Osmotic pump evaluation

GENERAL METHODS FOR
DESIGN AND EVALUATION OF
OSMOTIC PUMPS

Presented By: Guided By:
Chintan N. Vora Mr. Priyal R. Patel

Introduction:

 Osmotic device are most promising strategy based
systems for controlled drug delivery.
 Osmotic pump offers many advantages over other
controlled drug delivery systems, i.e. improved
patient compliance with reduced dosing frequency
and more consistence and prolonged therapeutic
effect with uniform blood concentration. Moreover
they are slightly inexpensive and production scale
up is easy.

OSMOSIS:

• Osmosis refers to the process of movement of solvent from lower
concentration of solute towards higher concentration of solute across a
semipermeable membrane until there is an equal concentration of fluid
on both sides of the membrane.
• Osmotic pressure is a colligative property.
• Difference between diffusion and osmosis:
• In diffusion both the solute and solvent molecules migrate freely
whereas if the solution is confined in a membrane permeable only to
solvent molecules, it is known as osmosis.
• Osmotic pressures of concentrated solutions of soluble solutes
commonly used in controlled formulations are extermely high because
high osmotic pressures are responsible for high water flow across semi-
permeable membrane.
• Eg: Sodium chloride – 356 atm.
Fructose – 355atm.

Material used in formulation of Osmotic Pumps.

1) Semi permeable Membrane:
 It is used to controlled the amount of water entering to dosage
form.
 Cellulose acetate is a commonly employed semi permeable
polymer for the preparation of osmotic pumps.
 Others are poly (vinyl methyl) ether copolymers, poly
(orthoesters), poly acetals and selectively permeable poly
(glycolic acid) and poly (lactic acid) derivatives can be used as
semi permeable film forming materials .

2) Hydrophilic and Hydrophobic Polymers:
 These polymers are used in the formulation development of
osmotic systems for making drug containing matrix core.

 The highly water soluble compounds can be co-entrapped in
hydrophobic matrices and moderately water soluble compounds
can be co-entrapped in hydrophilic matrices to obtain more
controlled release.
 Swellable polymers are used for the pumps containing moderately
water soluble drugs since they increase the hydrostatic pressure
inside the pump due to their swelling nature where as non-
swellable polymers are use in case of highly water soluble drugs.
 The selection is based on the solubility of the drug as well as the
amount and rate of drug to be released from the pump.

3) Wicking Agents:
 A wicking agent is defined as a material with the ability to draw
water into the porous network of a delivery device. A wicking agent
is of either swellable or non-swellable nature.
 Eg;collodial silicon dioxide,kaolin, titanium dioxide,sodium lauryl
sulphate,low molecular weight polyvinyl pyrollidone,etc.

4) Osmogens:
 Osmogens are essential ingredient of the osmotic formulations. They
maintain the osmotic presser in side the tablet of core and thus provide
the controlled release.
 Eg: inorganic salts and carbohydrates.

5) Surfactants :
 Surfactants are particularly useful when added to wall forming material.
They produce an integral composite that is useful for making the wall of
the device operative.
 Eg:polyoxyethelynated glyceryl recinoleate,glyceryl laurate,etc.

6) Coating Solvents:
 Solvents suitable for making polymeric solution that is used for
manufacturing the wall of the osmotic device include inert inorganic and
organic solvents.
 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),etc.

7) Plasticizers:
 Plasticizers increase the workability, flexibility and permeability of the
fluids. Generally from 0.001 to 50 parts of a plasticizer or a mixture of
plasticizers are incorporated in to 100 parts of wall forming materials.
 Eg.dialkyl phthalates,alkyl adipates,citrates,benzoates,myristares,etc.

8) Pore Forming Agents:
 These agents are particularly used in the pumps developed for poorly
water-soluble drug and in the development of controlled porosity or
multi-particulate osmotic pumps. These pore-forming agents cause the
formation of micro porous membrane. E.g. sucrose, glucose, fructose,
mannose, lactose, sorbitol, and mannitol .
 The microporous wall can be formed in situ by a pore formerby its
leaching during operation of the system. The pores can be formed prior
to operation by gas formation within coating polymer solutions which
result inpores in the final form of the wall.

