Chronotherapeutics: Optimisation of Therapeutic Outcomes

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Chronotherapeutic drug delivery system

Have you ever wondered why statin drugs must be administered in evening instead or rather than morning? It’s because hepatic cholesterogenesis occur in evening hours even in the fasting states. Hence efficacy of statins is affected to much extent when it is not administered at correct time. Many individuals takes medicine prescribed as “once daily’’ without considering the time of day for administration. Evidence shows that timing is much important. Such timing effect is controlled by “circadian rhythm’’, also called biological rhythm or biological clock of our bodies. The term circadian is derived from the Latin, circa meaning “around/about” and die means “day”. These biologic rhythms are observed as adaptive adjustments to cyclic environmental changes occurring over the course of the day, a month, or a season.

The rhythm is driven by a group of “clock genes” that are widely observed in animals, plants, bacteria, and even cultured cells. In mammals, the core clock genes are rhythmically expressed in the suprachiasmatic nucleus, the central clock in the hypothalamus, as well as almost all peripheral tissues, where they control thousands of genes called clock controlled genes (CCGs) in a circadian manner, affecting various biochemical and physiological processes

Differences in physiology according to the time of day, time of month, time of year, or even the period in one’s life holds the discipline of chronobiology.

Chronobiology is the science concerned with the biological mechanism of the diseases according to a time structure.

Chronopathology is Study of biological rhythms in disease processes and morbid and mortal events.

Chronopharmacology is the science concerned with the variations in the pharmacological actions of various drugs over a period of time of the day. The word, Chronopharmacology (including chronopharmacokinetics and chronopharmacodynamics), was composed to describe the study of the relationship between drugs and biological rhythms, notably circadian rhythm.

Chronopharmacokinetics is the Study of biological rhythm effects on the absorption, distribution, and elimination of medications.

Chronotherapeutics is the purposeful alteration of a drug level to match rhythms in order to optimize therapeutic outcomes and minimize side effects. It is the discipline concerned with the delivery of drugs according to inherent activities of a disease over a certain period of time.

The endocrine system provides many examples illustrating chronobiology. Timing of puberty and monthly alteration in hormones that initiates menses. Some components of the endocrine system follow a diurnal pattern of activity. There are a number of hormones that are secreted in the morning including, catecholamines, cortisol, plasma renin, angiotensin and aldosterone. In contrast, melatonin, growth hormone, prolactin, gastric acid, luteinizing hormone, adreno-corticotrophic hormone (ACTH) and follicle-stimulating hormone, peak in the evening or during sleep. There are consequences to the circadian changes in these hormones. For example, the increase in catecholamines in the morning promotes platelet aggregation. This is especially important since fibrinogen also increases, and the body’s own endogenous t-PA decreases, promoting a procoagulant state with increased blood viscosity.

Normally, circadian rhythms are synchronized according to internal biologic clocks related to the sleep-wake cycle. Most people sleep at night and rise in the morning. In night-shift workers (who typically sleep during the day), most circadian rhythms are shifted to match their sleep-wake cycle. The goal of chronotherapeutics is to match the timing of treatment with the intrinsic timing of illness. Studies identified various drugs that display significant variation in concentrations or effects, or both, over 24 hours. Perfect example is heparin. Even when it is administered at a constant infusion rate, the activated partial thromboplastin time and the risk of bleeding vary significantly according to the hour of the day and are higher at night. The narrower the therapeutic window (i.e., risk-benefit ratio) for a specific drug, the more important the implication of the circadian variation in plasma levels.

