitoring technology is therefore required to establish a correct diagnosis.[19]

The respiratory system

Lung function is also affected by circadian rhythms. Lung function in healthy patients is reduced during the early hours of the morning. However, this change is more pronounced in asthmatic patients. The decrease in lung function can vary between 25 and 50%.[13] Moreover, airway resistance in asthmatic patients increases progressively at night.[22–25] At night the lungs are more sensitive to bronchoconstrictors such as ace-tylcholine and histamine.[10,13,26] A survey conducted by Turner-Warwick demonstrated that of 7600 asthmatic patients interviewed, 74% awoke from sleep with asth-matic symptoms.[27] The first-line treatment of asthma involves the inhalation of corticosteroids that directly inhibits inflammatory cells. A study conducted on individuals affected with asthma showed that dosing an inhaled corticosteroid once daily at 15:00 h was as effective as four times daily dosing.[28] In another study,

Table 1. Hormones and their circadian rhythmicity.

Circadian rhythmicityHormone/biological functions

affected

Late at night or early during sleep

Gastric acid secretion

White blood cell count

Calcitonin gene-related protein

Atrial natriuretic peptide

Peaks during sleep Growth hormone

Thyroid stimulating hormone

Melatonin

Prolactin

Follicle stimulating hormone

Adrenocorticotropic hormone

Luteinizing hormone

Peaks during the morning Cortisol

Renin

Angiotensin

Vascular resistance

Platelet aggregation

Blood viscosity

Peaks at noon Hemoglobin

Insulin release

Peaks during the evening Triglycerides

Urinary diuresis

Cholesterol

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dosing with inhaled corticosteroids at 08:00 and 17:30 h were compared to four times daily dosing. The outcome of the study proved that dosing at 17:30 h was effective as dosing four times daily, however dosing at 08:00 h did not produce results comparable to four times daily dosing.[29] Optimal dosing of inhaled corticosteroids was thus between 15:00 and 17:30 h. These observations highlight the significance of dosing medication in syn-chrony with the body’s circadian rhythms.

The skeletal system

Both osteoarthritis and rheumatoid arthritis follow a circadian rhythm. Patients suffering from rheumatoid arthritis are more likely to experience pain symptoms during the morning. Furthermore, the concentration of interleukin-6 and C-reactive protein is subjected to a cir-cadian rhythm. Patients with rheumatoid arthritis also display circadian rhythms in joint pain and finger swell-ing. These debilitating symptoms are in phase with the circadian rhythms of pain.[30] Osteoarthritic patients, on the other hand, have less pain during the morning when compared to the rest of the day.[31,32] Non-steroidal anti-inflammatory drugs are widely used for the treatment of arthritis. Studies have shown that a large dose taken twice daily is more effective than four smaller doses, provided that one of the doses is taken at night.[13]

The gastrointestinal system

The functioning of the gastrointestinal tract is also sub-ject to a circadian rhythm. Gastric secretion increases during the night whereas gastric and intestinal motility decreases. A previous study conducted revealed that gastric emptying rates for meals consumed at 20:00 h was on average 50% slower than the same meal con-sumed at 08:00 h.[33] This observation has implications on the pharmacokinetics of orally administered drugs. The drug disintegration, dissolution and absorption may be slower at night. In addition, the increase in acid secretion may exacerbate duodenal ulcers in affected patients.[32] As a result of this circadian rhythm a once daily dosage in the evening has been advocated.[9,32]

The role of circadian rhythms in glaucoma

In the United States open angle glaucoma is the sec-ond leading cause of blindness[34]. Primary open angle glaucoma is characterized by atrophy of the optic nerve, increased intraocular pressure and visual defects.[1,34] The main cause of primary open angle glaucoma is an increased intraocular pressure due to a reduction in aqueous humor drainage. The secretion of aqueous humor follows a circadian rhythm with a greater quan-tity secreted during the day as compared to the night.

