CONTROLLED DRUG DELIVERY SYSTEM

INTRODUCTION

Controlled release is the tailorable delivery of compounds (e.g., drugs, proteins, fertilizers, nutrients,
and other biologically active agents) at an effective level in response to time and stimuli (e.g., pH,
temperature, enzymes, UV light, magnetic fields, osmosis).

OR

An ideal dosage regimen of drug therapy is one which rapidly attained the required plasma
concentration and maintained for the entire period of treatment.

ADVANTAGES OF CONTROLLED DRUG THERAPY

 This delivery system improved the patient compliance especially with long-term treatments for
chronic diseases
 Conventional dosages form produce fluctuation in plasma drug concentration. These
fluctuations depend on the drug kinetics within the body like absorption, distribution,
metabolism and excretion. Controlled release eliminates this type of fluctuation in plasma drug
concentration.
 Reduction in dose and dosing frequencies
 Maintenance of required drug concentration in plasma thus eliminates the failure of drug
therapy and improved the efficiency of treatments.
 A suitable delivery system for drugs which having a short biological half-life (3-4 hrs.) and drug
rapidly eliminate from the body.
 Stabilization of medical condition (because of more uniform drug levels)
 Improvement in bioavailability of some drugs because of spatial control
 Economical to the health care providers and the patient

DISADVANTAGES

 Dumping is a major disadvantage of CRDDS, which refers to the rapid release of a relatively
large quantity of drug from a controlled release formulation. This phenomenon becomes
hazardous with potent drugs.
 Poor in-vivo & in-vitro correlations
 Difficult to optimize the accurate dose and dosing interval
 Patient variability affects the release rate like GI emptying rate, residential time, fasting or non-
fasting condition, etc.
 Cost per unit dose is higher when compared with conventional doses

Characteristics That May Make a Drug Unsuitable for Control release Dosage
Form

» Short elimination half-life

» Long elimination half-life
» Narrow therapeutic index
» Poor absorption
» Active absorption
» Low or slow absorption
» Extensive first pass effect
Conventional release systems (e.g., tablets, capsules, etc.) release pharmaceutical drugs very rapidly
once administered in the body, which result in an abrupt increase in drug concentration in the
bloodstream and quick reduction within a short period of time. Repeated dosing may be required to
maintain the drug concentration in the effective range. Such fluctuation of plasma drug level may be
toxic and/or result in poor drug effectiveness, as shown in Fig. 1. The frequent administration of
conventional dosing may also cause displeasure to patients. In contrast, controlled release systems are
designed to improve drug release kinetics and thus effectiveness of the drug therapy; the drug level in
the bloodstream increases and then remains constant in the effective range, between minimum
effective and maximum desired levels, in a sustained fashion, as illustrated in Fig. 1. Compared to
conventional release systems, these systems provide many advantages including maximal drug
efficacy, minimal side effects, and reduced drug accumulation with chronic dosing and drug level
fluctuation.

FIG 1
FACTORS INFLUENCING THE DESIGN AND ACT OF CONTROLLED RELEASE
PRODUCTS

Physiological properties

(1) Aqueous Solubility’s: Most of the active pharmaceutical moiety (API) are weakly acidic or basic
in nature that affect the water solubility of API. Weak water soluble drugs are difficult to design the
controlled release formulations. High aqueous solubility drug show burst release followed by a rapid
increment in plasma drug concentration. These types of drugs are a good candidate for CRDDS. The
pH dependent solubility also creates a problem in formulating CRDDS. BCS class-III & IV drugs are not
a suitable candidate for this type of formulations

(2) Partition coefficient (P-value): P-value denotes the fraction of the drug into oil & aqueous phase
that is a significant factor that affects the passive diffusion of the drug across the biological membrane.
The drugs are having high or low P value not suitable for CR, it should be appropriate to dissolve in
both phase

(3) Drug pKa: pKa is the factor that determined the ionization of drug at physiological pH in GIT.
Generally, the high ionized drugs are poor candidates for CRDDS. The absorption of the unionized drug
occurs rapidly as compared to ionized drugs from the biological membranes. The pKa range for an
acidic drug that ionization depends on the pH is 3.0 to 7.5 and for a basic drug it lay between 7 and 11

(4) Drug stability: Drugs that are stable in acid/base, enzymatic degradation, and other gastric fluids
are good candidates for CRDDS. If drug degraded in the stomach and small intestine, it not suitable for
controlled release formulations because it will decrease in bioavailability of concern drug

(5) Molecular size & molecular weight: The molecular size & molecular weight are two important
factors which affect the molecular diffusibility across a biological membrane. The molecular size less
than 400D is easily diffuse but greater than 400D create a problem in drug diffusion

(6) Protein binding: The drug-protein complex act as a reservoir in plasma for the drug. Drug
showing high plasma protein binding are not a good candidate for CRDDS because the protein binding
increases the biological half-life. So there is no need to sustain the drug release

Biological factors

(1) Absorption: Uniformity in rate and extent of absorption is an important factor in formulating the
CRDDS. However, the rate limiting step is drugged release from the dosage form. The absorption rate
should rapid then release rate to prevent the dose dumping. The various factors like aqueous
solubility, log P, acid hydrolysis, which affect the absorption of drugs

For a drug to be a variable candidate for per oral CRDDS, its absorption mechanism must be by
diffusion throughout the entire GI tract. The term diffusion here refers to the dual pathway of
absorption either by partitioning into the lipid membrane (across the cells) or by passing through
water filled channels (between the cells). It is also important that absorption occurs from all segments
of the GI tract which may depend on the drug’s pKa, the pH in the segment, binding of drug to mucus,
blood flow rate, etc. The absorption process seems to be highly dependent on the hydrodynamics in
the GI lumen.

Even though that first order and square root of time release can result in highly effective drug delivery
systems it is widely believed that the ultimate goal is zero order release profile.
Zero order release invitro release will produce zero order in vivo release and zero order in vivo
absorption only if; (1) the entire GI tract behaves as a one compartment model, i.e. the various
segments throughout the GI tract are homogeneous with respect to absorption, and (2) drug release
rate is the rate limiting step in the absorption process.

With first order release on the other hand, smaller and smaller amounts are released per unit of time
with increasing time. Assuming that rate of absorption gets slower past the small intestine due to
increased viscosity, decreased mixing, and decreased intestinal surface area, less drug is absorbed.