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There are various conditions which show a circadian pattern and advantage could be taken by timing and adjusting the administration of drugs according to the circadian rhythm of the disease. Some of the examples are:

  1. Arthritis
  2. Myocardial infarction
  3. Peptic ulcer
  4. Hypertension
  5. Hypercholesterolemia
  6. Bronchial asthma
  7. Cerebrovascular accidents

Hypertension

Systolic blood pressure rises approximately 3 mm Hg/hour for the first 4-6 hours post-awakening, while the rate of rise of diastolic blood pressure is approximately 2 mm Hg/hour. The difference between normotensive and hypertensive patients is the level of blood pressure throughout the day. The peak blood pressure is between 6 am and noon. With activation of the sympathetic nervous system prior to awakening, blood pressure begins to increase. Heart rate also increases. The blood pressure declines from mid-afternoon and is minimum at midnight. In most hypertensive patients, there is a rather marked rise in blood pressure upon awakening that is called the morning or “a.m.” surge. These changes in blood pressure parallel the morning activation in catecholamines, renin, and angiotensin. Activity and sleep influence the level of blood pressure throughout the day. Patients with autonomic dysfunction have their lowest blood pressure during standing and highest blood pressure when supine.

Normally, blood pressure declines 10% to 20% from the activity period to the sleep period. Patients with less than a 10% reduction in daytime blood pressure are referred to as ‘non-dippers’. Research suggests that a blunted nocturnal decline in blood pressure may be due to diminished sodium excretory capacity, alteration in the autonomic nervous system, or other factors. In addition, nondippers are more likely to have a secondary cause of hypertension. Endocrine causes include diabetes mellitus, pheochromocytoma, primary aldosteronism, liquorice intoxication, Cushing’s syndrome, and high dose corticosteroids.

There are four antihypertensive medications that are chronotherapeutic medications: verapamil (Covera HS, Verelan PM), propranolol (InnoPran XL) and diltiazem (Cardizem LA), and there are more products available as understanding of chronobiology expands.

Advantage of these formulations are that delivery of the active drug tailored/matched to the typical circadian rhythms and heart rate, and the patients are better covered or get efficacy in the early morning when cardiovascular need appears to be greatest, and the effects of traditional medications seems to diminish the timings of various antihypertensives and can be adjusted according to their, half-life, duration of action and onset of action                                                                                                                                                                  Bronchial asthma

Asthma is the most common disease with the largest circadian variation. Because asthma has such a striking circadian variation, several types of chronotherapy have been tried. In one study, use of a timed-release formulation of theophylline (Theo- 24) achieved therapeutic drug concentrations during the night and avoided toxic levels during the day when the dose was ingested at 3 pm. In addition, oral prednisone has been shown to be much more effective in improving several features of nocturnal asthma (i.e., overnight fall in forced expiratory volume in 1 second [FEV1], 4 am FEV1, and response to a standard dose of inhaled beta2 agonist) when administered at 3 pm rather than 8 am. Another study showed that a single daily dose of inhaled corticosteroids, when administered at 5:30 pm rather than 8 am, was nearly as effective as four doses a day.

Hypercholesterolemia

Administration of an HMG-CoA reductase inhibitor alsoknown as statins is more effective at lowering serum cholesterol levels than the same dose given in the morning. Initially, studies involving morning dosing of HMG-CoA reductase inhibitors failed to show a reduction in cardiovascular morbidity and mortality. When the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were first introduced, morning dosing was recommended. This strategy was re-evaluated after the discovery of the circadian rhythm of cholesterol biosynthesis, in which higher rates of cholesterol intake and hepatic cholesterogenesis occur during the evening hours, even in the fasting state.

Cerebrovascular accidents

A major objective of chronotherapy for cardiovascular disease is to deliver the drug in higher concentration during time of greatest need and in lesser concentrations when the need is less. The cerebrovascular accidents have been shown to occur on the first hours of morning between 10 A.M. and 12 noon, and the incidence declines steadily during the evening and the midnight. ACE inhibitors are more effective when administered during night. Atenolol, Nifedipine and amolodipine are more effective when administered at night.

Data from recent studies demonstrate that antihypertensives and antianginal therapy can be designed to mimic the circadian rhythms. Future research will evaluate whether timings of drug delivery has an effect on the outcomes like control of hypertension, silent ischemia, myocardial infarction and quality of life.