The two hormones with concentrations that are lower at night than during the day and are known to be responsi-ble for the circadian rhythm of aqueous humor secretion are cortisone and epinephrine/adrenalin.[35]

The role of circadian rhythms in cancer

In order to achieve efficacious therapeutic outcomes, patients suffering from cancers often receive treatment where the dosage of drug is near the maximum tolerated dose. As a result, the possibility of toxicity to normal cells is always present. Normal cell physiology follows a 24-hour clock. By synchronizing the dosing schedule of chemotherapeutic agents to coincide with the circadian rhythm of cells, the cytotoxicity of chemotherapeutic agents may be reduced. Levi et al.[36] reported that the circadian dosing time influences the extent of toxicity of more than thirty different anticancer drugs. For example, platinum analog complexes such as cisplatin, carbopla-tin and oxiliplatin are best tolerated near the middle of the nocturnal activity span of laboratory mice whereas 5-flurouracil is best tolerated when it is administered 12 hours earlier than the platinum analogs.[36,37] In another example, a study was conducted where the survival rates of patients suffering from acute lymphoblastic leukemia were measured. Eighty percent of patients were alive and disease-free after five years when dosed with 6-mer-captopurine and methotrexate during the evening and only 40% of patients survived when dosed with the same medication during the morning.[36] Thus, chronomodu-lated pumps have been developed in order to allow for the time-variable delivery of chemotherapeutic agents. Multi-channel programmable-in-time infusion pumps make it possible to deliver up to four different drugs during the patient’s usual activities. Examples include 5-fluorouracil and cisplatin.[36]

Chronotherapy and drug delivery

In recent years, extensive emphasis has been placed on drug delivery systems that provide sustained, zero-order drug release.[38] With sustained release preparations, drug release is maintained within a therapeutic window over a prolonged period, thereby reducing peak-to-trough fluctuations and ultimately decreasing side-effects and the dosage frequency (Figure 1).

However, zero-order drug release is not ideal when treating chronotherapeutic disorders where pulsatile drug delivery is necessary and drug may be released after a lag-phase at predetermined time intervals. Pulsatile drug delivery offers advantages such as extended day-time or night-time activity, reduced side-effects, reduced dosing frequency and dose size, improved patient compliance and lower treatment costs. Using the concept of circadian rhythms, it is possible to treat

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Drug delivery technologies for chronotherapeutic applications 605

chronotherapeutic disorders via specialized drug deliv-ery systems. Chronotherapeutics is a branch of therapy that involves synchronizing the drug application in a manner that coincides with circadian rhythms in order to achieve an optimal therapeutic success.[40] A major objective of chronotherapy is to deliver drugs to targeted sites in the body in higher concentrations when they are most needed. Conventional controlled release drug delivery systems used in the treatment of chronothera-peutic conditions are not designed to complement the circadian rhythm. In order to achieve optimal success, drug release should coincide with the body’s circadian rhythm and ought to occur after predetermined time delays such that drug release within a 24-hour period is in synchrony with the biological determinants of the disease.

An in-depth knowledge of circadian rhythms is of great significance when administering a drug delivery system, as numerous drugs display variations in their pharma-cokinetics and pharmacodynamics. For example, a drug delivery system administered in the morning may not have the same pharmacokinetic properties when admin-istered at night. This can be attributed to the gastric ion concentration, stomach emptying rate and blood flow to the gastrointestinal tract, hepatic bile function, renal blood flow, glomerular filtration, and tubular function that follows a 24-hour rhythm.[19,20] The pharmacokinetic properties of numerous drugs are affected by circadian rhythms, as listed in Table 2. Chronotherapeutics does not necessarily have to include new drug molecules, but instead established drugs may be incorporated into innovative drug delivery systems or devices that can be employed to improve their efficacy. This can be accomplished by unequal morning and evening dosing of a 12-hour drug delivery system, superior timing of a once-a-day formulation or by the development of novel drug delivery systems that are able to release drug over a