In any case, the drug release from the CRDDS should not be influenced by pH changes within the GI
tract, by enzymes present in the lumen, peristalsis, etc

For all practicality, the one compartment open model is quite suitable to design CRDDS for most drugs

2) Biological half-life (t1/2): In general the drug is having short half-life required frequent dosing
and suitable candidate for controlled release system. A drug with long half-life required dosing after a
long time interval. Ideally, the drugs having t1/2 2-3 hrs are a suitable candidate for CRDDS. Drugs
have t1/2 more than 7-8 hrs not used for controlled release system

[The shorter the t ½ of a drug the larger will be the fluctuations between the maximum steady state
concentration and maximum steady state concentration upon repetitive dosing. Thus drug product
needs to be administered more frequently.]

(3) Dose size: The CRDDS formulated to eliminate the repetitive dosing, so it must contain the large
dose than conventional dosage form. But the dose used in conventional dosage form give an indication
of the dose to be used in CRDDS. The volume of sustained dose should be as large as it comes under
acceptance criteria

The longer the extent of duration the larger the total dose per unit delivery system needs to be. Hence
there is a limitation to the amount of drug that can be practically incorporated into such a system.

(4) Therapeutic window: The drugs with narrow therapeutic index are not suitable for CRDDS. If the
delivery system failed to control release, it would cause dose dumping and ultimate toxicity

The therapeutic concentrations are the desired or target steady state peak concentrations (Css max),
the desired or target steady state minimum concentrations (Css min), and the mean steady state
concentration (Css avg). The difference between Css max and Css min is the fluctuation. The smaller
the desired fluctuation the greater must be the precision of the dosage form performance.

The lower Css, the smaller Vz, the longer t ½, the higher F and The less amount of drug is required to
be incorporated into a CRDDS.

(5) Absorption window: The drugs which show absorption from the specific segment in GIT, are a
poor candidate for CRDDS. Drugs which absorbed throughout the GIT are good candidates for
controlled release

Pharmacokinetic parameters for drug selection

Elimination half-life (t ½)

Drugs having a t ½ and 8 hours are ideally suited for CRDDS. If the t ½ is less than 1 hour the dose size
required to be incorporated for a 12 hour or 24 hour duration dosage form may be too large. If the t ½
is very long there is usually no need for a CRDDS, unless it is simply intended for a reduction in
fluctuation of steady state blood levels.
Terminal disposition rate constant (Ke or λz)

The terminal disposition rate constant or elimination rate constant can be obtained from the t ½ and
is required to predict a blood level time profile.

Total clearance (CL)

CL is a measure of the volume of distribution cleared of drug per unit of time. It is the key parameter
in estimating the required dose rate for CRDDS, and predicting the steady state concentration.

Intrinsic absorption rate constant (Ka)

The intrinsic absorption rate constant of the drug administered per oral in the form of a solution
should be high, generally by an order of magnitude higher than the desired release rate constant of the
drug from the dosage form, in order to insure that release process is the rate controlling step.

Apparent volume of distribution (Vz)

The Vz is the hypothetical volume of a drug would occupy if it were dissolved at the same concentration
as that found in blood. It is the proportionality constant relating the amount of drug in the body to the
measured concentration in the blood.

POLYMERS AS BIOMATERIALS FOR DELIVERY-SYSTEMS

Constant rate of drug release cannot be achieved from a non-biodegradable polymer based controlled
release device. Hence bio degradable polymers are being widely used

Bio degradable polymers have properties of degrading in biological fluids with progressive release of
dissolved or dispersed drug. Applications involved in implanted, injected or inserted. (In contraceptive
implant n in anticancer therapies)

Advantage of this sort of polymeric device is that unlike others, it does not require surgical removal
even after it has delivered the drug contained in it. In +n their break down products are natural, bio
compatible which overcomes the problems of toxicity.

2 reasons for bio degradable r:

1st it was recognised that surgical removal of drug depleted delivery s/y was difficult n non-removal
may pose toxicological problems

2nd diffusion controlled delivery s/y though r excellent means of achieving predetermined rates of
drug delivery, it is limited by polymer permeability n character of drug

3 basic approaches govern the design of drug delivery s/y containing custom synthesised bio
degradable polymer:

1. Erosion of polymer surface with concomitant release of physically entrapped drug.

2. Cleavage of covalent bond b/w the polymer n drug occurring in two polymer bulk or at surface
followed by diffusional drug loss

3. Diffusion controlled release of physically entrapped drug with bio absorption of polymer delayed
until after drug depletion
The earliest of these polymers were originally intended for other, nonbiological uses, and were
selected because of their desirable physical properties, for example:

 Poly (urethanes) for elasticity.

 Poly (siloxanes) or silicones for insulating ability.
 Poly (methyl methacrylate) for physical strength and transparency.
 Poly (vinyl alcohol) for hydrophilicity and strength.
 Poly (ethylene) for toughness and lack of swelling.
 Poly(vinyl pyrrolidone) for suspension capabilities

To be successfully used in controlled drug delivery formulations, a material must be chemically inert
and free of leachable impurities. It must also have an appropriate physical structure, with minimal
undesired aging, and be readily process able. Some of the materials that are currently being used for
controlled drug delivery include

 Poly(2-hydroxy ethyl methacrylate)

 Poly (N-vinyl pyrrolidone).
 Poly (methyl methacrylate).
 Poly (vinyl alcohol).
 Poly (acrylic acid).
 Polyacrylamide.
 Poly (ethylene-co-vinyl acetate).
 Poly (ethylene glycol).
 Poly (methacrylic acid).

However, in recent years additional polymers designed primarily for medical applications have
entered the arena of controlled release. Many of these materials are designed to degrade within the
body, few of them among these include:

 Polylactides (PLA).
 Polyglycolides (PGA).
 Poly (lactide-co-glycolides) (PLGA).
 Polyanhydrides.
 Polyorthoesters.

Originally, Polylactides and Polyglycolides were used as absorbable suture material, and it was a
natural step to work with these polymers in controlled drug delivery systems. The greatest advantage
of these degradable polymers is that they are broken down into biologically acceptable molecules that
are metabolized and removed from the body via normal metabolic pathways. However, biodegradable
materials do produce degradation by-products that must be tolerated with little or no adverse
reactions within the biological environment.

