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Department of Pharmacy (Pharmaceutics) | Sagar savale

Mr. Sagar Kishor SavaleMr. Sagar Kishor Savale

Department of Pharmaceuticsavengersagar16@gmail.com

2015-016

• Introduction

• Need for Pulsatile drug delivery

• Advantages

• Methodologies or Approaches

• Recent techniques for Pulsatile System

• Evaluation of pulsatile drug delivery system

• Case studies

• Conclusion

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MatrixDevices

MembraneDevices

Diffusion-Controlled

Controlled Release Systems

BiodegradableSystems

PendantChain Systems

Chemically-Controlled

Solvent-Activated

Osmotically-Controlled

Swelling-Controlled

Rupture-Controlled

PulsatileDelivery

SinglePulse

OsmoticallyRuptured

PolymerDissolution

Erodiblepolymer

Multiple Pulse

Electrically-Stimulated

Ultrasonically-Controlled

Magnetically-Controlled

Temperature-Controlled

Inflammationinduced

pH-Sensitive

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Pulsatile drug delivery are the system in which rapid & transient release of an active molecule within a short time period immediately after a predetermined off release period. i.e. lag time

The Pulsatile effect i.e. the release of drug as a “pulse” after a lag time has to be designed in such a way that complete and rapid drug release should follow the lag time. Such systems are also called time-controlled as the drug release is independent of the environment.

The system deliver the drugs at: right time right place right quantity

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These systems are designed in such a way that there is rapid and transient release of a certain amount of drug molecule within a short time period immediately after a certain lag period.

The lag period may very as per the requirement in disease condition .The typical graph of pulsatile drug delivery differs from controlled release is shown in figure.

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Avoiding drug degradation in GIT.

Drugs which develop biological tolerance.

Drug with extensive first pass metabolism .

Drug targeted to specific site in the intestinal tract.

Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology.

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Disease Chronological behavior

Drugs used

Peptic ulcer Acid secretion is high in the afternoon and at night

H2 blockers

Asthma Precipitation of attacks during night or at early morning hour

β-2 agonist, Antihistaminic

Cardiovascular diseases BP is at its lowest during the sleep cycle and rises steeply during the early morning

Nitroglycerin, Calcium channel blocker, ACE inhibitors etc.

Arthritis Pain in the morning and more pain at night

NSAIDs, Glucocorticoids

Diabetes mellitus Increase in the blood sugar level after meal

Sulfonylurea, Insulin, Biguanide

Attention deficit syndrome

Increase in DOPA level in afternoon

Methylphenidate

Hypercholesterolemia Cholesterol synthesis is generally higher during night than during day time

HMG-CoA-reductase inhibitors

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• Reduced dosage frequency.

• Reduction in dose size.

• Extended daytime or night time activity.

• Improved patient compliance .

• Drug loss is prevented by first pass metabolism.

• It can give “a new lease of life” & a “new therapeutic dimenssion” for existing drug molecule.

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• There are innumerable approaches for PDDS. In a broad point of view methodologies for PDDS can be categorized in to 3 ways:

I. Time controlled

systems

II. Stimuli induced systems

III. Hydrogel systems

• Osmotic Pressure based systems

• Systems with Rupturable coatings

• Systems with Erodible/swellable coatings

• Capsular systems with polymeric plugs

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• The Port System constitute of a gelatin capsule coated with a semi permeable membrane (e.g., cellulose acetate) housing an insoluble plug (e.g., lipidic) and an osmotically active agent with the drug formulation.

• Mechanism• Upon contact with the aqueous medium, water diffuses

across the semi permeable membrane, resulting in increased inner pressure that ejects the plug after a lag time.

• The lag time is manipulated controlled by coating thickness.

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• These systems depend on the disintegration of the coating for the release of drug.

• The pressure necessary for the rupture of the coating can be achieved by the effervescent excipients, swelling agents, or osmotic pressure.

• An effervescent mixture of citric acid and sodium bicarbonate was incorporated in a tablet core coated with ethyl cellulose.

• Mechanism: The carbon dioxide gas developed after

penetration of water into the core resulted in a pulsatile release of drug after rupture of the coating.

• Lag time increases with increasing coating thickness and increasing hardness of the core tablet.

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• Most of the pulsatile drug delivery systems are

reservoir devices coated with a barrier layer.

• This barrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly.

