Suraj C. (ADDS)

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SURAJ C. 1st M.Pharm

Dept. of Pharmaceutics AACP

RATE CONTROLLED DDS

• There are three classifications that’s comes under rate controlled drug delivery system.

1) Rate preprogrammed drug delivery system

2) Activation-modulated drug delivery system

3) Feedback-regulated drug delivery system

1. RATE PREPROGRAMMED DDS

• Release of drug from delivery system has been preprogrammed at specific rate profiles.

• This was accomplished by system design, which controls the molecular diffusion of drug

molecules in and across the barrier with or surrounding the delivery system.

• Fick’s law of diffusion are often followed.

• These system are further classified as:

1) Polymer Membrane Permeation-Controlled DDS

2) Polymer Matrix Diffusion-Controlled DDS

3) Micro reservoir Partition-controlled DDS

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Suraj C. (ADDS) A. Polymer Membrane Permeation-Controlled DDS

• A drug formulation is totally or partially encapsulated within a drug reservoir compartment.

• The drug release surface is covered by a rate-controlling polymeric membrane having specific

permeability.

• The drug reservoir may exist in solid, solution or suspension form.

• The polymeric membrane can be fabricated by a non-porous polymeric material or a micro

porous membrane.

• The encapsulation of drug formulation inside the reservoir compartment is by injection molding,

spray coating, capsulation, micro encapsulation or other techniques.

• Different size and shape of DDS can be fabricated as in diagram.

• The rate of drug release (Q/t) from Polymer Membrane Permeation CDDS should be a constant

value,

Q/t = Km/r Ka/m Dd Dm CR

Km/r Dm h d + Ka/m Dd hm

Km/r = partition coefficient for interfacial partitioning of drug from reservoir to rate controlling

membrane.

Ka/m = partition coefficient for interfacial partitioning of drug from rate controlling membrane to

surrounding aqueous diffusion layer.

Dm = diffusion coefficient in rate controlling membrane, thickness hm

Dd = diffusion coefficient in aqueous diffusion layer, thickness h d

CR = concentration of drug in reservoir compartment.

• The release of drug is controlled at a preprogrammed rate by controlling partition coefficient,

diffusivity and thickness of rate controlling membrane.

E.g.- Progestasert IUD, (intrauterine device)

The drug reservoir is a suspension of progesterone crystals in silicone medical fluid and is

encapsulated in vertical limb of T-shaped device walled by a non porous membrane of

Ethylene Vinyl Acetate Copolymer.

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Suraj C. (ADDS) It is designed to deliver progesterone in uterine cavity at a daily dosage rate of at least

65mcg/day to achieve contraception for one year.

E.g- Ocusert System (an ocular insert)

The drug is a thin disk of pilocarpine complex sandwich between two transparent sheets of

micro porous ethylene vinyl complex membrane.

The micro porous membrane permit the tear fluid to penetrate into the drug reservoir

compartment to dissolve pilocarpine complex.

The drug molecule are released at a constant rate of 20 or 40 mcg/hr for management of

glaucoma for upto 7 days.

B. Polymer Matrix Diffusion-Controlled DDS

• Drug reservoir is prepared by homogenously dispersing drug particles in a rate controlling polymer

matrix fabricated from either a lipophilic or hydrophilic polymer.

• Drug dispersion in polymer matrix is by

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Suraj C. (ADDS) 1) Blending therapeutic dose of finely ground drug particles with a liquid polymer or highly viscous

base polymer followed by cross linking of polymer chains.

2) Mixing drug solids with a rubbery polymer at an elevated temperature.

• Drug polymer dispersion is then molded or extruded to form a drug delivery device of various

shapes and sizes designed for specific application.

• The rate of drug release from this Polymer Matrix Diffusion CDDS is time dependent,

Q/t½ = (2ACRDP) ½

A = initial drug loading dose in polymer matrix.

CR = drug solubility in polymer (drug reservoir conc. in system)

DP = diffusivity of drug molecules in polymer matrix.

