document

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

INTRODUCTION

St Joseph’s College of Pharmacy ,Cherthala . 1


INTRODUCTION

Biological rhythms are an adaptive phenomena relating to predictable changes in

environmental factors that regulate many body functions like metabolism, sleep pattern,

hormone production, hormone production and physiology .Variation in body function cause

changes both in diseases state and in plasma drug concentration. Many functions of the

human body vary considerably in a day. These variations cause changes both in disease state

and in plasma drug concentrations. Human circadian rhythm is based on sleep activity cycle,

is influenced by our genetic makeup and hence, affects the body’s functions day and night

(24-hour period) 1. The dependence of bodily functions in certain disease states on circadian

rhythm is well known. A number of hormones are released by the brain in the morning, while

others are released during sleep. Blood pressure and heart rate are highest during the hours of

6.00 a.m. to 12.00 noon 2. Diseases, such as hypertension, asthma, peptic ulcer, arthritis, etc,

follow the body's circadian rhythm . Many systems in the human body such as

cardiovascular, pulmonary, hepatic and renal systems show variation in their function

throughout a typical day. They are naturally synchronized by the internal body clocks and are

controlled by the sleep wake cycle. Each bodily system exhibits a peak time of functionality

that is in accordance with these rhythmical cycles. Similarly, disease states affect the function

of some of these systems in the body and therefore, they too exhibit a peak time of activity

within a circadian rhythm .

CHRONOBIOLOGY 3:

The term "Chrono" pertains to time and "Biology" is the science of life, thus,

chronobiology concerns with the observation of every metabolic event goes through rhythmic

changes in time that can be measured from seconds to seasons . Typical examples are levels

of plasma testosterone and cortisol, which typically peak in the early morning, and the

secretion of growth hormone, which peaks during sleep.



CHRONOPHARMACOKINETICS 3:

Studies show that time of drug administration especially with reference to circadian rhythm

can impact the kinetics and dynamics of various classes of medicines studies have been

reported that the time of administration of many drugs is a possible factor in variation of the

pharmacokinetics of a drug. . Different pharmacokinetics constraints of time like elimination



rate, peak concentration, volume of distribution, and AUC of a number of drugs are affected

by circadian rhythms relates to the dosing-time, which could be expressed as rhythm-

dependent, under the divergences in the effects of drugs.

CHRONOTHERAPEUTICS 3:

It refers to the clinical practice of harmonizing delivery of the drug in accordance with

body's circadian rhythm including ailment states to create maximum benefit and minimizing

harm .

CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 3:

ChrDDs refers to a treatment method in which in vivo drug availability is timed to match

circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side

effects.

OBJECTIVES OF WORK:

The aim of project work is to study in general about various pharmaceutical aspect

of chronotherapeutic drug delivery system in solving many formulation problem and to

conduct literature survey and characterisation ,to summarise the further scope as well as in

application in pharmacy

IDEAL CHARACTERISTICS OF CHRONOTHERAPEUTIC DRUG DELIVERY

SYSTEM 4:

Ideal ChrDDS should:

be 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 and individual patient to differentiate between awake – sleep status).

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.



ADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 5 :

1. Extended day time activity or night time activity.

2. Reduced side effect.

3. Reduced dosage frequency.

4. Reduction in dose size.

5. Improved patients compliance.

6. Lower daily cost to patient due to fewer dosage unit are required by the patients

7. Drug adapt to suit circadian rhythm of body function or diseases.

8. Drug targeting to specific site. e .g colon

9. Avoids degradation of in upper gastrointestinal tract.(proteins and peptides) .

10. Drug loss is prevented by extensive first pass metabolism.

11. Extended release of drug in pulsatile manner .

12. Right timing and the amount of medication optimizes the drug's desired effects and

minimize the undesired ones.

DISADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM5:

1. It develops a non 24 hours sleep wake syndrome after the treatment as the

person sleeps for over 24 hours during the treatment. It’s not quite common but

the degree of risk is not known.

2. Person may also be sleep deprived sometimes. Person become less productive during

chronotherapy and staying awake till the other schedule will be bit uncomfortable.

3. Medical supervision is mandatory for this therapy. And regular consulting of sleep

speacitists is recommended.

4. One has to keep himself awake till the next sleep schedule .so he have to get

himself busy so that he stay awake till the other schedule.

5. Person going through the therapy may feel unusually hot or cold sometimes.

6. Have to consult the doctor regularly to avoid side effect.

7. Major drawbacks of existing oral chronotropic systems are their dependence human

action to trigger the drug release.



APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM



APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 6:

Controlled release formulations can be divided into subgroups of rate-controlled

release, delayed-release and pulsed-release formulations. Delayed-release formulations

include time controlled release and site specific dosage forms .When constant drug plasma

levels need to be avoided, as in chronotherapy, time-controlled or pulsed-release formulations

are preferable, especially in the treatment of early morning symptoms. By timing drug

administration, plasma peak is obtained at an optimal time and the number of doses per day

can be reduced. Saturable first-pass metabolism and tolerance development can also be

avoided .

