INTRODUCTION:
Oral controlled
release (CR) systems most popular amongst all the drug delivery system. Because
of pharmaceutical agents can be delivered in a controlled manner over a long
period. Conventional oral drug delivery system supply continues release of
drug, which cannot control the release of the drug and effective concentration
at the target site.
The
bioavailability of drug from these formulations may vary significantly,
depending on factor such as physico-chemical
properties of the drug, presence of excipients
various physiological factors such as the presence or absence of food, pH of
the GI tract, GI motility etc. To overcome this problem a number of design
option are available to control or modulate the drug release from a dosage
form. Drugs can be delivered in a controlled pattern over a long period of time
by the process of osmosis. Drug delivery from this system is not influenced by
the different physiological factors within the gutlumen
and the release characteristics can be pre-dicted
easily from the known properties of the drug and the dosage form. Osmotic ally
controlled drug delivery system, deliver the drug in a large extent and the
delivery nature is independent of the physiological factors of the
gastrointestinal tract and these systems can be utilized for systemic as well
as targeted delivery of drugs. Osmotically controlled
oral drug delivery systems utilize osmotic pressure for controlled delivery of
active agents. Osmotically Controlled Drug Delivery
System (OCDDS) Osmotic devices are the most calculable controlled drug delivery
system (CDDS) and can be employed as oral drug delivery systems. Osmotic
pressure is used as the driving force for these systems to release the drug in
a controlled pattern. Osmotic pump tablet (OPT) generally consists of a core
including the drug, an osmotic agent, other excipients
and semi permeable membrane coat.
HISTORICAL ASPECTS OF OSMOTIC PUMPS: [6-9 ]
About 75 years
after discovery of the osmosis principle, it was first used in the design of
drug delivery systems. Rose and Nelson, the Australian scientists, were
initiators of osmotic drug delivery. In 1955, they developed an implantable
pump, which consisted of three chambers: a drug chamber, a salt chamber
contains excess solid salt, and a water chamber. The drug and water chambers
are separated by rigid semi permeable membrane. The difference in osmotic
pressure across the membrane moves water from the water chamber into the salt
chamber. The volume of the salt chamber increases because of this water flow,
which distends the latex diaphragm separating the salt and drug chambers,
thereby pumping drug out of the device. The design and mechanism of this pump
is comparable to modern push-pull osmotic pump. The major disadvantage of this
pump was the water chamber, which must be charged before use of the
pump. The pumping rate of this push-pull pump is given by the equation.
dM/dt = dV/dt
x c
In general, this
equation, with or without some modifications, applies to all other type of osmoti systems.
Figure 1. Rose-Nelson Pump
Several
simplifications in Rose-Nelson pump were made by Alza
Corporation in early 1970s. The Higuchi-Leeper pump
is modified version of Rose- Nelson pump. It has no water chamber and
the device is activated by water imbibed from the surrounding environment. The
pump is activated when it is swallowed or implanted in the body. This pump
consists of a rigid housing, and the semi permeable membrane is supported on a
perforated frame. It has a salt chamber containing a fluid solution with excess
solid salt. Recent modification in Higuchi-Leeper
pump accommodated pulsatile drug delivery. The pulsatile release was achieved by the production of a
critical pressure at which the delivery orifice opens and releases the drug.
Further simplified variant of Rose-Nelson pump was developed by Higuchi and The
euwes. This pump comprises a rigid, rate controlling
outer semi permeable membrane surrounding a solid layer of salt coated on the
inside by an elastic diaphragm and on the outside by the membrane. In use,
water is osmotic ally drawn by the salt chamber, forcing drug from the drug
chamber.
Figure 2. Higuchi-Leeper Pump
Figure 3. Theeuwes miniature osmotic pump
In 1975, the
major leap in osmotic delivery occurred as the elementary osmotic pump for oral
delivery of drugs was introduced. The pump consists of an osmotic core
containing the drug, surrounded by a semi permeable membrane with a delivery
orifice. When this pump is exposed to water, the core imbibes water osmotically at a controlled rate, determined by the
membrane permeability to water and by the osmotic pressure of the core formulation.
As the membrane is nonexpendable, the increase in volume caused by the
imbibitions of water leads to the development of hydrostatic pressure inside
the tablet. This pressure is relieved by the flow of saturated solution out of
the device through the delivery orifice. This process continues at a constant
rate until the entire solid agent inside the tablet has been dissolved and only
a solution filled coating membrane is left. This residual dissolved agent
continues to be delivered at a declining rate until the osmotic pressure inside
and outside the tablet is equal. Normally, the EOP delivers 60-80% of its
contents at a constant rate, and there is a short lag time of 30-60 min as the system
hydrates before zero order delivery from the EOP is obtained .
ADVANTAGES: [5, 10]
· Easy to formulate and simple in operation.
· Deliveries may be delayed or pulsed if
desired.
· Prolonged therapeutic effect with uniform
blood concentration.
· Improve patient compliance with reduced
frequency.
· Drug release is independent of gastric pH
and hydrodynamic condition.