• The release of drug is controlled at a preprogrammed rate by controlling the loading dose, polymer

solubility of drug and diffusivity of drug in polymer matrix.

E.g.- Nitro-Dur is a transdermal DDS

It is fabricated by first heating an aqueous solution of water soluble polymer, glycerol and

polyvinyl alcohol.

The temperature of solution is then gradually lowered and nitroglycerine and lactose triturate

are dispersed just above the congealing temperature of solution.

The mixture is then solidified in mold at or below room temperature and then sliced to form a

medicated polymer disk.

It is designed for application onto intact skin for 24hr to provide a continuous transdermal

infusion of nitroglycerine at a dosage rate of 0.5mg/cm2/day for treatment of angina pectoris.

C. Micro reservoir Partition-controlled DDS

• In this type of preprogrammed DDS drug reservoir is fabricated by micro dispersion of an

aqueous suspension of drug using a high energy dispersion technique in a biocompatible

polymer such as silicone elastomers, to form a homogenous dispersion of many discrete

microscopic drug reservoirs.

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Suraj C. (ADDS) • Different shapes and sizes of drug delivery system devices can be fabricated from this micro

reservoir DDS by molding or extrusion.

• Depending on physicochemical properties of drug and the desired rate of drug release rate, the

device can be further coated with a layer of biocompatible polymer to modify the mechanism and

release rate.

• Rate of drug release dQ/dt is

dQ/dt = Dp Dd m Kp ( n Sp – Dl Sl (1-n) { 1 + 1 }

Dp hd + Dd hp m Kp hl Kl Km

m =a/b

a =ratio of drug conc in bulk of elution solution over drug solubility in the same medium.

b =ratio of drug conc at the outer edge of the polymer coating membrane over the drug

solubility in same polymer.

n =ratio of drug conc at the inner edge of interfacial barrier over the drug solubility in the

polymer matrix.

Kl =partition coefficient for interfacial partitioning of drug from liquid compartments to

polymer matrix.

Km =partition coefficient for interfacial partitioning of drug from polymer matrix to polymer

coating membrane.

KP =partition coefficient for interfacial partitioning of drug from polymer coating membrane to

elution solution.

Dl =diffusivity of drug in liquid layer surrounding the drug particles.

DP =diffusivity of drug in polymer coating membrane enveloping polymer matrix.

Dd =diffusivity of drug in hydrodynamic diffusion layer surrounding the polymer coating

membrane.

hl, hp, hd = thickness.

Sl =solubility of drug in liquid compartments.

Sp =solubility of drug in polymer matrix.

• Release of drug molecules from this type of CDDS can follow either dissolution or matrix

diffusion-controlled process depending on relative magnitude of Sl and Sp.

E.g.- Transdermal nitro disc system.

The drug reservoir is formed by first preparing a suspension of nitroglycerine and lactose

triturate in an aqueous solution of 40% PEG 400 and dispersing it homogenously with

isopropyl palmitate, as dispersing agent, in a mixture of viscous silicone elastomers by high

energy mixing and then cross linking the polymer chain by catalyst.

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Suraj C. (ADDS) It is then molded to form a solid medicated disk, on a drug-impermeable metallic plastic

laminate. It provides nitroglycerine at a daily dose of 0.5mg/cm2 for once-a-day medication of

angina pectoris.

2. ACTIVATION-MODULATED DDS

• Here the release of the drug molecule from delivery system is activated by some physical,

chemical or bio-chemical process and/or facilitated by energy supplied externally.

• Regulating the process applied or energy input controls the rate of drug release.

• The rate of drug release is controlled by regulating process applied or energy input.

• Classification is based on nature of process applied/type of energy used.