These degradation products both desirable and potentially nondesirable must be tested thoroughly,
since there are a number of factors that will affect the biodegradation of the original materials. The
various important factors indicating the breadth of structural, chemical, and processing properties
that can affect biodegradable drug delivery systems are listed below:

» Chemical structure
» Chemical composition
» Distribution of repeat units in multimers
» Presence of ionic groups
» Presence of unexpected units or chain defects.
 » Configuration structure.
» Molecular weight.
» Molecular-weight distribution.
» Morphology (amorphous/semi crystalline, microstructures, residual stresses).
» Presence of low-molecular-weight compounds.
» Processing conditions.
» Annealing.
» Sterilization process.
» Storage history.
» Shape.
» Site of implantation.
» Adsorbed and absorbed compounds (water, lipids, ions, etc.).
» Physicochemical factors (ion exchange, ionic strength, and pH).
» Physical factors (shape and size changes, variations of diffusion coefficients, mechanical
stresses, stress- and solvent induced cracking, etc.).
» Mechanism of hydrolysis (enzymes versus water).

Diffusion

Diffusion: is a process of mass transfer of individual molecules of a substance as a result of random

molecular motion. The driving force for diffusion is usually the concentration gradient.
 CLASSIFICATION OF CONTROLLED RELEASE SYSTEM

Control release dosage form Release Formulation

Designs
1. Dissolution controlled release

» Encapsulation Dissolution control

» Seed or granule coated
» Micro encapsulation
» Matrix Dissolution control

2. Diffusion controlled release

» Reservoir type devices
» Matrix type devices

3. Diffusion and Dissolution controlled systems

4. Ion exchange resins

5. Osmotically controlled release

The controlled release system divided into following major classes based on
release pattern (TECHNICAL SOPHISTICATION)

(1) Rate pre-programmed drug delivery system

(2) Activated modulated drug delivery system

(3) Feedback regulated drug delivery system

(4) Site targeting drug delivery system

(1) Rate pre-programmed drug delivery system:

In this, the release of drug molecule from the delivery system is pre-planned with particular flow rate
profile of medicine. The system controls the molecular diffusion of drug molecules in or across the
barrier medium within or surrounding the delivery system. Fick’s law of diffusion are often followed
Further classified as

a) Polymer membrane permeation controlled system

Ex: i. Norplant sub dermal implant (levonorgestrol, encap/sd)
ii. Occusert system (Pilocarpine – Ethylene acetate mem)
iii. Transderm-Nitro (disp. Of Nitroglycerine-lactose triturate)
b) Polymer matrix diffusion-controlled system
Ex: i. Nitro-Dur (Nitroglycerin)
ii. Compudose sub dermal implant (Estradiol)
c) Micro reservoir partition controlled system
Ex: i. Nitrodisc (Nitroglycerin)
ii. Sub dermal Synvro-Mate-C implant (Norgestomet-PEG 400)

a. Polymer membrane permeation controlled system

 In this type of preprogramed DDS, a drug formulation is totally or partially encapsulated within
a drug reservoir compartment
 Drug release surface is covered by a rate controlling polymeric membrane having a specific
permeability
 The drug reservoir may exist in solid, suspension or solution form
 The polymer membrane can be fabricated from:
 A non-porous (homo/heterogeneous) polymer material
 A micro porous
 The encapsulation of drug formulation can be accomplished by injection, molding, spray
coating, capsulation, microencapsulation or other techniques
 The rate process can be controlled by :
» Partition co efficient
» Diffusivity of drug molecule
» Thickness of rate controlling membrane

An example of this type of implantable drug delivery system is A Norplant Sub dermal Implant and
Occusert Systems.

Occusert system
In this device, the solid drug reservoir, which is a thin disc of Pilocarpine alginate, is sandwiched
between two transparent sheets of micro porous membrane fabricated from ethyvinly acetate
copolymer.

It is designed permit the tear fluid to penetrate the micro porous membranes, to dissolve and to carry
out Pilocarpine at a constant rate of 20 to 40 mcg/hr. for weekly management of glaucoma
Norplant is implanted under the skin in the upper arm of a woman, by creating a small incision.

• inserting the capsules in a fanlike shape.

• Insertion of Norplant usually takes 15 minutes

• The contraceptive works within 24 hours and lasts up to five years.

Progestasert IUD

 The drug reservoir is a suspension of progesterone & barium sulphate in silicone medical fluid & is
encapsulated in the vertical limb of a T-shaped device walled by a non-porous membrane of ethylene-
vinyl acetate co-polymer.

 It is designed to deliver natural progesterone continuously in uterine cavity at a daily dosage rate of
at least 65 μg/day to achieve contraception for 1 year.
 Polymeric Membrane Permeation Controlled Release Drug Delivery System
Advantages:
1. Less fluctuation in drug blood levels.
2. Frequency reduction in dosing.
3. Improved patient convenience & compliance.
4. Increased safety margin of the high potency drugs.
5. Reduction in total health care cost.
Disadvantages:
1. Decreased systemic availability in comparison to immediate release conventional dosage forms.
2. Poor in vivo – in vitro correlation.
3. Possibility of dose dumping.
4. Retrieval of drug is difficult.
5. Higher cost of formulation.