Time

0 2 4 6 8 10

Pla

sma

Con

cent

ratio

n

0

20

40

60

80

100

Minimum Effective concentrationMaximum safe concentrationControlled release formulationConventional Release formulation

Figure 1. Difference in peak plasma concentrations between a con-ventional formulation and a controlled release formulation.[39]

Table 2. Drugs that are affected by circadian rhythms.Class of drug DrugBeta-blockers Acebutolol

AtenololBisoprololMetoprololNadololPropranololSotalol Carvedilol

Calcium channel blockers AmlodipineNifedipineVerapamil

Angiotensin converting enzyme (ACE) inhibitors

EnalaprilCaptoprilPerindoprilLisinopril

Diuretics IndapamideHydrochlorothiazideTorsemideFurosemide

Nitrates Glyceryl-trinitrateIsosorbide-mononitrateIsosorbide-dinitrate

Miscellaneous DigoxinCancer Cisplatin

Cyclosporin5-FluorouracilMethotrexate

Antiasthmatics TheophyllineAminophyllineOrciprenalineIsoprenalineTerbutalineBudesonideAdrenaline

Psychotropics DiazepamHaloperidolMidazolamLorazepamAmitriptylineLithiumCarbamazepineValproic Acid

AT1-receptor antagonists Irbesartan

LosartanAntihistamines Terfenadine

CyproheptadineAnalgesics Acetylsalicylic Acid

KetoprofenParacetamolIndomethacinPiroxicamMorphineIbuprofenFentanyl

Gastrointestinal tract (GIT) drugs CimetidineRanitidineOmeprazoleLansoprazole

Antibiotics AmpicillinGentamycin

Cholesterol lowering drugs BezafibrateClofibrateSimvastatin

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24-hour period in a coordinated mode to the biological rhythms.[19]

Overview of chronopharmaceutical technologies

One of the first commercially available oral products to employ the use of chronotherapy is the long-acting bronchodilator Uniphyl® (theophylline) (Purdue Frederick Co., Norwalk, Connecticut, USA). Chronopharmaceutical technologies currently avail-able include: CONTIN® (Purdue Pharma, Pickering, Ontario, Canada), Chronotropic® and Pulsincaps® (Catalent Pharma Solutions, Somerset, New Jersey, USA), CEFORM® (Biovail Corporation, Mississauga, Ontario, Canada), TIMERx® (Penwest Pharmaceutical Company, Danbury, Connecticut, USA), OROS® (DURECT Corporation, Cupertino, California, USA), CODAS® (Elan Corporation, Gainesville, Florida, USA), Egalet® (Egalet a/s, Værløse, Copenhagen, Denmark) and Diffucaps® (Eurand Pharmaceuticals, Yardley, Pennsylvania, USA). Table 3 defines the significant applications of the described technologies in oral drug delivery.[32]

CONTIN®

CONTIN® technology (Purdue Pharma, Pickering, Ontario, Canada), involves combining a drug and hydrophilic polymer followed by selective hydration with a polar solvent and fixation through a higher aliphatic alcohol. A molecular coordination complex is formed between a cellulose polymer and a substituted aliphatic alcohol. The result is a complex that can be utilized as a matrix for controlled drug release. The complex has a uniform porosity which may be varied.[41] This tech-nology is employed in the long-acting bronchodilator Uniphyl®. Although CONTIN® technology functions as a conventional sustained release matrix system; research suggests that evening administration demonstrates an improved lung function as compared to patients taking Uniphyl® twice daily. When taken at night, Uniphyl® causes theophylline blood levels to peak during the early hours of the morning when lung function is known to decrease, making this the first commercial product to be indirectly used a chronopharmaceutical.[41,42]