• The time lag depends on the

thickness of the coating layer . 16

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• A general -design of such systems consists of an insoluble capsule body housing a drug and a plug.

• The plug is removed after a predetermined time lag due to swelling, erosion, or dissolution.

• The Pulsincap® system is an example of such

a system that is made up of a water-insoluble capsule body filled with drug formulation.

• Upon contact with dissolution medium or

gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a time lag.

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• a) Insoluble but permeable and swellable polymers

e.g., polymethacrylates

• b)Erodible compressed polymers e.g., hydroxypropylmethyl cellulose,

polyvinyl alcohol, polyethylene oxide

• c) Enzymatically controlled erodible polymer e.g., pectin

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• This consists of pellet cores comprising drug and succinic acid coated with ammonio-methacrylate copolymer USP/NF type B.

• The time lag is controlled by the rate of water influx through the polymer membrane. The water dissolves acid and the drug in the core.

• The acid solution in turn increases permeability of the

hydrated polymer film. • The different types of acids that can be used include

succinic acid, acetic acid, glutaric acid, tartaric acid, maliec acid, or citric acid

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• Hydrogel : A polymer network that is not soluble in water, but is super-absorbent.

• Stimuli responsive hydrogels can absorb or release their contents based on environmental conditions. Stimuli include:

• Temperature• pH• Ionic Strength• Presence of certain chemicals

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They are insoluble due to the tie points i.e., physical cross links like entanglement.

Exampels include:PIPAAmPEO-PPO-PEOPLGA-PEO-PLGA grafted co-polymers.

In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulates drug release in swollen state.

For example polyN-isopropylacrylamide (PIPAAm) responds to a specific range of temperature.

Below 32 C PIPAAm forms a “skinny layer” & changes to hydrophobic which is impermeable to water.

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Low pH

High pH

Protect drug

Release drug

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Release of the drug after stimulation by an biological factor or external stimuli .

It is classified into two types stimuli induced pulsatile system

Chemical stimuli induced pulsatile systemi. pH sensitive drug delivery system .

ii. Inflammation-induced system

iii. Glucose responsive insulin release

iv. Drug release from gels responding to antibody concentration

External stimuli

i.Micro electro release system

ii.Electro Responsive release

iii.Magnetically induced release27

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The system include insulin immobilized in the hydrogel

Glucose

Glucose oxidase

Gluconic acid

Change in pH

Swelling of the polymer

Insulin release

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Insulin by virtue of its action reduces blood glucose level & consequently gluconic acid level also get decreased & system turns to the deswelling mode thereby decreasing the insulin release.

Examples of the pH sensitive polymers include N, N-dimethylaminoethyl methacrylate, chitosan, polyol etc.

• Electro responsive pulsatile release

Electrically responsive delivery systems are prepared from polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus, pH-

responsive as well as electro-responsive.

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• Examples of naturally occurring polymers include hyaluronic acid, chondroitin sulphate, agarose, carbomer, xanthan gum and calcium alginate.

• The synthetic polymers are generally acrylate and methacrylate derivatives such as partially hydrolyzed polyacrylamide, polydimethylaminopropyl acrylamide

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• A micro fabricated device has the ability to store and

release multiple chemical substances on demand.

• Another development in MEMS technology is the microchip.

• The microchip consists of an array of reservoirs that

extend through an electrolyte-impermeable substrate.

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• The microchip consists of an array of reservoirs that

extend through an electrolyte-impermeable substrate.

• The prototype microchip is made of silicon and contains a number of drug reservoirs, each

reservoir is sealed at one end by a thin gold membrane of material that serves as an anode in an electrochemical reaction and dissolves when an electric potential is applied to it in an electrolyte solution.

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• When release is desired, an electric potential is applied between an anode membrane and a cathode, the gold membrane anode dissolves within 10-20 seconds and allows the drug in the reservoir to be released.

• This electric potential causes oxidation of the anode material to form a soluble complex with the electrolytes which then dissolves allowing release of the drug.

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• Dissolution studies.

• Simulated rupture tests with polymer films

• Lag time and drug release of pulsatile capsules

• Water uptake studies with the pulsatile tablets.

• gamma scinitgraphic technology

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• The lag time of pulsatile release tablets is defined as the time when the outer coating starts to

rupture.

• The lag time of the pulsatile capsules was determined by visual observation in a USP paddle apparatus (medium: phosphate buffer USP pH 7.4, 37°C, and rotation speed 50 rpm).