b. Polymer matrix diffusion-controlled system [mainly Diffusion

controlled release ]
Diffusion, the migration of a substance from a region of higher concentration to a region of lower
concentration, is a very important factor in controlled release systems. In diffusion-controlled
dosage forms, drug molecules have to diffuse through a polymer membrane or a polymer matrix
to be released. In diffusion controlled release systems, drugs are trapped in and released via
diffusion through inert water-insoluble polymeric membranes (reservoir systems) or polymeric
matrices (monolithic systems). The only difference between the two types is whether a drug is
surrounded by a polymer membrane or distributed throughout the polymer matrix.
Diffusion-Controlled Drug-Release Formulation Polymers
Cellulose (Ethyl cellulose), Chitin, Collagen, Nylon, Poly (alkyl cyanoacrylate), Polyethylene, Poly
(ethylene-co-vinyl acetate), Poly (hydroxyethyl methacrylate), Poly (hydroxypropylethyl
methacrylate), Poly (methyl methacrylate), Poly (vinyl alcohol-co-methacrylate), Poly (vinyl
chloride), Polyisobutene, Polyurethane, Silicone rubber
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
  The reservoir devices are classified based on porosity of a polymer membrane.
 In nonporous reservoir systems, drug molecules have to diffuse through the polymer
membrane.
 On the other hand, in micro porous reservoir systems, drug molecules are released by
diffusion through micropores that are usually filled with either water or oil.
 Micro porous membranes can be prepared by making hydrophobic polymer membranes in
the presence of water-soluble materials such as poly (ethylene glycol), which can be
removed from the polymer matrix by dissolving in aqueous solution. Alternatively, micro
porous membranes can be prepared by stretching the formed membranes. Porous
polyethylene or polypropylene membranes used in transdermal patches are usually
prepared by stretching thin polymer membranes
Reservoir devices with nonporous membranes
Diffusion of drug molecules through nonporous, homogeneous, dense polymer membranes (i.e.,
solution-diffusion membranes) occurs through the free space between polymer chains
Occusert® system is an ocular insert that releases Pilocarpine either 20 or 40 g/hr. for the
management of glaucoma for up to 7 d. A thin disk of Pilocarpine alginate complex is sandwiched
between two transparent sheets of nonporous EVA copolymer. The membranes permit the tear fluid
to penetrate into the drug reservoir compartment to dissolve Pilocarpine from the complex.
Progestasert® IUD A suspension of progesterone crystals in silicone medical fluid is wrapped with
nonporous EVA copolymer. Its daily release rate is at least 65 g/d for 1 year
Reservoir devices with micro porous membranes
Drug diffusion through micro porous membranes occurs through liquid-filled pores within the
membrane for water-soluble drugs, the diffusion through water-filled pores will be much faster than
diffusion through nonporous hydrophobic membranes. For hydrophobic drugs, the pores can be filled
with hydrophobic liquids such as oils. Micropores are usually not straight and have geometrically
longer average path than the thickness of the membrane. Thus, drug molecules actually have to diffuse
longer distance than the thickness of the membrane to be released.

a. Polypropylene film
i. Transderm-Scop® (Alza/Ciba-Geigy) Transderm-Scop®, developed by Alza, is the first transdermal
product
of motion-induced nausea. Scopolamine in a mineral oil reservoir has to diffuse through the oil-
impregnated polypropylene film. The drug is also dispersed in the adhesive polymer (e.g.,
polyisobutylene adhesive) to form a solid drug reservoir. Thus, Transderm-Scop® is a multilaminate
dosage form.
ii. Catapres-TTS® (transdermal therapeutic system). This was also developed by Alza in 1984. It
delivers clonidine at the rate of 0.1–0.3 mg/day for 7 d in the treatment of hypertension. Its reservoir
system is made of mineral oil-polyisobutylene colloidal silica. Oil impregnated polypropylene film is
used for controlling drug release.
b. EVA copolymer film
i. Transderm-Nitro® (Transdermal Therapeutic system by Alza/Ciba-Geigy) The drug reservoir is a
dispersion of Nitroglycerin-lactose triturate (i.e., suspension) in the silicone medical fluid (i.e., oil).
The drug release of from the reservoir is controlled by the rate-controlling micro porous membrane
of EVA copolymer. It delivers Nitroglycerin at dosage rate of 0.5 mg/cm2/d for relief of anginal attacks.
ii. Estraderm® (Ciba-Geigy) this is the first product which used a skin absorption enhancer. Estradiol
is dissolved in ethanol and HPMC reservoir and is released over 3–4 d for the relief of postmenopausal
syndrome.

MONOLITHIC / MATRIX SYSTEM:

 If a drug is loaded by soaking a polymer matrix in a drug solution, the drug concentration
inside the matrix cannot be higher than the drug solubility (i.e., the concentration of a
drug in a saturated solution at a certain temperature), if the partition coefficient of a
drug is 1. In this case, the monolithic device is called a monolithic solution. If a drug is
added in such a way that the drug concentration inside a polymer matrix is larger than
the drug solubility, the device is called a monolithic dispersion.
 In diffusion-controlled dosage forms, drug molecules have to diffuse through the
polymer membrane or polymer matrix to be released. Drug diffusion through polymer
membrane or polymer matrix depends on the size of drug molecules and space available
between polymer chains. Even though the space between polymer chains may be
smaller than the size of drug molecules, drug can still diffuse through the polymer chains
owing to the continuous movement of polymer chains by Brownian motion.
 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.
  The diffusion controlled release systems possess many advantages such as the potential to
obtain zero-order release kinetics with a constant drug source, the ease to control release rate
by adjusting the physicochemical properties of polymeric carriers, and the low cost of the
system.
 However, this is not completely safe because of dose dumping from accidentally damaged
systems, which may be may be toxic.
 In some cases, a surgical procedure may be necessary to remove the device. Obtaining perfect
zero-order release kinetics and releasing high-molecular weight drugs can also be challenging.
Examples of monolithic dispersions
a. Silicone rubber
i. Nitrodisc® (Searle) (known as Microseal Drug Delivery System) A suspension of Nitroglycerin and
lactose triturate in an aqueous solution of 40% PEG 400 is prepared by dispersing it homogeneously
with isopropyl palmitate, as dispersing agent, in a mixture of viscous silicone elastomer, which is then
cross-linked by catalyst. The resultant drug-polymer dispersion is then molded to form a solid
medicated disk in situ on a drug impermeable metallic plastic laminate, with surrounding adhesive
rim, by injection molding under instantaneous heating. Nitrodisc® transdermal system releases
nitroglycerin at the rate of 0.5 mg/cm2/d.
b. PVP-PVA matrix
i. Nitro-Dur I® (Key Pharm) (known as Transdermal Infusion System) Nitro-Dur I® is a transdermal
patch delivering 0.5 mg/cm2/d of nitroglycerin for the treatment of angina pectoris. An aqueous
solution of glycerol, poly (vinyl alcohol), and PVP (i.e., plasticized PVP–PVA system) is heated. The
temperature of the solution is gradually lowered and nitroglycerin and lactose triturate are dispersed
just above the congealing temperature of the solution. The mixture is solidified in a mold at or below
room temperature. Then, it is sliced to form a medicated polymer disk. An adhesive rim is surrounding
the medicated disk.
DISSOLUTION-CONTROLLED DRUG RELEASE
In dissolution-controlled drug-release devices, the drug release is controlled by dissolution of either
polymeric membranes surrounding the drug core or polymeric matrix containing the drug. Since the
dissolution of polymeric materials is the key to this mechanism, all the polymers used are water
soluble or degradable in water. The drugs are coated with or encapsulated within slowly dissolving
polymeric membranes (reservoir systems) or matrices (monolithic systems), respectively.
Some Polymers used in Dissolution-Controlled Formulations
Natural Polymers Synthetic Polymers
Proteins: Water-soluble polymers:
Albumin Poly(acrylic acid)
Gelatin Poly(ethylene glycol)
Poly(vinyl alcohol)
Polyvinylpyrrolidone
Pluronics
Poloxamers
Polysaccharides: Biodegradable Polymers:
Alginate Poly(caprolactone)
Chitosan Poly(glycolic acid)
Carboxymethylcellulose, sodium salt Poly(beta-hydroxybutylate)
Hydroxyethylcellulose Poly(lactic acid)
Hydroxypropylcellulose
Hydroxypropylmethylcellulose
Methylcellulose
Starch (thermally modified)
Xanthan gum
The choice of a particular polymer for a particular controlled-release dosage form depends on the
nature of the dosage form (i.e., dissolution mechanism, delivery period, delivery route, delivered drug,
etc.). Biodegradable polymers are hydrophobic and thus water insoluble. They, however, undergo
hydrolysis and break down into smaller units. Even though they are not water soluble they are
degradable in the body. Since the degradation products are biocompatible they are widely used in
controlled drug delivery. The dissolution-controlled drug-delivery systems can be divided into two
different subgroups: encapsulated dissolution systems (or reservoir system) and matrix dissolution
systems.
ENCAPSULATED DISSOLUTION SYSTEM (RESERVOIR SYSTEM)

