Osmotic Systems
16
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Transcript of Osmotic Systems
16Osmotic Systems
Nipun DavarTranscept Pharmaceuticals, Inc., Point Richmond, California, U.S.A.
Brian Barclay and Suneel GuptaALZA Corporation, Mountain View, California, U.S.A.
THERAPEUTIC OBJECTIVES
Because drug delivery is programmed in osmotic systems, fluctuations of drug levels in
the body are substantially reduced compared with conventional, immediate-release (IR),
or sustained-release (SR) products. IR of drug may result in peak levels and higher-than-
desirable doses shortly after administration and less-than-adequate doses as the tablet
dissolves. In contrast, osmotic systems keep blood or tissue drug levels within a pre-
determined range to enhance safety, efficacy, and reliability of treatment (Fig. 1).
Another benefit of programmed delivery by osmotic system technology is the
reduction or elimination of side effects resulting from the rapid rise and high plasma drug
concentrations seen with IR dosage forms. Metering the drug within a suitable concen-
tration range may improve patient acceptability, particularly in chronic regimens (Fig. 2).
Additionally, unlike many traditional platforms, some osmotic systems can be
designed to deliver two or more drugs at different rates; such combinations may optimize
the efficacy of each drug and improve therapeutic value. Osmotic systems also allow
controlled delivery of drug over time, and dosing is reduced as compared to that with
conventional IR therapies taken several times a day. In most cases, once- or twice-daily
administration is possible using osmotic technology, and this may improve patient
compliance.
DESIGN
Though many variations have been proposed, osmotic systems can be classified in one of
two categories, regardless of site of delivery (i) those with an osmotic driving member
that swells and (ii) those without. Further, beyond this categorization, most osmotic
systems feature a rate-controlling membrane and some means for drug release (e.g., a
delivery orifice, or membrane pores).
The first modern-day application of osmotic pressure in an implantable device for
fluidic delivery was described by Rose and Nelson (1). Subsequently, similar principles
were invoked by Theeuwes (2) in the design of a series of platforms allowing zero-order
release of drugs to the gastrointestinal tract (GIT). The first of these, the elementary
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osmotic pump (EOP), represents the simplest type of osmotic systems and comprises a
solid compact surrounded by a rate-controlling membrane that has an exit portal, or
orifice (Fig. 3). In practice, water from the GIT passes through the membrane and dis-
solves the hydrophilic components (e.g., drug and any adjunct osmotic agents), and these
are subsequently expelled through the orifice.
As suggested in the general design equation below, the steady-state rate of delivery
(Z0) is governed by the permeability (K) and thickness (h) of the rate-controlling
membrane, the aqueous solubility of the drug (SD), the difference in osmotic pressure
across the membrane (Dp), and the surface area available for water transport across the
membrane (A):
Z0 ¼ KA��SD=h ð1Þ
7
2325
27
79
20
21
0
5
10
15
20
25
30
Edema Headache Flushing Dizziness Palpitations
Nifedipine capsules
Procardia XL
FIGURE 2 Relative frequency of side effects in anginal patients treated with immediate-release
nifedipine capsules or Procardia XL.
0
20
40
60
80
100
120
140
160
180
200
0 4 8 12 16 20 24
Time (hr)
Pla
sma
conc
entr
atio
n of
nife
dipi
ne (
ng/m
L)Procardia XL(R), N = 24Procardia
FIGURE 1 Steady state plasma profiles of nifedipine on day 5 for single dose Procardia XL�
compared to immediate-release nifedipine capsules (t.i.d.).
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Zero-order delivery is maintained as long as a saturation concentration is sustained
within the osmotic core. As additional water is imbibed into the tablet, the delivery rate
(Z) follows t1/2 kinetics, as described in Equation (2):
Z ¼ Z0=ð1þ Z0t=SDVÞ2 ð2Þwhere t is the time of release and V is the core volume.
