Chronotherapeutic Drug Delivery

Dept. of Pharmaceutics, IIT-BHU, Varanasi 1

CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMSP

REPARED BY:

SARITA YADAV

Ph.D Research Scholar

DEPTT. OF PHRMACEUTICS


INTRODUCTIONDEVELOPMENTSCHRONOTHERAPEUTICSIDEAL ChrDDSTHEORETICAL APPROACHESTYPESOF DOSAGE FORMMARKETED PRODUCTSADVANTAGES AND LIMITATIONSEVALUATIONCONCLUSION

CONTENTS


INTRODUCTIONRecent studies have revealed that diseases have

predictable cyclic rhythms and and understanding of these rhythms is required in development of chrDDS.

Mechanical rhythms in our body. They are: Circadian rhythm (24 hr cycle) Ultradian(more than one cycle per day) Infradian(less than one cycle per day)

Drugs also follow some rhythms in their ADME process Every event in body follows some rhythm so by tracing

those rhythms will be helpful in deciding the right time of therapy

The timing of medication can improve outcome in selected chronic conditions.


DISEASE CIRCADIAN RHYTHM

DRUGS

Hypertension Peaks during morning hrs Verapamil ,Atenolol. Felodipine

Asthma Airway resistance increases progressively at nights during the sleep

Oral corticosteroids, Theophylline and B-2 agonist

cancer Tumor blood flow and growth rate greater during daily activity phase

Anticancer drugs (vincristine , paclitaxal)

Rheumatoid Arthritis

Peak in the morning and decreases throughout day

NSAIDs

Duodenal ulcer Acid secretion is max in the night while emptying and motility slower

H-2 antagonist, proton pump inhibitors

Stroke/heart attack

Incidence is higher in early morning

Calcium channel blocker’s

CIRCADIAN RHYTHMS OF DISEASES


CHRONOTHERPEU

TICS

CHRONOPHARMACOKINETIC

S

CHRONOBIOLOGYCHRONOPHA

RMACOLOGY

CHRONOPHARMACEUTICS

DEVELOPMENT


CHRONOTHERAPEUTICS

The term "chrono" refers to the rhythmic changes that every metabolic event undergoes with time

Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects.

Release of drug at desired time as per the pathophysiological need of disease in pulsatile manner.

Chronotherapeutic drug delivery system (ChrDDS)


SHIFT FROM CONV. SR TO ChrDDSMore focus on pulsatile delivery of the drugs as

compared to continuous release zero order release.Factors are:• Biological rhythms in diseases• First pass metabolism• Biological tolerance

• Local therapeutic need• Gastric irritation or drug instability in gastric fluid • Drug absorption differences in various gastrointestinal

segments


IDEAL ChrDDS

Non-toxic within approved limits of useHave a real-time and specific triggering biomarker for a

given disease state, Have a feed-back control system (e.g. self-regulated and

adaptative capability to circadian rhythm )Be biocompatible and biodegradable, especially for

parenteral administrationBe easy to manufacture at economic cost Be easy to administer in to patients in order to enhance

compliance to dosage regimen. Ideal chrdds is not yet available on the market


THEORETICAL AND FORMAL APPROACHES

A general approach to model and analyze circadian pharmacodynamics is based on cosinor rhythmometric methods.

f(t) may be the pharmacodynamic/ pharmacodynamic (PK/PD) factor that is time (t) dependant.

M is the mesor (midline, value about which oscillation occurs), A the amplitude (half the difference between the highest and lowest

values), The angular frequency (radian/unit time, which depends on the

complete cycle of process) C is the residuals. Ʈ is the time interval between two successive maxima.


CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

The drug release from is based on pulsatile systems Single-unit pulsatile systemsSingle-unit pulsatile systems are further sub-divided into capsule-

based and tablet-based systems. Consists of a drug containing core and a barrier in the form of a polymer releases whole drug from the formulation at one after a well defined lag time with burst which is optimized depending on the peak symptom manifestation of the disease condition such as hypertension, asthma, arthritis etc.


Multiple unit pulsatile systemA multiple pulse system delivers the drug in divided doses in

concomitant pulses Provide advantages such as reduced dose, no risk of dose

dumping, flexible release patterns, and increase bioavailability with less intra and intersubject variability.

Conti..


MULTIPULSE FELODIPINE CAPSULE

Designed to deliver pulsatile release of FELO every 6 h during daytime, the capsule comprised of four tablets . The first composed only from a FELO/PVP nanodispersion (0 h) without having any coating layer, the second having a PVP/HPMC 64/36 w/w coating layer (6 h), the third composed from PVP/HPMC 43/57 w/w coating layer (12 h) and the forth being a PVP/HPMC 25/75 w/w coating layer (18 h).


