APPROACHES TO CONTROLLED

RELEASE ORAL DRUG DELIVERY

SYSTEMS

ORAL PRESSURE CONTROLLED DDS

BY-NIKHIL A. BHANDIWAD

M.PHARM 1ST YEAR

DEPARTMENT OF PHARMACEUTICS

Osmotically Controlled Drug Delivery System

• Conventional oral drug delivery systems are known to provide an immediate release of drug, in which one cannot control the release of the drug and effective concentration at the target site. The bioavailability of drug from these formulations may vary significantly, depending on factors such as physico-chemical properties of the drug, presence of excipient, various physiological factors such as the presence or absence of food, pH of the GI tract, GI motility, etc.

• To overcome this limitation of oral route is replaced by parenteral route.

• This route offers the advantage of 1. reduced dose 2. targeting of site 3. avoiding GI stability 4. Hepatic by-pass of drug molecule.

Novel Drug Delivery System

• In recent years novel drug delivery systems have been developed which has achieved a very big milestone in the Pharmaceutical sector.

• Sustained and consistent blood level of drug can be achieved within the therapeutic window.

• Enhanced bioavailability• Reduced inter patient variability• Customized delivery profiles• Decreased dosing frequency• Improved patient compliance

Novel Drug Delivery System

• The drug release can be modulated by different ways but the most of novel drug delivery systems are prepared using matrix, reservoir or osmotic principle.

• In matrix systems, the drug is embedded in a polymer matrix and the release takes place by partitioning of drug into the polymer matrix and the surrounding medium.

• In contrast, reservoir systems have a drug core surrounded by a rate controlling membrane.

• The osmotic systems utilize the principles of osmotic pressure for the delivery of drugs in both the routes oral as well as parenteral.

CLASSIFICATION OF CONTROLLED DRUG DELIVERY SYSTEMS

• Controlled drug delivery system is classified as follows:

1. Rate pre-programmed drug delivery systems

2. Activation-modulated drug delivery systems

3. Feedback-regulated drug delivery systems

4. Site targeting drug delivery systems

Types of Rate pre-programmed drug delivery systems

1. Polymer membrane permeation-controlled drug delivery systems

2. Polymer matrix diffusion-controlled drug delivery systems

3. Micro reservoir partition- controlled drug delivery systems

Types of Activation-modulated drug delivery systems

• Physical means

1. Osmotic Pressure- activated drug delivery systems

2. Hydrodynamic pressure- activated drug delivery systems

3. Vapour pressure- activated drug delivery systems

4. Mechanically activated drug delivery systems

5. Magnetically activated drug delivery systems

6. Sonophoresis –activated drug delivery systems

7. Iontophoresis-activated drug delivery systems

8. Hydration-activated drug delivery systems

• Chemical means

1. pH –activated drug delivery systems

2. Ion-activated drug delivery systems

3. Hydrolysis-activated drug delivery systems

• Biochemical means

1. Enzyme-activated drug delivery systems

2. Bio chemical-activated drug delivery system

Types of Feedback- regulated drug delivery systems

1. Bio erosion- regulated drug delivery system

2. Bio responsive drug delivery systems

3. Self-regulating drug delivery systems

• Types of Site targeting drug delivery systems-

Osmotic drug delivery systems comes under the category of physical means of activation modulated drug delivery system.

OSMOTIC DRUG DELIVERY SYSTEMS

• Osmosis-Osmosis can be defined as the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane.

• It is driven by a difference in solute concentrations across the membrane that allows passage of water, but rejects most solute molecules or ions.

• Osmotic systems utilize the principle of osmotic pressure for the delivery of drugs.

• Drugs release from these systems is independent of pH and other physiological parameter.

• It is possible to modulate the release characteristic by optimizing the properties of drug and system.

• These systems can be used for both oral and parenterals route of administration.

• Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS).

• Parenteral osmotic drug delivery includes implantable

Osmotic pressure

• In 1886, Vant Hoff identified an underlying proportionality between osmotic pressure, concentration and temperature. He revealed that osmotic pressure is proportional to concentration and temperature and the relationship can be described by following equation-

Π = Ø c RTWhere,

Π = Osmotic Pressure

Ø = Osmotic Coefficient

c = Molar concentration

R = Gas constant

T = Absolute temperature

Advantages• Easy to formulate and simple in operation.

• Improve patient compliance with reduced frequency.

• Prolonged therapeutic effect with uniform blood concentration.

• They typically give a zero order release profile after an initial lag.

• Deliveries may be delayed or pulsed if desired.

• Drug release is independent of gastric pH and hydrodynamic condition.

• The release mechanisms are not dependent on drug.

• A high degree of in-vitro and in-vivo correlation (IVIVC) is obtained in osmotic systems.

• Higher release rates are possible with osmotic systems compared with conventional diffusion controlled drug delivery systems.