The EOP can be quite effective in delivering compounds of moderate solubility,
ideally in the range of 50–400mg/mL. For others that are less soluble, the achievable
release rate as defined in Equation (1) is low, as the steady-state rate is proportional to
the aqueous solubility of the drug. Alternatively, for entities with extremely high sol-
ubility, the fraction of drug delivered at zero-order (FZ0) is low relative to that delivered
under t1/2 conditions per Equation (3), where the zero-order fraction approaches zero for
an infinitely soluble compound:
FZ0 ¼ 1� SD=r ð3Þwhere SD is the drug solubility and r is the osmotic core density.
To resolve the shortcomings of the EOP, a second type of osmotic multi-
compartment platforms, known as Push-PullTM osmotic systems, were developed to
include an expandable component that effectively displaces a hydrating drug formulation
(3). In its simplest form, a single drug compartment is conjoined with a polymeric
expansion compartment that forms a bi-layer tablet. The modified core is, in turn,
enveloped by a rate-controlling membrane that contains a delivery orifice for the drug
layer (Fig. 4). In practice, the osmotically active drug compartment and push compart-
ment hydrate as water from the GIT passes through the rate-controlling membrane. While
a hydrophilic drug solution or, alternatively, a lipophilic drug suspension is formed in
the drug layer (4), water entering the push layer begins hydrating a water-swellable
hydrophilic or lightly cross-linked polymer that sometimes contains osmotic agents. The
push-compartment composition in turn expands, displacing the drug solution or sus-
pension, through the delivery orifice. As both the push (expansion) layer and pull (drug)
layer are osmotically active, the principle design equation governing drug release (Z0)represents a sum of the two components:
Z0 ¼ K=hðAD��D þ AP��PÞCD ð4Þwhere AD, AP are the surface areas available for water transport across the membrane into
the drug layer and push layer, respectively; DpD, DpP are the osmotic pressure
Water
Delivery orifice
Rate-controllingmembrane
Drug-containingosmotic core
FIGURE 3 Schematic of EOP. Abbreviation: EOP, elementary osmotic pump. Source: FromRef. 2.
Osmotic Systems 495
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differentials across the membrane for the drug layer and push layer, respectively; and CD
is the drug concentration at the delivery orifice and is a function of formulation type and
degree of hydration.
As the delivery rate is dependent on drug concentration and not necessarily drug
solubility, further utility is gained with the Push-Pull system relative to the EOP.
Moreover, a multitude of drug layer and push layer combinations are possible in
addressing specific delivery requirements, two of which are displayed in Figure 5.
A listing of various osmotic systems in use is shown in Table 1. Included are platforms
for oral, subcutaneous, colonic, and ruminal delivery. Of particular note are those that
have been used in commercial products:
1. OsmodexTM: Allegra D� 24-Hour [Osmotica (Wilmington, NC, USA)/Sanofi
Aventis (Paris, France)].
2. SCOTTM: AltoprevTM [Andrx, Division of Watson (Corona, CA, USA)], Fortamet�
(Andrx).
3. EOP-PM: Teczem� [Merck (Whitehouse Station, NJ, USA)], Tiamate� (Merck).
4. Zer-OsTM: Tegretol� XR [Novartis (Basel, Switzerland)].
5. MODAS�: Brom-12 [Elan (Dublin, Ireland)].
6. EOP: Accutrim� [ALZA, Division of Johnson & Johnson (Mountain View, CA)/
Novartis], Osmosin� (ALZA), Efidac/24� (ALZA/Novartis), Sudafed� 24 hour
(ALZA).
7. EOP-NEC: Volmax� [ALZA/Muro, Division of Glaxo Smith Kline (Brentford,
UK)].
8. Push-Pull: Procardia XL� [ALZA/Pfizer (New York, NY)], Ditropan (Lyrinel)
XL� (ALZA), Glucotrol XL� (ALZA/Pfizer), Cardura� XL (ALZA/Pfizer),
Minpress XL� (AlpressTM LP) (ALZA/Pfizer), DynaCirc CR� (ALZA/Novartis).