Chronotopic®

The Chronotopic® technology provides the versatility of delayed, time-dependant pulsatile drug delivery as well as colon specific drug release. The delivery system comprises a drug-loaded core coated with hydroxypro-pylmethylcellulose (HPMC), a swellable hydrophilic polymer. The HPMC coating undergoes a glassy-rubbery transition when in contact with aqueous fluid. The drug

is then released across the gel-layer either by diffusion and/or erosion. The onset of drug release and lag-time are controlled by the thickness and viscosity grade of the HPMC coat employed during formulation.[43–45] Furthermore, the application of a gastro-resistant film onto the polymer-coated core of the system, overcomes the variability in gastric transit-time and allows for colon-specific drug release.[45–48] The film allows the system to stay intact until reaching the intestine where it eventu-ally erodes and exposes the HPMC layer to the intestinal fluid thus allowing the system to be pH-responsive. The tablet matrix is prepared by firstly granulating the drug with a range of excipients which is then compressed. A mixture of HPMC and PEG solutions are then spray-coated onto the core and allowed to dry. Thereafter a coating of Eudragit® is applied onto the outer surface of the tablet matrix.[45]

Pulsincaps®

Pulsincaps® technology (Catalent Pharma Soulutions, Somerset, New Jersey, USA) consists of a water insolu-ble drug-loaded capsule. The capsule is sealed with a

Table 3. Orally administered chronopharmaceuticals currently on the market.

Trade Name Drug

Chrono- pharmaceutical

technology

Rationale for use in

chronotherapy

Cardizem® LA Diltiazem HClVerapamil HCl

CEFORM® Hypertensive management to reduce morning blood pressure surge

Covera® HS Verapamil HCl OROS® Hypertensive management to reduce morning blood pressure surge

InnoPran® XL Propranolol Diffucaps® Hypertensive management to reduce morning blood pressure surge

Uniphyl® Theophylline CONTIN® Asthma management to reduce early morning bronchocon-striction

Verelan® PM Verapamil CODAS® Hypertensive management to reduce morning blood pressure surge

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Drug delivery technologies for chronotherapeutic applications 607

swellable hydrogel plug comprising polymers such as the poly(methacrylates), hydroxypropylmethylcellu-lose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, saturated polyglycolate d-glycerides, glyceryl monooleate or pectin.[48,49] The capsule is then coated with an enteric layer that dissolves upon reaching the small intestine where the polymeric plug begins to swell resulting in a lag-phase prior to drug release. The plug then expands and is pushed outward to affect drug release. The variation in dimensions of the plug and its point/depth of insertion into the capsule determines the lag-time produced prior to drug release.[43,48–52] Pulsincaps® technology has the versatility of allowing one or more minitablets, coated tablets, solutions, or multiparticulates to be loaded within the capsule for delivery of drug in a chronotherapeutic manner.[48]

CEFORM®

CEFORM® technology (Biovail Corporation, Mississauga, Ontario, Canada) involves the production of microspheres that are uniform in shape and size. The microspheres have a diameter ranging from 150–180 µm with a high drug-loading capacity that may be applied in a wide variety of drug delivery systems including capsules, suspensions, tablets, effervescent tablets and sachets.[32,52,53] The technology involves subjecting biode-gradable polymers or bioactive agents to a combination of thermal gradients, mechanical forces, and flow-rates during processing. CEFORM® technology has been used to develop the chronopharmaceutical Cardizem® LA which is a once-daily diltiazem formulation.[32]

TIMERx®

Penwest Pharmaceutical Company (Danbury, Connecticut, USA) has developed SyncroDose™ that uses Penwest’s TIMERx® patented matrix technology. The technology enables drugs to be delivered after a predetermined lag-phase that coincides with the circa-dian rhythm or allows drug to be delivered to various sites within the gastrointestinal tract. The SyncroDose™ tablet consists of an inner drug-loaded core and a sur-rounding compression coating (Figure 2). The TIMERx®