In this system, the drug release is controlled by the thickness and the dissolution rate of the polymer
membrane surrounding the drug core. Once the coating polymer membrane dissolves, the entire drug
is immediately available for dissolution and absorption.

If the polymer membranes are of varying thickness that dissolve immediately, 3 h, 6 h, and 9 h after
the administration, the dosage form containing all four different spheres can effectively release drug
for up to 12 h. In the above example, only three different polymer membrane thicknesses were used,
so the dosage form is a repeat action dosage form that may not produce zero-order release. If,
however, a spectrum of different polymer membrane thicknesses is used, zero-order release is
possible. The coated drug particles can be directly compressed into tablets or placed in capsules.
Examples of large encapsulated dissolution systems are shown below:
1. Plendil®: felodipine extended-release tablets by Astra Merck, Inc. Felodipine (calcium channel
blocker) tablets are surrounded by a second layer of gel-forming substance (HPMC) that is activated
upon contact with GI fluid. The gel-forming layer also contains felodipine. Felodipine is released over
12 h at a controlled rate by diffusion and through gradual attrition of the gel layer (Figure 9.2). The
type and amount of gel-forming substance determines the drug-release rate. Dose dumping may occur
if the tablet is divided or crushed. The time to maximum concentration of 10 mg of the immediate
release formulation was 1 h compared with 2.9 h for the ER formulation.
MATRIX DISSOLUTION SYSTEM
In this type of devices, the drug is homogeneously distributed throughout the polymer matrix. Drug
molecules are released as the polymer matrix dissolves. Since the size of the matrix decreases as more
drug is released, the amount of drug released is also decreased. Thus, the drug release rate decreases
and it results in nonzero-order release.
1. Micro matrix® systems
Small, spherical matrix systems can be prepared by some of the processes. The granules obtained are
either filled into hard gelatin capsules or compressed into tablets. Tempule® capsule is an example
of the capsule dosage form. Examples of tablet dosage forms are Extentab®, Timespan®, Repetab®,
Dospan®, and Chronotab®.
2. Macro matrix systems
a. Adalat CC®

Adalat CC® is an extended-release formulation for nifedifine from Bayer. It is a tablet consisting of
three parts: exterior film coat for light protection; outer coat for slow release of nifedifine; and inner
core for fast release of nifedifine (Figure 9.3). The film coat is made of hydroxypropylmethylcellulose,
polyethylene glycol, ferric oxide, and titanium dioxide. The outer coat and inner core are made of
hydroxylpropylcellulose, lactose, corn starch, crospovidone, microcrystalline cellulose, silicon dioxide,
and magnesium stearate.
The outer coat, slow-release formulation, contains nifedifine distributed in a matrix of a hydrophilic
gel-forming polymer. On contact with gastric fluid, an erosion process begins at the tablet surface. The
nifedifine contained in the matrix is dissolved and absorbed as the tablet passes through the GI tract.
With advancing erosion of the outer coat, the fast-release inner core of nifedifine is exposed and begins
to dissolve. The decreasing rate of nifedifine released from the tablet’s outer coat is compensated by
the increasing nifedifine release rate from its inner core.

Dissolution & Diffusion Controlled Release system

Controlled release systems will never be dependent on only dissolution or diffusion. In dissolution and
diffusion combination systems, drugs are trapped in partly soluble polymeric membranes or matrices
that will dissolve to create pores (Pores are created due to dissolution of parts of membrane). The
pores allow aqueous media to flow into the core of the system to drive the diffusion of encapsulated
drugs. In general, either one mechanism (dissolution or diffusion) or a combination of both can occur
during the release process. However, in some cases, one mechanism can be dominant over the other
to allow easy mathematical description, such as dissolution rate-limited or diffusion controlled release
 Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose
membrane.
(2) Activated modulated drug delivery system
In this, the release of drugs from the delivery system is controlled or activated by the some physical,
chemical and biological process or by any supplied external energy source. Drug release controlled by
the energy input or any applied process.

Classification:
(3) Feedback regulated drug delivery system
In this, a physiological response activates the release of drugs from the carrier. A triggering agent
activates the process of release of the drug, such as a biochemical substance, in the body via some
feedback mechanisms. The rate of drug release is synchronized by the concentration of a triggering
agent that is detected by a sensor used in the feedback-regulated drug delivery system.

Feedback regulated drug delivery system are divided into three part:
1. Bioerosion regulated Ex: Urea activated Hydrocortisone
2. Bioresponsive Ex: Glucose triggered Insulin
3. Self-regulating Ex: Glycosylated Insulin- Concanavalin A

1. Bio-erosion-regulated DDS
 The system consisted of drug dispersed bioerodible matrix fabricated from poly (vinyl methyl ether)
half ester, which is 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.
2 Bio-responsive DDS
 In this system, the drug reservoir is contained in a device enclosed by a bio-responsive polymeric
membrane whose drug permeability is controlled by the concentration of biochemical agent in the
tissue where the system is located.
E.g. glucose-triggered insulin drug delivery system.