9. COERTM: Covera-HS� [ALZA/Searle, Division of Pfizer (New York, NY)].
10. Push-Pull LCT: Concerta� (ALZA), INVEGATM [Janssen, Division of Johnson &
Johnson (Titusville, NJ)].
11. DUROS�: Viadur� (ALZA/Bayer Healthcare, W. Haven, CT, USA).
OsmodexTM
In its simplest form, the Osmodex osmotic system (5) comprises a drug-containing core
and, optionally, other osmotic excipients with appropriate dissolution aids, binders, and
lubricants, all surrounded by a semi-permeable membrane with at least one delivery
orifice. The membrane-coated tablet is covered by a film or compressible layer that
contains the active agent, or a second drug, and other film-forming materials and dis-
solution aids. The composition of the external coating may be adjusted to moderate the
Rate-controlling membrane
Osmotic push layer
Delivery orifice
Osmotic drug layer
FIGURE 4 Schematic of bi-layer Push-
PullTM osmotic system. Source: From
Ref. 4.
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delivery of the active agent upon introduction to the GIT. With activation, the external
layer hydrates and eventually dissolves, leaving the membrane-coated osmotic core,
which functions similarly to an EOP.
SCOTTM
In its basic form, SCOTTM, or Single Composition Osmotic Tablet (6), is composed of an
osmotic core containing drug, an osmotic agent, a water-swellable polymer, and,
optionally, a water-soluble polymer encompassed by a membrane of water-insoluble
polymer and augmented with optional plasticizers or pore formers. During operation,
water from the GIT penetrates the membrane, dissolves the pore-forming component,
and, at the same time, hydrates the osmotic core. The water-swellable polymer assists in
enlarging the tablet. Because of hydrostatic pressure build up within the core, the
membrane forms openings that allow the passage of hydrated core material to the GIT.
Clear overcoat
Drug overcoat
Osmotic pushlayer
Delivery orifice
Osmotic druglayer 1
Osmotic druglayer 2
Rate-controllingmembrane
Osmotic drug layer 1 Delivery orifices
Rate-controlling membrane
Osmoticpush layer
Osmotic drug layer 2(B)
(A)
FIGURE 5 Schematics of two tri-layer osmotic systems. Schematic (A) represents a three-layer
LCT Push-Pull system composed of two drug layers with differing drug concentrations, wherein
c1 < c2 for generating ascending release profiles. Schematic (B) expresses a three-layer tablet
with two drug layers externally positioned to an internal push layer. Drug concentration or type
can be varied to achieve the appropriate delivery pattern. Source: From Refs. 12 and 14.
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EOP-PM
The EOP-Porous Membrane (PM) (7), is a direct variant of the EOP. More specifically,
an osmotically active core of drug and optional osmotic excipients is surrounded by a
rate-controlling membrane composed of a water-insoluble polymer and leachable, water-
soluble components. In practice, water enters the membrane and dissolves the water-
soluble components, leaving passageways for counterflow of the solubilized core
materials; a discrete delivery orifice is not necessary.