· The release mechanisms are not dependent on
drug.
· They are well characterized and understood.
· A high degree of in-vitro and in-vivo
correlation (IVIVC) is obtained in osmotic systems.
DISADVANTAGES: [5,10]
· Expensive.
· Dose dumping.
· Rapid development of tolerance.
· Size hole is critical.
· Retrieval therapy is not possible in the
case of unexpected adverse events.
· If the coating process is not well
controlled there is a risk of film defects, which result in
· dose dumping.
Table 1.
Osmotic pressures of saturated solution of commonly used osmogents
[11, 14]
|
Compounds
of mixture |
Osmotic
pressure (atm) |
|
Lactose-Fructose |
500 |
|
Dextrose-Fructose |
450 |
|
Sucrose-Fructose |
430 |
|
Mannitol-Fructose |
415 |
|
Sodium chloride |
356 |
|
Fructose |
335 |
|
Lactose-Sucrose |
250 |
|
Potassium chloride |
245 |
|
Lactose-Dextrose |
225 |
|
Mannitol-Dextrose |
225 |
|
Dextrose-Sucrose |
190 |
|
Mannitol-Sucrose |
170 |
|
Sucrose |
150 |
|
Mannitol-Lactose |
130 |
|
Dextrose |
82 |
|
Potassium sulphate |
39 |
|
Mannitol |
38 |
|
Sodium phosphate tribasic.
12H2O |
36 |
|
Sodium phosphate dibasic. 7 H2O |
31 |
|
Sodium phosphate dibasic. 12 H2O |
31 |
|
Sodium phosphate monobasic. H2O |
28 |
|
Sodium phosphate dibasic. Anhydrous |
21 |
Figure 4: CPOP
tablet before and after dissolution studies
CONTROLLED-POROSITY
OSMOTIC PUMP (CPOP) [15, 16]:
The
controlled-porosity osmotic pump tablet concept was developed as an oral drug
delivery system by Zentner et al (1985, 1991),
Zentner and Rork (1990), Appel and Zentner (1991), and Mc
Cell and et al. (1991). The controlled-porosity osmotic pump tablet
(CPOP) is a spray-coated or coated tablet with a semi permeable membrane (SPM)
containing leachable pore forming agents. They do not have any aperture to
release the drugs; drug release is achieved through the pores, which are formed
in the semi permeable wall in situ during the operation. In this system,
the drug, after dissolution inside the core, is released from the osmotic pump
tablet by hydrostatic pressure and diffusion through pores created by the
dissolution of pore formers incorporated in the membrane (Fig. 4). The
hydrostatic pressure is created either by an osmotic agent or by the drug
itself or by a tablet component, after water is imbibed across the semi
permeable membrane. This membrane after formation of pores becomes permeable for
both water and solutes. A controlled-porosity osmotic wall can be described as
having a sponge like appearance. The pores can be continuous that have micro
porous lamina, interconnected through tortuous paths of regular and irregular
shapes. Generally, materials (in a concentration range of 5% to 95%) producing
pores with a pore size from 10 Å -100 m can be used . This system is generally
applicable for only water-soluble drugs as poorly water soluble drugs cannot
dissolve adequately in the volume of water drawn into the OPT. Recently this
problem was overcome by adding agents like sulfobutyl
ether--cyclodextrin (SBE)7m--CD or hydroxypropyl--cyclodextrin
(HP--CD) as solubilizing and osmotic agents. Several
approaches have been developed to prepare the porous membrane by spray coating
using polymer solutions containing dissolved or suspended water-soluble
materials. The rate of drug release can also be varied by having different
amounts of osmogents in the system to form different
concentrations of channeling agents for delivery of the drug from the device.
Incorporation of the cyclodextrin-drug complex has
also been used as an approach for the delivery of poorly water-soluble drugs
from the osmotic systems, especially controlled-porosity osmotic pump tablets.
ADVANTAGES:[17]
a) The
controlled porosity osmotic pump can be following zero order kinetics and thus
better
control over the
drug’s in vivo performance is possible.
b) The drug
release is independent of the gastric pH and hydro dynamic conditions.
c) The delivery
rate of drug from these systems is highly predictable and can be programmed by
modulating the terms.
d) Drug release
from the controlled porosity osmotic pump exhibits significant in vitro-in
vivo correlation
[IVIVC] with inspecificlimits.
e) No need of
drilling.
f)The rational
for this approach is that the presence of water in GIT is relatively constant,
at least in terms of the amount required for activation and control
lingosmotically base technologies.
g) Production
scale-up is easy.
DISADVANTAGES:
[17]
a) Retrieval of
therapy is not possible in the case of unexpected adverse events.
b) Drug release
from the osmotic systems is affected to some extent by the presence of food.
c) If the
coating process is not well controlled there is a risk of film defects, which
results in
dose dumping.