ENTERIC COATED SYSTEM 6:

Enteric coatings have traditionally been used to prevent the release of a drug in the

stomach Enteric coatings are pH sensitive and drug is released when pH is raised above 5 in

the intestinal fluid. These formulations can be utilised in time-controlled drug administration

when a lag time is needed. Because of the unpredictability of gastric residence, such systems

cannot be the first choice when a time-controlled release is required. In the treatment of

nocturnal asthma, as albutamol formulation containing a barrier coating which is dissolved in

intestinal pH level above about 6, has been successfully used. The system contains a core

which is film coated with two polymers, first with HPMC and then with a gastro-resistant

polymer (Eudragit),cellulose acetate phthalate, hydroxyl propylmethylcellulose are used for

coating which protects the dosage forms from the acidic environment of the GIT and allows

delivery of the drug to the small or large intestine based on solubility, pH and coating

thickness of the polymeric layer .In this system the duration of the lag phase in absorption

can be controlled by the thickness of the HPMC layer. Enteric coated systems are used for

site specific and time controlled drug delivery.



2 .LAYERD SYSTEM 6:

These are one or two impermeable or semi permeable polymeric coatings (films or

compressed) applied on both sides of the core . To allow biphasic drug release, a three-layer

tablet system was developed . The two layers both contain a drug dose. The outer drug layer

contains the immediately available dose of drug. An intermediate layer, made of swellable

polymers ,separates the drug layers. A film of an impermeable polymer coats the layer

containing the other dose of drug. The first layer may also incorporate a drug-free hydrophilic

polymer barrier providing delayed (5 h) drug absorption. Multi-layer tablet system it consists

of a matrix core containing the drug dose. This kind of three layer device has been used in

the treatment of Parkinsonian patients using L-- dopa/ benserazide. Night time problems and

early-morning symptoms of Parkinsonism can be avoided by using a dual release

formulation, which allows daily doses of drug to be reduced and leads to extent of

bioavailability 40 % greater than when a traditional controlled release formulation is

employed

3.TIME-CONTROLLED EXPLOSION SYSTEM(TES) 7:

These have been developed for both single and multiple unit dosage forms . In both

cases, the core contains the drug, an inert osmotic agent and suitable disintegrates. Individual

units can be coated with a protective layer and then with a semi permeable layer, which is the

rate controlling membrane for the influx of water into the osmotic core. As water reaches the

core ,osmotic pressure is built up. The core ultimately explodes, with immediate release of

the drug. The explosion of the formulation can also be achieved through the use of swelling

agents. Lag time is controllable by varying the thickness of the outer polymer coating .

4.SIGMOID RELEASE SYSTEM(SES) 7:

For the pellet-type multiple unit preparations, SRS containing an osmotically

active organic acid have been coated with insoluble polymer to achieve different lag-times .

By applying different coating thicknesses, lag times in vivo of up to 5 hours can be achieved.

Release rates from SRS, beyond the lag time, has been found to be independent of coating

thickness.



6.PRESS-COATED SYSTEM 8:

Delayed-release and intermittent-release formulations can be achieved by

press-- coating. Press coating, also known as compression coating, is relatively simple and

cheap, and may involve direct compression of both the core and the coat, obviating the need

for a separate coating process and the use of coating solutions. Materials such as hydrophilic

cellulose derivatives can be used and compression is easy on a laboratory scale. On the other

hand, for large-scale manufacture, special equipment is needed. The major drawbacks of the

technique are that relatively large amounts of coating materials are needed and it is difficult

to position the cores correctly for the coating process .In recent years, various controlled

release, especially time-controlled release, drug delivery systems based on compression

coating technology have been studied. Most of such formulations release drug after a lag

phase, followed by a rapid dissolution of the core. a press coated device in which the inner

core contains the drug and the outer coat is made of different types of polymers. The outer

barrier, which controls drug release, can be either swellable or erodible. Lag times can be

varied by changing the barrier formulation or the coating thickness . Hydrophilic polymers

such as hydroxypropyl methylcellulose and sodium alginate have been used in the coat to

control drug release.

7.PULSINCAP 8:



It is a single unit system comprised of a water insoluble capsule body enclosing the

drug reservoir. The capsule body is closed at one end with a swellable hydro gel plug.

Various hydro gels such as hydroxypropyl methylcellulose, hydroxypropyl,polyvinyl

pyrrolidone are used as plug materials. Enzymatically controlled erodible polymers such as

pectin can also be used as plugging material. When the capsule comes in contact with water it

absorbs water and swells. After a lag time the plug gets pushed out and the drug gets release

rapidly in the form of a pulse. The total length of the plug, its position of the insertion into the

capsule and the polymer used for making the plug controls the lag time of the system. Rapid

release of the drug can be ensured by the inclusion of effervescent agents, super disintegratnts

and osmotic agents.

8.SWELLING AND ERODIDLE SYSTEM 9:

Swelling and erodible systems released after the lag time. The coating layer is made up

of various hydrophilic polymers .In addition to this enteric coating can be applied outside to

overcome the gastric pH effect on the drug. The lag time of the system can be controlled by

thickness of the polymeric coat and the viscosity grade of the polymer used.

9.MULTIPARTICULATE SYSTEM 9:

More reliable gastric emptying pattern is observed for multiparticulate systems and is

based on changes in membrane permeability and rupture of the coating. The drug is coated on

non-peril sugar seeds followed by coating with swellable polymeric layer. The swelling

agents include super disintegrates, effervescent agents and osmotic agents. Upon ingress of

water, the swellable layer expands resulting in rupture of the film and rapid drug release.