Drug is released at the desired site within intestinal tract

Environment of git control the release like pH , enzymes, git transit time

Treatment of local IBD ulcerative colitis ,crohn disease

Limitation-GIT transit times vary (patient, food intake, stress, and illness)

Drug is released after a lag time according to the worsening of disease condition

Release controlled by different formulation approaches (coating)

Treatment of hypertension asthma, arthritis, ulcer etc.

Reduction in dose/dosing

SITE SPECIFIC DELIVERY

TIME CONTROLLED SYSTEM


VARIOUS APPROACHES TO DESIGN ChrDDS

Time controlled chronotropic systems. • Capsule based system eg pulsincap• Reservoir systems with rupturable polymer coating • Reservoir systems with soluble or eroding polymer coating • Enteric coated systems• Osmotic controlled system• Pulsatile systems based on changed membrane

permeability • Low density floating pulsatile systems


Conti…Stimuli induced pulsatile drug delivery

systems • Glucose-responsive insulin release devices • Inflammation induced pulsatile drug delivery systems • Enzyme catalysed pulsatile chronotropic systems• Temperature induced pulsatile drug delivery systems

Externally regulated pulsatile drug delivery systems


TIME CONTROLLED RESERVOIR SYSTEMS WITH RUPTURABLE POLYMER COATING

This consists of core containing active drugCoated with polymers which rupture after a certain lag time Whole amount of FELO is released within the first 30 min.


GLUCOSE RESPONSIVEDEVICES

PH SENSITIVE HYDROGEL

GLUCOSE OXIDASE

GLUCOSE

GLUCORONIC ACID

SWELLING OF POLYMER AND INSULIN RELEASE

These devices consists of ph sensitive hydrogels (chitosan, n-dimethyl amino ethyl methacrylate etc) and insulin release depends on level of glucose into body.


Certain cells like tumor cells posses some what different temperature with respect to other, their temperature is raised due to their higher metabolic rate.

For targeting tumors, a pulsatile drug delivery system can be designed by utilizing thermoresponsive hydrogel system.

These polymers undergo swelling/deswelling phenomena in response to temperature change which modulates drug release from these systems.

YH Bae. et al developed indomethacin pulsatile drug delivery system in temperature range of 20°C-30°C by using reversible swelling properties of copolymers of N-isopropyl acrylamide and butyrylacrylamide.

TEMPERATURE INDUCED PULSATILE DRUG DELIVERY SYSTEMS


TICKING CAPSULEThese systems are modulated to release

drug by some external stimuli like magnetic field, ultrasound, electrical effect and irradiation.

When these external forces are applied on the system, conductors present in the delivery system get sensitized to trigger the release of drug from the dosage form and as the external stimuli is removed, drug release ceases.

Examples magnetic beads in an implant; photo chemically controlled systems

EXTERNALLY REGULATED PULSATILE DRUG DELIVERY

SYSTEMS


TYPES OF DOSAGE FORMS THAT CAN BE DESIGNED

Simple polymer coated tablet

Compression coated/press coated tablets

Penwest’s TIMERx controlled release technology press coated tabletsInner core formulate such that the drug is released in intestine, Outer core consist of hydrophilic matrix (xanthan and locust bean gum)

TIMERx

Eg .Enteric coated system


Core in cup tablets

Layered tablets

The system consists of three different parts, a core tablet, containing active ingredient, an impermeable outer shell and a top cover layer-barrier of a soluble polymer.

Layered systems both layers contain a drug dose .An intermediate layer, made of swellable polymers, sepatrates an immediate release and a controlled release .

GEMINEX


CAPSULE SYSTEM WITH COATINGR.P scherer International Corporation

Michigan USEach capsule is composed of a water

insoluble body enclosing the drug reservoir and a water soluble cap, and also contains the drug dose which is sealed with a hydrogel plug.

After a lag time , the swollen plug is ejected from the capsule and the drug is then released into the small intestine or colon.

Deliver a dose of dofetilide following a 5-h delay to the lower GIT tract

PULSINCAP™


Double coated hard gelatin capsules and double coated tablets

The capsules are filled with active pharmaceutical ingredient either for single pulse or multi-pulse release

Coated with inner swelling layer An external water insoluble semipermeable polymeric

coating.The time required by swelling layer to rupture outer

coating surves the purpose of desired lag time required in chrono therapy of disease.

Pulsatile release muliparticulate systems .

These can be developed in various types of dosage forms

like: Pellets , Granules, Microspheres, Beads ,

Nanoparticles .


ADVANTAGES Biological rhythms are taken into consideration Right timing and the amount of medication optimizes

the drug's desired effects and minimize the undesired ones.