matrix system comprises xanthan gum, a semi-synthetic bacterial polysaccharide, locust bean gum and a plant polysaccharide. These polysaccharides interact syner-gistically with secondary and tertiary components.[54,55] A ratio of between 1:3 and 3:1 of xanthan gum to locust bean is preferably employed. A possible mechanism for the interaction between the xanthan gum and locust bean involves interfacing between the helical regions of the xanthan gum and the unsubstituted regions of the locust bean. This interaction allows for the formation of a high-strength gel similar to the effects of crosslinking in hydrogels. The tablet core is prepared by wet granu-lation and then compressed. The TIMERx® matrix is prepared by blending the polymers and other excipients using a wet-granulation technique. Compression coat-ing is then used to enclose the drug-loaded core.[54] The SyncroDose™ technology is able to release drug after a predetermined lag-phase with maximum plasma levels achieved in 5 hours. Upon contact with gastric fluid, the combined polysaccharides interact and swell to form a taut gel with a gradual eroding core from which drug is released.[32,43,52,56] While the outer polysaccharide core may swell, the inner drug core remains intact. As the tablet moves along the gastrointestinal tract through the pylorus and into the duodenum, the outer swella-ble coating undergoes erosion. After approximately 3.5 hours, erosion of the coating is complete, exposing the drug-loaded core to the intestinal environment where drug is released. Inclusion of a surfactant into the drug-loaded core confers immediate drug release capabilities. Alternatively, the core may be formulated as a control-led release matrix allowing for sustained release. The swelling of the matrix also results in a reduction in the bulk density, thus creating buoyancy and allowing the gel-mass to float on the gastric contents. Furthermore, depending on the size of the original tablet matrix, the gel-mass may swell to a degree that allows the system to obstruct the opening of the pylorus.[54] The physico-chemical properties of the xanthan gum may be consid-ered to be self buffering.[54] As a result the xanthan gum is not sensitive to pH variations along the gastrointestinal tract. Xanthan gum also has mucoadhesive properties allowing the drug delivery system to be retained in the stomach affording the TIMERx® matrix the versatility to additionally be used as a gastroretentive drug delivery system.

OROS®

An OROS® osmotic pump patented by the DURECT Corporation (Cupertino, California, USA) utilizes an osmotic mechanism to provide pre-programmed, con-trolled drug delivery. The drug delivery technology com-prises a drug-loaded compartment, a push compart-ment and a semi permeable membrane (Figure 3). The

Coating

Drug Core

Figure 2. Schematic diagram showing Penwest’s SynchroDose™ technology using the patented TIMERx® matrix.[57]

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drug compartment is made up of drug and poly(ethylene oxide) (PEO) granulated with a solution of poly(vinyl pyrolidine) (PVP). The push compartment comprises PEO, hydroxypropylmethylcellulose (HPMC), sodium chloride and black ferric oxide that is granulated with HPMC. The drug compartment and the push compart-ment are then compressed into a bi-layered core. The entire core, or alternatively only the drug compart-ment, is sub-coated with a 95% hydroxyethylcellulose (HEC) and 5% poly(ethylene glycol) (PEG) solution that facilitates a drug-free interval of 2–5 hours. Thereafter, the sub-coated drug core is coated with a semi-perme-able membrane comprising 60% cellulose acetate, 35% hydroxypropylcellulose (HPC) and 5% PEG. An orifice is then drilled into the outer and inner cores to link the drug layer with the exterior of the drug delivery system. Finally the osmotic pump is dried for 96 hours to remove residual solvent and a further 2 hours to eliminate any excess moisture.[57] Drug release occurs due to the influx of fluid across the semi-permeable membrane into the push compartment. The increase in osmotic pressure forces drug to diffuse through the microscopic orifice. The OROS® technology provides a uniform non-varying rate of drug release allowing blood concentrations to be maintained within narrower limits for longer periods.[58] In addition, the release mechanism is less vulnerable to changes within the gastrointestinal tract due to the semi-permeable membrane being permeable to only water thus facilitating pH-independent drug release.[59] The technology was employed in formulating the chronop-harmaceutical, Covera-HS® (verapamil), an antihy-pertensive. The product facilitates delayed overnight drug release to prevent the surge in blood pressure that occurs in patients during the early morning. While the technology has been applied to certain products, it has a few limitations. Manufacturing the system has proven to be complicated with the need for a laser-drilled hole

in the semi-permeable coating. In addition, clogging of the hole may limit drug release. Drying time also poses a challenge as the drug delivery system requires a fairly extensive drying period of four days.

