Pharma Times - Vol. 42 - No. 12 - December 201020

Article

Biological rhythms are an adaptive phenomena relating to predictable changes in environmental factors that regulate many body functionslike metabolism, sleep pattern, hormone production and physiology. Matching of drug release to the circadian rhythms of the body is thebasic concept for chronotherapeutic drug delivery systems. The safety and efficacy of a drug can be improved by coordinating the peakplasma concentration during 24 hrs of the rhythms. The time controlled drug delivery systems or the pulsatile drug delivery systems are thebest approach for chronotherapy. Pulsatile drug delivery systems offers rapid and transient release of certain molecules within a short timeperiod immediately after a predetermined off release period, i.e., lag time. As these systems deliver the drug at the right time in the rightamount and hold good promise for patients suffering from chronic disorders like asthma, myocardial infarction, angina pectoris, hypertension,ulcer, epilepsy and arthritis which show circadian dependency. Various systems like capsular systems, osmotic systems and others basedon the use of soluble or erodible coatings or rupturable and permeable membrane systems are summarized in this article.

ChronopharmacologyChronopharmacology is the study of

predictability in time differences in the effectsand pharmacokinetics of the drug both inexperimental animals and human beings.Chronopharmacology of living organisms arecomposite of rhythms with varying frequencyranging from seconds to seasons.Chronobiological frequency is the circadianrhythm that approximates the earth 24 hrrotation. Chronopharmacology investigatesboth effects and side effects of the drug onthe temporal changes in biological functions.Circadian rhythm in the rate of absorption,hepatic conjugation and urinary excretioncontributes towards variation inresponsiveness of the drug. Selection of thecorrect timing for drug administration hasbeen shown to be important in certain clinicalsituations like asthma, arthritis, hypertension,angina and epilepsy. The drug therapy canbe optimized by tailoring the dosing schedulebased on chronobiological pattern 1,2.

ChronopharmacokineticsChronopharmacokinetics can be

defined as the study of rhythm dependentchanges in pharmacokinetic patterns suchas absorption, distribution, metabolism andelimination of the drug. Chronopharma-cokinetics studies are needed for betterunderstanding of non-linear behavior of adrug. Circadian rhythm in gastric acidsecretion, gastric motility, gastric blood flowand urinary pH play an important role in timedependent variation of drug plasmaconcentration. Chrono-pharmacokineticsincludes the temporal aspects of absorption,distribution, metabolism and elimination ofthe drug.

Chronotherapeutic Drug Delivery SystemsRita Lala*, Nikita A. Nandgaonkar**Prin K. M. Kundnani College of Pharmacy, 23, Jote Joy Bldg., Rambhau Salgaonkar Marg, Cuffe Parade, Mumbai - 400005.

Temporal aspects of drugabsorption

Temporal changes in gastric pH,motility, digestive secretions, gastric bloodflow, membrane permeability and gastricemptying may be involved. Variation inabsorption is due to the presence of food,posture and galvanic form of the drug. Mostof the lipophilic drugs seem to be absorbedfaster when they are taken early morning.Chronopharmacokinetics studies also havebeen reported for menstrual rhythms e.g.Sodium salicylate absorption varies alongwith the menstrual cycle with maximum inmid of the menstrual cycle.

Drug distributionIt is related to changes in binding with

plasma proteins that are involved in drugtransport from the site of administration tothe receptor site. For acidic and basic drugs,variations in free plasma drug levels exist.The temporal binding protein for acidic drugsvaries with the dark phase. Changes areinvolved in membrane passage andaccumulation of the drug e.g. Cisplatinbinding is found to be minimum in theafternoon and maximum in the morning.

Drug metabolismHepatic clearance of a drug is

influenced by the rate of blood flow to theliver, enzymatic transformation and variationin the percent of protein binding. Biologicalfactors that modify drug metabolism areenzyme secretion, endocrine function,environmental factors such as lightningschedule and feeding habits that synchronizethe endogenous rhythms e.g. the clearanceof a drug having a high extraction ratio suchas Lidocaine and Propranolol are found tobe high at night than in the day.

Drug eliminationCircadian rhythm affects the glomerular

filtration rate. The filter load is maximum atday time and minimum at night. Thisdifference between day and night timedepends on life style, posture, activity andmeal times. The rate of excretion of a drugwhich is completely removed during a singlepassage through the kidney such as para-aminohippuric acid shows variation due tocircadian changes in the renal blood flow.The concentration of plasma anti-diuretichormone (ADH) shows marked differencewith diurnal value lower than the nocturnalones. Drugs which get eliminated during daytime in healthy adults are 20 % quicker thannocturnally.

ChronopharmacodynamicsChronopharmacodynamics deals with

rhythmic changes with the drug includingeffects indicating temporal but not randomlydistributed drug susceptibility or sensitivityof organisms or target tissues down to thecellular or sub cellular level3,4. Fig. 2represents the relation of some physiologicalparameters with human biological clock.

Chronotherapy andchronotherapeutics

Chronotherapy aims at establishingmaximum drug effect or reducing undesirableside effects by determining the best biologicaltime for drug dosing thus helping to increasethe therapeutic index of the drug. Matchingdrug release with the circadian rhythm of thebody is used as a basic concept for new drugdelivery systems for safety and efficacy ofthe drug by coordinating the peak plasmaconcentration of the drug with the circadianrhythm of the body. Chronotherapeuticsrefers to the clinical practice of synchronizing

E-mail : * r_r_lala@yahoo.co.in, **nikkita006@gmail.com

Pharma Times - Vol. 42 - No. 12 - December 2010 21

drug delivery in a manner consistent with thebody's circadian rhythm to producemaximum health benefits and minimumharm. Pulsatile drug delivery systems aretime and site-specific drug delivery systems,thus providing special and temporal deliveryand increasing patient compliance. Pulsatilerelease is beneficial when constant drugrelease or zero order release is not required.Different release patterns are shown inFig. 3. It is a time programmed drug releasesystem. The release of the drug as a pulseis designed in such a way that completeand rapid release of the drug follows thelag time6-8.