• The release from osmotic systems is minimally affected by the presence of food in gastrointestinal tract.

• The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters.

Disadvantages

• Rapid development of tolerance.

• Retrieval is not possible in the case of unexpected adverse events.

• Expensive.

• If the coating process is not well controlled there is a risk of film defects, which results in dose dumping.

• Size of orifice is critical.

CLASSIFICATION OF OSMOTIC DRUG DELIVERY SYSTEM

Implantable-1. The Rose and Nelson Pump2. Higuchi Leeper Pump3. Higuchi Theuwes Pump4. Implantable mini Osmotic Pump Oral Osmotic Pump Single Chamber Osmotic Pump- Elementary Osmotic Pump Multi Chamber Osmotic Pump- Push Pull Osmotic Pump,

Osmotic Pump with non expanding second chamber. Specific types- Controlled Porosity Osmotic Pump, Osmotic

bursting osmotic pump, Monolithic Osmotic System etc.

Implantable Osmotic DDS

• The Rose and Nelson Pump

• Rose and Nelson were two Australian physiologists interested in the delivery of drugs to the gut of sheep and cattle. Their pump was never patented.

• The pump consists of 3 chambers: a drug chamber, a salt chamber containing excess solid salt and a water chamber.

• The drug and water chambers are separated by a rigid semi permeable membrane.• The difference in osmotic pressure across the membrane moves water from water

chamber into salt chamber.• The volume of salt chamber increases because of this water flow, which distends

the latex diaphragm separating the salt and drug chambers, there by pumping drug out of the device.

• The pumping rate of Rose and Nelson pump is given by eqn-dMt/dt=(dv/dt)C

where dMt/dt= Drug release ratedv/dt= vol of water into salt chamber

C= Concentration of drug in drug chamber• Alza Corporation represented the 1st series of Rose and Nelson pump.

Implantable Osmotic DDSThe Higuchi Leeper Pump

• In Higuchi Leeper Pump there is no water chamber and the device activates after penetration of water inside from surrounding environment.

• This model is widely used for veterinary use.• This type of pump is either swallowed or implanted in the body of animal for

delivery of antibiotic or growth hormones.• It consists of a rigid housing and semi-permeable membrane.• A layer of low melting waxy solid, such as microcrystalline paraffin wax is used in

place of elastic diaphragm to separate drug and osmotic chamber.• Recent modifications accommodate pulsatile drug delivery which is achieved by

production of critical pressure at which the delivery orifice opens and drug is released.

Implantable Osmotic DDSThe Higuchi Theuwes Pump

• This device consists of rigid housing made up of SPM which is strong enough to withstand the pumping pressure developed inside the device due to permeation of water.

• The drug is loaded only prior of application of device.• The release of drug from device can be controlled by use of salt chamber altering the

permeability characteristics of outer membrane and orifice.• Osmotic pump of this form are available under trade name of Alzet.• A mixture of citric acid and sodium bi-carbonate in salt chamber in presence of water

generate CO2 gas exerting a pressure on the elastic diaphragm eventually delivering the drug from the device.

Implantable Osmotic DDSImplantable mini Osmotic Pump

• Implantable Mini osmotic pump shown in the above figure it is composed of three concentric layers-the drug reservoir, the osmotic sleeves and the rate controlling semi permeable membrane. The additional component called flow moderator is inserted into the body of the osmotic. The inner most compartment of drug reservoir which is surrounded by an osmotic sleeve, a cylinder containing high concentration of osmotic agent.

• The osmotic sleeve is covered by a semi permeable membrane when the system is placed in aqueous environment water enters the sleeve through semi permeable membrane, compresses the flexible drug reservoir and displaces the drug solution through the flow moderator.

• These pumps are available with variety of delivery rates between 0.25 to 10ml per hour and delivery duration between one day and four weeks.

Single Chamber Osmotic PumpElementary Oral Osmotic Pump

• The elementary osmotic pump is a new delivery system for drugs. It delivers the agent by an osmotic process at a controlled rate. Control resides in the:

A) Water permeation characteristics of a semi permeable membrane surrounding the formulating agent

B) Osmotic properties of the formulation. • In its simplest embodiment the system is constructed by coating an

osmotically active agent with the rate controlling semi permeable membrane. This membrane contains an orifice of critical size through

which agent is delivered.• The dosage form after coming into contact with aqueous fluids, imbibes

water at a rate determined by the fluid permeability of the membrane and osmotic pressure of the core formulation.

• This osmotic imbibition’s of water result in formation of a saturated solution of drug within the core, which is dispensed at controlled rate from the delivery orifice in the membrane.

• Though 60 -80 percent of drug is released at a constant rate from the EOP, a lag time of 30-60 minute is observed in most of the cases as the system hydrates before zero order delivery from the system begins.