CODAS®

Chronotherapeutic Oral Drug Absorption System (CODAS®) manufactured by Elan Corporation (Florida, USA) is a multiparticulate drug delivery system that pro-vides a delayed onset of drug release, resulting in release that more accurately compliments circadian rhythms. The technology comprises a drug-loaded core and a mul-tilayered membrane surrounding the core. Both the core and the multilayered membrane comprise water soluble and water insoluble polymers. When the multiparticu-lates are exposed to water, the water-soluble polymer dis-solves and drug diffuses through the pores present in the coating (Figure 4). The water-insoluble polymer acts as a barrier and maintains the release of the drug.[32,60] The CODAS® technology has been applied to the chronop-harmaceutical, Verelan® PM (verapamil). This formu-lation is designed to release verapamil 4–5 hours after ingestion. When taken at bed-time, a maximum plasma concentration is achieved in the early hours of the morn-ing when blood pressure is known to rise.[15]

Diffucaps®

Diffucaps® manufactured by Eurand Pharmaceuticals (Pennsylvania, USA) is a multiparticulate-based drug delivery system also capable of delivering drug to the body according to circadian rhythms. The drug is lay-ered onto a neutral core which may comprise an inert

Laser-drilled delivery orifice

Semi-permeable membrane

Expanded pushcompartment

Osmotically activepolymeric pushcompartment

Figure 3. Schematic showing the mechanics of drug release from the OROS® technology.[2]

Membrane

Drug-load

Pores produced by solublecomponent of polymer membrane

Figure 4. Schematic diagram illustrating the mechanics of drug release from the CODAS® technology.

Release controlling polymer

Protective coating oradditional control polymer

Drug layerCore granules or crystals

Figure 5. Schematic diagram illustrating the various layers sur-rounding a Diffucaps® bead.[62]

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Drug delivery technologies for chronotherapeutic applications 609

particle such as sugar spheres, crystals or granules. An inert binder is used to bind the drug particles to the inert core[61]. Examples of such binders include PEO, HPMC, HPC and PVP. Drug particles are dissolved or suspended in a 5–10% solution of binder. The drug-loaded core is then coated with a plasticized enteric coating and thereafter coated with a mixture of water insoluble and enteric polymers (Figure 5). Examples of water insolu-ble polymers include ethylcellulose, polyvinyl acetate and methacrylate polymer such as Eudragit® RS. Enteric polymers include cellulose acetate phthalate, hydroxy-propylmethylcellulose phthalate and shellac. In order to separate the various layers a thin layer of HPMC is typically used.[61] The multiparticulates are < 1 mm in diameter and by combining them with different release profiles, a composite release profile can be achieved. In addition, the technology may also comprise an organic acid within a membrane layer that may optionally be added between the second and third coating in order to further modulate the lag-phase of drug release. The tech-nology provides the versatility of combining two or more drugs in order to increase patient compliance and has been used to produce a chronopharmaceutical product known as InnoPran® XL.

Egalet®

Egalet® (Egalet a/s, Copenhagen, Denmark) technology uses erosion instead of diffusion to control drug release and has the potential to be employed in chronothera-peutics. The technology comprises an impermeable shell with two lag plugs enclosing a drug-loaded core (Figure 6).[63] The lag-phase is dependent on the length and the composition of the plugs. The impermeable shell comprises ethylcellulose and cetostearyl alcohol, whereas the plug consists of PEG and PEO.[63] The matrix is designed to erode upon contact with the gastrointes-tinal fluid, though gastric fluid should not diffuse in

the system until the point of drug release. This reduces hydrolysis and luminal enzymatic activity. Ideally a bal-ance should exist between erosion and diffusion such that the surface area exposed to the dissolution media is constant ensuring zero-order drug release.[63] The design also allows for more than one drug to be combined in a single drug delivery system. In addition, by varying the outer plug, different release profiles may be obtained.