 The insulin reservoir is encapsulated within a hydrogel membrane having pendant -NR2 groups.
 In alkaline solution, -NR2 groups are neutral and membrane is un-swollen and impermeable to
insulin.
 As Glucose, a triggering agent penetrates into the membrane to form gluconic acid.

 The - NR2 groups are protonated to form NR2 H+ and the hydrogen membrane then become swollen
and permeable to insulin molecules. The amount of insulin delivered is thus bio-responsive to the
concentration of glucose penetration the insulin delivery system.
3. Self-regulated DDS
 This type of FR-DDS depends on a reversible and competitive binding mechanism to activate and to
regulate the release of drug.
 In this system the drug reservoir is a drug complex encapsulated in an impermeable 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.
Osmotic Drug Delivery Systems
CONCEPT OF OSMOSIS

Osmolarity: Osmolarity is the number of osmoses per litter of solution.

Osmolality: Osmolality is the number of osmoses per Kg of water.

Osmosis: Osmosis refers to the process of association of solvent molecules from lesser
concentration to higher concentration across a semi permeable membrane.

Osmotic Pressure: Osmotic pressure is a colligative property of a solution in which the scale of
osmotic pressure of the solution is self-governing on the number of separate entities of solute present
in the solution. Osmotic pressure produced due to imbibitions of fluid from external atmosphere into
the dosage form regulates the delivery of drug from osmotic device. Speed of drug release from
osmotic pump is straightly proportional to the osmotic pressure developed due to imbibitions of fluids
by Osmogens.
OR
It is the hydrostatic pressure produced by a solution in a space divided by a semipermeable membrane
due to difference in concentration of solutes. (The pressure is exerted in the walls of semipermeable
membrane is known as Osmotic Pressure)
Advantages of Osmotic Drug Delivery System:

 Higher release rates are possible from osmotic systems than with conventional diffusion based
drug delivery systems
 The delivery rate of zero-order is achievable with osmotic systems.
 For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic
conditions.
 The release rate of osmotic systems is highly predictable and can be programmed by
modulating the release control parameters.
 Extended release of a large amount of highly water-soluble drug by utilizing counter polymer
in polyethylene oxides
 A high degree of in vivo- in vitro correlation (IVIVC) is obtained in osmotic systems.
 Decrease frequency of dosing.
 Reduce the rate of rise of drug concentration in the body.
 ent of pH of the
environment.
 Delivery is independent of hydrodynamic condition, this suggest that drug delivery is
independent of G.I. motility.
 Sustained and consistence blood level of drug within the therapeutic window.
 Improve patient compliance.
 High degree of in vitro- in vivo correlation is obtained in osmotic system.
 Reduce side effect.
 Delivery rate is also independent of delivery orifice size within the limit.

Disadvantages of Osmotic Drug Delivery System:

1. Cannot crush or chew products: Osmotic pump tablet should not be crushed or chewed as it can lead
to loss of the ‘slow release’ characteristics as well as toxicity.
2. Release rate: The drug release rate can be altered by food and gastric transit time; as a result
differences may arise in the release rate between doses.
LIMITATION:

1. It may cause irritation or ulcer due to release of saturated solution of drug.

2. Special equipment is required for making an orifice in the system.
3. Residence time of the system in the body varies with the gastric motility and food intake

Principles of Osmosis:
They deliver the drug at a zero-order profile. An osmotically dispersion formulation (Fig.2) comprises
of:
1. A water permeable membrane forming a part or all the walls of enclosure surrounding
2. An activated agent.
3. An additive known as an osmotically attractant which together exhibit an osmotic pressure.
Basic components

Drug:
Drug having following characteristics are suitable for formulation
1. It should have short half-life.
2. Prolonged release of drug should be desired.
3. It should be potent in nature.
4. Solubility of drug should not be very high or very low.

Semi permeable membrane:

The membrane should possess certain characteristics, 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. Some of the polymers that can also used.
SEMIPERMEABLE MEMBRANE FORMING POLYMER:
Cellulose acetate, cellulose dilacerate, cellulose triacetate, cellulose propionate, cellulose acetate
butyrate, ethyl cellulose and eudragits
HYDROPHILIC AND HYDROBHOBIC POLYMERS
Used in the formulation development of osmotic systems containing matrix core.
Selection of polymer is based on
» solubility of drug
» The amount and rate of drug to be released from the pump.
Examples of hydrophilic polymers HEC (Hydroxy ethyl cellulose) CMC (carboxy methyl cellulose)
HPMC (hydroxyl propyl methyl cellulose) high molecular weight poly (vinyl pyrrolidone)
Examples of hydrophobic polymers: EC (ethyl cellulose) & wax materials, etc.
 Hydrophilic matrices are 4 moderately water soluble compounds
 Hydrophobic matrices are 4 entrapping highly water soluble compound
 Mixture of both are 4 highly water soluble compound
 Polymers are also Swellable or non Swellable
 Swellable polymers are used 4 moderately soluble drugs & non Swellable polymer are 4 highly
soluble compounds.
Wicking agent:
Wicking agent is defined as a material with the ability to draw water into porous network of a delivery
device.
 A wicking agent is of either Swellable or non-Swellable nature.
 They are characterized by having the ability to undergo physiosorption with water.
 Physiosorption is a form of absorption in which the solvent molecules can loosely adhere to
surface of the wicking agent via Van der waals interactions between the surface of the wicking
agent and the absorbed molecule.
 The function of the wicking agent is to carry water to surfaces inside the core of the tablet there
by creating channels or a network of increased surface area.
 Materials, which suitably for act as wicking agents include colloidal silicon dioxide, kaolin,
titanium dioxide, alumina, niacinamide, sodium lauryl sulphate (SLS), low in weight poly (vinyl
pyrolidone) PVP , m-pyrol, bentonite, magnesium aluminium silicate, polyester and
polyethylene. SLS, colloidal silica and PVP are non swellable wicking agents.
SOLUBILIZING AGENTS
Non swellable solubilizing agents are classified into three groups:
1. Agents that inhibits crystal formation of the drugs or otherwise act by complexation of drug
(e.g., PVP, PEG, and cyclodextrins)
2. A high HLB micelle forming surfactant, particularly anionic surfactants (e.g., Tween 20, 60,
80, poly oxy ethylene or polyethylene containing surfactants and other long chain anionic
surfactants such as SLS).
3. Citrate esters and their combinations with anionic surfactants (e.g., alkyl esters particularly
triethyl citrate)
SURFACTANTS