TABLE 1 Osmotic System Classification and Application
Platform Typea Application
Elementary osmotic pump (2)
(equilibrium core)
1 Moderately water-soluble drugs; zero-order delivery
Push-Pull (4) (bi-layer tablet) 2 Low-to-highly water-soluble drugs; zero-order
delivery
Osmodex (5) 1 Low-to-highly water-soluble drug or drugs
ALZETTM (15) 2 Liquid/slurry/suspension drug delivery in animal
studies
OSMETTM (15) 2 Liquid/slurry/suspension drug delivery in human
studies
EOP-porous membrane (7) 1 Moderately water-soluble drug delivery
COER (11) 2 Low-to-highly water-soluble drugs; delayed release
delivery
Push-Pull LCT (12) 2 Low-to-highly water-soluble drugs; patterned
delivery
L-OROS� (16) (liquid OROS�) 2 Liquid/suspension/emulsion drug delivery;
zero-order release
MOVS (17) 1 or 2 Low-to-moderately water-soluble drugs; extended
zero-order or step function delivery
OROS�-CT (18) 2 Low-to-highly water-soluble drugs; colonic delivery
SCOT (6) 1 Low-to-highly water-soluble drug delivery
Zer-Os (8) 1 Slightly water-soluble drugs; zero-order delivery
EnSoTrol� (19) 1 Low (requiring dissolution enhancement) to highly
water-soluble drug delivery
Pull–Push–Pull (14) (tri-layer
tablet)
2 Low-to-highly water-soluble two-drug or single drug
patterned delivery
MODAS� (9) 1 Moderately water-soluble drug (with buffering
option) delivery
EOP–non-equilibrium core (10) 1 Moderately water-soluble drugs; patterned delivery
Push-StickTM (20) 2 Low water-soluble drugs; high drug loading, zero-
order delivery
DUROS (13) 2 Liquid/suspension/emulsion subcutaneous delivery
of potent drug for up to 1 year
VITSTM (21) 2 Liquid/suspension/emulsion subcutaneous drug
delivery in bovines and porcines for up to 1 year
RUTSTM (22) 2 Drug delivery from a wax matrix to bovine rumen for
up to 1 year
aType 1: osmotic platform without expandable driving member; Type 2: osmotic platform with expandable driv-
ing member.
Abbreviations: CT, colonic therapy; EOP, elementary osmotic pump; LCT, longitudinally compressed tablet;
MODAS, Multiporous Oral Drug Absorption System; MOVS, membrane osmotic valve system; RUTS, Rum-
inal Therapeutic System; SCOT, Single Composition Osmotic Tablet; VITS, Veterinary Implantable Therapeu-
tic System.
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Zer-OsTM
The Zer-Os osmotic system (8) comprises a core of active agent (typically lipophilic)
with osmotic agents, a gelling polymer and, optionally, a drug crystal habit modifier
enveloped by a rigid rate-controlling membrane with a delivery orifice. Upon exposure to
the GIT, water penetrates the membrane and begins hydrating the osmotic core, which
becomes fluid. Owing to the gelling polymer, sufficient viscosity is maintained in the
core to form a drug suspension that allows its delivery through the orifice.
MODAS�
Particularly useful for the delivery of water-soluble compounds, the Multiporous Oral
Drug Absorption System (9) is similar to the EOP-PM, except that soluble components in
the semi-permeable, rate-controlling membrane may be tailored so there is proper per-
meation of water into the core and drug diffuses through the membrane to the GIT. Core
buffers may also be included to minimize the effect of pH on drug dissolution.
EOP-NEC
The EOP-Non-Equilibrium Core (NEC) (10), is a direct variant of the EOP. The designs
of the two platforms are similar–drug plus osmotic excipients in a core surrounded by a
rate-controlling membrane featuring a delivery orifice—but the difference between the
equilibrium core and the NEC is the specific mass ratio of osmotic excipient to drug. In
the former, this ratio expresses the mutual solubility of drug in an osmotic-excipient-
saturated solution for an EOP; in the latter, osmotic excipients that affect drug solubility
(e.g., common-ion effect for drug solubility suppression) are used. Because drug sol-
ubility is modulated by the osmotic excipient concentration in the core, increasing or
reducing the mass ratio of osmotic excipient to drug allows extended zero-order or pulsed
delivery.
COERTM
As the name suggests, the Controlled-Onset Extended-Release (COER) platform (11),
allows control over the onset of delivery, when such a release pattern is indicated (e.g.,
early morning delivery to coincide with natural circadian rhythms). An effective form for
chronotherapy, the COER can be designed to offer a delay in onset of drug delivery of
about 0.5–7.0 hours, depending on the composition and thickness of the polymeric film
applied to the osmotic core. Typically, slowly hydrating hydrophilic polymers are
employed as the basis for the formulation because they slow the penetration of water into
the osmotic core and delay the release of drug through the orifice.
