Controlled Release Oral Drug Delivery System

Controlled Release Oral Drug Delivery System

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D.

Dept of PharmaceuticsKLE University College of PharmacyBelgaum-590010, karnataka, India

Cell No: 00919742431000E-mail: [email protected]

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KLE College of Pharmacy, Nipani.

Contents Overview of Digestive system Introduction Advantages Disadvantages Dissolution Diffusion Combination of Dissolution & Diffusion Osmotic pressure controlled system Hydrodynamically balanced systems pH controlled Ion exchange controlled systems References6th December

2012 2KLE College of Pharmacy,

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Concept

Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time.

Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT.

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Controlled Release System

Matrix

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Plasma concentration time profile

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Challenges in Oral Drug Delivery

Development of drug delivery system Delivering a drug at therapeutically effective rate to desirable site.

Modulation of GI transit time Transportation of drug to target site.

Minimization of first pass elimination 6th December


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Advantages

Total dose is low.

Reduced GI side effects.

Reduced dosing frequency.

Better patient acceptance and compliance.

Less fluctuation at plasma drug levels.

More uniform drug effect

Improved efficacy/safety ratio.6th December 2012 7


Disadvantages

Dose dumping.

Reduced potential for accurate dose adjustment.

Need of additional patient education.

Stability problem.6th December 2012 8


Mechanism aspects of Oral drug delivery formulation

1.Dissolution : 1. Matrix 2. Encapsulation

2.Diffusion : 1. Matrix 2. Reservoir

3.Combination of both dissolution & diffusion.

4.Osmotic pressure controlled system6th December 2012 9


Dissolution Definition

Solid substances solubilizes in a given solvent.

Mass transfer from solid to liquid.

Rate determining step: Diffusion from solid to liquid.

Several theories to explain dissolution – Diffusion layer theory (imp) Surface renewal theory Limited solvation theory.6th December


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Noyes Whitney Equation

dc/dt = kD.A (Cs – C )dc/dt = D/h A. (Cs – C)

dc/dt = Dissolution rate. k= Dissolution rate constant (1st order). D = Diffusion coefficient/diffusivity Cs = Saturation/ maximum drug solubility. C =Con. Of drug in bulk solution. Cs-C=concentration gradient. h =Thickness of diffusion layer.

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Matrix Type Also called as Monolith dissolution

controlled system.

Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate.

First order drug release.

Drug release determined by dissolution rate of polymer.

Eg. Dimetane extencaps, Dimetapp extentabs.

Soluble drug

Slowly dissolving matrix



Matrix devices

In this system the solid drug dispersed in to the insoluble matrix.



Encapsulation Called as Coating dissolution

controlled system.

Dissolution rate of coat depends upon stability & thickness of coating.

Masks colour,odour,taste,minimising GI irritation.

One of the microencapsulation method is used.

Eg. Ornade spansules,

Chlortrimeton Repetabs

Soluble drug

Slowly dissolving or erodible coat



Diffusion

Major process for absorption.

No energy required.

Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attainded.

Directly proportional to the concentration gradient across the membrane.



Matrix Diffusion Types

Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion

1. Also called as Glassy hydrogels.Popular for sustaining the release of highly water soluble drugs. 2. Materials used are hydrophilic gums. Examples : Natural- Guar gum,Tragacanth. Semisynthetic -HPMC,CMC,Xanthum gum. Synthetic -Polyacrilamides. Examples: Glucotrol XL, Procardia XL



Matrix system

Rate controlling step:

Diffusion of dissolved drug in matrix.



Advantage and Disadvantage of Matrix and Reservoir system

Matrix system1. Suitable for both non-

degradable and degradable system.

2. No danger of ‘dose dumping’ in case of rupture.

3. Achievement of ‘zero order’ release is difficult

Reservoir system

1. Degradable reservoir systems may be difficult to design.

2. Rupture can result in dangerous ‘dose dumping’

3. Achievement of ‘zero order’ release is easy.



Methods to develop the Reservoir devices

a) Press coating (slowly soluble films and coating)b) Air suspension techniques

• The microencapsulation process is commonly used procedure to drug particle incorporated in to tablet or capsule.

• In most cases drug is incorporated in coating film as well as in the microcapsule.

• The care should be taken during placement into tablet or capsule dosage forms to minimize fragmentation or fusion of the particle both effects will alter release characteristics.



