IMPLANTABLE DRUG DELIVERY SYSTEM (IDDS)

INTRODUCTION
Lafarge introduced the implantable system concept for sustained release drug
administration in 1861. It was first introduced to produce steroid hormones – containing
solid implants for long-term delivery.

Implantable drug delivery systems allow targeted and localized drug delivery and may
achieve a therapeutic effect with lower concentrations of drugs. As a result, they may
minimize potential side-effects of therapy, while offering the opportunity for increased
patient compliance. This type of system also has the potential to deliver drugs which
would normally be unsuitable orally, because it avoids first pass metabolism and
chemical degradation in the stomach and intestine, thus, increasing bioavailability.

Implantable drug delivery systems are designed to be placed under the skin and release
drugs into the blood circulation without repetitive insertion of needles. Therefore, IDDS
is defined as “a sterile drug delivery device for subcutaneous implantation having
the ability to deliver drugs at a controlled rate over a prolonged time period,
comprising a rod-shaped polymeric inner matrix with an elongated body and two
ends”.

IDEAL PROPERTIES OF AN IMPLANTABLE DRUG DELIVERY SYSTEM

1) It should be environmentally stable: Implantable system should not breakdown
under the influence of light, air, moisture, heat, etc.
2) Biostable: Implantable systems should not undergo physiochemical degradation
when in contact with biofluids (or drugs).
3) It should be biocompatible: Implantable systems should neither stimulate immune
response (otherwise the implant will be rejected) nor thrombosis and fibrosis
formation.
4) Removal: Implantable systems should be removability when required.
5) Non-toxic or Non-carcinogenic: The degradation products or leached additives
should be completely safe.
6) Implantable systems should have minimum surface area, smooth texture and
structural characteristics similar to the tissue in which it is to be implanted to avoid
irritation.
7) Implantable systems should release drugs at a constant predetermined rate for a
predetermined period.
8) It should be easy to manufacture and sterilize
9) It should enable rate-controlled drug release.
10) It should improve patient compliance by reducing the drug dosing frequency
throughout the treatment period.
11) It should be relatively inexpensive.
12) It should have a good mechanical strength.
13) It should be free from surgical procedure.
ADVANTAGES
Implantable drug delivery system has the following advantages:
1) Convenience: With implantation therapy, the patients can be provided with
medication outside the hospital with nominal medical surveillance.
2) More effective and more prolonged action.
3) Better control over drug release.
4) A significantly small dose is sufficient.
5) Compliance: Reduction or complete abolition of patient-involved dosing increases
compliance significantly.
6) Improved Drug Delivery: An implantable drug delivery system delivers the drug
locally or in the blood circulation with negligible intervention from biological or
metabolic barriers.
7) Potential for Controlled Release: An implantable drug delivery system delivers the
drug by zero-order controlled release kinetics, thereby reducing the dosage
frequency and increasing patient compliance.
8) Potential for Intermittent Release: Extremely programmable pumps enable
intermittent release of drugs in response to factors, like cardiac rhythm, metabolic
needs, etc.
9) Flexibility: Various types of flexibilities, like materials, methods of manufactures,
etc., are available in implants. They permit controlled delivery of hydrophilic as well
as lipophilic drugs.

DISADVANTAGES
Implantable drug delivery system has the following disadvantages:
1) Invasive: For inserting implants, the patients have to undergo a major or a minor
surgical process.
2) Termination: Non-biodegradable polymeric implants need to be surgically removed
from the body at the end of the treatment.
3) Danger of Device Failure: If the device fails to operate properly during the
treatment due to any reason, the device should be surgically removed from the
patient’s body.
4) Limited to Potent Drug: Only potent drugs (effective even in very small amount)
can be used since the device, a chance of adverse reaction due to this local high
concentration always exists.
5) Biocompatibility issues

MECHANISM OF DRUG RELEASE FROM IMPLANTABLE

THERAPEUTIC SYSTEM
A large number of mechanisms are being designed since many years to obtain
controlled release delivery of drugs for a prolonged time period using implantable drugs.
Currently, these approaches are designed as follows:
1) Polymer Membrane Permeation Controlled Drug Delivery System
i) In this controlled drug delivery device, drug reservoir is encapsulated within a
capsule-shaped or spherical compartment.
ii) This system is covered with a rate controlling polymeric membrane.
iii) The drug reservoir can be either solid particles or solid particles dispersed in
a liquid or solid dispersing medium.

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 iv) The drug reservoir system is encapsulated within the polymeric membrane by
encapsulation, microencapsulation, moulding, extrusion, etc.
v) For example, Norplant sub-dermal implant.

2) Polymer Matrix Diffusion controlled Drug Delivery System

i) In this controlled drug delivery device, the reservoir is formed by dispersing
the solid particles in a lipophilic or hydrophilic polymer matrix.
ii) This dispersion can be obtained by dispersing the solid drug dosage form in
the liquid or semi-solid polymer matrix at room temperature and then by
cross-linking of polymer chains.
iii) The drug-polymer dispersions are then moulded or extruded to form drug
delivery devices of various shapes.
iv) It can be prepared by dissolving the drug solid or the polymer in an organic
solvent and then by conservation or solid evaporation at an elevated
temperature under vacuum to form microsphere.
v) For example, Compudose implant

3) Membrane-Matrix Hybrid Type Drug Delivery System

i) This device is a hybrid of polymer membrane permeation and polymer matrix
permeation-controlled drug delivery systems.
ii) Alike the polymer membrane permeation-controlled drug delivery system, this
device follows the constant drug release kinetics. Therefore, it reduces the
chances of dose dumping from the reservoir compartment.
iii) Alike the matrix diffusion system, the drug reservoir of this device is prepared
by homogenous dispersion of solid drug particles in a polymer matrix.
iv) However, the total reservoir in this device is encapsulated in a rate controlling
polymeric membrane.
v) Thus, membrane-matrix hybrid type delivery system is a sandwich type
implantable device.
vi) For example, Norplant II sub-dermal implant.