More effective use of already existing drugsReduction of dose requirement Reduced dosage frequency Lower daily cost to patient due to fewer dosage units

required by the patient in therapy.


Cont...Avoids degradation of in upper gastrointestinal tract.

(proteins and peptides)Drug targeting to specific site like colon, cancer. Protection of gastric mucosa from irritating drugs. Improved patient compliance. Drug loss is prevented by extensive first pass metabolism Extended release of drug in pulsatile manner

LIMITATION is for patients who do shift work (alternate day and night) for whom chronotherapy may be too complicated.


MARKETED CHRONOTHERAPEUTIC SYSTEMS

CHRONOTROPIC® SYSTEM PULSINCAP SYSTEMOROS CTCODAS TIMERX

GEMINEXDIFFUCAPS CEFORM GEOMATRIX™CONTIN


EVALUATION OF ChrDDS PARAMETERS TO BE EVALUATED

EVALUATION OF POLYMERS

EVALUATION OF POLYMER DRUG INTERACTION

EVALUATION OF DOSAGE FORM

Thermal analysisDSC, DTA, (FT-IR)SEM, TEM.

In-vitro evaluationIn- vivo evaluation


Routine evaluation- Tablets -Hardness, friability, disintegration tests , wt. VariationCapsule- Moisture content, size , shapeMulti-particulate -Flow rate , angle of repose, content

uniformity, particle size distribution.In-vitro dissolution tests (modified USP type 2 app.) are

done to determine lag time in delivery and release profile of dosage form.

In-vivo studies are done in animals like rabbit , rat etcSuccess of dosage form depends on clinical trials done on

human volunteer’s.

DOSAGE FORM EVALUATION


CURRENT & FUTURE ASPECTSThe future of chronotherapeutics seem to be quite

promising as pulsatile release exhibit several advantages over the traditional zero or first order drug delivery mechanisms in certain disease states

The pulsatile release (site or time specific) most often is achieved by using different polymers in coating layers or by changing the coating thickness.

From technological point of view, multiparticulate systems seem to be more efficient and it can become even more sophisticated when coating technologies are incorporated.

Increasing number of multiparticulate coated systems would become commercially available in the years to come.


Circadian rhythm of the body is an important concept for understanding the optimum need of drug in the body

ChrDDS is one such system that, by delivering drug at the right time, right place and in right amounts, holds good promises to benefit the patients suffering from chronic problems like arthritis, asthma, hypertension etc.

Thus designing of proper pulsatile drug delivery will enhances the patient compliance, drug delivery to the target site and minimizes the undesired effects.

These drug delivery systems are still in the early developmental stage and much research will have to be conducted for such systems become practical clinical alternatives

CONCLUSION


M Nagar, S Singhai1, V.S. Chopra1*, Namrata Gautam2, Piyush Trivedi Chronotropic Systems; an Emerging Trend in Drug Delivery for Pulsed Release in Chronopharmacotherapy International Journal of Pharmaceutical and Clinical Research 2010; 2(1): 10-19 10

Bi-Botti C. Youan* Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery?. Journal of Controlled Release 98 (2004) 337– 353

MH. Smolensky, Nicholas A. Peppas Chronobiology, drug delivery, and chronotherapeutics. Advanced Drug Delivery Reviews 59 (2007) 828–851.

J Sajan*, TA Cinu, AJ Chacko, J Litty and T Jaseeda. Chronotherapeutics and Chronotherapeutic Drug Delivery Systems Tropical Journal of Pharmaceutical Research, October 2009; 8 (5): 467-475

Anil K. Anal Time-Controlled Pulsatile Delivery Systems for Bioactive Compounds. Recent Patents on Drug Delivery & Formulation 2007, 1, 73-79

Chronobiology and chronotherapeutics Jha N1, Bapat S2Kathmandu University Medical Journal (2004) Vol. 2, No. 4, Issue 8, 384-388

Lida E. Kalantzi1, Evangelos. Karavas 1, Efthimios X. Koutris 1 and Dimitrios N. Bikiaris2Recent Advances in Oral Pulsatile Drug Delivery . Recent Patents on Drug Delivery & Formulation 2009, 3, 49-63

Evangelos Karavas a,b, Emmanouel Georgarakis b, Dimitrios Bikiaris c, Felodipine nanodispersions as active core for predictable pulsatile chronotherapeutics using PVP/HPMC blends as coating layer International Journal of Pharmaceutics 313 (2006) 189–197.

www.pharmainfo.com www.circadianrhythm.com

REFERENCES

http://www.pharmainfo.com/


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Chronotherapeutic Drug Delivery

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