Peptic ulcer disease

Maximal acid secretion, peptic ulcer disease pain, and perforation of gastric and duodenal ulcers are more common at night. In the past, histamine2 antagonists were administered at regular intervals around the clock, on the basis of pharmacokinetic properties. However, administration of these drugs at bedtime is more effective. Nocturnal administration not only reduces acid secretion more effectively but also promotes ulcer healing and reduces ulcer recurrence.

Arthritis

The new cyclooxygenase-2 (COX-2) inhibitors effectively relieve osteoarthritis symptoms when taken in the morning; better results are obtained in rheumatoid arthritis when part of the dose is taken in the evening.

Circadian Rhythms and the Severity or Manifestation of Clinical Disease

Disease or Syndrome Circadian Rhythmicity Drugs used
Osteoarthritis

 

Symptoms worse in the middle/latter portion of the day NSAIDs, glucocorticoids
Sudden cardiac death Incidence highest in ventricular tachycardia morning after awakening Nitroglycerine, Calcium channel blockers, Ace inhibitors

 

Peptic ulcer disease Symptoms worse in the early (sleep) a.m. H2 blockers

 

Hypercholesterolemia
Cholesterol synthesis is generally high during night than day HMG COA reductase inhibitors (Statins)

 

Bronchial asthma Exacerbations more common during sleep B2agonists,antihistamine

 

Diabetes mellitus
Increase in blood sugar level after meal Sulfonyl urea, insulin, bioguanide

 

Rheumatoid arthritis Symptoms are most intense on awakening NSAIDs, glucocorticoids
Angina pectoris. Chest pain and ECG changes more common during the early a.m

 

Nitroglycerine, Calcium channel blockers, Ace inhibitors

 

Stroke Incidence greatest in the early a.m
Allergic rhinitis Worse in early a.m./upon arising antihistamine

Ideal characteristics for chronotherapeutic drug delivery systems should be:

  1. Self-regulated and adaptive capability to circadian rhythms
  2. Be biocompatible and biodegradable.
  3. Non-toxic with the usage of delivery systems.
  4. Associate with real time and specific triggering biomarkers for a given disease state.

Advantages

  • Reduced frequency in dosage schedule
  • Improved patient acceptability and compliance
  • Minimization of side effects
  • Biological tolerance
  • Protection of stomach mucosa from gastric irritation drugs
  • Drugs with high first pass effects can be delivered efficiently without loss of drug.
  • Drug targeting to specific sites such as colon is possible

Limitations of pulsatile drug delivery system

  • Multiple manufacturing steps in multiparticulate pulsatile drug delivery system.
  • Incomplete release.
  • In-vivo variability in single unit pulsatile drug delivery system.
  •  Low drug load.

Classification of pulsatile drug delivery systems

Pulsatile drug delivery system is classified into four classes:

Time controlled pulsatile release

  1. Capsular system
  2. Port system
  3. Delivery by solubility modulation
  4. Delivery by reservoir systems

External stimuli induced system

  1. Electrically stimulated Pulsatile system
  2. Magnetically stimulated Pulsatile system
  3. Ultrasonically stimulated Pulsatile system

Multi-particulate system

  1. Pulsatile system based on rupturable coating (Time controlled expulsion system)
  2. Pulsatile delivery by change in membrane Permeability
  3. Sigmoidal release system
  4. Low density floating multiparticulate pulsatile systems

Stimuli induced

Internal stimuli induced pulsatile system

  1. Temperature induced system
  2. Chemical stimuli induced system
  3. pH sensitive drug delivery system

 

Pulsicap system: It consists of a water insoluble capsule body filled with the drug and a cross-linked hydrogel plug which swells upon contact with dissolution medium or gastrointestinal fluids pushing it out of the capsules.

Port systems: It consists of a gelatin capsule in a cellulose acetate semi permeable membrane and inside insoluble plug and osmotically active ingredient along with the drug. When it imbibes the gastric fluids resulting in increased inner pressure that ejects the plug after a lag time.