4) Microreservoir Partition Controlled Drug Delivery System

i) In this controlled drug delivery device, the drug reservoir is a suspension of
drug crystals in an aqueous solution of water-miscible polymer and it also
forms a homogenous dispersion.
ii) Microencapsulation is obtained by high energy dispersion technique.
iii) By extrusion and moulding methods, these drug delivery devices can be
obtained of different sizes and shapes.
iv) As per the physiological properties of the drug, this device can be coated with
a layer of biocompatible polymer to modify the mechanism and rate of drug
release.
v) For example, Syncromate implant

5) Osmotic Pressure-Activated Drug Delivery System

i) In this controlled drug delivery device, osmotic pressure is the main source of
energy to activate and modulate drug delivery at the implantation site.
ii) In this system, the drug reservoir is either a solution or a semi-solid state
within a semi-permeable compartment with controlled water permeability.

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 iii) For example, Alzet osmotic pump

6) Vapour Pressure-Activated Drug Delivery System

i) In this controlled drug delivery device, vapour pressure is the main source of
energy to activate controlled drug delivery.
ii) In this system, the drug reservoir is a solution contained in an infusate
chamber.
iii) Infusate chamber is separated from the vapour pressure chamber via freely
movable bellows.
iv) Vapour pressure chamber contains a vaporizable fluid, e.g., fluorocarbon,
which vaporizes at body temperature and creates vapour pressure that
forcefully moves the bellows in upward direction.

7) Magnetically-Activated Drug Delivery System

i) In this controlled release drug delivery device, electromagnetic energy is the
main source of energy to activate controlled drug delivery and to control the
rate of drug delivery.
ii) This drug delivery device is incorporated with a magnetic wave triggering
mechanism.
iii) A sub-dermally implantable, magnetically-modulated hemispherical drug
delivery device was fabricated by positioning a tiny donut-shaped magnet at
the centre of a polymer matrix.
iv) This matrix contains a homogenous dispersion of a drug with low polymer
permeability at a rather high drug-polymer ratio to form hemispherical pellet.
v) The external surface of hemispherical pellet is covered with a pure polymer,
e.g., ethylene vinyl acetate copolymer.
vi) By applying an external magnetic field, the drugs are activated by the
electromagnetic energy to release from the pellet at a much higher rate of
delivery.
vii) For example, Bovine Serum Albumin (BSA) is given via this device.

CONCEPT OF IMPLANTS
An implant is a medical device that is used as a replacement of a missing biological
structure to support a damaged biological structure or enhance the functioning of an
existing biological structure. Medical implants are man-made devices in contrast to a
transplant (a transplanted biomedical tissue).
The surface of implants in contrast with the body is made up of a biomedical material,
e.g., titanium, silicone and apatite, whichever is the most functional. Sometimes,
implants contain electronics, e.g., artificial pacemaker and cochlear implants. Some
implants, like subcutaneous drug delivery devices in the form of implantable pills or
drug-eluting stents, are bioactive.

Implants for drug delivery are several types:

1. In situ forming implants (In situ depot forming systems):
(a) In situ precipitating implants:
These implants are formed from drug containing in a biocompatible solvent. The
polymer solution form implants after subcutaneous (s.c.) or intramuscular (i.m.) injection
and contact with aqueous body fluids via the precipitation of polymers. In situ

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precipitating implants are formulated to overcome some problems associated to the
uses of biodegradable microparticles:
i) Requirement for their constitution before injection
ii) Inability to remove the dose one injected.
iii) Relatively complicated manufacturing procedures to produce a sterile, stable and
reproducible product.

(b) In situ microparticle implants:

This type of implants is formed to overcome the disadvantages associated with in situ
precipitating implants. These are:
i). High injection force.
ii). Local irritation at the injection site.
iii). Variability in the solidification rates.
iv). Irregular shape of the implants formed depending on the cavity into which the
implants are introduced (implanted).
v). Undesirable high initial burst release of drugs.
vi). Potential solvent toxicity.
These in situ implantable systems consist of internal phase (drug-containing polymer
solution or suspension) and a continuous phase (aqueous solution with a surfactant, oil
phase with viscosity enhancer and emulsifier). The two phases are separately stored in
dual-chambered syringes and mixed through a connector before administration.

2. Solid implants:
Solid implants are generally cylindrical monolithic devices implanted by a minor surgical
incision or injected via a large bore needle into the s.c. or i.m. tissues. Subcutaneous
(s.c.) tissue is an ideal location because of its easy access to implantation, poor
infusion, slower drug absorption and low reactivity towards foreign materials.
In these implants, drugs may be dissolved, dispersed or embedded in a matrix of
polymers or waxes/lipids that control the releasing via dissolution and/or diffusion,
bioerosion, biodegradation, or an activation process, such as hydrolysis or osmosis.
These systems are generally prepared as implantable flexible/rigid moulded or extruded
rods, spherical pellets, or compressed tablets. Polymers used are silicone,
polymethacrylates, elastomers, polycaprolactones, polylactide-co-glycolide, etc.,
whereas waxes include glyceryl monostearate. Drugs generally presented in such
implantable systems are contraceptives, naltrexone, etc.

3. Infusion devices:
Infusion devices are intrinsically powered to release the drugs at a zero order rate and
the
drug reservoir can be replenished from time to time. Depending upon the mechanism by
which these implantable pumps are power to release the drugs. These are 3 types:
i) Osmotic pressure activated drug delivery systems
ii) Vapor pressure activated drug delivery systems
iii) Battery powered drug delivery systems.

Osmotic pumps:
Osmotic pumps are designed mainly by a semi-permeable membrane that surrounds a
drug reservoir. The membrane should have an orifice that will allow drug release.

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Osmotic gradients will allow a steady inflow of fluid within the implant. This process will
lead to an increase in the pressure within the implant that will force drug release trough
the orifice. This design allows constant drug release (zero order kinetics). This type of
device allows a favourable release rate but the drug loading is limited.
The historical development of osmotic systems includes seminal contributions such as
the Rose-Nelson pump, the Higuchi-Leeper pumps, the Alzet and Osmet systems, the
elementary osmotic pump, and the push-pull or GITSR system.
Recent advances include the development of the controlled porosity osmotic pump,
systems based on asymmetric membranes, and other approaches.