• These system are suitable or delivery of drugs having moderate water solubility.

Multi Chamber Osmotic PumpPush –Pull Osmotic Pump

• Push pull osmotic pump is a modified EOP through, which it is possible to deliver both poorly water soluble and highly water soluble drugs at a constant rate.

• This system resembles a standard bilayer coated tablet. One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients. This polymeric osmotic agent has the ability to form a suspension of drug in situ.

• The other layer contains osmotic and colouring agents, polymer and tablet excipients. These layers are formed and bonded together by tablet compression to form a single bilayer core.

• The tablet core is then coated with semipermeable membrane. After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet.

• When the system is placed in aqueous environment water is attracted into the tablet by an osmotic agent in both the layers.

• The osmotic attraction in the drug layer pulls water into the compartment to form in situ a suspension of drug.

• The osmotic agent in the nondrug layer simultaneously attract water into that compartment, causing it to expand volumetrically and the expansion of non drug layer pushes the drug suspension out of the delivery orifice.

Multi Chamber Osmotic PumpOsmotic Pump with Non Expanding Second Chamber

Specific types • Controlled Porosity Osmotic Pump

• The pump can be made with single or multi compartment dosage form, in either form, the delivery system comprises a core with the drug surrounded by a membrane which has an asymmetric structure, i.e. comprises a thin dense skin layer supported by a porous substructure.

• The membrane is formed by phase inversion process controlled by the evaporation of a mixed solvent system.

• Membrane is permeable to water but impermeable to solute and insensitive pore forming additive dispersed throughout the wall.

• When exposed to water, low levels of water-soluble additive are leached from polymer materials that were permeable to water yet remained insoluble.

• Then resulting sponge like structure formed the controlled porosity walls of interest and was substantially permeable to both water and dissolved drug agents.

• Rate of drug delivery depends upon the factors are water permeability of the semi permeable membrane and the osmotic pressure of the core formulation, thickness and total surface area of coating.

• All of these variable are under the control of the designer and do not vary under physiological condition, leading to the robust performance.

• The rate of flow of water into the device can be represented as

dv / dt = Ak / h (Dp-DR)

Where

dv/dt = Rate of flow of water

k = Membrane permeability

A = Area of the membrane

Dp = Osmotic pressure difference

DR = Hydrostatic pressure difference

h = Thickness of the membrane

Osmotic Bursting Osmotic Pump

• This system is similar to an EOP expect delivery orifice is absent and size may be smaller.

• When it is placed in an aqueous environment, water is imbibed and hydraulic pressure is built up inside until the wall rupture and the content are released to the environment.

• Varying the thickness as well as the area the semipermeable membrane can control release of drug. This system is useful to provide pulsated release.

Specific typesMonolithic Osmotic System

• It constitutes a simple dispersion of water-soluble agent in polymer matrix.

• When the system comes in contact in with the aqueous environment, water imbibition’s by the active agents takes place rupturing the polymer matrix capsule surrounding the drug., thus liberating it to the outside environment. Initially this process occurs at the outer environment of the polymeric matrix, but gradually proceeds towards the interior of the matrix in a serial fashion.

• However this system fails if more then 20 –30 volumes per litre of the active agents is incorporated in to the device as above this level, significant contribution from the simple leaching of the substance take place.

Factors affecting drug release rate

• Solubility

1. APIs for osmotic delivery should have water solubility in the desired range to get optimized drug release.

2. However, by modulating the solubility of these drugs within the core, effective release patterns may be obtained for drugs which might otherwise appear to be poor candidate for osmotic DDS.

Factors affecting drug release rate• Solubility –modifying approaches

1. Use of swellable polymers: vinyl acetate copolymer, polyethylene oxide have uniform swelling rate which causes drug release at constant rate.

2. Use of wicking agents: These agents may enhance the surface area of drug with the incoming aqueous fluids. e.g. colloidal silicon dioxide, sodium lauryl sulfate, etc. Ensotrol® technology uses the same principle to deliver drugs via osmotic mechanism.

3. Use of effervescent mixtures: Mixture of citric acid and sodium bicarbonate which creates pressures in the osmotic system and ultimately controls the release rate.

4. Use of cyclodextrin derivatives: They are known to increase solubilityof poorly soluble drugs. The same phenomenon can also be used for the osmotic systems.

5. Use of alternative salt form: Change in salt form of may change solubility.

6. Use of encapsulated excipients: Solubility modifier excipient used in form of mini-tablet coated with rate controlling membrane.

7. Resin Modulation approach: Ion-exchange resin methods are commonly used to modify the solubility of APIs. Some of the resins used in osmotic system are Poly (4-vinyl pyridine), Pentaerythritol, citric and adipic acids.

8. Use of crystal habit modifiers: Different crystal form of the drug may have different solubility, so the excipient which may change crystal habit of the drug can be used to modulate solubility.