Factor effecting constant drug release

• Polymer ratio in the coating The increase the polymer ratio decrease in drug release due to

leaching effect.

• Film thickness The drug release rate from an insoluble membrane is expected to

increase as the membrane thickness decreases.

• Hardness of microcapsule The hardness of microcapsule increase, prolong the time of drug

release. 6th December 2012 20


Higuchi Equation

Q = DE/T (2A.E Cs)Cs.t)1/2

Where , Q=amt of drug release per unit surface area at time t. D=diffusion coefficient of drug in the release medium. E=porosity of matrix. Cs=solubility of drug in release medium. T=tortuosity of matrix. A=concentration of drug present in matrix per unit volume.



Reservoir System

Also called as Laminated matrix device. Hollow system containing an inner core surrounded

in water insoluble membrane. Polymer can be applied by coating or micro

encapsulation. Rate controlling mechanism - partitioning into

membrane with subsequent release into surrounding fluid by diffusion.

Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate.

Examples: Nico-400, Nitro-Bid



Reservoir System

Rate controlling steps :

Polymeric content in coating, thickness of coating, hardness of microcapsule.



Dissolution & Diffusion Controlled Release system

Drug encased in a partially soluble membrane.

Pores are created due to dissolution of parts of membrane.

It permits entry of aqueous medium into core & drug dissolution.

Diffusion of dissolved drug out of system.

Eg. Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane.

Insoluble membrane

Pore created by dissolution of soluble fraction of membrane

Entry of dissolution fluid

Drug diffusion





Osmotic Pressure Controlled Drug Delivery

System

Introduction

The oral drug delivery has been popular most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs.

The bioavailability of drug from these formulations may vary significantly, depending on factors such as physico-chemical properties of the drug, presence of excipients etc.

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. 6th December

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Introduction Osmotic pressure is used as driving force for these

systems to release the drug in controlled manner. Osmotic drug delivery technique is the most interesting and widely acceptable among all other technologies used for the same.

These systems can be used for both route of administration i.e. oral and parenterals. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS).

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Principle

Here osmotic pressure is used as the power/source or energy to activate and control the release of drug from the device. In this system, the drug reservoir contains the drug either in the form of solid or as solution, which is enclosed within a semipermiable housing having controlled water permeability. The drug is activated to release in solution form at a constant rate through a special delivery orifice.

The rate of drug release is modulated by controlling the gradient of osmotic pressure.(i.e. differences in osmotic pressure b/w the drug delivery system and the external environment)

Oral controlled release: Osmotic tablet

technology Once- or twice-daily dosing regimens for crystalline and

enhanced-bioavailability drugs is often desired and needed to maximize therapeutic effect, patient safety, and compliance.

Bend Research has developed two proprietary tablet technologies that provide drug release in a predictable, reliable manner. Both dosage forms are driven by osmotic/hydrostatic pressure and provide steady-state, zero-order release that is generally independent of GI pH and agitation.

These attributes minimize patient-to-patient variability and allow accurate prediction of in vivo performance from in vitro dissolution testing. A wide range of release rates is possible. 6th December


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Osmotic swellable-core technology

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A bi-layer tablet containing an insoluble, semipermeable coating with a delivery orifice

Preferred API and dose:

poorly water soluble, or bioavailability-enhanced forms ; low to moderate dose.

A single-layer tablet containing an insoluble, asymmetric microporous coating produced by controlled phase separation

Preferred API and dose: water soluble; low to high dose.

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Osmotic asymmetric membrane technology



Oral osmotic pumps

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Elementary osmotic pump


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Acutrim tablet It is an oral osmotic pressure controlled G.I. DDS. this systems are

fabricated by encapsulating an osmotic drug core containing an osmotically active drug or a combination of an osmotically inactive drug with an osmotically active salt like Nacl, within a semipermiable membrane made from cellulose acetate polymer.

A delivery orifice with a controlled diameter is drilled, using a laser beam, through the coating membrane for controlling the drug release.

The polymer membrane is not only semipermiable in nature but is also rigid & capable of maintaining the structural integrity of the G.I. DDS during the course of drug release. It is permeable to the influx of water in G.I.T. but impermeable to drug solutes.

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Acutrim tablet



Modifications

The external surface of the semipermiable membrane can be coated with a layer of bioerodable polymer like enteric coating, it regulate the penetration of GI fluid through the semipermiable membrane & target the delivery of a drug to the lower region of the GIT.