Emerging advances in oral chronotherapeutic drug delivery technology

The search for innovative drug delivery systems applicable to chronotherapy is ensuing with increasing intensity. It has been suggested that the ideal chrono-therapeutic drug delivery systems should have the fol-lowing properties: (1) Be non-toxic, (2) have a real-time and specific triggering biomarker for a given disease state, (3) biocompatibility and biodegradability, (4) be cost effective, and (5) encompass ease of administration to ensure patient compliance.[19,32]

A tablet in capsule device

A novel drug delivery system based on a “tablet in cap-sule device” capable of producing up to three pulses of drug release, has been developed by Li et al.[65] The device comprises a water soluble cap, impermeable capsule body, and two multi-layered tablets which are filled within the capsule body and sealed with a water-soluble cap. The capsule is also filled with lactose and a modulating barrier layer (Figure 7).

The impermeable capsule comprises ethylcel-lulose (EC), while the rapid release layer comprises

Drug layer

Polymeric layers providinga lag-phase

Figure 6. Schematic showing the mechanics of drug release from the Egalet® Time Release System.[64]

Soluble cap

Rapidly releasinglayers

Impermeablecapsule body

Lactoselayer

Modulatingbarrier

Filler

Figure 7. Schematic representing the tablet in capsule device.[65]

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crospovidone and lactose. HPMC, sodium alginate, carbopol and carboxymethylcellulose were evaluated for use as the modulating barrier, with alginate and HPMC displaying the best results. The drug release pro-file achieved by this device shows three phases of drug release within a 12-hour period. By manipulating the quantity of polymer in the barrier layer, the lag-phase between the pulses could be controlled. In addition, dif-ference in lag-time was observed when the tablets were inserted into various locations within the capsule body. Although this technology allows for the combining of three doses into a single system, the manufacturing process might prove time consuming as each compo-nent of the device is prepared separately.

Core-in-cup tablet technology

Efentakis et al.[66] developed a drug delivery system based on core-in-cup technology. The device comprises a drug containing core tablet an outer impermeable layer and a top cover. The bottom and the circumference wall comprised an inactive material which surrounded the drug core. The core comprised cellulose acetate pro-pionate. The top layer comprised a soluble polymer such as sodium carboxymethylcellulose, sodium alginate and PEO. Upon contact with dissolution media, the top cover absorbs fluid and swells creating a barrier between the dissolution media and the inner drug containing core. The time taken for the swollen layer to erode determines the lag-time. Once, the top layer has eroded drug release occurs. Drug release from this formulation displays a lag-phase between 50–245 min depending on the type of polymer and drug used. Thereafter drug is released rap-idly suggesting drug is released in a sigmoidal manner.

A coated drug-core tablet matrix

Lee et al.[67] developed a hydroxypropylmethylcellulose tablet matrix comprising an inner drug core and an outer drug coating. The inner drug core was prepared using direct compression of the drug and polymer. The core was then coated with a drug containing aqueous-based polymeric Eudragit® RS30D dispersion. The tablet was able to provide a bi-phasic release profile with an initial zero-order release followed by a second phase of drug release. However the tablet was ineffective in generating a lag-phase.

A bi-layered tablet

A study by Karavas et al.[68] involved the construction of a bi-layered tablet that provided a lag-phase fol-lowed by drug release. The bi-layered tablet makes use of felodipine and PVP as a drug core and a HPMC/PVP blend surrounding the core. The combination of HPMC

and PVP served to enhance the mucoadhesive proper-ties of the tablet. Upon exposure to dissolution media the outer layer disintegrated exposing the core to the gastric contents and thus allowing drug release. The lag-time was dependent on the swelling/erosion of the HPMC/PVP matrix. Varying the ratio of the HPMC to PVP also affected the lag-time.