 Act by regulating the surface energy of materials to improve their blending in to the composite
and maintain their integrity in the environment of use during the drug release period.
 Examples: polyoxyethylenated glyceryl recinoleate, polyoxyethylenated castor oil having
ethylene oxide, glyceryl laurates, etc
Osmotic agent:
These are also known as osmogens or osmogents and are used to create osmotic pressure inside the
system. When the solubility of drug is low then the drug will show zero order release but at a slow
rate. To enhance the release rate osmotic agent is added in the formulation. Osmotic agent creates a
very high osmotic pressure gradient inside the system and increases release rate of drug.
For the selection of osmogen, the two most critical properties to be considered are osmotic activity
and aqueous solubility.
Osmotic agents are classified as,
» Water-soluble salts of inorganic acids: Magnesium sulphate, Sodium chloride, Sodium sulpahte,
Potassium chloride, Sodium bicarbonate, etc.
» Water-soluble salts of organic acids: Sodium and potassium acetate, magnesium succinate,
sodium benzoate, sodium citrate, sodium ascorbate
» Carbohydrates: Mannose, sucrose, maltose, lactose
» Water-soluble amino acids and organic polymeric Osmogens: Sodium carboxy methyl cellulose,
hydroxy propyl methyl cellulose, hydroxy ethyl methyl cellulose, Methylcellulose, Polyethylene
oxide, polyvinyl pyrollidone etc.
Coating agent:
Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic
device include inert inorganic and organic solvents that do not adversely harm the core, wall and other
materials.
The typical solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl
alcohol, ethyl acetate, cyclohexane, carbon tetrachloride, water etc. The mixtures of solvents such as
acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water (90:10), methylene chloride-
methanol (79:21), methylene chloride-methanol water (75:22:3) etc. can be used
Plasticizers:
Permeability of membranes can be increased by adding plasticizer, which increases the water diffusion
coefficient
Different types and amount of plasticizers used in coating membrane also have a significant
importance in the formulation of osmotic systems. They can change visco-elastic behaviour 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
» Diacetate- for low permeability
» Tri ethyl citrate
» Diethyl tartarate or Diacetin- for more permeable films
Pore forming agent:
The pore-forming agents cause the formation of micro porous membrane. The micro porous wall may
be formed in situ by a pore-former by its leaching during the operation of the system. The pore-
formers can be inorganic or organic and solid or liquid in nature.
Alkaline metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium
sulphate, potassium sulphate, potassium phosphate etc.,
Alkaline earth metals such as calcium chloride and calcium nitrate,
Carbohydrates such as sucrose, glucose, fructose, mannose, lactose, sorbitol, mannitol and diols
Polyols such as poly hydric alcohols and polyvinyl pyrrolidone
FLUX REGULATORS

 It assist in regulating the fluid permeability through membrane.

 Add to the wall forming material.
 Examples:Poly hydric alcohols (poly alkylene glycols) & low molecular weight glycols(poly
propylene, poly butylene and poly amylene)

FACTORS INFLUENCING THE DESIGN OF OSMOTIC CONTROLLED DRUG

DELIVERY SYSTEMS
1. Drug Solubility
2. Delivery Orifice

Drug Solubility

For the osmotic system, solubility of drug is one of the most essential parameters affecting drug release
kinetics from osmotic pumps. The kinetics of osmotic drug release is directly related to the drug
solubility within the drug core. Assuming a tablet core of pure drug, the portion of core released with
zero-order kinetics is given by equation.
F (z) = 1 – S/ρ
Where, F (z) = fraction released by zero-order kinetics, S = drug’s solubility (g/cm3) and ρ = density
(g/cm3) of the core tablet.
Some of the approaches that have been used to change the drug solubility within the core include:
(1) Co-compression of the drug with excipients, which change the drug’s solubility within the core,
(2) Use of fizzy mixtures to speed up the release of badly soluble drug from the orifice
(3) use of various cyclo dextrin derivatives to solubilize poorly water soluble drug,
(4) Use of substitute salt form that has best possible water solubility
(5) Use of encapsulated excipients
(6) Use of lyo tropic crystals
(7) Use of wicking agents.

Delivery Orifice

Greater part of osmotic delivery systems contain at least one delivery orifice formed in the membrane
for drug release. Size of delivery orifice must be optimized to manage the drug release from osmotic
system. The size of the delivery orifice must be lesser than a maximum size to minimize drug delivery
by diffusion through the orifice.
Methods to produce a delivery orifice in the osmotic tablet coating are:
1. Laser Drill: for producing sub-millimeter size hole in tablets. Normally, CO2 laser beam (with
output wavelength of 10.6 μ) is used for drilling purpose. It offers outstanding consistency
characteristics at low costs.
In simple words, the tablets in which holes are to be formed are stimulating in the hopper. The tablets
drop by gravity into the slots of the revolving feed wheel and are approved at an approved velocity to
the passageway forming location.
2. Indentation that is Not Covered during the Coating Process: Indentation is made in core tablets
by using customized punches having needle on upper punch. This indentation is not enclosed during
coating process which acts as a trail for drug release in osmotic system
3. Use of Leachable Substances in the Semi Permeable Coating: Inclusion of water-soluble
additives in the membrane wall is the most extensive reported method for the configuration of pores
in CPOP take place. These water-soluble additives dissolved and coming in make contact with water,
leaving behind pores in the membrane through which drug release takes place.
4. Systems with Passageway Produced In-Situ: The system consists of a tablet core of the drug along
with water-swell able polymer and osmotic agents, which is bounded by a rate-controlling membrane.
In contact with the aqueous environment, water is imbibed osmotic ally at a prohibited rate and water
swell able polymer expands as the osmotic agents dissolves and increases the osmotic pressure within
the tablet. This results in a rate controlled small development of the partly hydrated core.