Delivery by solubility modulation: Systems composites of modulated agents sodium chloride and drug, lesser amounts of NaCl is required to maintain saturated fluid entering the osmotic device which
facilitates pulse release.

Delivery by reservoir system with erodible or soluble barrier coatings: Barrier layer was coated over to the reservoir device of pulsatile drug delivery where the barrier erodes or dissolves after a specific lag period enabling the drug to get released rapidly from the reservoir core.

Electro responsive pulsatile release: Drug release is facilitated by the action of applied electric field on rate controlling membrane containing polyelectrolytes.

Magnetically induced pulsatile system: With the incorporation of magnetic materials such as magnetite, iron, nickel, cobalt in to capsule or tablets by the external influence of magnetic field. We can position drug at a specific place or slow down its access to unwanted sites thus changing the time or extent of drug absorption in
to stomach or intestine.

Ultrasonically stimulated: Interaction of Ultrasound With biological tissues, improving the drug permeation through biological barriers, such as skin. Mechanism mainly involved here is the absorption of acoustic energy by the fluids or tissues and oscillating bubbles cause non thermal effect along with the non cavitational effects such as radiation pressure, radiation torque and acoustic streaming

Multiparticulate system: Drug release from these systems depends on parameters such as type of coating, pH dependent coating, insoluble coating under all physiological conditions influences the solubility changes at some point in G.I. tract and facilitates slow erosion.

Reservoir with rupturable polymeric coating or time controlled explosion system: Super-disintegrants incorporated in as swelling agents facilitating the time burst release of particulates upon ingress of water. Initially the drug coated on non-peril seeds followed by a swellable layer and an insoluble top layer coating. In vitro in vivo correlation studies reported that time controlled explosion systems with a lag time of 3 hrs appearance of drug in blood and maximum release noted after 5 hrs.

Sigmoidal release systems: It consists pellets comprising of different acids such as succinic acid, acetic acid, glutamic acid, malic acid, citric acid, coated with ammonia methacrylate copolymer usp/ nf type b. water influx turns the drug core to acid solution in turn increases the permeation of the hydrated polymer film.

Low density floating multiparticulte pulsatile systems: Especially for the drugs having absorption window in the stomach low density floating micro particle pulsatile dosage forms retain the drug in stomach for a longer period and not influencing by the pH fluctuations and gastric emptying.

Thermoresponsive pulsatile release: Hydrogels at their transient temperatures undergo substantial reversible volume changes in response to change in temperature. Among the various polymers available N-isopropylacrylamide is probably the most extensively used.

Chemical stimuli induced pulsatile release: Stimuli sensitive delivery systems release the drug in presence of biological factors like enzymes, pH or any other chemical stimuli example; Development of a gel composed of poly-N-isopolycrylamide with phenylboronic acid moieties that showed a remarkable change in the swelling induced by glucose.

pH sensitive drug delivery systems: pH dependent polymers enabled the drug to release in the desired pH range such as eudragit, pthallates, carboy methyl cellulose, methacryllic acid especially polymers like eudragit L and S favoured the colon targeting.

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Pulsicap system

 

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Port systems

Marketed products of chronotherapeutic drug delivery systems

Technology

Rationale Products Company
DIFFUCAPS®

 

A multiparticulate system consisting of an inactive core, coated with an active pharmaceutical ingredient mixed with a water-soluble composition. This may be in the form of beads, pellets or granules.

 

Innopran® XL containing Propranolol for use in hypertension

 

Eurand Pharmaceuticals LTD, Dayton, Ohio, USA

 

CODAS®

 

Chronotherapeutical oral drug absorption system consisting of drug loaded beads that are coated with release-controlling polymer. Polymer consists of water-soluble and water-insoluble polymers to induce a lag time

 

Verelan® PA containing verapamil for use in hypertension

 

Elan Drug Technologies, San Francisco, CA, USA

 

TIMERx®

 

A novel polysaccharide system that adopts the use of xanthan gum and locust bean gum in the presence of secondary and tertiary components, to form water-soluble granules

 

Tablet within a tablet to obtain different chronotherapeutic profiles. Geminex® is an improvement which provides the potential for dual therapy.