NON-DEGRADABLE SYSTEMS
Several types of non-degradable implantable drug delivery systems are available in the
market, of which the non-degradable matrix systems and reservoir systems are the
most common forms.

In the polymeric matrix system, the drug is homogenously dispersed within the matrix
material. The polymeric matrix material enables slow diffusion of the drug to provide
sustained drug release from the delivery system.
In the reservoir-type system, a compact drug core is surrounded by a permeable non-
degradable membrane whose thickness and permeability properties can control the
diffusion of drug into the body. The release kinetics of drug from this system suggests
that if a constant equilibrium exists between the drug concentration in the reservoir and
the inner surface of the enclosed membrane, the driving force for diffusional release of
the agent is constant and zero-order release kinetics of the drug from the delivery
system is obtained. However, this system has a few disadvantages:

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1) Since these systems have a non-degradable outer membrane, a minor surgical
process is required to remove the delivery system from the body after the release of
drug.
2) Membrane rupture may also occur that leads to drug dumping, which depending on
the type of drug involved in the reservoir gives rise to toxic side effects from drug
plasma concentrations that exceed maximum safety levels. Thus, due to the
chances of drug dumping, the reservoir system has become a less popular drug
delivery method.

Matrix systems are also used as non-degradable implants, consisting of

homogeneously distributed drug in a solid non-biodegradable polymer. Alike the
reservoir systems, matrix systems also enable diffusion of drug particles through the
non-degradable fibrous network of the polymer to obtain sustained drug release.
However, the release kinetics of drug is not constant and depends on the volume
fraction of the agent in the matrix. Greater the concentration of the dissolved agent
in the matrix, greater is the release from the system.

Magnetically controlled release system is another type of non-degradable system, in

which small magnetic beads are uniformly dispersed in a polymer. When this system is
exposed to a biological system, the drug undergoes normal diffusion due to a
concentration gradient. On the other hand, when this system is exposed to an external
oscillating magnetic field, larger quantities of drug are released quickly. This type of
drug delivery system has a major advantage of controlling the release kinetics of drug
by using external magnetic stimuli.

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BIODEGRADABLE SYSTEMS
Biodegradable delivery systems are more popular than the non-degradable systems.
The major advantages of biodegradable systems that insert polymers are used for
fabricating the delivery system and these polymers ultimately get absorbed or excreted
by the body. This eradicates the need for surgical removal of the implant after the end of
treatment and thus patient acceptance and compliance are enhanced.

Development of biodegradable systems is more complicated than formulating non-

degradable systems. Many variables should be considered during the fabrication of new
biodegradable systems. Degradation kinetics of the polymer (in vivo) should remain
constant to maintain sustained drug release. The degradation rate of polymer in the
body is also affected by many factors. Any change in body pH or temperature can also
transiently increase or decrease the degradation rate of the system. The surface area of
delivery system also plays an important role in its degradation. Surface area of the
implantable system decreases with its erosion. Thus, the change in shape of the drug
delivery system should be considered during the formulation design. A more uniform
and constant release can be attained by using geometrical shapes whose surface area
does not change with time when the system gets eroded. A flattened slab-type shape
with no edge erosion gives a zero-order release kinetic profile.

Some manufacturers have designed systems consisting of a bioerodible inert core

coated with the active drug matrix to minimize the problem of change in surface area
that occurs during system erosion. Another problem of bioerodible systems is that drug
diffusion from the polymer matrix occurs at a rate slower than that of the bioerosion of
the system. Diffusion of the drug also depends on the chemical nature of the polymeric
substance used in the formulation of the drug delivery system. This problem should be
overcome during the development of bioerodible systems as they are intended to be
used for extended release of drug or when the drug has a narrow therapeutic index.

At present, there are 2 different types of biodegradable delivery systems.

The first type is a reservoir system, which is similar to the non-degradable reservoir
system in structure and also in drug release mechanism. These bioerodible systems
consist of an exterior polymeric membrane that degrades at a slower rate than the
expected rate of drug diffusion through the membrane. Therefore, the membrane
remains intact and the drug is completely released. In the end, the exterior polymeric
membrane degrades (in vivo) and gets excreted.

The second type of bioerodible system is monolithic type, in which the drug dispersed
in a polymer, gets slowly eroded (in vivo) by biological processes at a controlled rate.

The most popular biodegradable polymers under investigation are polyglycolic acid,
polylactic acid, polyglycolic-lactic acid, polyaspartic acid and polycaprolactone. Ethyl
vinyl acetate copolymer matrices for the delivery of macromolecular drugs (such as
insulin) have also been studied.

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APPLICATIONS
Some applications of IDDS are:
1) Ocular Disease: Different implantable systems, including membrane-controlled
devices implantable silicone devices and implantable infusion systems, have been
investigated to provide prolonged ocular drug delivery.
Ocusert, containing pilocarpine base and alginic acid in a drug reservoir surrounded
by a release-rate controlling ethylene-vinyl acetate membrane, is an example of
membrane-controlled system.
This system provides an initial burst followed by a near zero-order delivery of
pilocarpine at 20-40 µg/hr for a week. Ocusert is well-tolerated in adults and gives a
satisfactory control of intraocular pressure with negligible side effects; but it is poorly
tolerated in geriatrics where most of the therapeutic need exists.

2) Contraception: FDA has recently approved the marketing of Norplant, a sub-

dermal implant for long-term delivery of levonorgestrel (contraceptive agent). This
device consists of six silicone membrane capsules, each containing 36 mg of
levonorgestrel, which are placed sub-dermally on the inside of the upper arm or
forearm in a fan-shaped pattern through a trocar from a single trocar entry point.
Cumulatively these capsules deliver 70µg/day (in vitro) and 90 µg/day (in vivo) for
the first 100 days with a steady decrease to 30µg/day at about 800 days. This
delivery rate continues for 5 years.
Other polymer-based systems being studied for contraception include vaginal ring
of silicon rubber, which is used for 3-6 months with a removal period of one week
monthly during menstruation; progestasert, an intrauterine drug-releasing device of
ethylene vinyl acetate copolymer, which lasts for a year; and suspensions of
injectable microspheres or rods of biodegradable polymers.