9) Flux Regulators:
• Flux enhancing or flux decreasing agents are added to the wall
forming material in regulating the fluid permeability of flux throuugh
wall.
• Eg:polyhydric alcohols, polybutylene,polypropylene,etc.

Types of Osmotic Pumps:
1 Implantable osmotic pumps:
3)Rose Nelson Pump

The pump composed of three chambers: a drug chamber, a salt
chamber holding solid salt, and a water chamber. A semi
permeable membrane separates the salt from water chamber. The
major problem associated with Rose Nelson pumps was that the
osmotic action begin whenever water came in contact with the
semi permeable membrane. This needed pumps to be stored
empty and water to be loaded prior to use.

2) Higuchi Leeper Osmotic Pump

• Pulsatile delivery could be achieved by
using Higuchi Leeper pump; The Pulsatile
release of drug is achieved by drilling the
orifice in elastic material that stretches
under the osmotic pressure. Pulse release
of drug is obtained after attaining a certain
critical pressure, which causes the orifice to
open. The pressure then reduces to cause
orifice closing and the cycle repeats to
provide drug delivery in a Pulsatile fashion.

3) Higuchi Theeuwes Osmotic Pump

In this device, the rigid housing is consisted of a semi
permeable membrane. The drug is loaded in the device only
prior to its application, which extends advantage for storage of
the device for longer duration. The release of the drug from
the device is governed by the salt used in the salt chamber
and the permeability characteristics of the outer membrane.

4) Implantable mini osmotic pump:Alzet
pump.

• It is composed of three concentric layers- the
drug reservoir,the osmotic sleeve and the rate
controlling semi–permeable membrane.
• It contains an additional component called flow
moderator is inserted into the body of the
osmotic pump after filling.
• When the system is placed in aqueous
environment water enters the sleeve through
semipermeable membranr,compresses the
flexible drug reservoir and displaces the drug
solution through the flow moderator.

2 Osmotically controlled oral drug delivery :
(1)- Elementary osmotic pump (EOP) :

Single layer tablet for delivery of drugs having moderate water
(Alza Corp., USA) solubility.
Can be utilized for zero-order delivery as well as pulsed release .

Elementary osmotic pump:

 Elementary osmotic pump:
 A novel elementary osmotic pump was developed for
multidrug delivery treatments of type 2 diabetes.
 According to a study from People's Republic of China, "A
simple elementary osmotic pump (EOP) system that could
deliver metformin hydrochloride (MT) and glipizide (GZ)
simultaneously for extended periods of time was developed
in order to reduce the problems associated with multidrug
therapy of type 2 noninsulin-dependent diabetes mellitus. In
general, both highly and poorly water-soluble drugs are not
good candidates for elementary osmotic delivery.

 Push–pull osmotic pump Bilayer tablet, used to deliver
drugs having low to high water (Alza Corp.) solubility.

 Products such as Ditropan XL (oxybutynin chloride), Procardia
XL (nifedipine), and Glucotrol XL (glipizide) are based on this
technology.

 An oral osmotic system which can deliver theophylline and
salbutamol sulphate simultaneously for extended period of time
was developed and characterized in a view to reduce the
problems associated with the multidrug therapy of asthma.
Simple controlled porosity osmotic pump contained both drugs
(in freely soluble form) did not provide satisfactory extended
release of theophylline. A modified two-layered, push–pull
osmotic system was developed by using the basic designs of
various oral osmotic pumps, such as controlled porosity osmotic
pump (CPOP), elementary osmotic pump (EOP) and push–pull
osmotic pump (PPOP).

 OROS-CT (Alza Corp.) For targeted delivery to colon
and can be used for local or systemic therapy.

 The effects of two oxprenolol oral osmotic (OROS) delivery systems
on heart rate and blood pressure before and during recovery from
exercise at a predetermined load were examined in twelve patients
with hypertension previously responding to beta-blocker
monotherapy. Haemodynamic responses were attenuated during the
24 h after single and repeated (15 days') once daily administrations of
10/170 and 16/260 oxprenolol OROS.
 At 24 h after repeated doses, compared to placebo there were
significant reductions in resting blood pressure and in heart rate
immediately following exercise. Attenuation of heart rate after
exercise was dose related but differences between the systems with
respect to resting heart rate and blood pressure were inconsistent.
Antihypertensive responses after repeated doses were greater than
those after single doses.