Several delivery systems based on ion exchange principle have been developed. Other used

polymers such as Eudragits RS30D. It contains positively charged quaternary ammonium

groups in the side chain accompanied by negative hydrocolloid counter ions. The ammonium



groups interact with water, change the permeability and allow water to penetrate in to the

core layer in a controlled manner.

10.ULTRASOUND DRUG DELIVERY SYSTEM 9:

Ultrasound is an enhancer for improvement of drug penetration through biological

barriers such as skin, blood vessels etc. The ultrasound effect enhances degradation of the

polymer in which the drug molecules are incorporated. The drug can be released by repeated

ultrasound exposure. Pulse delivery is achieved by on off application of ultrasound.

.



CHRONOPHARMACEUTICAL TECHNOLOGIES



CHRONOPHARMACEUTICAL TECHNOLOGIES 10:

Currently key technologies in chronopharmaceutics includes:

CONTINR

PHYSICO- CHEMICAL MODIFICATION OF A.P.I:

OROSR

CODASR

CEFORMR,

DIFFUCAPSR

CHRONOTOPIC TECHNOLOGY:

EGALET TECHNOLOGY:

GEOCLOCK TECHNOLOGY:

CHRONOMODULATING INFUSION PUMPS



CHRONODOSE SYSTEM:

CRYSTAL RESERVOIR SYSTEM:

TIMERxR

CONTROLLED-REALSE MICROCHIPS

PORT TECHNOLOGY

THREE DIMENSIONAL PRINTING(3DP) TECHNOLOGY

1.CONTINR TECHNOLOGY 10:

In this technology, molecular coordination complexes are formed between a cellulose

polymer and a non-polar solid aliphatic alcohol optionally substituted with an aliphatic group

by solvating the polymer with a volatile polar solvent and reacting the solvated cellulose

polymer directly with the aliphatic alcohol, preferably as a melt. This constitutes the complex

having utility as a matrix in controlled release formulations since it has a uniform porosity

(semi permeable matrixes) which may be varied . This technology has concretely enabled the

development of tablet forms of sustained-release aminophylline, theophylline, morphine, and

other drugs. Research suggested that evening administration of UniphylR (anhydrous

theophylline) tablets represented a rational dosing schedule for patients with asthma who

often exhibit increased broncho constriction in the morning. CONTINR technology provides

for closer control over the amount of drug released to the bloodstream, and benefits patients

in terms of reducing the number of doses they need to take every day, providing more

effective control of their disease (particularly at night), and reducing unwanted side effects .

2.PHYSICO- CHEMICAL MODIFICATION OF A.P.I 10:

Method is used to modify the physicochemical properties (e.g. .solubility, partition

coefficient, membrane permeability, etc.) of the API to achieve the Chronopharmaceuticals

objective. The rationale for such approach is based on the solubility and permeability are

critical factors governing drug bioavailability. Typical examples of the use of this strategy in

chronotherapy are those of antihyperlipidemic statins (HMG-Co A reductase inhibitors) and

ant ulcerative agents(histamine H2 receptor-antagonists) . Basically, the introduction a

methyl group in the chemical structure of lovastatin leads to the production of simvastatin.

Such modifications change the melting point (m.p.) of these compounds from 174.5 to 135–



138 jC for lovastatin and simvastatin, respectively .Molecular weight and m.p. of compounds

are related to their solubility. Physicochemical modifications affect the time to reach the

maximum plasma concentration (Tmax) for these compounds. The Tmax varies from 2 to 4

h for lovastatin and simvastatin, respectively. Prodrug approach may also be used to obtain a

ChrDDS. For example, lovastatin and simvastatin are lactone prodrugs that are modified in

the liver to active hydroxyl acid forms. Since, they are lactones, they are less water soluble

than other statins .

3.OROS TECHNOLOGY 11:

OROSR technology uses an osmotic mechanism to provide pre-programmed,

controlled drug delivery to the gastrointestinal tract. The dosage form comprises a wall

compartment. The active drug is housed in a reservoir, surrounded by a semi-permeable

membrane/wall (e.g. cellulose esters, cellulose ethers and cellulose ester–ethers) and

formulated into a tablet. The tablet is divided into two layers, an active drug layer and a layer

of osmotically active agents (e.g. polyethylene oxide)) comprising means for changing from a

non-dispensable viscosity to a dispensable viscosity when contacted by fluid that enters the

dosage form. while the cap is made of proprietary water‐permeable blends of

polycaprolactone and flux enhancers For example, water from the gastrointestinal tract

diffuses through the membrane at a controlled rate into the tablet core, causing the drug to be

released in solution or suspension at a pre determined rate. This creates a ‘pump’ effect that



pushes the active drug through a hole in the tablet. This technology, especially the OROSR

Delayed Push– Pull System, also known as controlled on extended release (COER) was used

to design Covera-HSR, a novel antihypertensive product. It actually enabled delayed,

overnight release of verapamil to help prevent the potentially dangerous surge in BP that can

occur in the early morning .