Advantages of such drug deliverysystems include controlled onset andextended release of the drug. The deliveryprofile of the drug is designed to complementthe circadian pattern of the disease and therate of the drug release is independent ofpH, posture and food. Various systems likecapsular systems, osmotic systems etc.based on the use of soluble or erodiblecoatings, use of rupturable and permeablemembranes system have been developed9.

1) Enteric coated systems

It is the traditional method used toprevent the degradation of pH sensitivedrugs and localizes the drug in the GIT.Enteric coated polymers such as Eudragits,cellulose acetate phthalate, hydroxy-propylmethyl cellulose are used for coatingwhich protects the dosage forms from theacidic environment of the GIT and allowsdelivery of the drug to the small or largeintestine based on solubility, pH and coatingthickness of the polymeric layer. Entericcoated systems are used for site specific andtime controlled drug delivery10.

2) Pulsincap

It is a single unit system comprised of awater insoluble capsule body enclosing thedrug reservoir. The capsule body is closedat one end with a swellable hydrogel plug.Various hydrogels such as hydroxy-propylmethyl cellulose, hydroxypropyl,polyvinylpyrrolidone are used as plugmaterials. Enzymatically controlled erodablepolymers such as pectin can also be usedas plugging material. When the capsulecomes in contact with water it absorbs waterand swells. After a lag time the plug getspushed out and the drug gets release rapidlyin the form of a pulse. The total length of theplug, its position of the insertion into thecapsule and the polymer used for making theplug controls the lag time of the system.Rapid release of the drug can be ensuredby the inclusion of effervescent agents, superdisintegratnts and osmotic agents11,12.

3) Osmotic systems

In the case of the osmotic system,osmotic pressure acts as a driving force forthe pulsatile drug release. The system

consists of application ofa semi permeablemembrane around thecore of an osmoticallyactive drug or a drugcombined with anosmotic agent. Thedelivery orifice is drilled into the system by lasertechnique or a high-speed mechanical drill.When the system comesin contact with fluid, dueto the differences in theosmotic pressure, thedrug inside the system ispumped out at controlledrate. A lag time of 1-10hr can be achieveddepending on thethickness, orifice diameter and concentrationof an osmotic agent. e.g. Port system. Thissystem consists of a capsule coated with asemi permeable membrane. The capsuleacts as a reservoir of the drug and osmoticagent. Water enters into the system throughthe semi permeable membrane and leads tothe development of osmotic pressure andexpulsion of the drug after a desired lagtime13.

4) Swelling and erodible systems

In this system the drug reservoir issurrounded by a polymeric barrier layer thatswells and gets dissolved when it is incontact of dissolution media and drug isreleased after the lag time. The coating layeris made up of various hydrophilic polymers.In addition to this enteric coating can beapplied outside to overcome the gastric pHeffect on the drug. The lag time of thesystem can be controlled by thickness of thepolymeric coat and the viscosity grade ofthe polymer used14-17.

5) Compression coated systems

It involves direct compression of thecore with the coating material avoiding theneed for the separate coating proceduresand the use of coating solutions. In case ofsome compression coated systems, theoutermost layer provides the rapidlyreleasing initial dose. The pulsatile systemis formed due to the alternate drug free anddrug containing layers. Normally usedexcepients and conventional compressiontechniques can be utilized for production.The limitation of the system is that centralposition of the core layer cannot be assured.The system can be two or three component,that is two or three layered tablet. One layerprovides the initial dose of the drug whileother layers are formulated with thecomponents that are insoluble in gastricmedia but dissolves in intestine. The tabletcan be coated with a semi permeablepolymeric coating layer that controls drugrelease18-20.

6) Multiparticulate systems

More reliable gastric emptying patternis observed for multiparticulate systems andis based on changes in membranepermeability and rupture of the coating. Thedrug is coated on non-peril sugar seedsfollowed by coating with swellable polymericlayer. The swelling agents include superdisintegrants, effervescent agents andosmotic agents. Upon ingress of water, theswellable layer expands resulting in ruptureof the film and rapid drug release. Severaldelivery systems based on ion exchangeprinciple have been developed. Other usedpolymers such as Eudragits RS30D. Itcontains positively charged quaternaryammonium groups in the side chainaccompanied by negative hydrocolloidcounter ions. The ammonium groups interactwith water, change the permeability and allowwater to penetrate in to the core layer in acontrolled manner21,22.

7) Ultrasound drug delivery systems

Ultrasound is an enhancer forimprovement of drug penetration throughbiological barriers such as skin, bloodvessels etc. The ultrasound effect enhancesdegradation of the polymer in which the drugmolecules are incorporated. The drug canbe released by repeated ultrasoundexposure. Pulse delivery is achieved by on-off application of ultrasound23,24.

ConclusionIf drug released is designed in a time

controlled manner and maximum drug ismade available at peak time, optimization ofthe therapy can be achieved for diseases thatfollows the circadian rhythm. A significantamount of progress has been made towardsdeveloping pulsatile chronotherapeutic drugdelivery systems that can effectively treatdiseases with non-constant drug releasedosing therapies.

Fig. 3: Drug release pattern a: pulsatile release b:conventional release c: sustained release.

Pharma Times - Vol. 42 - No. 12 - December 201022

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