A. Physical means;

1. Osmotic Pressure-Activated DDS

2. Hydrodynamic Pressure-Activated DDS

3. Vapor Pressure-Activated DDS

4. Mechanically-Activated DDS

5. Magnetically-Activated DDS

6. Sonophoresis-Activated DDS

7. Iontophoresis-Activated DDS

8. Hydration-Activated DDS

B. Chemical means;

1. pH-Activated DDS

2. Ion-Activated DDS

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Suraj C. (ADDS) 3. Hydrolysis-Activated DDS

C. Biochemical means;

1. Enzyme-Activated DDS

2. Biochemical-Activated DDS

A. Physical Means:

1. Osmotic Pressure-Activated DDS

• It depends on osmotic pressure to activate the release of drug.

• In this system, drug reservoir can be solution or a solid formulation and is contained within a semi

permeable housing with controlled water permeability.

• For drug delivery system containing solution formulation the intrinsic rate of drug release Q/t is,

Q/t= Pw Am (πs – πe)

hm

• For drug delivery system containing solid formulation the intrinsic rate of drug release Q/t is,

Q/t= Pw Am (πs – πe) Sd

hm

Pw = water permeability of semipermeable housing.

Am = effective surface area of semipermable housing.

hm = thickness of semipermable housing.

πs – πe = differential osmotic pressure between drug delivery system with osmotic pressure πs and

the environment with osmotic pressure πe.

Sd = aqueous solubility of drug contained in solid formulation.

• Release of drug is activated by osmotic pressure and controlled at a rate determined by water

permeability, effective surface area of semi permeable housing and osmotic pressure gradient.

E.g. - Acutrim,

an oral rate-controlled drug delivery system is a solid tablet of water soluble and osmotically

active phenylpropanolamine (PPA) HCl enclosed within a semi permeable membrane made

from cellulose triacetate. Semi permeable layer is further coated with PPA for immediate

release.

In GIT, GI fluids will dissolve immediately releasable layer, which provides initial dose and its

water components then penetrates through the semi permeable at a rate determined by

Pw.Am/hm to dissolve the controlled release dose of PPA under osmotic pressure differential

created (πs – πe), the PPA solution is delivered at a controlled rate through an orifice predrilled

by a laser beam.

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Suraj C. (ADDS) It is designed to provide a controlled delivery of PPA for duration of 16hr for appetite

suppression in a weight control program.

E.g- Alzet,

Alzet osmotic pump the drug reservoir which is normally a solution formulation ,is contained

within collapsible, impermeable polyester bags whose external surface is coated with a layer of

osmotically active salt, such as sodium chloride .

This reservoir compartment is then completely sealed inside a rigid housing walled with a

semipermeable membrane at the implantation site the water component in the tissue fluid

penetrates through the semipermeable housing at a rate determined by PwAm/hm to dissolve

osmotically active salt .

This creates an osmotic pressure in the narrow spacing between the flexible reservoir

compartment wall and regid semipermeable housing.

Under the osmotic pressure the resesvoir compartment is forced to reduce its volume and drug

solution is delivered at a controlled rate.

The drug concentration in the solution, different doses of drug can be delivered at a constant

rate for a period of 1-4 weeks.

2. Hydrodynamic Pressure-Activated DDS:

• It is fabricated by enclosing a collapsible, impermeable container, which contains a drug

formulation to form a drug reservoir, inside a rigid shape retaining housing.

• A composite laminate of an absorbent layer and a swellable, hydrophilic polymer layer

(polyhydroxyalkylmethacrylate) is sandwiched between drug reservoir and the housing.

• In GIT, the laminate absorbs GI fluid through annular opening at the lower end of the

housing and swells generating hydrodynamic pressure which forces the drug reservoir

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Suraj C. (ADDS) compartment to reduce in volume and causes the liquid drug formulation to release through the

delivery orifice.

• The rate defined by:

Q/t= Pf Am (θs-θe)

h m

Pf = fluid permeability.

Am = effective surface area of wall.

hm = thickness of wall with annular openings.

θs-θe = differences in hydrodynamic pressure between drug delivery system and environment.