The coating membrane of the DDS can be constructed from a laminate of two or more semipermiable membranes with differential permeabilities.

The osmotic pressure controlled GI delivery system can be further modified to constitute two compartments separated by a movable partition. The osmotically active compartment absorbs water from GI fluid to creat an osmotic pressure that acts on the partition forces it to move upward and to reduce the volume of the drug reservoir compartment and to release the drug formulation through the delivery orifice .



Modifications

Modifications

This system has been applied to the development of a GI-delivery system for the oral controlled delivery of Nifedipine .

Further more, a two compartment GI-delivery system has been applied to the simultaneously GI-controlled delivery of two drugs, such as Oxprenolol sebacinate and Hydralazine HCl, from separate compartment, simultaneously and independently at different delivery rates.

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Push 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. When this tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and tablet excipients. These layer 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 non-drug 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.




Osmotic pump with non-expanding second chamber

The second category of multi-chamber devices comprises system containing a non-expanding second chamber. This group can be divided into two sub groups, depending on the function of second chamber.

In one category of these devices, the second chamber is used to dilute the drug solution leaving the devices. This is useful because in some cases if the drug leaves the oral osmotic devices in a saturated solution, irritation of GI tract is a risk.


Example: - The problem that lead to withdrawal of osmosin, the device consist of a normal drug containing porous tablet from which drug is released as a saturated solution. However before the drug can escape from the device it must pass through a second chamber.

Water is also drawn osmotically into this chamber either because of osmotic pressure of drug solution or because the second chamber contain, water soluble diluents such as NaCl.6th December


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This type of devices consist of two rigid chamber, the first chamber contains a biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride, the second chamber contains the drug. In use water is drawn into both the chamber through the surrounding semi permeable membrane.

The solution of osmotic agent formed in the first chamber then passes through the connecting hole to the drug chamber where it mixes with the drug solution before exiting through the micro porous membrane that form a part of wall surrounding the chamber. The device could be used to deliver relatively insoluble drugs.


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This system is similar to an EOP except 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.


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Osmotic bursting pump



Controlled Porosity Osmotic Pumps

In this type two layers of membrane are applied on pumps .

The inner is microporous membrane, which is made up of cellulosic material containing some pore forming agents. A semipermeable membrane cover this layer.

When the system is placed in an aqueous environment the soluble components of first layer of coating dissolve, resulting in a microporous , which provides greater flux of water into the system.



In this system particles of osmotic agents are coated with an elastic semipermeable membrane.

These coated particles are then mixed with the relatively insoluble drug and tableted and coated with the rigid semipermeable membrane in usual way.

When this system is placed in an aqueous environment, water is drawn through the two membranes in-turn into the osmotic agent particles, which swell and hydrostatic force delivers the insoluble drug out of the pump.

Pumps for insoluble drugs



Sandwiched osmotic tablets

It is composed of polymeric push layer sandwiched between two drug layers with two delivery orifices.

When placed in the aqueous environment the middle push layer containing the swelling agents swells and the drug is released from the two orifices situated on opposite sides of the tablet and thus SOTS can be suitable for drugs prone to cause local irritation of the gastric mucosa.



Sandwiched osmotic tablets

Osmotic Pressure Controlled System



Osmotic drug delivery system for oral and parenteral use offer distinct and practical advantage over other means of delivery. The following advantages contributed to the popularity of osmotic drug delivery system.

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. They are well characterized and understood. The release mechanisms are not dependent on drug. A high degree of in-vitro and in vivo correlation .



Advantages

The rationale for this approach is that the presence of water in GIT is relatively constant, at least in terms of the amount required for activation and controlling osmotically base technologies.

Disadvantages Costly . If the coating process is not well controlled there is a risk of

film defects, which results in dose dumping. Size hole is critical .



Advantages & Disadvantages

Product name Active Design Dose

Acutrim Phenylpropanolamine

Elementary pump

75 mg

Alpress LP Prazosin Push-pull 2.5-5 mg

Cardura XL Doxazosin Push-pull 4.8 mg

Ditropan XL Oxybutinine chloride

Push-pull 5, 10 mg

Efidac 24 Pseudoephedrine

Elementary pump

60 mg , 180 mg

Glucotrol XL Glipizide Push-pull 5, 10 mg6th December 2012 58


Marketed products

Introduction This system is either capsule or tablet form is designed to prolong

GI residence time in an area of the GIT to maximize drug reaching its absorption site in solution state & hence ready for absorption.