Factors affecting drug release rate

• Osmotic PressureThe next release-controlling factor that must be

optimized is the osmotic pressure gradient between inside the compartment and the external environment.

The simplest and most predictable way to achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment.

The following table shows osmotic pressure of commonly used solutes in CR formulations-

Compound Osmotic Pressure

Lactose-Fructose 500

Mannitol-Fructose 415

Sodium-Chloride 356

Potassium Sulphate 39

Sodium Phosphate

tribasic.12H2O

36

Sodium Phosphate

dibasic anhydrous

29

Factors affecting drug release rate

• Size of Delivery Orifice

• To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug deliver by diffusion through the orifice.

• Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system.

• The typical orifice size in osmotic pumps ranges from 600μ to 1 mm.

• Methods to create a delivery orifice in the osmotic tablet coating are:

Mechanical drill Laser drill Indentation Use of leachable substances in the permeable

membrane

Basic Components of Osmotic Systems

• Drug-• It should have a short biological half-life and which is used for prolonged

treatment are ideal candidate for osmotic systems.

• Examples- Diltiazem HCl, Carbamazepine, Metoprolol, Oxprenolol, Nifedipine, Glipizide etc.

• Osmotic Agent- Osmotic components usually are ionic compounds consisting of either

inorganic salts or hydrophilic polymers.

Different type of osmogents can be used for such systems are catergorized as

water-soluble salts of inorganic acids like MgCl2, MgSO4, NaCl

water-soluble salts of organic acids like sodium and potassium acetate, magnesium succinate, sodium benzoate sodium citrate, sodium ascorbate.

Carbohydrates like mannose sucrose, maltose lactose

Water soluble amino acids

Organic polymeric osmogents

Basic Components of Osmotic Systems

• Semipermeable Membrane-• An important part of the osmotic drug delivery system is the SPM housing. • Therefore, the polymeric membrane selection is key to osmotic delivery

formulation. • The membrane must possess certain performance criteria such as: Sufficient wet strength and water permeability Should be biocompatible Rigid and non-swelling Should be sufficient thick to withstand the pressure within the device.• Any polymer that is permeable to water but impermeable to solute can be

used as a coating material in osmotic devices. e.g. Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl cellulose and Eudragits.

Basic Components of Osmotic Systems

• Plasticizers-• Different types and amount of plasticizers used in coating membrane also

have a significant importance in the formulation of osmotic systems.

• They can change viscoelastic behavior of polymers and these changes may affect the permeability of the polymeric films.

• Some of the plasticizers used are as below:

Polyethylene glycols

Ethylene glycol monoacetate; and diacetate- for low permeability

Tri ethyl citrate

Diethyl tartarate or Diacetin- for more permeable films

EVALUATION OF OSMOTIC TABLET:• Evaluation of Powder

Weight of Powder

Bulk density

Tapped density

Carr’s index

Angle of repose

• Evaluation of Osmotic tablet

Hardness

Thickness

Friability

Weight uniformity

Drug content

In vitro Dissolution study

• Effect of Osmotic Pressure

• Effect of PH on drug release

• Stability study

MARKETED PRODUCTS• Elementary Osmotic Pump

• Push-Pull Osmotic Systems

Brand Name API

Efidac24 Chlorpheniramine

Acutrim Phenylpropanolamine

Sudafed24 Pseudoephedrine

Volmax Albuterol

MinipressXL Prazocine

Brand Name API

Procardia Nifedipine

Covera HS Verapamil HCl

Invega Paliperidone

MARKETED PRODUCTS

• Implantable Osmotic SystemsBrand Name API

Viadur Leuprolide acetate

Chronogesic Sufentanil

Conculsions

The therapeutic value of a pharmaceutical product depends on own parts; the rate profile of drug absorption and the pharmacodynamics of the drugs. Osmotic system technology has been extended to allow rate controlled constant drug delivery over a wide range of drugs. Delivery rates can be designed to the limits imposed by GI transit time and absorption capacity. The development of once daily formulations successfully can be acquired by osmotic systems for short half-life drugs.

References• International Journal of Research in Pharmaceutical and

Biomedical Sciences ‘A Review on Osmotic Drug Delivery System’ by Padma Priya, Ravichandran V and Suba V ; Vol. 4 (3) Jul– Sep 2013, Pg No 810-821.

• INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY ‘OSMOTIC PUMP DRUG DELIVERY- A NOVEL APPROACH’ by Deepak Singla, SL. Hari Kumar and Nirmala; Volume 2(2)-2012, Pg No 661-670.

• INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ‘A REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM’ by HarnishPatel, Upendra Patel, Hiren Kadikar, Bhavin Bhimani, DhirenDaslaniya & Ghanshyam Patel; Volume 3(4)-2012 , Pg No 88-94.

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