3) Dental Application: Polymeric implants have been studied for dental applications
involving local prolonged administration of fluoride anti-bacterials and antibiotics.
Stannous fluoride was incorporated in different dental cements to evaluate
sustained-release fluoride delivery. Another dispersed in the hydroxyethyl
methacrylate and methyl methacrylate copolymer hydrogel coated with an outer
layer of same copolymers in different proportion to be rate-limiting in drug release.
The 8mm long device contains 42mg of fluoride in the core and is attached to the
buccal surface of the maxillary first molar to release fluoride for 30 days at the rate of
0.5mg/day. Increased fluoride concentration in the saliva of the subject was found to
cause erythema or small ulcers in the buccal mucosal opposite to the device.

Ethylcellulose slabs containing polyethylene glycol and chlorhexidine

(antibacterial) have also been evaluated. These slabs can be cut to fit the
periodontal pocket and can be quickly inserted with minimal discomfort to the
patient. Acrylic polymers have also been evaluated for such a system.
Sustained-release implants of hollow cellulose fibres, containing 20%
chlorhexidine gluconate solution. This device is placed in periodontal pockets and

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 significantly relieves discomfort, reduces gingival flow, and lessens bleeding on
probe.
Matrix systems of ethylene-vinyl acetate copolymer and releasing tetracycline
(on site therapeutic system are also being clinically evaluated to treat periodontal
disease.

4) Immunization: Polymeric implants are being tested for enhanced immune

response to antigens to provide pulsatile or continuous administration of the antigen
over a prolonged time period. Immunization efficacy of ethylene-vinyl acetate
copolymer pellets containing bovine serum albumin as model antigen was also
evaluated, and the immune response was comparable to that achieved by two
injections of bovine serum albumin in Freund's adjuvant (an o/w suspension
containing bacteria).

5) Cancer: Silicone rod implants (similar to those used for delivering

levonorgestrone) have been tested for delivery of testosterone propionate or ethinyl
estradiol in prostate cancer patients.
Lupron depot is an implantation system used for providing one month depot
release of leuprolide acetate (a synthetic analogue of Gonadotropin-Releasing
Hormone (GnRH)].
This implant consists of biodegradable microspheres prepared from polylactic-
glycolic copolymer at 50:50 compositions. Zoladex is an implantation system used
for providing one month depot release of goserelin acetate from a biodegradable
implantable rod for treating prostate cancer.

6) Narcotic Antagonists: Naltrexone has been evaluated in implant from long-term

delivery of narcotic antagonists. Naltrexone freebase, its hydrochloride or the
pamoate acid salt has been prepared in various polymers and dosage forms for
prolonged narcotic antagonist activity. Though in vitro delivery of up to 50 days has
been achieved by some of the systems, in vivo duration of release was found to be
shorter.
Polylactide, polylactic glycolide and polycaprolactone-co-lactide polymers were
evaluated in biodegradable polymer-coated microspheres, containing naltrexone
base. Diffusion-controlled, linear naltrexone release was observed from the coated
microspheres for about 50 days. These microspheres produced morphine antagonist
response in implanted rats for 60 days.

7) Other Applications: Many insulin-delivery systems have been prepared and

evaluated for a biofeedback approach. Biodegradable implantable delivery systems
have been developed to provide prolonged release of antibiotic.
These are biofeedback-controlled system, where the drug release rate depends on
the body's need for the drug at a given time. Therapeutically, these systems may
come closest to duplicating the release from a gland (like, the pancreas). Various
mechanisms have been used to obtain self-regulated delivery.

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 OSMOTIC PUMP DRUG DELIVERY SYSTEM

Introduction
Osmotic pump-controlled release preparation is one of the most promising and
effective dosage form as it is independent of all the physiological and
physiochemical factors. This system also optimizes the process and formulation
parameters, e.g., solubility, concentration and osmotic pressure of core
component(s), size of delivery orifice, and nature of rate-controlling membrane, and
thus modulates the rate and pattern of drug release.

A significant development made in the osmotic delivery devices is their capability to

deliver drugs with moderate and extreme solubility. These devices also deliver drugs
as liquids to enhance permeability and to deliver insoluble drugs that can dispense
sub-saturated solutions of drugs. Osmotic pump drug delivery technology can be
used to deliver high drug doses meeting high drug loading requirements.

ADVANTAGES
Osmotic pump drug delivery systems offer the following advantages:
1) They provide zero-order delivery rate.
2) They provide delayed or pulsed drug delivery.
3) The delivery rate is greater than that attained by diffusion-based system(s) of
comparable size.
4) In vitro drug delivery rate can be predicted with accuracy using mathematical
equations, which are highly correlated with in vivo drug delivery rate.
5) Their drug delivery rate is independent of pH variations in the environment,
including in the GIT.
6) Their drug delivery rate is independent of agitation in the outside environment,
including gastrointestinal motility.
7) The drug release rate is highly predictable and programmable.
8) Drug delivery occurs in the solution form ready for absorption, with osmotic
pump stimulating as a liquid dosage form prepared in situ.
9) Their drug delivery rate is independent of delivery orifice size within limits.
10) They can be incorporated with drugs having varying solubility.
11) These devices can be easily fabricated using conventional pharmaceutical,
manufacturing equipment.

DISADVANTAGES
Osmotic pump drug delivery systems have the following disadvantages:
1) They are expensive as special equipment is required for making an orifice in the
system.
2) Size of the pores is critical.
3) Dose dumping may occur due to the film defects, which might occur if the coating
process is not well-controlled.
4) Retrieval therapy is not possible due to unexpected adverse events.
5) Residence time of the system in the body varies with the gastric motility and food
intake.
6) They might cause irritation or ulcers due to release of saturated drug solution.