• Release of drug molecule from this type system is activated by hydrodynamic pressure and

controlled at a rate determined by fluid permeability, effective surface area of wall and

hydrodynamic pressure gradient.

3. Vapor Pressure activated DDS:

• In this type of system the drug reservoir is contained inside the infusion compartment.

• It is physically separated from pumping compartment by freely movable partition.

• The pumping compartment contains a fluorocarbon fluid that vaporizes at body temperature at the

implantation site and creates a vapor pressure.

• Under the vapor pressure created the partition moves upward, this forces the drug solution in the

infusion compartment to be delivered through a series of flow regulator and delivery cannula into

blood circulation at a constant flow rate.

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Suraj C. (ADDS) • The rate of delivery Q/t is defined by,

Q/t= d4 (Ps-Pe)

40.74 µl

d = inner diameter of delivery cannula

l = length of delivery cannula

µ = viscosity of drug formulation

Ps-Pe = difference between vapor pressure in pumping system compartment (Ps) and pressure

at implantation site.

• Release of drug is activated by vapor pressure and controlled at a rate determined by differential

vapor pressure, formulation viscosity and size of delivery cannula.

E.g. - Infusaid

Development of implantable infusion pump (infusaid) for constant infusion of heparin in

anticoagulation treatment, insulin in anti-diabetic medication, morphine for patients with

intense pain of terminal cancer.

4. Mechanically Activated DDS:

• In this type of activation CDDS the drug reservoir is a solution formulation retained in a container

equipped with a mechanically activated pumping system.

• A measured dose of drug formulation is reproducibly delivered into a body cavity.

• The volume of solution delivered is controllable as a small as 10-100µl, and is independent of the

force and duration of activation applied as well as the solution volume in the container.

E.g. - Metered-dose nebulizer

for intranasal administration of a precision dose of buserlin (synthetic analogue of LHRH and

insulin)

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Suraj C. (ADDS) 5. Magnetically-Activated DDS:

• In this type of system, the drug reservoir is a dispersion of peptide or protein powders in a

polymer matrix from which macromolecular drug can be delivered at a relatively slow rate.

• This low rate of delivery can be improved by incorporating an electromagnetically triggered

vibration mechanism into the polymeric delivery device combined with a hemispherical design.

• A sub-dermally implantable, magnetically activated drug delivery device is fabricated by first

positioning a tiny magnet ring in the core of a hemispherical drug-dispersing polymer matrix and

then coating its external surface with a drug impermeable polymer such as ethylene-vinyl acetate

copolymer or silicone elastomers, except one cavity at the center of flat surface.

• This uncoated cavity is positioned directly above the magnet ring, which permits a peptide drug to

be released.

• It is used to deliver protein drugs, such as bovine serum albumin, at a low basal rate, by a simple

diffusion process under non triggering conditions.

• As the magnet is activated to vibrate by an external electromagnetic field, the drug molecules are

delivered at a much higher rate.

6. Sonophoresis-Activated DDS:

• This type of DDS utilizes ultrasonic energy to activate the delivery of drugs from a polymeric

drug delivery device.

• The system can be fabricated from either a non-degradable polymer such as ethylene-vinyl

acetate copolymer or a bioerodible polymer,such as poly [bis (p-carboxy phenoxy) alkane

anhydride.

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Suraj C. (ADDS) 7. Iontophoresis-Activated DDS:

• This type of system uses electrical current to activate and modulate the diffusion of a charged

drug molecule across a biological membrane, like skin, in a manner similar to passive diffusion

under a concentration gradient.

• Iontophoresis- facilitated skin permeation rate of a charged molecule i consists of three components

and is expressed by,

Jiisp=Jp+Je+Jc

JP = Passive skin permeation flux.

JP = KsDs dc

Hs

Je = Electrical current- driven permeation flux.

Je = ZiDiF Ci dE

RT hs

Jc = Convective flow-driven skin permeation flux.

Jc = K CsId

Ks = partition coefficient for interfacial partitioning from donor solution to stratum corneum.