4.CODASR TECHNOLOGY 11:

The Chronotherapeutic Oral Drug Absorption System (CODASR) is a

multiparticular system which is designed for bedtime drug dosing, incorporating a 4–5 h

delay in drug delivery. This delay is introduced by the level of non-enteric release-controlling

polymer applied to drug loaded beads. The release controlling polymer is a combination of

water soluble and water insoluble polymers. As water from the gastrointestinal tract comes

into contact with the polymer coated beads, the water soluble polymer slowly dissolves and

the drug diffuses through the resulting pores in the coating. The water insoluble polymer

continues to act as a barrier, maintaining the controlled release of verapamil . The rate of

release is essentially independent of pH, posture and food. The night time dosing regimen of

(CODASR-Verapamil)was not associated with excessive BP reductions during the sleeping

hours. The CODASR verapamil extended release capsules (VerelanR PM) as ChrDDS

actually provided enhanced BP reduction during the morning period when compared with

other time intervals of the 24-h dosing period .

5.CEFORMR TECHNOLOGY 11:

The CEFORMR technology allows the production of uniformly sized and shaped

microspheres of pharmaceutical compounds. This ChrDDS approach is based on

‘‘meltspinning’’,which means subjecting solid feedstock i.e. biodegradable polymer/bioactive

agents combinations to the combination of temperature, thermal gradients, mechanical forces,

flow, and flow rates during processing. The microspheres obtained are almost perfectly

spherical, having a diameter that is typically 150–180 Am, and allow for high drug content.

The microspheres can be used in a wide variety of dosage forms, including tablets, capsules,

suspensions, effervescent tablets, and sachets. The microspheres may be coated for controlled

release either with an enteric coating or combined into a fast/ slow release combination. This



technology has been actually used to develop CardizemR LA, 1-day diltiazem formulation as

ChrDDS .

6.DIFFUCAPSR TECHNOLOGY 12:

In the DIFFUCAPSR technology, a unit dosage form, such as a capsule for

delivering drugs into the body in a circadian release fashion, comprises of one or more

populations of drug containing particles (beads, pellets, granules, etc.). Each bead population

exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag

time of 3–5 h. The active core of the dosage form may comprise an inert particle or an acidic

or alkaline buffer crystal (e.g. cellulose ethers), which is coated with an API-containing film-

forming formulation and preferably a water-soluble film forming composition (e.g. hydroxyl

propylmethylcellulose,polyvinyl pyrrolidone) to form a water-soluble/dispersible particle.

The active core may be prepared by granulating and milling and/or by extrusion and

spheronization of a polymer composition containing the API. Such a ChrDDS is designed to

provide a plasma concentration–time profile, which varies according to physiological need

during the day, i.e. mimicking the circadian rhythm and severity/manifestation of a

cardiovascular disease, predicted based on pharmacokinetic and pharmacodynamic

considerations and in vitro/in vivo correlations. This technology has been used to formulate

the first and recently FDA approved propranolol containing ChrDDS (InnopranR XL) for the

management of hypertension. Diffucaps beads are <1.5 mm in diameter and can be filled into

capsules or compressed into orally disintegrating tablets.

Advantages of Diffucaps

• Ideal for drugs exhibiting poor solubility in lower intestinal pH, in environments with pH

above 8.0, or in physiological fluids

• Can combine multiple drugs and/or multiple release profiles in

the same dosage form

• Simple formulation of dose‐proportional strengths.

• Can minimize food effect



Cross section of Diffucaps

7.CHRONOTOPIC TECHNOLOGY 13:

It consists of a core containing drug reservoir coated by a

hydrophilic polymer hydroxylpropyl methylcellulose (HPMC). An additional enteric‐coated

film is given outside this layer to over come intra‐subject variability in gastric emptying rates.

The lag time and the onset of action are controlled by the thickness and the viscosity

grade of HPMC.



8.EGALET TECHNOLOGY 13:

It offers a delayed release. System consists of an impermeable shell with two lag plugs,

active drug after the inert plugs have eroded, the drug is released, thus a lag time occurs.

Time of release can be modulated by the length and composition of the plugs. The shells are

made of slowly biodegradable polymers (such as ethyl cellulose) and include plasticizers

(such as cetostearyl alcohol), while the matrix of the plugs is made up of a mixture of

pharmaceutical excipients including polymers like polyethylene oxide (PEO). g is

sandwiched between the plugs.

: Egalet: (a) Intact Unit (b) Erosion of the time delay insert plugs, and (c) Drug release



9.GEOCLOCK TECHNOLOGY 14:

Geoclock tablets have an active drug inside an outer tablet layer consisting of a mixture

of hydrophobic wax and brittle material in order to obtain a pH‐independent lag time prior to

core drug delivery at a predetermined release rate. developed to achieve an on–off switching

drug delivery for transdermal application via the externally repeated cycle of temperature

change.

X ray of Geoclock tablets

10.CHRONOMODULATING INFUSION PUMPS 14:

The portable pumps are usually characterized by a light weigh (300–500 g) for easy

portability and precision in drug delivery. For example portable programmable multi-channel

pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a

sufficiently large patient population. Specifically, a clinical phase III trial involving several

patients with metastatic gastrointestinal malignancies compared a flat versus the

chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in

both tolerability and response rates in patients with metastatic colorectal cancer receiving

chronotherapy.



11.CHRONODOSE SYSTEM 14 :

The ChronoDose system is a revolutionary drug delivery device, worn like a wristwatch,

which can be pre-programmed to administer drug doses into the body automatically, at

different times of the day and with varying dose sizes.

12..CRYSTAL RESERVOIR SYSTEM 14:

A transdermal system for chronotherapy of asthma. A thermo responsive membrane was

developed to achieve an on–off switching drug delivery for transdermal application via the

externally repeated cycle of temperature change.



