CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

PREPARED BY:
SARITA YADAV

Ph.D Research Scholar DEPTT. OF PHRMACEUTICS IIT-BHU

Dept. of Pharmaceutics, IIT-BHU, Varanasi

CONTENTS
INTRODUCTION DEVELOPMENTS CHRONOTHERAPEUTICS IDEAL ChrDDS THEORETICAL APPROACHES TYPESOF DOSAGE FORM MARKETED PRODUCTS

ADVANTAGES AND LIMITATIONS

EVALUATION CONCLUSION
Dept. of Pharmaceutics, IIT-BHU, Varanasi 2

INTRODUCTION
Recent

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.
Dept. of Pharmaceutics, IIT-BHU, Varanasi 3

Dept. of Pharmaceutics, IIT-BHU, Varanasi

CIRCADIAN RHYTHMS OF DISEASES

DISEASE
Hypertension

CIRCADIAN RHYTHM
Peaks during morning hrs

DRUGS
Verapamil ,Atenolol. Felodipine Oral corticosteroids, Theophylline and B-2 agonist Anticancer drugs (vincristine , paclitaxal)

Asthma

Airway resistance increases progressively at nights during the sleep Tumor blood flow and growth rate greater during daily activity phase

cancer

Rheumatoid Arthritis
Duodenal ulcer

Peak in the morning and decreases NSAIDs throughout day

Acid secretion is max in the night while emptying and motility slower Incidence is higher in early morning
Dept. of Pharmaceutics, IIT-BHU, Varanasi

H-2 antagonist, proton pump inhibitors Calcium channel blockers

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Stroke/heart attack

DEVELOPMENT
CHRONOBIOLOGY
CHRONOPHARMACOLOGY
CHRONOPHARMACOKINETICS

CHRONOTHERPEUTICS

CHRONOPHARMACEUTICS
Dept. of Pharmaceutics, IIT-BHU, Varanasi 6

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)
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SHIFT FROM CONV. SR TO ChrDDS

More 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
Dept. of Pharmaceutics, IIT-BHU, Varanasi 8

IDEAL ChrDDS
Non-toxic within approved limits of use Have 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 administration Be 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
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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. is the time interval between two successive maxima.
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CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

The drug release from is based on pulsatile systems Single-unit pulsatile systems Single-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.

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 Multiple unit pulsatile system A 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..

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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).
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SITE SPECIFIC DELIVERY

Drug is released at the

TIME CONTROLLED SYSTEM

Drug is released after a lag

desired site within intestinal time according to the tract worsening of disease condition Environment of git control Release controlled by different the release like pH , formulation approaches enzymes, git transit time (coating) Treatment of local IBD Treatment of hypertension ulcerative colitis ,crohn asthma, arthritis, ulcer etc. disease Limitation-GIT transit times Reduction in dose/dosing vary (patient, food intake, stress, and illness)
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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
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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
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TIME CONTROLLED RESERVOIR SYSTEMS WITH RUPTURABLE POLYMER COATING

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

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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.
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TEMPERATURE INDUCED PULSATILE DRUG DELIVERY SYSTEMS

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 20C-30C by using reversible swelling properties of copolymers of N-isopropyl acrylamide and butyrylacrylamide.
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EXTERNALLY REGULATED PULSATILE DRUG DELIVERY SYSTEMS

These systems are modulated to release
TICKING CAPSULE

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
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Dept. of Pharmaceutics, IIT-BHU, Varanasi

TYPES OF DOSAGE FORMS THAT CAN BE DESIGNED

Simple polymer coated tablet
Eg .Enteric coated system

Compression coated/press coated tablets

Penwests TIMERx controlled release technology press coated tablets Inner core formulate such that the drug is released in intestine, Outer core consist of hydrophilic TIMERx matrix (xanthan and locust bean gum)
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 Core in cup 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 tablets Layered systems both layers GEMINEX contain a drug dose .An intermediate layer, made of swellable polymers, sepatrates an immediate release and a controlled release . Dept. of Pharmaceutics, IIT-BHU, Varanasi

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CAPSULE SYSTEM WITH COATING

R.P scherer International Corporation

Michigan US Each 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
Dept. of Pharmaceutics, IIT-BHU, Varanasi

PULSINCAP

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 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, Nanoparticles .

Microspheres,

Beads ,
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Dept. of Pharmaceutics, IIT-BHU, Varanasi

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 drugs Reduction of dose requirement Reduced dosage frequency Lower daily cost to patient due to fewer dosage units required by the patient in therapy.
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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.
Dept. of Pharmaceutics, IIT-BHU, Varanasi 26

MARKETED CHRONOTHERAPEUTIC SYSTEMS

CHRONOTROPIC SYSTEM PULSINCAP SYSTEM OROS CT CODAS TIMERX GEMINEX DIFFUCAPS CEFORM GEOMATRIX CONTIN
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EVALUATION OF ChrDDS
PARAMETERS TO BE EVALUATED

EVALUATION OF POLYMERS

EVALUATION OF DOSAGE FORM EVALUATION OF POLYMER DRUG INTERACTION

Thermal analysis DSC, DTA, (FT-IR) SEM, TEM.

Dept. of Pharmaceutics, IIT-BHU, Varanasi

In-vitro evaluation In- vivo evaluation

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DOSAGE FORM EVALUATION

Routine evaluation Tablets -Hardness, friability, disintegration tests , wt. Variation

Capsule- Moisture content, size , shape

Multi-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 etc Success of dosage form depends on clinical trials done on human volunteers.
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CURRENT & FUTURE ASPECTS

The 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.
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CONCLUSION
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 Dept. of Pharmaceutics, IIT-BHU, Varanasi 31

REFERENCES

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) 828851. 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) 189197. www.pharmainfo.com www.circadianrhythm.com

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Thank you.

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