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PRINCIPLE OF OSMOSIS
Abbenollet submitted the first report of osmotic effect in 1748. However, Pfeffer
obtained the first quantitative measurement in 1877 in his experiment, in which he
separated a sugar solution from pure water using a membrane (permeable to water but
impermeable to sugar). A flow of water occurs into the sugar solution that cannot be
halted until a pressure (p) is applied to the sugar solution. Pfeffer showed that this
pressure is the osmotic pressure (p) of the sugar solution and is directly proportional to
the solution concentration and absolute temperature. After a few years, Vant Hoff
showed the analogy between these results and ideal gas laws by the following
expression:
p = jcrt

Where, j = Osmotic coefficient of the solution.

c = Molar concentration of sugar in the solution.
г = Gas constant.
t = Absolute temperature.

Concentrated solution of soluble solutes (used in controlled release formulation) has an

extremely high osmotic pressure that ranges from 30atm for sodium phosphate to
500atm for a lactose-fructose mixture. This is because their osmotic pressure can
produce high water flow across semi-permeable membrane. The osmotic water flow
through a membrane is given by the following equation:
dv/dt = AQDp/L
Where,
dv/dt = Water flow across the membrane of area A, thickness L, and permeability
Q (cm2).
Dp = Osmotic pressure difference between the two solutions on either side of
the membrane.

This equation is used for completely permeable selective membrane, which is

permeable to water but completely impermeable to osmotic agent.

BASIC COMPONENTS OF OSMOTIC PUMPS

Osmotic pumps consist of the following components:
1) Drug: Osmotic pump systems can be incorporated with water-soluble as well as
water-insoluble drugs. The drugs incorporated in the osmotically controlled drug
delivery systems should have short biological half-lives of up to 2-6 hours, high
potency, and should be required for chronic treatment.
Some ideal drug candidates to be used for the formulation and evaluation of osmotic
pump drug delivery systems include antihypertensive agents, e.g., Nifedipine,
Verapamil, Metoprolol, Captopril, Diltiazem hydrochloride, Carvedilol, Valsartan;
anti-diabetic agents, e.g., Glipizide, Glimepiride;
NSAIDs, e.g., Ketorolac, Ibuprofen, Diclofenac sodium, Aceclofenac, etc.

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2) Osmotic Agents: These are ionic compounds that consist of either inorganic salts
(e.g., sodium chloride, potassium chloride, magnesium sulphate, sodium sulphate,
potassium sulphate, and sodium bicarbonate) or hydrophilic polymers (e.g., sodium
carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl
cellulose, methylcellulose, polyethylene oxide, and polyvinyl pyrrolidine).
Sugars, like glucose, sorbitol, sucrose and inorganic salts of carbohydrates can also
be used as effective osmotic agents. These agents are used for fabricating the
osmotic device so that concentration gradient can be maintained across the
membrane by generating a driving force for the uptake of water and for maintaining
drug uniformity in the hydrated formulation.

Classifications along with the examples of compounds that can be used as

osmogens.
Table 5.1: Compounds that can be Used as Osmogens Categories
Categories Examples
Water-soluble salts Magnesium chloride or sulphate, chloride and sulphate
of inorganic acids salts of lithium, sodium or potassium, and sodium or potassium
hydrogen phosphate.
Water-soluble salts Sodium or potassium acetate, magnesium succinate,
of organic acids of organic acids sodium benzoate, sodium citrate, and sodium
ascorbate.
Carbohydrates Arabinose, xylose, ribose, glucose, fructose, galactose,
mannose, sucrose, maltose, raffinose, and lactose.
Water-soluble Glycine, leucine, alanine, and methionine.
amino acids
Organic polymeric Sodium carboxy methyl cellulose, HPMC, hydroxyethyl
osmogens methyl cellulose, cross-linked PVP, polyethylene oxide,
Carbopol, and polyacrylamides.

3) Semi-Permeable Membrane: This plays an important role in the modulation of drug

release from the osmotic drug delivery system. The membrane should be stable to
the outer and the inner environment of the device. It should be rigid, inert, and
should maintain its dimensional integrity so that a constant osmotic driving force can
be provided during drug delivery. This membrane should be selectively permeable to
avoid the loss of osmogen by diffusion across the membrane during the passage of
drugs and other ingredients present in the compartment.

This membrane should be biocompatible and should have sufficient water

permeability to retain the desired water flux rate. The transmission rates of water
vapour can be used for estimating water flux rates. Polymers that are permeable to
water but impermeable to solute can be used as a coating material in osmotic
devices, e.g., cellulose esters like cellulose acetate, cellulose acetate butyrate,
cellulose triacetate, and ethyl cellulose, and Eudragits. Semi-permeable membrane
should exhibit sufficient wet strength (-105) and wet modulus to retain its
dimensional integrity during drug delivery.

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4) Plasticisers: These are used in the coating membrane of osmotic drug delivery
system. They change the visco-elastic behaviour of the polymers, thus affect the
permeability of the polymeric films. The changes in visco-elastic behaviour of the
polymers can be controlled by using plasticisers of different types and in different
amounts. Polyethylene glycols, ethylene glycol monoacetate, ethylene glycol
diacetate for low permeability, triethyl citrate and diethyl tartrate or diacetin are the
examples of some commonly used plasticisers.

5) Flux Regulators: These agents are added in the osmotic drug delivery systems to
regulate the permeability of fluid. Hydrophilic substances, like polyethylene glycols
(300-6000 Daltons), polyhydric alcohols, and polyalkylene glycols, can improve the
flux; while the hydrophobic materials, like phthalates substituted with an alkyl or
alkoxy (e.g., diethyl phthalate or dimethoxy ethyl phthalate), can reduce the flux.
Insoluble salts or oxides are considerably water-impermeable, and thus can be used
for this purpose.