Multiparticulate-based chronotherapeutic drug delivery systems

Enteric-coated microspheres were developed for colonic drug delivery by Maestrelli et al.[69]. These calcium pecti-nate microspheres may be applied to chronotherapeutic disorders as well as for local treatment of the colon. The microspheres were formed by homogeneously dissolv-ing pectin in distilled water and then adding drug. The dispersion was then passed through a nozzle into a solu-tion of calcium chloride. The microspheres were formed immediately by ionotropic gelation. Coating of the micro-spheres involved immersing the spheres in a solution of Eudragit® S100 and allowing them to dry by solvent evaporation. Drug release studies were performed in pH 1.2, 6.6 and 7.4. Results obtained from the study showed negligible drug release at pH 1.2, < 10% drug release in simulated intestinal fluid followed by complete release in the colon. Though this drug delivery device produces an initial lag-phase, it is targeted for colonic delivery and does not provide pulsatile drug release.

Sher et al.[31] made use of floating and pulsatile tech-nology in order to develop a chronotherapeutic drug delivery system to be employed in the treatment of cancer. This was achieved with no excipient-low-density microporous beads loaded with ibuprofen. The drug was loaded onto porous Accurel MP 1000® microparti-cles using melt and solvent evaporation techniques. The microparticles were tested for 6 hours in pH 1.2 followed by 3 hours in pH 7.2. Drug release proved to be minimal while floating in the stomach, followed by a burst of drug release at a pH of 7.2 suggesting sigmoidal drug release. Similar results were obtained by Badve et al.[70] where hollow porous calcium pectinate beads were developed. In vivo studies conducted on rabbits showed promising results with gastric floatation lasting for 5 hours.

Dashevsky and Mohamad[71] introduced a pulsatile rupturable drug delivery system consisting of a drug core, a swelling layer comprising a super-disintegrant and binder, and an insoluble polymeric coating com-prising ethylcellulose. Drug was layered onto sugar pel-lets followed by layering with either 5% suspension of croscarmellose sodium, low-substituted HPC or sodium starch glycolate in a 2% HPC solution. Thereafter the beads were coated with aqueous ethylcellulose disper-sion. Drug release occurs following entry of fluid into the system, which triggers swelling and causes the outer

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Drug delivery technologies for chronotherapeutic applications 611

membrane to rupture. Drug release comprised a lag-time that was determined by the coating layer followed by rapid drug release indicating sigmoidal drug release.

These technologies do have their limitations mainly due to their complicated manufacturing procedures. In addition, multiparticulates have not been extensively tested in humans where they may behave in a very dif-ferent manner to that exhibited in vitro. In terms of the drug release profiles achieved, only the “Tablet in cap-sule device” was able to provide more than one pulse of drug release.

Conclusions

The concept that the body is in a constant homeostatic equilibrium is no longer true. Evidence suggests that the body’s internal clock alters homeostatic control during a 24-hour period leading to fluctuations in certain inte-gral processes such as blood pressure control, cortisol release and gastric acid secretion. With the identification of numerous conditions that follow a circadian rhythm, a superior understanding of chronotherapy is required in the medical and pharmaceutical fields. As numerous drugs are influenced by the daily time-scale, it is dis-concerting that so few chronopharmaceuticals exist on the market. To date, no drug delivery system is able to satisfy all the requirements of chronotherapeutics. The ideal chronotherapeutic drug delivery system should: (1) Deliver the drug after a predetermined time interval, (2) deliver the drug when it is most needed in a 24-hour period, and (3) reduce drug release when not needed (e.g., in the case of hypertension, when the patient is asleep). The search for innovative drug delivery systems applicable to chronotherapy is ensuing with increasing intensity. Extensive research in this field is a necessity in order to improve patient outcomes with research going as far as human studies.

Acknowledgements

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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