13.TIMERxR TRCHNOLOGY 15:

The TIMERxR technology (hydrophilic system) combines primarily xanthan and locust

bean gums mixed with dextrose. The physical interaction between these components works to

form a strong, binding gel in the presence of water. Drug release is controlled by the rate of

water penetration from the gastrointestinal tract into the TIMERxR gum matrix, which

expands to form a gel and subsequently releases the active drug substance. This system can

precisely control the release of the active drug substance in a tablet by varying the proportion

of the gums, together with the third component, the tablet coating and the tablet

manufacturing process. Potential application of this technology is the development of an oral,

CR opioid analgesic oxymorphone .

14.CONTROLLED-REALSE MICROCHIPS 15:

An alternative method to achieve pulsatile or Chronopharmaceuticals drug release

involves using micro fabrication technology. A solid-state silicon microchip that can provide

controlled release of single or multiple chemical substances on demand. The release

mechanism was based on the electrochemical dissolution of thin anode membranes covering

micro reservoirs filled with chemicals in solid, liquid or gel form. Initially conducted

proof-of-principle release studies with a prototype microchip using gold and saline solution

as a model electrode material and release medium, and demonstrated controlled, pulsatile

release of ch poly(L-lactic acid) and had poly(D,L-lacticco- glycolic acid) membranes were

fabricated that released four pulses of radio labelled dextran, human growth hormone or

heparin. This technology has the potential to be used in the design of ChrDDS with a better



control over drug release kinetic in order to match biological requirement over a versatile

period of time.

15.PORT TECHNOLOGY 16:

The Programmable Oral Release Technologies (PORT) system is a uniquely coated,

encapsulated system that can provide multiple programmed release of the drug. It contains a

polymeric core coated with a semipermeable, rate-controlling polymer. Poorly soluble drugs

can be coated with solubilising agents, to ensure a uniform controlled release from the dosage

form. In the capsule form, the gelatine capsule is coated with a semi permeable, rate-

controlling polymer. Active medicament mixed with an osmotic agent is kept inside the

capsule shell. A water-insoluble plug is used to seal the capsule shell. Immediate release

compartment can be added according.

The Port System - consists of a gelatine capsule coated with a semi permeable

membrane (e.g.: cellulose acetate) housing an insoluble plug ( e.g.: lipidic) and an

osmotically active agent along with the drug formulation . When it comes in contact with the

aqueous medium, water diffuses across the semi permeable membrane, resulting in increased

inner pressure that ejects the plug after a – time lag. The time lag is controlled by the

thickness of semi permeable membrane. In order to deliver drug in liquid form, an

osmotically driven capsular system was developed. In this system, liquid drug is absorbed

into highly porous particles, which release the drug through an orifice of a semi permeable

capsule supported by an expanding osmotic layer after the barrier layer is dissolved. The

capsular system delivers drug by the capsule's osmotic infusion of moisture from the body.

The capsule wall is made up of an elastic material and possesses an orifice. As the osmosis

proceeds, the pressure within the capsule rises, causing the wall to stretch. The orifice is

small enough so that when the elastic wall relaxes, the flow of the drug through the orifice

essentially stops, but when the elastic wall is distended beyond threshold value, the orifice

expands sufficiently to allow drug release at a required rate. Elastomers, such as styrene-

butadiene copolymer have been suggested .



16.THREE –DIMENTIONAL PRINTING (3DP) TECHNOLOGY 16:

Three-dimensional printing (3DP) is a novel technique used in the fabrication of complex

oral dosage delivery pharmaceuticals, based on solid freeform fabrication methods. It is

possible to engineer devices with complicated internal geometries, varying densities,

diffusivities, and chemicals. Different types of complex oral drug delivery devices have been

fabricated using the 3DP process: immediate-extended release tablets, pulse release,

breakaway tablets, and dual pulsatory tablets. The enteric dual pulsatory tablets were

constructed of one continuous enteric excipient phase into which diclofenac sodium was

printed into two separated areas. These samples showed two pulses of release during in vitro

with a lag time between the pulses of about four hours. This technology is the basis of the

Therefore technology.



MARKETED PRODUCTS 17:

A.P.I Product Manufacturer Chr.technology Indication

VerapamilHCL Covera HS Pfizer OROS Hypertension

VerapamilHCL VerelanPM Schwarz CODAS Hypertension

Famotidine Pepcid Merk PMAPI Ulcer

Theophyllin Uniphyl ER Purduepharma. CONTIN Asthma

Simvastatin Zocor Merck PMAPI Hyperlipedimia

DiltiazemHCL Cardiazem LA Biovail CFFORMR Hypertension

Propranolol InnopranXL Glaxo DIFFUCAPSR Hypertension

Simvastatin Lopovas Merk PMAPI Hyperlipedimia

Famotidine Gaster Astellas PMAPI Ulcer



EVALUATION TECHNIQUES



EVALUATION TECHNIQUES 18:

1)STABILITY STUDY 18:

A short term stability test was conducted by storing tablets in glass bottles at 25°C and

40°C for three months. Then product evaluated for, buoyancy, drug content and invitro

dissolution test and appropriate results obtained.