• We can go either with plcebo or with the drug itself.

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• The %water uptake of pulsatile release tablets was determined in medium-filled containers placed in a horizontal shaker (100 ml of 0.1 N HCl, 37 0C, 74 rpm, n = 3).

• At predetermined time points, the tablets were removed from the dissolution medium, carefully blotted with tissue paper to remove surface water, weighed and then placed back in the medium up to the time when the coating of the tablet ruptured. The %water uptake was calculated as follows:

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• The %water uptake was calculated as follows:

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gamma scinitgraphic technology

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a b c d

Image (a) was taken immediately Image (b) was taken at 3 hrs.Image (c) & (d) at 5 & 6 hrs respectively.

• Spheroidal Oral Drug Absorption System (SODAS)

• Chronotherapeutic Oral Drug Absorption System (CODAS)

• EURANDs pulsatile and chrono release System

• Magnetic Nanocomposite Hydrogel

• GEOCLOCK® Technology 41

Technology used Drugs marketed

CODAS Verelan® PM

EURANDS Propranolol hydrochloride (CRR)

GEOCLOCK Lodotra™

PULSYS™ Moxatag™

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• Avinash R. Tekade, and Surendra G. Gattani , “Development and evaluation of pulsatile drug delivery system using novel polymer”, Pharmaceutical Development and Technology, 2009; 14(4): 380–387

• Aim : To develop a PDDS using a plug made up of a novel material & to show the effect of the plug which is independent of the ratio of drug as to polymer taken in the preparation of microspheres.

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• Preparation of TPH microspheres • Microspheres of anhydrous TPH were prepared by solvent evaporation method.

Drug and Eudragit S 100 in various ratios like 2:1, 1:1, 1:1.5 and 1:2 w/w were dissolved in a sufficient quantity of ethanol. An ethanolic solution of the drug and polymer was then poured slowly into 100 mL liquid paraffin containing 1% span 80 at 15°C with continuous stirring at 1000 rpm to form uniform emulsion.

• Preparation of cross-linked gelatin capsules• A total of 25 mL of 15% (v/v) formaldehyde was taken into a dessicator and a pinch

of potassium perman-ganate was added to it, to generate formalin vapors.

• Preparation of hydrocolloid plug• Plug for seal-ing the capsule body was prepared by compressing equal amount of

DRG and lactose using 5 mm punches and dies on rotary tablet press keeping varying thickness and hardness values .

• The joint of the capsule body and cap was sealed with a small amount of the 5% ethyl cellulose ethanolic solution.The sealed capsules were completely coated by dip coatingmethod with 5% CAP in 8:2 (v/v) mixture of acetone: ethanol,plasticized with dibutylphthalate (0.75%)

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• PDDS can effectively tackle the chronotherapeutic problem as it is modulated according to body's circadian clock giving release of drug after a specified time lag.

• Plus it can give “a new lease of life” & a “new therapeutic dimenssion” for existing drug molecule.

• And a golden future is awaiting for PDDS with many marketed formulations yet to develop.

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• Tekade AR, Gattani SG. “Development and evaluation of pulsatile drug delivery system using novel polymer”. Pharm Dev Tech 2009; 14(4): 380–387.

• Veena S Belgamwar, M.V.Gaikwad, G.B.Patil, S.Surana , “Pulsatile drug delivery system” , Asian Journal of Pharmaceutics - July-September 2008;141-145 .

• A.K. Anal, “Time-Controlled Pulsatile Delivery Systems for Bioactive Compounds”, Recent Patents on Drug Delivery & Formulation 2007; 1:73-79 .

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• Anita Lalvani,SD Satani,”PULSATILE DRUG DELIVERY SYSTEM”, Indian journal of pharmaceutical sciences (jul-2007) 490-497.

• Akihiko Kikuchi, Teruo Okano,” Pulsatile drug release control using hydrogels”, Advanced Drug Delivery Reviews 54 (2002) 53–77

• Lida E. Kalantzi, Evangelos. Karavas,” Recent Advances in Oral Pulsatile Drug Delivery “, Recent Patents on Drug Delivery & Formulation 2009, 3: 49-63

• • Sharma GS, Srikanth MV, Uhumwangho , “Recent trends

in pulsatile drug delivery systems - A review” International Journal of Drug Delivery 2 (2010)

200-212

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