Hydrodynamically balanced system are also known as floating drug delivery system. HBS have a bulk density lower than gastric fluid & hence remain floating in the stomach.

This is a hydration activated drug delivery system depends on the hydration induced swelling process to activate the release of drug. In this system the reservior is homogenously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymer.

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Principle

Principle



Hydrodynamic pressure activated drug delivery system can be fabricated by enclosing a collapsible, impermeable container, which contains a liquid drug formulation to form a drug reservoir compartment inside a rigid shape retaining housing a composite laminate of an absorbent layer and a swellable, hydrophilic polymer layer is sandwiched between the drug reservoir compartment and the housing.

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Principle

Rate controlling factors: Fluid permeability , Effective area of wall with openings , Hydrodynamic pressure gradient.





Formulation and development of Hydrodynamically balanced system (HBS) or Floating drug delivery system(FDDS)

FORMULATION

20-75% w/w of one or more gel forming hydrocolloid are incorporated into the formulation and then compressing these granules into a tablet (or encapsulating into capsules).

e.g., Hydroxy ethyl cellulose, Hydroxy propyl cellulose, Hydroxy propyl methyl cellulose & Sodium carboxy methyl cellulose.





Classification of FDDS

These floating drug delivery system employ matrices from swellable polymers like Methocel or Chitosan & effervescent components such as Sodium bicarbonate & Tartaric or Citric acid or matrices having chambers of liquid components that gasify at body temperature.

The matrices are prepared in such a manner that when they come in contact with stomach fluid , CO2 is generated, & retained entrapped in hydrocolloid gel.

This leads to an upward flow of the dosage form and maintains it in a floating condition.

A single layered tablet can be prepared by initially mixing the CO2 generating component in tablet matrix. A bilayered tablet may be compressed in which gas liberating component is present in hydrocolloid layer and the drug is compressed in other layer of sustain release



EFFERVESCENT FLOATING DOSAGE FORMS

Multiple type of floating dosage system



Multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills.

The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac.

When this system was immersed in the buffer at 37ºC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/mL.

It was found that the system had good floating ability independent of pH and viscosity and the drug (para-amino benzoic acid) released in a sustained manner(Figure ,A and B).

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Figure . (A) Multiple-unit oral floating drug delivery system. (B) Working principle of effervescent floating drug delivery system.


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Multiple type of floating dosage system

Triple-layer tablet floating dosage system



Swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly ethylene oxide (PEO) as the rate-controlling polymeric membrane excipients.

The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. HPMC and PEO were the major rate-controlling polymeric excipients.

Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release.



The floatation was accomplished by incorporating a gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers.

The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat.

The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole.


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Figure- Schematic presentation of working of a triple-layer system. (A) Initial configuration of triple-layer tablet. (B) On contact with the dissolution medium the bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes. (D) and (E) Tablet erodes completely.


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FORMULATION:

It includes; Gel forming or swellable cellulose type of

hydrocolloids & polysaccharides. Matrix forming polymers (polycarbonate,

polyacrylate, polymethacrylate & polystyrene).

NON -EFFERVESCENT FLOATING DOSAGE FORMS



Gel forming hydrocolloids swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within gastric environment. The air thus trapped by the swollen polymer imparts buoyancy to the dosage form.

The gel barrier controls the rate of solvent penetration into the device & the rate of drug release from the device.

It maintains a bulk density of less than 1 and thus remains buoyant in the gastric fluid inside the stomach for up to 6 hrs; conventional dosage forms disintegrate completely within 60 min and are emptied totally from the stomach shortly afterward.

MECHANISM



Advantages of HDDS



Disadvantages of HDDS

PRODUCT ACTIVE INGREDIENT

MADOPAR LEVODOPA & BENSERZIDE

VALRELEASE DIAZEPAM

TOPALKAN ALUMINIUM MAGNESIUM ANTACID

ALMAGATE FLAT COAT ANTACID

LIQUID GAVISON ALGINIC ACID & NaHCO36th December 2012 78


Marketed products



HBS system can remain in the stomach for longer period hence can release the drug over a prolong period of time.

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or proximal part of small intestine ( e.g., Riboflavin & Furosemide).

Drugs that have poor bioavailability because of site specific absorption from the upper part of GIT are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.

FDDS also serves as an excellent drug delivery system for the eradication of Helicobacter pylori, which can cause chronic gastritis & peptic ulcers.