2)DRUG CONTENT 19:

To evaluate a tablet potential for efficacy, the amount of drug per tablet needs to be

monitored from tablet to tablet, and batch to batch. To perform the test, 10 tablets were

crushed using mortar pestle. Quantity equivalent to 100 mg of drug was dissolved in 100 ml

phosphate buffer pH 6.8, filtered and diluted up to 50μg/ml, and analyzed

spectrophotometrically. The concentration of drug was determined using standard calibration

curve.

3)PARTICLE SIZE ANALYSIS 19:

The core pellets were subjected to sieve analysis using a set of standard sieves (1700,

1400, 1000, 710, and 600 mm) in a vibratory sieve shaker for a period of 10 min. The weight

distribution data were fitted into log-normal distribution and the geometric mean diameter

was computed from the log probability plots

4)BUNOYANCY DETERMINATION 19:

The buoyancy test of triple layer tablet and floating pulsatile release 25 tablets was studied

by placing them in 500 ml beaker containing 0.1 N HCl, then tablet from same batches were

placed in dissolution test apparatus containing 0.1N HCl, maintained at 37+-0.1◦C and

agitated at 100 rpm. The floating onset time (time period between placing tablet in the

medium and buoyancy beginning) and floating duration of tablet was determined by visual

observation.



5) INVITRO DISSOLUTION STUDY 20:

Invitro dissolution test was performed using USP type II dissolution test apparatus. The

drug release study was carried out in 0.1 N HCl for 2 h, mixed phosphate buffer of pH 5.5 for

1 hour, phosphate buffer of pH 6.8 for 2 hour followed by mixed phosphate buffer of pH 7.5

till the end of the test. The temperature of the dissolution fluid was maintained at 37±0.5°

with a stirring speed of 100 rpm. The samples withdrawn every hour were filtered (0.22 µm,

Millipore) and assayed spectrophotometrically dissolution data was analyzed to calculate the

amount of drug released and percentage cumulative drug released at different time intervals.

6)STUDY OF IN- PROCESS QUALITY CONTROL(IPQC) PARAMETERS 20:

The Weight Variation of the tablets was evaluated on 20 tablets using a Digital Balance

–Sartorius CP124S. Friability test was performed at the speed of 25rpm with tablets dropping

from height of six inches with each revolution for 4minutes on automated Friabilator EF-2

USP .Hardness was evaluated curves (n = 6). All dissolution studies were performed in

triplicate.

9)SWELLING CHARACTERISTICS 21:

To evaluate the water penetration characteristics, the tablets were exposed to 500 ml

distilled water in three different beakers for 6 h, and then evolution of tablet surface area was

carried out by recording the change in diameter and thickness of the tablets. Change in

surface area of the tablets was calculated by using following formula.

SA =2

Where, SA = Surface area and r = Radius of tablet

10)SCANNING ELECTRON MICROSCOPY (SEM) 21:

Morphology and surface topography of the core and the coated pellets were studied by

scanning electron microscopy. The samples were mounted on the SEM sample stab, using a

double-sided sticking tape and coated with gold (200A°) under reduced pressure (0.001 torr)



for 5 min using an Ion sputtering device The gold-coated samples were observed under the

SEM and photomicrographs of suitable magnifications obtained.

APPLICATIONS OF CHRONOTHERAPEUTIC DRUG

DELIVERY SYSTEM



APPLICATIONS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 22:

The potential benefit of chronotherapeutic pharmaceuticals has been demonstrated by a

number of DDS developed for timed release of drugs having a chronobiological behaviour or

when symptoms of the diseases are circadian dependent.

1) CARDIOVASCULAR DISEASES 22:

Increase in risk of myocardial infarction between 6 am and noon was found. Blood pressure

was soaring in the morning, with a rise at about 6 am and increasing further from 7 am. Blood

pressure reaching its lowest point around 3 am by gradual declination throughout the day and

especially during sleep .The time of awakening, an increase in physical activity, serum

cortisol level and catecholamine levels which all increases blood pressure, heart rate and

myocardial contractility .cholesterol intake and hepatic cholesterogenesis takes place during

the evening hours irrespective of fed/fasting state. An evening administration of an HMG-

CoA reductase inhibitor lowered serum cholesterol levels than morning dosing .HMG-CoA

reductase inhibitors could be taken between the evening meal and bed time .

Chronopharmaceuticals for cardiovascular diseases have been studied extensively.

Presently, four drugs have been successfully incorporated into Chronopharmaceuticals for

clinical use. The first established chronotherapeutic DDS for timed-release of

antihypertensive /antianginal agent is OROS technology developed and marketed by Alza for

controlled onset and extended release (COER) formulation of verapamil hydrochloride tablet

(Covera HS, Pharmacia, USA) to reduce the peak morning of cardiovascular events.. A

second chronotherapeutic drug delivery approach for hypertension was developed by Elan

using chronotherapeutic oral drug absorption system (CODAS) technology for formulation of

verapamil hydrochloride-ride capsule (Verelan PM, Schwarz Pharma, USA). Cardizem LA

(Diltiazem hydrochloride), which is used for hypertension and angina was approved by the



FDA is marketed by Biovail. Innopran XL (Propranolol hydrochloride) extended release

capsule is used for hypertension and was approved by the FDA and marketed by Reliant

Pharmaceuticals, which utilizes the Eurand's Diffucaps technology.