Push-PullTM LCT
The Push-Pull LCT (12), an example of which is exhibited in Figure 5(A), differs from
the previously described Push-Pull in its geometry. By decreasing the contact surface area
between the drug layers and push layer, residual drug levels are reduced, typically to
< 2% of the total dose in the LCT. Also, the revised geometry in an LCT composed of up
to five layers may comprise any combination of drug, push, and delay compartments to
achieve the delivery pattern of choice (e.g., ascending, pulsed).
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DUROS�
Designed as an implantable dosage form, the DUROS system is capable of delivering
potent drugs for up to 1 year for systemic or tissue-specific therapy (13). The platform
consists of a titanium tube with a delivery portal at one end and a rate-controlling
membrane at the other. Internally, an expandable piston of high molecular weight
hydrophilic polymers and adjunct osmotic agents is placed adjacent to the membrane.
Finally, a drug reservoir situated next to the piston contains potent drug compounds in
solution or suspension. Upon activation, water passes through the membrane and into the
piston, which expands upon hydration and displaces a like volume of the drug com-
partment. As a result, drug is delivered at a controlled rate through the delivery portal and
into the surrounding tissue.
FORMULATION
Many of the formulation attributes of IR dosage forms are applicable in the successful
design of an osmotic system. For example, drug stability, particle size distribution,
polymorphism, intrinsic dissolution, and excipient interactions, among others, remain
concerns for the osmotic systems formulator. In addition, particular attention is paid to
drug and osmotic excipient mutual solubility and the osmotic pressure of the key con-
stituents for the EOP (equilibrium core). To maximize the amount of drug delivered at a
zero-order rate, the mutual solubility should be minimized, but only to the extent that an
appropriate release rate can be maintained. Equation (5) is often used to estimate the
fraction of zero-order release (FZ0) from an equilibrium core:
FZ0 ¼ 1� ST=r ð5Þwhere ST is the mutual solubility (drug þ osmotic excipient) and r is the osmotic core
density.
Another factor to consider is the solubility ratio of drug to prospective osmotic
excipient (SD/SO). Too high or too low a ratio may impact tablet size, depending on the
dose required.
In addition to selecting an appropriate drug-osmotic excipient combination that
maximizes the fraction of drug delivered at zero-order and maintains a reasonable tablet
size for the given dose, other ingredients such as binders, lubricants, buffers, dis-
integrants, or wicking agents may be necessary to reduce to tablet friability during
subsequent processing (e.g., membrane coating) and optimize dissolution of the core as
water is imbibed through the rate-controlling membrane.
Common osmotic excipients in the EOP include organic and inorganic salts and
mono- or polysaccharides of compendial status. For some drug substances, incorporation
of an osmotic agent with buffering capacity may be advantageous in fixing core pH, in
maintaining a preferential pH for solution stability, or in improving the solubility char-
acteristics of the drug (23).
Binders, such as hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone
(PVP), or hyroxypropylcellulose, are routinely used in the formulation to strengthen the
tablet, while lubricants, such as magnesium stearate, calcium stearate, or stearic acid, are
included to facilitate the compression process.
To ensure that core dissolution is not a rate-limiting factor in the release of drug
through the orifice, disintegrants, or wicking agents may be necessary to maintain
a saturated solution within the EOP. Materials including cross-linked PVP,
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croscarmellulose sodium, or microcrystalline cellulose are typically considered for
these applications.