6) Wicking Agents: These agents have the ability to draw water into the porous
network of a delivery device. They are either swellable or non-swellable in nature.
They can undergo physisorption with water (a type of absorption in which the solvent
molecules loosely adhere to surfaces of the wicking agent via Van der Waals forces
between the surface of wicking agent and the adsorbed molecule).
The wicking agents carry water to surfaces in the tablet core, and thus create
channels or a network of increased surface area. Colloidal silicon dioxide, kaolin,
titanium dioxide, alumina, niacinamide, Sodium Lauryl Sulphate (SLS), low
molecular weight Poly Vinyl Pyrrolidone (PVP), m-pyrol, bentonite, magnesium
aluminium silicate, polyester, and polyethylene are the examples of some
commonly used wicking agents.

7) Pore-Forming Agents: These agents are used in the osmotic pumps for poorly
water-soluble drugs and in the development of controlled porosity or multi-particulate
osmotic pumps. A microporous membrane in situ is formed by the leaching of a
pore-former 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 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 are the examples of some commonly used pore-
forming agents.

8) Coating Solvents: Solvents are used for making polymeric solution that is used for
manufacturing the wall of osmotic device. Inert inorganic and organic solvents that
do not adversely affect the core, wall and other materials are typically used.
Methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol,
ethyl acetate, cyclohexane, carbon tetrachloride, water, etc. are the examples of
some commonly used solvents.

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 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., are also widely used as coating solvents.

CLASSIFICATION
Osmotic pumps are generally divided into oral and implantable systems and oral
osmotic drug delivery systems are classified as shown:

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DUROS Technology
DUROS technology provides a bi-compartment system separated by a piston. One
compartment consists of osmotic engine formulated with excess of solid NaCl so that it
remains present throughout the delivery and results in a constant osmotic gradient.
One end of this compartment has a semi-permeable membrane through which water is
drawn into the osmotic engine, and a large and constant osmotic gradient is established
between the tissue water and the osmotic engine.

The other compartment consists of a drug solution with an orifice from which the drug is
released due to the established osmotic gradient. This provides site-specific and
systemic drug delivery when the pumps are implanted in human body. The pumps are
preferably implanted subcutaneously in the inside of the upper arm. The delivery period
ranges from a few days to a year.

Materials used in this technology should be screened for compatibility, and should be
biocompatible. The final drug product is sterilised by radiation sterilisation (gamma). In
case the drug formulation cannot withstand sterilising doses of radiation, a DUROS sub-
assembly is radiation sterilised and the drug formulation is added in the final aseptic
operation. Henceforth, the system materials are also screened for their ability to
withstand sterilising doses of radiation.
DUROS technology can potentially provide more flexibility than the competitive products
regarding the types of drugs that can be administered, including proteins, peptides, and
genes, because the drug dispensing mechanism does not depend on the drug
substance.

ALZET Osmotic Pumps

ALZET osmotic pumps are miniature, implantable pumps used for research in mice,
rats, etc. These infusion pumps can continuously deliver drugs, hormones, and other
test agents at controlled rates from one day to six weeks without requiring external
connections or frequent handling that eliminates the need for repeated night time or
weekend dosing.
ALZET pumps are implanted subcutaneously or intraperitoneally, and can be used for
systemic administration for targeted drug delivery. They can be attached to a catheter
for localisation of the drug effect and for intravenous, intracerebral, or intra-arterial
infusion to deliver different compounds, like antibodies, chemotherapeutic drugs,
cytokines, growth factors, hormones, and peptides.

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ALZET pumps operate by osmotic displacement. An empty reservoir present in the core
of the pump is filled with the drug or hormone solution to be delivered.
This reservoir is separated via semi-permeable membrane from the chamber containing
salt. The chamber surrounding the reservoir consists of a high concentration of salt; due
to which water enters the pump through the semi-permeable membrane. Entry of water
increases the volume in the salt chamber, thus compressing the flexible reservoir and
delivering the drug solution into the animal through the exit port.

ROSE AND NELSON PUMP

Rose and Nelson developed the first osmotic device in 1955. This device is the
forerunner of the modern osmotically controlled drug delivery systems. The pump has
three chambers, i.e., a drug chamber with an orifice, a salt chamber, and a water
chamber.
The first two chambers (drug and salt chambers) are separated by the latex diaphragm
and the latter two (salt and water chambers) are separated by semi-permeable
membrane.

Osmotic pressure difference exists across the water and salt chamber; due to which,
water flows unidirectionally from the water chamber to the salt chamber, thereby
gradually increasing the volume of salt chamber. This increased volume in the salt
chamber distends the latex diaphragm (that
separates the salt and drug chambers), and
thus pushes the drug through the orifice at a
constant rate.

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This device was originally used for veterinary purposes for delivering drugs in the gut.
One disadvantage of the Rose-Nelson pump is that the water chamber needs to be
charged before every use. This problem was overcome with Pharmetrix device in
which the water chamber was separated with an impermeable seal that was broken
before administering the pump.

HIGUCHI-LEEPER PUMP
Higuchi-Leeper pump is the simplified form of three-chambered Rose-Nelson pump.
The first series of Higuchi-Leeper pumps was launched by ALZA Corporation in 1970. It
also consisted of three compartments, i.e., drug, salt and water compartments. The only
difference between Rose-Nelson and Higuchi-Leeper pump is that the latter does not
have a separate water chamber.

Higuchi-Leeper pump is bullet-shaped, and has a rigid housing with an orifice at the top
and a perforated support at the bottom. The inner surface of the porous membrane
support has a fixed semi-permeable membrane. A movable separator is present that
separates the housing into two chambers. The space between the movable separator
and the semi-permeable membrane is filled with saturated solution of magnesium
sulphate (having excess of solid magnesium sulphate).
The front chamber is added with the drug and other required additives. When water,
from the surrounding environment, enters through the semipermeable membrane, the
volume of lower chamber increases and the device gets activated.
Due to the increased chamber volume, the movable separator shifts towards the orifice
and releases the drug at a constant rate. Higuchi-Leeper pump can be stored for a few
weeks to months.

Two most important modifications of Higuchi-Leeper pump are the use of closely fitting
half shells to form the pump and a telescopic housing with expandable driving
members. The most recent modification of Higuchi-Leeper pump is the use of pulsatile

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drug delivery. By producing a critical pressure at which the orifice opens and releases
the drug, the pulsatile release of drug can be achieved.