 

Penwest Pharmaceuticals, Danbury, CT, USA

 

OROS®

 

As osmotic pump system comprising a central drug reservoir surrounded by a semi-permeable membrane, which is surrounded by osmotically active agents in tablets with a strategically laser-drilled orifice

 

Covera® HS containing verapamil for use in hypertension

 

Alza Corporation, Mountainview, CA, USA

 

CONТlN®

 

Drug blended with hydrophilic cellulose, then hydrated with polar solvent and fixed with a higher aliphatic alcohol to produce a semi-permeable matrix with uniform porosity Uniphyl® once daily theophylline MS Contin® and Oxycontin® for use in pain management

 

Purdue Frederick, Norfolk, CT, USA

 

PULSYSTM

 

A novel pulsatile release technology that consists of one immediate-release and two delayed-release components with the use of soluble and insoluble coatings.

 

MoxatagTM containing amoxicillin for use in antibiotic therapy

 

Middlebrook Pharmaceuticals, Westlake, Texas, USA

 

PULSINCAP

 

Consists of a drug reservoir housed within a water-soluble capsule body. The open end is plugged with swellable polymers that are pushed out when in contact with fluid, releasing drug from the reservoir

 

A versatile system that can create lag times as well as allowing tablets/ minitablets, solutions or beads to be housed within the capsule body.

 

R.P. Scherer International Corporation, Troy, MI, USA

 

CEFORM®

 

Biodegradable polymers/bioactives are subjected to varying temperature, thermal gradients and flow processes to produce microspheres of uniform size and shape (150-180μm)

 

Cardizem® LM containing diltiazem for use in hypertension.

 

Fuisz Technologies, Chantilly, VA, USA

 

 

 

Patents involving different types of pulsatile delivery systems with advanced formulation approaches.

Mode of drug delivery Title (number) Rationale for chronotherapy and

features of patented systems

Capsule based

(delivery device

with orifice)

Delivery devices with pulsatile effect

(EP0627231)

Invention lies in the field of pulsatile delivery of drugs, nutrients. The pulsatile effect achieved by parameters as choice of elastic material for the band, the thickness of the band made from the elastic material, the configuration and location of the orifice, and the viscosity and surface tension of the active agent formulation
Oral tablet based IR gastrointestinal drug delivery system

(US6531152)

 

 

Diseases of alimentary tract, system able to release drug at specific locations within GIT.
Oral tablet based Pulsatile particles drug delivery system

(US5260069)

 

 

Hypertension, unit dosage form for delivering drugs into the body in a series of sequential, pulsatile fashion. The system can be used with drugs that cannot be released by diffusion through a porous coating such as Water-insoluble drugs

 

Oral tablet based Pharmaceutical compositions (US4897270) Infection of gram-positive and gram-negative microorganisms, conventional film-coated tablets reduce the bioavailability of cefuroxime axetil and the invention overcomes this by control of the film
coat rupture time and use of a tablet core, which disintegrates immediately following rupture of the film coat.
Oral tablet based Pharmaceutical tablet suitable to deliver the active substance in subsequent and pre-determinable times (US6294200) Gastroesophageal reflux disease, Pharmaceutical tablet dosage form, capable of delivering the active substance with three pulses to a pre-determinable release profile.
Oral tablet based

 

Controlled release flutamide composition (US5162117)

 

 

 

Prostate cancer, invention provides controlled release form which is designed to provide an IR dose and a second pulsed delayed release dose

 

Oral tablet based Delayed total release two pulse gastrointestinal drug delivery system (US6632451)  

 

Analgesic and anti-inflammatory, a two pulse delivery device for delivering one
Oral tablet based

 

Press coated pulsatile drug delivery system

suitable for oral administration (US6372254)

Anti-inflammatory, a press coated pulsatile drug delivery system with an immediate release and an extended release compartment with TPR

 

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