 However, reductions in resting and exercise heart rates
were consistently less on chronic therapy. This may
reflect enhanced expression of the partial agonist
activity of oxprenolol due to altered receptor sensitivity
after prolonged beta-blockade.

 The plasma oxprenolol profiles after both systems
indicated slow absorption and substantial concentrations
were apparent 24 h after drug administration.

 These observations suggest that both oxprenolol OROS
systems display sustained drug release and on once
daily dosing provide 24 h beta-blockade and control of
blood pressure at rest and following exercise.

L-OROS (Alza Corp.) Designed to deliver lipophilic
liquid formulations and is suitable for delivery of
insoluble drugs.

Various L-OROS systems available to provide
controlled delivery of liquid drug formulations include L-
OROS hardcap, L-OROS softcap and a delayed liquid
bolus delivery system. Each of these systems includes
a liquid drug layer, an osmotic engine or push layer
and a SPM coating.

The expansion of the osmotic layer results in the
development of hydrostatic pressure inside the
system, thereby forcing the liquid formulation to be
delivered at the delivery orifice.

(5)-Controlled porosity osmotic pump:

• It is an osmotic tablet where in the delivery
orifices (holes) are formed in situ through
leaching of water soluble pore forming agents
incorporated in SPM (e.g., urea, nicotinamide,
sorbitol, etc). Drug release rate from CPOP
depends on various factors like coating
thickness, solubility of drug in tablet core, level
of leachable pore forming agents and the
osmotic pressure difference across the
membrane.

 A controlled porosity osmotic pump (CPOP)
delivery system for sodium ferulate was
prepared with cellulose acetate (CA) as
semipermeable membrane, polyethyleneglycol
400 (PEG 400) as channeling agent and
dibutylphthalate (DBP) as plasticizer and
release controller. Effects of coating levels,
PEG and DBP content and amount of sodium
chloride on in vitro release were studied.
Coating formulations were optimized by a L[9]
(3[4]) orthogonal array design (OAD) with three
factors at three levels using statistical analysis.
Controlled porosity osmotic pump tablets of
sodium ferulate made with the optimal
formulation were found to have good in vitro
and in vivo release characteristics.

(6) Sandwiched osmotic tablet:

 The sandwiched osmotic tablet core, which is composed of a middle
push layer and two attached drug layers, has been prepared and
systematically studied with the purpose of delivering water-insoluble
nifedipine.

 The advantage of the sandwiched osmotic tablet system over the
commercialized push-pull osmotic tablet system is its simplicity of
preparation, as the surface identification was avoided. It was observed
that polyethylene oxides (PEO) with molecular weight (MW) of 300,000
and 8,000,000 g/mole were suitable for the thickening agent of drug
layer and the expandable hydrogel of push layer, respectively. The
weight ratio of 190/190 for drug layer/push layer was also found to be
suitable. It has been observed that PEO amount of the push layer and
the KCl amount of the drug layer had profoundly positive influence on
nifedipine release.
 A push layer/drug layer co-controlled osmotic delivery mechanism has
been proposed and the optimal tablet formulation has been obtained. It
was also found that PEO and nifedipine were miscible, which may
support the application of PEO in nifedipine dosage forms. Meanwhile,
the PEO/nifedipine binary phase diagram has been constructed. The
sandwiched osmotic tablet system can deliver nifedipine in an
approximate zero-order rate up to 24 hours. It may be potentially used
for the delivery of water-insoluble drugs.

• (7)-Multi-particulate delayed release system:

 A multiparticulate delayed release system based on coated pellets
containing an osmotic active ingredient is presented. The coating
consists of a semipermeable membrane of cellulose acetate. After
application water penetrates into the core and forms a saturated
solution of the soluble components.

 The osmotic pressure gradient induces a water influx resulting in a
rapid expansion of the membrane leading to the formation of pores.
The osmotic ingredient and the drug are released through these pores
according to a zero order kinetic.