HIGUCHI-THEEUWES PUMP
Higuchi and Theeuwes developed the simplest version of Rose-Nelson pump in 1976,
and named it the Higuchi-Theeuwes pump. It consists of a rigid, rate-controlling, outer
semi-permeable membrane surrounding a solid sodium chloride layer, below which
elastic diaphragm is present for housing the drug. This device is a double-walled closed
chamber, in which the outer wall is the semi-permeable membrane and the inner wall is
made up of a flexible collapsible material.
An osmotic agent is filled between the gap of outer and inner walls. The inner big
chamber is filled with the drug, having direct access to the external environment through
a narrow-elongated tube.
When the pump comes in contact with the aqueous environment, water imbibes into the
chamber, containing an osmotic agent, through the semi-permeable membrane. As a
result, the inner chamber containing the drug is compressed and it releases the drug
through the orifice at a constant rate.

In one of the modifications of Higuchi-Theeuwes pump, carbon dioxide gas pressure is

produced by adding a mixture of citric acid and sodium bicarbonate in the salt chamber.

MINI OSMOTIC PUMPS

Mini osmotic implantable pump was first designed by the Alza Corp. for conducting
experimental studies in animal models. Working of these pumps relies on the difference
in osmotic pressure between a compartment within the pump (the salt sleeve) and the
tissue environment in which the pump is implanted. Due to the high osmolarity of the
salt sleeve, water flux into the pump through a semi-permeable membrane that forms
the outer surface of the pump. The flexible reservoir becomes compressed as water
enters the salt sleeve. This further displaces the test solution from the pump at a
controlled, pre-determined compressed reservoir is not possible.

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ELEMENTARY OSMOTIC PUMP (EOP)
Elementary osmotic pump consists of an osmotically active agent coated with the rate
controlling semi-permeable membrane, having an orifice of a critical size for drug
delivery.
In this system, drug release occurs in a controlled pattern due to the water permeation
characteristics of a semi-permeable membrane surrounding the drug and osmotic
properties of the osmogen in formulation.
When the dosage form is exposed to the aqueous fluids, water imbibes from the
surroundings at a rate determined by the fluid permeability of the membrane and
osmotic pressure of the core formulation.

This osmotic imbibition of water forms a saturated solution of drug within the core, which
is dispensed at a controlled rate from the delivery orifice in the membrane. Around 60-
80% of drug is released at a constant rate from the EOP.
The lag time for this process is around 30-60 minutes in most of the cases as the
system hydrates before the beginning of zero-order delivery from the system.
This system is preferred for the drugs that are moderately soluble in water.

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OSMOTIC PUMP WITH NON-EXPANDING SECOND CHAMBER
A non-expanding second chamber is used in the second category of multi-chamber
devices. This group is further divided in two sub-groups based on the function of second
chamber.
In the first device, the second chamber is used for diluting the drug solution to be
released in the body. The drug solution is diluted because if the drug is released in a
concentrated form, it causes GIT irritation.

In the second device, there are two rigid chambers. The first chamber contains a
biologically inert osmotic agent (such as sugar or a simple salt, e.g., sodium chloride),
and the second one contains the drug. Water is drawn in both the chambers through the
surrounding semi-permeable membrane. As a result, osmotic agent solution is formed
in the first chamber, which then passes to the drug chamber through the connecting
hole.

In the drug chamber, the osmotic agent solution mixes with the drug solution before
leaving through the microporous membrane (forms a part of wall around the chamber).
This device is preferred for delivering water-insoluble drugs.

PUSH-PULL OSMOTIC PUMP (PPOP)

Push-pull osmotic pump is a modified form of elementary osmotic pump. It is used to
deliver poorly as well as highly water-soluble drugs at a constant rate. This system is
similar to a standard bilayer coated tablet, in which the upper layer consists of the drug
in a formulation of polymeric osmotic agent, and the other layer consists of tablet
excipients. This polymeric osmotic agent may form an in situ drug suspension.

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When this tablet imbibes water, the other layer contains osmotic agent, colouring
agents, polymer, and tablet excipients. These layers are formed and bonded by tablet
compression to form a single bilayer core, which is then coated with a semi-permeable
membrane. Once the coating has been done, a small hole is drilled through the
membrane on the drug layer side of the tablet (using a laser or mechanical drill). On
placing this system in aqueous environment, water gets attracted by an osmotic agent
in both the layers of the tablet. This osmotic attraction in the drug layer attracts water
into the compartment to form an in situ drug suspension.

In the non-drug layer, the osmotic agent simultaneously attracts water into that
compartment, thus expanding its volume. Such expansion of non-drug layer releases
the drug suspension through the delivery orifice.

CONTROLLED POROSITY OSMOTIC PUMP (COP)

Controlled porosity osmotic pump contains water-soluble additives in the coating
membrane, which dissolves on coming in contact with the aqueous environment.
This results in the formation of microporous membrane in situ.

A controlled porosity wall appears like a sponge, and is made up of materials producing
5-95% pores having 10A-100m pore size. This membrane is permeable to water as well
as to the dissolved solute. Water-soluble additives used in this pump are dimethyl
sulphone, saccharides, amino acids, sorbitol, etc.
5.2.6.11. Osmotic Pump for Insoluble Drugs
In this osmotic pump device, the osmotic agent particles (osmogens) are coated with an
elastic semi-permeable film. These particles are mixed with the insoluble drug and
compressed into a tablet. This tablet is then coated with a semipermeable membrane, in
which an orifice is created.
When the tablet is exposed to the aqueous environment, water imbibes into the osmotic
agent particles through the two membranes. As a result, the particles swell and push
the insoluble drug hydrostatically through the delivery orifice.

MULTI-PARTICULATE DELAYED RELEASE OSMOTIC SYSTEM

The multi-particulate delayed release system uses pellets, containing drug with or
without osmotic agent. These pellets are coated with an SPM, like cellulose acetate. On
exposing the pellets to an aqueous environment, water penetrates the core and forms a
saturated solution of soluble components. Water influx is induced by the osmotic
pressure gradient, and this causes rapid expansion of the membrane, and subsequent

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formation of pores. Osmotic ingredient and the drug are released through these pores
following the zero-order kinetics.