Ds = diffusivity across the skin.

Di = diffusivity of ionic species i in the skin.

Ci = donor concentration of ionic species i the skin.

Cs = concentration in skin tissues.

dE = electrical potential gradient across skin.

hs

dc = concentration gradient across skin.

hs

Zi = electrical valence of ionic species i.

Id = current density applied.

F = faraday constant.

K = proportionality constant.

R = Gas constant.

T = Absolute temperature.

E.g.-

New design of Transdermal Periodic Iontotherapeutic System (TPIS), which is capable of

delivering physiologically accepted pulsed direct current.

A typical example is Iontophoretic Transdermal delivery of Insulin in controlling

hyperglycemia in diabetic animals.

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Suraj C. (ADDS)

8. Hydration –Activated DDS:

• This type of system depends on hydration induced swelling process to activate the release of

drug.

• The drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from

hydrophilic polymer.

• The release of drug is controlled by the rate of swelling of polymer matrix.

E.g. - Valrelease tablets,

prepared by granulation of homogenous dispersion of Valium in hydrocolloid and excipients.

The granules are compressed to form tablets.

After oral intake the hydrocolloid in tablet absorbs GI fluid and forms a colloidal gel that starts

from the tablet surface and grows inwards.

The release of Valium molecules is then controlled by matrix diffusion through this gel barrier.

B. Chemical means:

1. pH-Activated DDS:

• This type of DDS permits the delivery of a drug only in the region with a selected pH range.

• It is fabricated by coating the drug containing core with a pH sensitive polymer combination.

• Gastric fluid labile drug is protected by encapsulating it inside a polymer membrane that resists the

degradative action of gastric pH, such as combination of ethyl cellulose and hydroxy

methylcellulose phthalate.

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Suraj C. (ADDS) • In stomach, coating membrane resists the action of gastric fluid and the drug molecules are thus

protected from acid degradation.

• After gastric emptying the drug delivery system travels to small intestine and intestinal fluid will

activate the erosion of intestinal fluid soluble hydroxy methylcellulose phthalate component from

coating membrane.

• This leaves a micro porous membrane of intestinal fluid insoluble polymer of ethyl cellulose,

which controls the release of drug from the core tablet.

• The drug solute is thus delivered at a controlled manner in intestine by combination of dissolution

and pore-channel diffusion.

• By adjusting the ratio of intestinal fluid soluble polymer to intestinal fluid insoluble polymer, the

membrane permeability of drug can be regulated as desired.

2. Ion-Activated DDS:

• An ionic or charged drug can be delivered by ion-activated DDS.

• It is prepared by first complexing an ionic drug with an ion exchange resin containing a suitable

counter ion.(Cationic drug with SO3- , anionic drug with N(CH3)3+ )

• The granules of drug-resin complex are first treated with an impregnating agent, PEG-4000, to

reduce the rate of swelling in an aqueous environment and then coated by air-suspension coating,

with a water insoluble polymer such as ethyl cellulose.

• This membrane serves as a rate controlling barrier to modulate the influx of ions as well as the

release of drug from the system.

• In electrolyte medium, such as gastric fluid, ions diffuse into system, react with drug-resin complex

and trigger the release of ionic drug.

• This system is exemplified by the development of Pennkinetic, which permits the formulation of

liquid suspension dosage form with sustained release drug properties for oral administration. Since

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Suraj C. (ADDS) GI fluid regularly maintains a constant level of ions, theoretically the delivery of drug from this

ion-activated oral drug delivery system can be maintained at a relatively constant rate.

3. Hydrolysis-Activated DDS:

• This type of activation controlled drug delivery system depends on hydrolysis process to activate

the release of drug molecules.

• Here, drug reservoir is either encapsulated in microcapsules or homogeneously dispersed in

microspheres or nanoparticles for injection.

• It can also be fabricated as an implantable device.

• All these systems are prepared by bioerodable polymer such as co(lactic-glycolic) polymer,

polyorthoester or poly anhydride.