BASIC COMPONENTS REQUIRED FOR
CONTROLLED -POROSITY OSMOTIC PUMP:
a) Drug
b) Osmotic agent
c) Semi permeable membrane
d) Channeling agents or pore forming agents.
a. Criteria for selection of a drug:[15,
16, 18]
Short biological Half-life (2- 6 hrs) High
potency Required for prolonged treatment
(e.g: Nifedipine, Glipizide, Verapamil and
Chlorpromazine hydrochloride).
b. Osmotic
agent: [15, 19, 20]
Polymeric osmogents are mainly used in the fabrication of osmotically controlled drug delivery systems and other
modified devices for controlled release of relatively insoluble drugs. Osmotic
pressures for concentrated solution of soluble solutes commonly used in
controlled release formulations are extremely high, ranging from 30 atm for sodium phosphate up to 500 atm
for a lactose-fructose mixture. These osmotic pressures can produce high water
flows across semi permeable membranes. The osmotic water flow across a membrane
is given by the equation,
dv/dt=
Where dv/dt, is the rate of water flow
across the membrane of area A, thickness l, permeability in cm3.cm/cm2.
h. atm.
Table 2. Specifications
for controlled- porosity osmotic pump [21]
|
Materials |
Specifications |
|
Plasticizers and flux
Regulating agents |
0 to 50, preferably 0.001
to 50 parts per 100 parts of wall material |
|
Surfactants |
0 to 40, preferably
0.001to 40 parts per 100 parts of wall material |
|
Wall thickness |
1 to 1000, preferably 20
to 500 m |
|
Micro porous nature Pore
forming additives |
5 to 95% pores between 10a
to 100 m diameter 0.1 to 60%, preferably 0.1 to 50%, by weight, based on the
total weight of additive and polymer |
Table 3. Specifications for core of controlled- porosity osmotic
pump[15]
|
Property |
Specifications |
|
Core loading (size) |
0.05 mg to 5 g or more
(include dosage forms for Humans and animals) |
|
Osmotic pressure developed
by a solution of core |
8 to 500atm typically,
with commonly encountered water soluble drugs and excipients.
|
|
Core solubility |
To get continuous, uniform
release of 90% or greater of the initially loaded core mass solubility, S, to
the core mass density,, that is S/, must be 0.1 or lower. Typically it occurs
when 10% of the initially loaded core mass saturates a volume of external
fluid equal to the total volume of the initial core mass. |
c. Semi permeable Membrane [22]
The membrane
should be stable to both outside and inside environments of the device. The
membrane must be sufficiently rigid so as to retain its dimensional integrity
during the operational lifetime of the device. The membrane should also be
relatively impermeable to the contents of dispenser so that osmogent
is not lost by diffusion across the membrane. Finally, the membrane must be
biocompatible. Some good examples for polymeric materials that form membranes
are cellulose esters like cellulose acetate, cellulose acetate butyrate,
cellulose triacetate, ethyl cellulose and Eudragits.
Ideal properties of semi permeable
membrane [23-25]
The semi permeable membrane must meet some performance
criteria,
a) The material must possess sufficient wet strength
(10-5 Psi) and wet modules so (10-5 Psi) as to retain its dimensional integrity
during the operational lifetime of the device.
b) The membrane must exhibit sufficient water
permeability so as to attain water flux rates (dv/dt) in the desired range. The water vapor transmission
rates can be used to estimate water flux rates.
c) The reflection coefficient or “leakiness” of the
osmotic agents should approach the limiting value of unity. But polymer
membranes must be more permeable to water.
d. Channeling
agents/ leachable pore forming agents [26-28]
These are the
water-soluble components which play an important role in the controlled drug
delivery systems. When the dissolution medium comes into contact with the semi
permeable membrane it dissolves the channeling agent and forms pores on the
semi permeable barrier. Then the dissolution fluid enters the osmotic system
and releases the drug in a controlled manner over a long period of time by the
process of osmosis. Some examples of channeling agents are polyethylene glycol
(PEG) 1450, -mannitol, bovine serum albumin (BSA), diethyl
phthalate, dibutylphthalate and sorbitol.
CONCLUSIONS:
It can be
concluded that the oral controlled-porosity osmotic pump system comprising a
monolithic tablet coated with a semi permeable membrane containing different
levels of pore forming agents can be developed for poorly water soluble drugs.
These osmotic devices could be designed and optimized to deliver poorly soluble
drugs at a controlled rate for extended periods of time by changing the drug:
osmogent ratio, type of channeling agent and its concentration. The rate of
release may be controlled through: 1) the level of pore formers incorporated
into the wall; 2) the nature of the insoluble polymer component of the wall; 3)
the thickness of the surface of the wall; 4) total solubility and osmotic
pressure of the core; and 5) the drug load in the core. The osmotic system may
be used to deliver drugs at a controlled rate over a period of 12 hours. This
system is simple to prepare with no drilling required and hence it can be used
in the field of controlled delivery of drugs.
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Received on 04.04.2016 Accepted on 20.04.2016
© Asian Pharma
Press All Right Reserved
Asian J. Res.
Pharm. Sci. 2016; 6(2): 101-106
DOI: 10.5958/2231-5659.2016.00014.X