CONCLUSION

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This type of GI delivery system is designed for the controlled release of acidic or basic drugs in GIT, at a rate independent of the variation in GI pH.


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pH controlled GI delivery systems



This system is prepared by first blending acidic or basic drug with one or more buffering agents,

Eg. Pri, sec, ter salt of citric acid.

Then granulating with excipients, to form small granules and then coating the granules with GI fluid permeable film-forming polymer.

Eg. Cellulose derivatives.

Formulation



Polymer coating controls the permeation of GI fluid.

The GI fluid permeating into the device is adjusted by the buffering agents to an appropriate constant pH.

This is the pH where drugs dissolve and is delivered through the membrane at the constant rate, regardless of the location of device in the alimentary canal.

Mechanism

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pH controlled GI Drug Delivery


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This system have been targeted for per-oral controlled drug delivery, taste masking of bitter drugs and intravascular drug release during elevated blood pH in certain CVS defects.

It includes the ionic polymers, for eg. Polyacrylamide, poly acrylic acid, poly methacrylic acid, etc.

pH responsive hydrogels



In aqueous media of appropriate pH and ionic strength, pendant groups, ionised and developed fixed charges on the fixed charges generating electrostatic repulsive forces responsible for pH dependent swelling or deswelling of the hydrogel, thereby controlling the drug release.

Mechanism



This system is designed in a monobasic or pulsatile pattern.

Peroral controlled drug delivery requires uniform drug delivery with increase in drug pH, gradient in different segments of GI Lumen.

Eg. Albumin cross-linked 1-vinyl-2-pyrrolidinone hydrogels were studied for their swelling behaviour at different values.

Swelling increases above pH 7, thus correlating with the maximal transit time of the drug delivery system through the intestine.

Drug release pattern



Pulsatile pattern of drug release is required in the diseased state exhibiting a rhythmic pattern.

For localised delivery of heparin and streptokinase based on poly( N-isopropyl acrylamide-co-methacrylic acid) hydrogel, were assessed for their swelling behaviour in response to pulses in temperature and pH.

Drug release pattern



pH- Activated Drug Delivery System

This system permits targeting the delivery of a drug only in the region with a selected pH range.

Drugs administered orally would encounter a spectrum of pH ranging from 7 in the mouth, 1 - 4 in the stomach and 5 - 7 in the intestine.

Since most drugs are weak acids or weak bases, their release is pH dendent.

However, buffers can be added to the formulation to help maintain a constant pH, like salts of citric acid, tartaric acid, phosphoric acid are commonly used.



pH Activated Drug Delivery System is fabricated by coating the drug-containing core with a pH–sensitive polymer combination.

For example, a gastric fluid labile drug is protected by encapsulating it inside a polymer membrane that resists the degradative action of gastric pH, such as the combination of Ethyl cellulose and Hydroxylmethylcellulose phthalate. In the stomach, coating membrane resists the action of gastric fluid (pH<3) & the drug molecule is thus protected from acid degradation.

After gastric emptying the Dosage form reaches the small intestine and comes in contact with intestinal fluid (pH>7.5) which activates the erosion of polymer - Hydroxylmethylcellulose phthalate from the coating membrane.





This leaves a microporous membrane of intestinal fluid insoluble polymer of Ethylcellulose, which controls the release of drug from the core tablet.

The drug solute is thus delivered at a controlled manner in the intestine.



Ion Exchange Resinates As Controlled Release Drug Delivery Systems

Introduction

It is an attractive method for Sustained Release drug delivery systems.

Drug release characteristics depend upon the ionic environment of the resin containing drug.

Therefore, it is less susceptible to environment conditions such as enzyme content and pH at the absorption site.6th December


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Introduction

This approach requires the presence of ions in solution, and therefore it would not be applicable to the skin, or other areas with limiting quantities of eluting ions.

Where as the Subcutaneous and Intramuscular routes have pool of available ions, and therefore, would be better suited for this approach.

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Principle

Resins are water-insoluble materials containing anionic or cationic groups in repeating units on the resin chain.

A Cation Exchange Resin generally has Sulphonic and Carboxylic functional groups as an integral part of the resin and an equivalent amount of cationic drug molecules.

An Anion Exchange Resin generally has quaternary ammonium groups and polyalkylamine functional groups as an integral part of the resin and an equivalent amount of anionic drug molecules.