Schultz and Kleinebudde conducted a study and reported that lag time and dissolution
rates depend on the coating level and osmotic properties of the dissolution medium.
They also stated that the dissolution characteristics depend on the membrane
components, like plasticiser and its concentration and lipophilicity. Due to these semi-
permeable walls, an osmotic device shows lag time before the beginning of drag
delivery. This property is considered as a disadvantage; however, it can be used
advantageously as some drugs (those for early morning asthma or arthritis) require
delayed release.

MONOLITHIC OSMOTIC SYSTEM

The monolithic osmotic system includes a simple dispersion of water-soluble agent in
polymer matrix. On exposing the system to aqueous environment, water imbibes
through the active agents, ruptures the polymer matrix capsule surrounding the drug,
and subsequently releases the drug to the outside environment. In the starting phase,
this process takes place in the outer environment of the polymeric matrix; but, slowly it
proceeds towards the interior of the matrix. This system, however, fails if the device is
incorporated with more than 20-30 units per litre of the active agents. This is because,
above this level, leaching of the substance takes place.

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COLON TARGETING ORAL OSMOTIC SYSTEM (OROS-CT)
The colon targeting oral osmotic system is used to formulate drugs prescribed for once
or twice a day for targeted delivery of drugs to the colon. The OROS-CT either contains
a single osmotic agent or five to six push-pull osmotic units filled in a hard gelatin
capsule. The push-pull osmotic unit is enteric coated.
The gelatin capsule dissolves but the tablets remain intact on coming in contact with the
gastric fluids. The enteric coating dissolves when the system enters the small intestine.
As a result, water imbibes into the core and the push compartment swells.
Simultaneously, flowable gel is formed in the drug compartment, which is pushed out of
the orifice at a rate controlled by the rate of water transport across the semi-permeable
membrane.

SANDWICHED OSMOTIC TABLETS (SOTS)

Sandwiched osmotic tablets consist of polymeric push layer sandwiched between two
drug layers having two delivery orifices with a semi-permeable membrane coating on
the tablet. On exposing the device to the aqueous environment, the middle push layer
containing the swelling agents imbibes water from the surrounding areas through the
semi-permeable membrane. As a result, the drug is released from the two orifices
present on opposite sides of the tablet. Thus, SOTS are preferably used for drugs that
may cause local irritation of the gastric mucosa.

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LIQUID ORAL OSMOTIC SYSTEM (L-OROS)
Liquid oral osmotic system delivers drugs as liquid formulations and imparts the
combined benefits of extended release with high bioavailability. Generally, this system
is of 3 types:
i) L-OROS hard cap
ii) L-OROS soft cap
iii) Delayed liquid bolus delivery system

Each system consists of a liquid drug layer, an osmotic engine or push layer and a
semi-permeable membrane coating. On exposure the system to the aqueous
environment, water permeates across the rate controlling membrane and thus the
osmotic layer gets activated. The expanded osmotic layer develops a hydrostatic
pressure inside the system. This pressure forces out the liquid formulation through the
delivery orifice.

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L-OROS hard cap and soft cap systems are designed for continuous drug delivery;
whereas, the L-OROS delayed liquid bolus drug delivery system is designed for
pulsatile drug delivery. The delayed liquid bolus delivery system has 3 layers, i.e., a
placebo delay layer, a liquid drug layer, and an osmotic engine. All these layers are
surrounded by a rate controlling semi-permeable membrane.

A delivery orifice is drilled on the placebo layer, at end of the capsule-shaped device.
Expansion of the osmotic engine first releases the placebo and thus delays the release
of drug layer. Release of drug can be extended up to 10 hours, and this depends on the
permeability of the rate controlling membrane and thickness of the placebo layer.

OSMOTIC MATRIX TABLET (OSMAT)

Osmotic matrix tablet is a novel system in which hydrophilic property of polymers are
utilised so that the polymers swell and jellify in aqueous medium resoling to form a
semi-permeable in situ. Drug release from such osmotically driven matrix system
(containing an osmogen) is controlled by osmotic phenomenon. Thus, OSMAT
uniformly combines the matrix and osmotic characteristics, and results in quantum
improvement in drug delivery from swellable mats systems. Manufacturing of osmotic
matrix tablets is very simple and precludes the procedures of coating a semi-permeable
membrane and drilling a delivery orifice.
This technology is very economic and can be used for various drugs.

EVALUATION
Evaluation of oral osmotic drug delivery systems includes the following range of studies:
1) In Vitro Evaluation: The oral osmotic drug delivery system, especially osmotic pump
tablets are evaluated by:
i) Visual Inspection: It includes visual inspection of the film for smoothness,
uniformity of coating, edge coverage, and lustre.
ii) Coating Uniformity: This parameter is evaluated by determining the weight,
thickness and diameter of the tablets before and after coating.
iii) Coat Weight and Thickness: This parameter is evaluated from depleted devices
following careful washing and drying of the film, using standard analytical
balance and screw gauge, respectively.
iv) Orifice Diameter: A pre-calibrated ocular micrometer is used for microscopic
study of the mean orifice diameter of osmotic pump tablet.

2) In Vitro Drug Release: Various methods, like vertically reciprocating shaker,

conventional US dissolution apparatus I and II, flow-through cell apparatus, etc. are
used for determining the in vitro delivery rate of drugs from osmotic systems.

3) In Vivo Evaluation: In terms of pH and motility, the intestinal tract environment of

humans is almost similar to that of dogs; therefore, dogs have been used for
determining the in-vivo delivery rate of drugs) from oral osmotic drug delivery systems
and for establishing in vitro-in vivo correlation (IVIVC). However, in vivo evaluation can
also be performed in healthy human volunteers, and various pharmacokinetic
parameters (such as Cmax, tmax, AUC, and MRT) and relative bioavailability are
estimated.

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