• The release of drug from polymer matrix is activated by hydrolysis induced degradation of

polymer chains and controlled by the rate of polymer degradation.

E.g. –

Development of LHRH releasing biodegradable subdermal implant designed to deliver

goserelin (synthetic LHRH analogue) for once-a-month treatment of prostate cancer.

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Suraj C. (ADDS) C. Biochemical means

1. Enzyme-Activated DDS:

• This type of activation controlled drug delivery system depends on enzymatic process to activate

the release of drug.

• In this system the drug reservoir is either physically entrapped in microspheres or chemically

bound to polymer chains from biopolymer, such as albumin or polypeptides.

• The release of drug is activated by enzymatic hydrolysis of biopolymers by a specific enzyme in

the target tissue.

E.g.-

Development of albumin microspheres that release 5-flurouracil in a controlled manner by

protease activated biodegradation.

3. FEED BACK-REGULATED DDS:

• The release of drug from delivery system is activated by a triggering agent, such as a

biochemical substance, in the body and also regulated by its concentration via some feedback

mechanism.

• Rate of drug release is controlled by the concentration of triggering agent detected by a sensor in

the feedback regulated mechanisms.

• Feedback regulated drug delivery concept was applied to,

A. Bioerosion-regulated DDS;

• The system consisted of drug-dispersed bioerodable matrix fabricated from poly (vinyl methyl

ether) half-ester, which was coated with a layer of immobilized Urease, in a solution with neutral

pH polymer erodes very slowly.

• In presence of urea, Urease at the surface of drug delivery system metabolizes urea to ammonia.

• This causes pH to increase and a rapid degradation of polymer matrix as well as the release of

drug molecules.

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Suraj C. (ADDS)

B. Bioresponsive DDS;

• In this system, the drug reservoir is contained in a device enclosed by a Bioresponsive polymeric

membrane whose drug permeability is controlled by the concentration of biochemical agent in the

tissue where the system is located.

E.g. –

Development of glucose-triggered insulin delivery system in which the insulin reservoir is

encapsulated within a hydrogel membrane having pendant-NR2 groups.

In alkaline solution - NR2 groups are neutral and membrane is un-swallon and impermeable to

insulin.

As glucose, a triggering agent penetrates into the membrane, it is oxidized enzymatically by

glucose oxidase entrapped in membrane to form gluconic acid.

The -NR2 groups are to protonated to form –NR2H+, and the hydrogel membrane then becomes

swollen and permeable to insulin molecules. The amount of insulin delivered is thus

Bioresponsive to the concentration of glucose penetrating the insulin delivery system.

C. Self-Regulating DDS;

• This type of feedback regulated drug delivery system depends on a reversible and competitive

binding mechanism to activate and to regulate the release of drug.

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Suraj C. (ADDS) • In this system the drug reservoir is a drug complex encapsulated a semipermable polymeric

membrane.

• The release of drug from the delivery system is activated by the membrane permeation of a

biochemical agent from the tissue in which the system is located.

E.g. –

Reversible binding of sugar molecules by lectin in the design of self regulating drug delivery

system. It first involves preparation of biologically active insulin derivatives in which insulin

is coupled with a sugar (maltose) and this into an insulin-sugar-lectin complex.

The complex is then encapsulated within a semi permeable membrane. As blood glucose

diffuses into the device and competitively binds at the sugar binding sites in lectin molecules,

this activates the release of bound insulin-sugar derivatives.

The released insulin-sugar derivatives then diffuse out of the device, and the amount of

insulin-sugar derivatives released depends on the glucose concentration. Thus a self regulating

drug delivery is achieved.

Drawback – release of insulin is nonlinear in response to the changes in glucose level.

A glucose level of 500 mg/dl triggers the release of insulin at only twice the rate of 50 mg/dl.

REFERENCES

1. Y.W. CHIEN – CONTROLLED DRUG DELIVERY, 2010.

2. Articles.

3. Internet

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