Resin type Chemical constitution StructureStrongly acidic cation

exchangerSulphonic acid group attached to a

styrene and divinylbenzene copolymerR – SO3

- H +

Weakly acidic cation exchanger

Carboxylic acid group attached to an acrylic and divinylbenzene copolymer

R – COO - Na +

Strongly basic anion exchanger

Quaternary ammonium group attached to a styrene and divinylbenzene

copolymer

R –N (CH3)3+ Cl-

Weakly basic anion exchanger

Polyalkylamine group attached to a styrene and divinylbenzene copolymer

R –NH (R)2+ Cl-



Types of Ion Exchange Resins



Types of Ion Exchange Resins



Mechanism



1. Drugs should have acidic and basic groups in their chemical

structure.

2. Biological half life should be between 2-6 hrs, drugs with t1/2 < 1

hr or > 8 hrs are difficult to formulate.

3. The drug is to be absorbed from all regions of GI tract.

4. Drugs should be stable sufficiently in the gastric juice.

Drugs Suitable for Resinate Preparation



Particle Size and form :

The rate of ion exchange reactions depend on the size of the resin particles.

Decreasing the size of resin particle significantly decreases the time required for the reaction to reach equilibrium with the surrounding medium.

Most of the ion exchange resins are available in the form of spherical beads. When the beads are immersed in water, they imbibe a limited amount of water to form a homogenous gel like structure.

Some Important Properties of Ion-Exchange Resins



Ion exchange resins have hydrocarbon network to which ionizable sulphonic acid groups are attached. The hydrogen ions are completely dissociated in the imbibed water and are free to diffuse through out the entire resin bead and hence can be exchanged for an equivalent amount ions of like charge.

Porosity : Porosity is defined as the ratio of the volume of the material to its mass. The limiting size of ions which can penetrate into a resin matrix depends strongly on the porosity.

Swelling :The swelling behavior of the resin has a marked effect on the release characteristics of drug resinates. The amount of swelling is inversely proportional to the degree of divinylbenzene crosslinking present in the resin.




Ion exchange capacity:

It is expressed in the terms of milliequivalents per gram of ion exchange resin.

eg. The exchange capacity of a cation exchange resin is usually found in the laboratory by determining the number of milligram equivalents of sodium ion which are absorbed by 1 gram of the dry resin in the hydrogen form.

The Resin ion exchanger should be Stable, Pure and free from toxicity.


The drug resin is then washed to remove the contaminating ions

and dried to form particles or beads.6th December 2012 103


General Preparation Of Drug Resinates



The release rate can be further controlled by coating the drug resin complex using microencapsulation .

Coated and uncoated drug resin complexes can be mixed in certain ratios and can be filled into capsules with excipients or suspended in a palatable flavored vehicle containing suitable suspending agents.

The release of drug from uncoated resin beads is expected to begin immediately while release from the coated form would be delayed giving sustained effect.

The drug containing resin granules are first treated with an impregnating polymer such as PEG 6000 to retard the rate of swelling in water and further coated with a water permeable polymer such as Ethyl Cellulose to control the rate of release.


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Adsorbents of Toxins

As Antacids

As Bile Acid binding agents

In treatment of Liver diseases

In Renal insufficiency

In Ophthalmology for glaucoma

Applications

1. Cholestyramine It is a quaternary ammonium anion exchange resin with basic groups attached to a stryne – divinyl benzene copolymer.

Used for the reduction of elevated serum cholestrol levels in patients with hypercholestrolemia.

2. Colestipol Similar anion exchange resin, used as a hypolipidemic drug. It increases the catabolic rate of low density lipoproteins and decreases cholestrol level.



Therapeutic applications

3. Sod. Polystrene It is a sulphonic cation exchange resin used in the treatment of hyperkalemia and renal failure.

4. Phenteramine A sympathomimetic amine used for the short term management of hypotension has also been formulated as ion exchange resins.

5.Dextromethorphan It is used as an Antitussive that raises the threshold of cough center in the CNS and suppresses cough.



Therapeutic applications



N K, Jain, Advanced in Controlled Drug Delivery System, pg no.290 -302

Yie w.chein, Novel Drug Delivery System, edition 2, vol-3,pg no.30 – 32

Joseph R. Robinson, Controlled drug delivery Fundamentals and Applications, pg no. 412 - 414

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References

Thank you E-mail: [email protected]

Cell No: 00919742431000



Controlled Release Oral Drug Delivery System

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