 In comparison with the sodium chloride free formulation the inclusion of
the osmotically active ingredient results in a completely different
dissolution behavior. Lag time and dissolution rate are dependent on
the coating level and the osmotic properties of the dissolution medium.
However, the dissolution rate is sufficient even with high coating levels
to obtain delayed release properties. The model proposed is supported
by data from determination of pellet swelling behaviour, sodium chloride
release, single pellet dissolution and release in media of different pH
and osmolality.

Advantages and application:
 Delivery of the Drug can be designed to follow
zero order kinetics.
 The Drug release from OCODDS is independent
to gastric pH and Hydrodynamic condition.
 The delivery rate of the Drug from the system is
highly predictable and can be pre programmed.

Disadvantages:

 Subject to dose dumping if membrane breaks
 [e.g. someone chews it]

 Slightly more expensive to formulate and complicated.

 Possible hole plugging

In Vitro Evaluation:

1. In vitro Dissolution:
 The in vitro release of drug from oral osmotic system has been
evaluated by the conventional USP paddle and basket type
apparatus. US patent described the use of commercial vankel
standard dissolution apparatus.
 The dissolution media is generally distilled water as well as
stimulated gastric fluid (for first 2-4 hr) and stimulated intestinal
fluids (for subsequent hours) have been used. The standard
specification, which are followed for the oral controlled drug
delivery systems are equivalently applied for oral osmotic pump.

2 Scanning Electron Microscopy
Coating membranes of formulation obtained before
and after complete dissolution of core contents can be
examined for their porous morphology by scanning
electron microscope.

3Effect of pH
To study the effect of pH and to assure a reliable
performance of the developed formulations
independent of pH, in vitro release studies can be
conducted in media of different pH.

4 Effect of Agitational Intensity
In order to study the effect of agitational intensity of
the release media, release studies were performed in
dissolution apparatus at various rotational speeds.

5 Effect of Osmotic Pressure
To confirm the major mechanism of drug release,
release studies of the optimized formulation can be
conducted in media of different osmotic pressure. To
increase the osmotic pressure of the release media
(pre-equilibrated to 37°C ± 1°C), mannitol (osmotically
effective solute) can be added.

6 Kinetics of Drug Release
the data obtained can be fitted in different models at
different time intervals and by using satistics we can
know kinetics of drug release.

Weigh the empty pump together with its flow moderator

Filling the pump is accomplished with a small syringe Draw the solution into the
syringe and attach the filling tube.

With the flow moderator removed, hold the pump in an upright position and insert
the filling tube through the opening at the top of the pump until it can go no
further. This places the tip of the tube near the bottom of the pump reservoir.

Push the plunger of the syringe slowly, holding the pump in an
upright position. When the solution appears at the outlet, stop filling and carefully
remove the tube.

Wipe off the excess solution and insert the flow moderator, overflow should be
wiped off.

Weigh the filled pump.

References:

(1) Handbook of Pharmaceutical Controlled Release Technology by
Donald
L. Wise
(2) Ansel’ Pharmaceutical dosage form and Drug delivery system by Ansel
(3) Biopharmaceutics and Pharmacokinetics A Treatise by D.M.
Brahmankar.
(4) Essentials of Medical Pharmacology by K.D. Tripathy.
(5) Jain.N.K.;Advances in controlled and novel drug delivery;2006;CBS
Publishers;1;pg18-39.
(6) Vyas S.P.;Khar.K.Roop;Controlled drug delivery,Concepts and
Advances;2002;Vallabh Prakashan;Delhi;1;pg477-501.
(7) Kanagale P, Lohray BB, Misra A, Davadra P, Kini R. Formulation and
Optimization of Porous Osmotic Pump–based Controlled Release
System of Oxybutynin. AAPS PharmSciTech. 2007; 8(3): Article 53.

(8) Journal of Controlled Release 35 (1995) 1-21 ; 57 (1999) 65-
73 ; 9 (2004) 75-89.

(9) European Journal of Pharmaceutics and Biopharmaceutics 68
(2008) 11-18 .
(10) International Journal of Pharmaceutics 311 (2006) 147-
156.

Osmotic pump evaluation

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