2) INFLAMMATORY DISEASES 22:

Inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, ankylosing

spondylitis and gout, exhibit profound circadian rhythms (variations) in the manifestation and

intensity of symptoms. Chronotherapeutic-type medications increase the effectiveness and

safety of treating arthritis disorders. Such drug delivery systems enhance the desired effects

of drugs and minimize side effects. The chronopharmacological studies of arthritic diseases

means determining the best time to administer drugs. Long-acting NSAIDs, like flubiprofen,

ketoprofen, tenoxicam and indomethacin taken at bedtime, ensure the adequate control of

prominent morning symptoms of rheumatoid arthritis, while the chronotherapy of

osteoarthritis involves the administration of drugs in relation to the time of day when pain is

worse. If pain is worse at night or early in afternoon, an evening once-a day NSAID schedule

is recommended. If pain is worse in the afternoon or night, a once-a-day morning or

noontime treatment schedule is best.

Rheumatoid arthritis is characterized by morning stiffness, where as the

symptoms often are bad in the afternoon and evening with osteoarthritis. Cyclooxygenase-2

inhibitors, when taken in the morning lessen osteoarthritis symptoms. In the case of

rheumatoid arthritis, more improved results are obtained when part of the dose is taken in the

evening

3) ASTHMA 23:

Circadian changes in normal lung function from alterations in pathophysiology and

inflammation needs to be applied clinically. Generally the worsening of asthma occurs at

night, and is often referred to as nocturnal asthma. A chronotherapeutic approach applied to

nocturnal asthma is particularly important to understanding the circadian changes when

choosing the dosage timing of medications. Several chronotherapeutic medications have been

proposed for treatment of nocturnal asthma. Oral steroids such as corticosteroids,

glucocorticoids and methylprednisolone administered at 8 a.m. rather than 8 p.m., for

example, have shown higher effectiveness in treating asthma. Other studies have shown that



oral administration of prednisolone at 3 p.m. rather than 8 a.m. improved lung function and

reduced airway inflammation more effectively in the treatment of nocturnal asthma. The

leukotriene active agents, including zileuton, zafirlukast and montelukast, have been proven

to alleviate the symptoms and the decrement in lung function in nocturnal asthma when used

chronotherapeutically.Once daily dosing in the evening of theophylline tablets showed

chronotherapeutic potential in the treatment of nocturnal asthma. Various tablet formulations

of long acting -agonists (albuterol, bambuterol, salmeterol and formoterol) have been used in

a chronotherapeutic approach for the treatment of asthma. Treatment of nocturnal asthma.

Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at

8 a.m. rather than 8 p.m.,

4)ONCOLOGY 23:

Optimal drug timing (chronotherapy) in oncology resulted in allowing high-doses to be

administered safely and most effectively with less toxicity, improved tumour control and

patient survival. Chronotherapeutic drugs under clinical trials have shown circadian-stage

dependent anti-cancer activity, confirming and emphasizing the importance of circadian drug

timing.

For that, modern oncology will demand circadian timing-stipulated, multi-drug regimens,

biological therapies and hybrid chemo biotherapies. The first chronopharmacological studies

of doxorubicin in for the treatment of a transplanted plasmacytoma in rats revealed that the

rate of tumour shrinkage is dependent upon the time of day that the drug is given. To date, the

toxicities and anti-tumour activities of at least 20 of the most commonly used

chemotherapeutic agents-cisplatin, oxaliplatine, carboplatin, epirubicin, 6-mercaptopurine,

methotrexate, 5-fluorouracil, vinblastine and cyclophosphamide-are documented as circadian

stage-dependent both in animals and for many in humans. Circadian-dependent activity of

some biological agents, most notably Interferon, and erythropoietin, have also been well

documented.

5)CEREBROVASCULAR ACCIDENTS24:

Cerebrovascular accidents are more common in the morning hours between 10A.M to 12

noon and it will decrease from noon to midnight. The main aim of chronotherapy in these



conditions is to deliver the drug in the higher doses in morning and little lower dose at noon

and in midnight times. Various ACE inhibitors like Atenolol, Nifedipine and amolodipine are

more effective when administered during night.

5) GASTROINTESTINAL DISEASES 24:

Peptic Ulcer Disease: A histamine antagonist when given at night shows the better result

unlike when given at regular intervals around the clock. This is because the more acid

secretion, more pain and perforation of gastric and duodenal ulcers are more subjective at

night rather than in day time.

6)ALLERGIC RHINITIS 24:

Early-morning hour episode of sneezing, nasal congestion and runny nose are common to

allergic rhinitis. Study also explained that a morning dose of antihistamine was not as

successful as the same dose given in the evening

7)RENAL DISEASES 24:

A repeated dosing study of high-dose active vitamin D3 in haemodialysis patients with

secondary hyperparathyroidism was conducted. A higher dose (3 mg) was given orally to 13

haemodialysis patients at 08.00 h or 20.00 h for 12 months by a randomized, cross-over

design with an 8-week washout period. Serum concentrations of calcium and inorganic

phosphate were determined by orthocresolphtalein complex method, and ammonium

molybdate method with an autoanalyser, respectively. The results indicate that a higher dose

of oral D3 is more effective and safe after dosing at evening in patients with renal

osteodystrophy .