Classification
Oral osmotic pump
 Single chamber osmotic pump
1. Elementary osmotic pump
 Multi chamber osmotic pump
1. Push pull osmotic pump.
2. Osmotic pump with non-expanding second chamber.
 Specific types
1. Controlled porosity osmotic pump.
2. Monolithic osmotic systems.
3. Osmotic bursting osmotic pump.
4. OROS – CT
5. Multi particulate delayed release systems (MPDRS)
6. Liquid Oral Osmotic System. (L-OROS)

Implantable
I. The rose and nelson pump
II. Higuchi – leeper pump
III.Higuchi –theeuwas pump
IV.Implantable mini osmotic pump
Type of Compositio Mechanism Advantages Figures
Osmotic n of Action
Pump

Single Osmotic core Imbibes Suitable for

chamber (containing water delivery of
Osmotic drug with or through the drugs having
Pump without an SPM moderate
Osmogens) because of water
Elementa coated with a the osmotic solubility
ry semi pressure
Osmotic permeable gradient and
Pump membrane forms a
(SPM) and a saturated
small orifice solution
is created in inside the
the device. This
membrane increases
the hydro
static
pressure
inside the
tablet and
forces the
soaked drug
solution
through the
oral cavity
present in
the
membrane.

Multi Two When the Delivers both

chamber compartmen dosage form greatly water-
osmotic ts: Upper comes in soluble
pump compartmen contact with (oxybutynin
t (drug the aqueous hydrochloride
Push-pull compartmen environmen ) and basically
osmotic t) contains t, both water
pump the drug compartmen insoluble
(PPOP) along with ts ingest the (nifedifine,
osmotic ally water at the glipizide)
active same time. drugs
agents. Because the
Lower lower
compartmen segment is
t (push devoid of
compartmen any orifice,
t) contains it expands
the and pushes
polymeric the
osmotic diaphragm
agents. into the
higher drug
chamber,
thereby
releasing
 the drug via
the release
orifice

Multi Multi- Purpose of Relatively un

chamber chamber second soluble drugs
osmotic devices chamber is can also be
pump comprise of either delivered
systems dilution of
Osmotic containing a drug
Pump non- solution exit
with Non- expanding the device
Expandin second (mostly
g Second chamber. useful in
Chamber managing
drugs with
high
incidence of
GI irritation)
or
immediate
delivery of
two drugs

Modified CPOPs are After Eliminates the

Osmotic related to coming in need for a
Pumps EOP, the only contact with separate
variation is water, water modern step
Controlle being that soluble and (creating
d the delivery preservative an orifice
porosity orifice from s present in using a laser
osmotic which the the coating drilling
pumps drug dissolves machine). Is
(CPOP) discharge and it Suitable for
takes place is results in an delivery of
produced by in situ drugs having
integration formation of intermediate
of a water- a micro water
soluble porous solubility and
preservative membrane limits of water
in the as shown in solubility by
coating. figure. The some
release of modifications
drug takes
place
through
these micro
porous
channels as
shown in
figure.
Monolith A simple Water MOTS for a
ic diffusion of a imbibitions water
Osmotic water- by the unsolvable
tablet soluble vigorous drug were
Systems mediator is agent takes industrialized
(MOTS) made in a place that by using gum
polymer ruptures the Arabic as the
matrix. polymer osmotic,
matrix suspending
capsule and growing
surrounding agent
the agent,
thus healing
it to the
outside
environmen
t

Osmotic Similar to an When it is This system is

bursting Elementary placed in an useful to
osmotic osmotic aqueous provide
pump pump expect environmen pulsated
delivery t, water is release.
orifice is
imbibed and
absent and hydraulic
size may be pressure is
smaller. built up
inside until
the wall
rupture and
the content
are released
to the
environmen
t.
.
OROS-CT OROS-CT is After
used as a coming in
once or twice contact with
a day the GIT fluid
formulation gelatin
for targeted capsule
delivery of dissolve and
drugs to the the enteric
colon. The coating
OROS-CT can prevents
be a single entry of
osmotic fluids from
agent or it stomach to
can be the system
comprised of as the
as many as system
five to six enters into
push pull the small
osmotic unit intestine the
filled in a enteric
coating
 hard gelatin dissolves
capsule and water is
imbibed into
the core
thereby
causing the
push
compartmen
t to swell. At
the same
time
flowable gel
is formed in
the drug
compartmen
t, which is
pushed out
of the orifice
at a rate,
which is
precisely
controlled,
by the rate
of water
transport
across the
semi
permeable
membrane.

Multi Pellets The osmotic

particula containing pressure
te drug with or incline
Delayed- without induces a
Release osmotic water influx,
System agent are resulting in
coated with a rapid
an SPM. expansion of
the
membrane,
leading to
the
formation of
pores. The
osmotic
component
and the drug
are free
through
these pores
 Liquid Two types: The growth To deliver
OROS L-OROS Soft Of the APIs as liquid
controlle cap and L- osmotic formulations
d release OROS hard layer results and combine
system cap. In Soft in the the
(L- cap, Liquid developmen reimburseme
OROS) drug t of nt of
formulation hydrostatic comprehensiv
is present in pressure, e release with
a soft gelatin thereby high
capsule, forcing the bioavailability
which is liquid . It is
enclosed formulation appropriate
with the to smash for controlled
barrier layer, through the delivery of
the osmotic hydrated lipophilic APIs
layer and the gelatin
release rate- capsule shell
controlling at the
membrane. delivery
In hard cap, orifice.
it consists of Water is
a liquid drug imbibed
layer and an across the
osmotic SPM,
engine, all increasing
enclosed in a the osmotic
hard gelatin engine,
capsule and which
coated with pushes next
SPM. to the fence,
releasing
the drug
through the
delivery
orifice.

HIGUCHI No water Used for

LEEPER chamber, veterinary
OSMOTI and the purpose. It
C PUMPS activation of is either
the device swallowed
occurs after or
imbibition of implanted in
the water body of an
from animal for
surrounding delivery of
environment antibiotics
. Has rigid or growth
housing. hormones to
animal.
HIGUCHI The rigid The release
THEEUW housing is of the drug
ES consisted of from the
OSMOTI a semi device is
C PUMP permeable governed by
membrane. the salt used
The drug is in the salt
loaded in the chamber
device only and the
prior to its permeability
application, characteristi
which cs of outer
extends membrane.
advantage Diffusional
for storage of loss of the
the device drug from
for longer the device is
duration. minimized
by making
the delivery
port in
shape of a
long thin
tube.