8)DIABETICS 25:

The most widespread application of chronotherapy is insulin pump, which is used to

administer insulin for the treatment of diabetes mellitus. With the insulin pump, patients can

customize insulin delivery to meet their particular requirements. Several systems were

developed to respond the change in glucose concentration like pH sensitive hydrogel

containing glucose-oxidase enzyme immobilized in hydrogel. As the blood concentration of

glucose rises, glucose oxidase converts glucose into gluconic acid, which changes the pH of



system. Due to change in pH, swelling of polymer takes place and this result into insulin

release. Insulin decreases the blood glucose level and consequently the gluconic acid level

also declines and system turns to de-swelling and hence decreasing the insulin release .

LITERATURE REVIEW



LITERATURE REVIEW

1. Halas M et al (1998) Formulated and evaluated of press coatedCapsule Device for

Chronotherapeutic Delivery attempt was made to deliver theophylline into colon by

taking the advantage of the fact that colon has a lower pH value (6.8) than that of the

small intestine (7.0–7.8). So, by using the mixture of the polymers, i.e. Eudragit L and

Eudragit S in proper proportion, pH dependent release in the colon was obtained 2.

2. Evans RMet al(1996 ) Formulated and evaluated Chronotherapeutic drug delivery for

in vitro multiparticulate system of insulin based on alginate spheres. In an

experiment, ferrite microparticles (1μm) and insulin powder were dispersed in sodium

alginate aqueous solution. The ferrite-insulin alginate suspension was later dropped in

aqueous calcium chloride solution which causes the formation of cross linked alginate

spheres, which were further cross linked with aqueous solution of poly(L-lysine) or

poly(ethylene imine) 6.

3. Kato H et al (2002) Formulated and evaluated Chronotherapeutic drug delivery for

ultrasound-enhanced polymer degradation system. During polymer degradation

incorporated drug as drug molecule within negatively charged P(AMPS-co-BMA)

hydrogels. By applying an electric field ion exchange between

transdermalTulobuterol ions and protons commenced at cathode, resulting in rapid

drug release from hydrogels. This rapid drug release was attributed to the electrostatic

force, squeezing effect, and electro-osmosis of the gel. Complete on-off drug release

was achieved, as no drug release was apparent without the application of electric

current 15.

4. Gupta et al (2003) Formulated and evaluated Chronopharmaceutical drug delivery

system of Theophylline and its pharmacokinetics in vivo and compaired

hardness ,friability, weight variation,drug content in-vivostudies in rabbit 20.

5. Michael et al (2009) Formulated and evaluated Chronotherapeutic drug delivery

system for Timed release film‐coated Felodipine tablets for chronotherapeutic

application in heart disease using guar gum and in combination with other



polymers.Tablets were subjected for the evaluation of particle size, encapsulation

efficiency ,swellable and in-vitro release27.

FUTURE PROSPECTS



FUTURE PROSPECTS26,27:

The medical and pharmaceutical scientists should now focus profoundly over the

importance of triggered/pulsed release of drugs. chronotherapeutic drug delivery system for

the treatment of primary open-angle glaucoma. Dual-action, chronotherapeutic drug delivery

system Controls intraocular pressure over 24 hours, reducing nocturnal pressure spikes

Increases patient compliance by easy, once-a-day insertion.PH-enzyme dependent

chronotherapeutic drug delivery system of theophylline for nocturnal asthma. . Biological

and chronobiological activities of synthetic or natural compounds. Chronotherapy in Indian,

Chinese, and other such traditional herbal medicine systems. Design and development of drug

delivery systems for treatment of diseases on chronopharmacologicalbasis . Development of

Drug targeting systems, protein and peptide delivery systems, sustained and controlled

release systems. Ability of the brain to repair DNA damage was at a minimum in the early

morning and reached a maximum in the evening due to the effects of an enzyme called XPA,

which is linked to skin cancer, it could suggest specific times of the day to avoid cancer-

causing sunrays.

Laminate ophthalmic insert that is administered once-a-day, at night, improving patient

compliance. The insert is produced from materials suitable for ophthalmic use, and is capable

of releasing two drugs at different rates. The first drug is released at a slow, continuous rate.

The second has a delayed onset and rapid release, to prevent possible IOP spikes during the

early morning. This innovative treatment represents the first chronotherapeutic



SUMMARY AND CONCLUSION



SUMMARY AND CONCLUSION

The effectiveness and toxicity of certain drugs depends on dosing time associated with

24hr rhythms under control of circadian clock. The application of biological rhythm to

pharmacotherapy can be correlated by approximate timing of dosing of drugs to synchronise

drug concentration to rhythms in diseases state. Advance in chronobiology and

chronopharmacology has demonstrated the importance of biological rhythms in the treatment

of diseases and this has led to a new approach to the development novel drug delivery

system-chronotherapeutic drug delivery systems.

Chronotherapeutic drug delivery systems is useful in the treatment of

diseases in which drug availability is the timed to match rhythms of diseases, in order to

optimise therapeutic effect and minimize side effect.Variouus technologies such as time

controlled,pulsed,triggered,programmed drug delivery devices have been developed and

extensively studied in recent years for chronotherapeutical drug delivery. Some of the

disease conditions where in chronotherapeutics are promising include duodenal ulcer,

cardiovascular diseases asthma, diabetics, neurological disorder, cancer, hypertension, hyper

cholestremia.

The use of chr.DDS offer a solution for delivery of drugs exhibiting a

chronobiological behaviour and such as DDS seems to constitute more dependable means of

matching drug level to biologic need and tolerance chronotherapeutics approach surely

provides the enormous scope for research and has promise for a bright future to control

diseases according to the body’s physiological needs.



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