The rate-controlling membrane in an EOP modulates the rate of water entering the
core and helps the osmotic system resist the hydrostatic pressures of gastrointestinal
transit. Further, depending on its reflection coefficient, the membrane may also moderate
changes in pH as the EOP or Push-Pull system traverses from the stomach (pH 1–2) to
the small intestine (pH 5–7). As such, cellulosic polymers are included as the base
material in many osmotic system membrane applications. More specifically, cellulose
acetate and its derivatives offer a useful range of permeabilities, as well as sufficient film
mechanical strength. In some cases, flux enhancers, such as HPMC, polyethylene glycol,
or polyethylene–polypropylene oxide copolymers, are included in the membrane for-
mulation for permeability adjustment of the base polymer. Further, in some osmotic
system designs (7), hydrophilic pore-forming materials are added to create passageways
in the membrane in situ, thus allowing solubilized core material to pass from the
coated tablet.
For the Push-Pull osmotic pump (3), the inclusion of an expandable member
requires proper selection of base material. Generally, hydrophilic polymers such as
carboxymethylcellulose sodium, cross-linked polyacrylic acid, or polyethylene oxide are
used along with adjunct osmotic excipients to produce appropriate water imbibition
characteristics in both the drug (pull) layer and the push layer.
More specifically, high molecular weight hydrophilic or lightly cross-linked
polymers comprising the push compartment are highly viscous and are capable of
expanding 2–10 times their original volume upon hydration. Additionally, sufficient gel
strength is maintained at the boundary layer to minimize mixing between the drug and
push regions as each hydrates.
For inclusion of water-insoluble drugs in the Push-Pull osmotic system (4), a
hydrophilic polymer must retain sufficient viscosity to form an in situ suspension of drug
in the hydrating polymer and remain sufficiently fluid to be expelled through an orifice.
Depending on the specific Push-Pull design, the low molecular weight grades of the
polymer species utilized in the push compartment may be appropriate as suspending
agents in the drug compartment.
MANUFACTURE
Many of the unit operations for manufacture of traditional dosage forms are applicable to
osmotic systems with a solid drug formulation. As displayed in Figure 6, the process train
for an EOP encompasses up to eight distinctive steps that commence with granulation (or
dry blending, if applicable) and finish with drying to remove excess process solvent from
the membrane coating procedure or, alternately, with overcoating and printing.
Several options are available for preparing the dry core ingredients for compression
into an appropriately sized compact. If the formulation is directly compressible, a simple
component blending in a diffusion mixer (24) may be possible. However, if granulation is
necessary to impart better uniformity or tablet characteristics, one of several techniques
may be employed, as summarized in Table 2.
Compression can be conducted by conventional means. Typically, any high-speed
rotary tablet press from Fette (Schwarzenbek, Germany), Manesty (Knowsley, UK), and
Courtoy (Halle, Belgium), or other manufacturers will suffice (24).
The rate-controlling membrane is generally applied by one of two means in the
manufacturing process. The first involves a coating solution comprising the membrane
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polymers dissolved in the appropriate solvent sprayed from a gun assembly onto a bed of
tablets rotating in a partially or fully perforated pan coater. Examples of suppliers include
Vector (Marion, IA, USA), Nicomac (Milano, Italy), and Glatt (Ramsey, NJ, USA),
among others (24). The coating process continues until the appropriate weight gain per
tablet is achieved or, alternately, the specified solution volume is applied. The second
technique employs a fluid-bed procedure, in which coating solution is sprayed from the
bottom of a column containing a fluidized bed of tablets. Equipment suitable for the
fluid-bed process can be supplied by Fluid Air (Aurora, IL, USA), Aeromatic-Fielder, a
Division of Niro Pharma Systems (Bubendorf, Switzerland), and BWI-Huttlin (Steinen,
Switzerland), among others (24). The coating endpoint is again determined by the weight
gain per tablet or the volume of solution applied.
Of all the unit operations involved in the synthesis of osmotic systems, the orifice-
drilling step is unique in the industry. The first-generation equipment comprises a
Hartnett carrier system coupled with a Coherent laser (Santa Clara, CA, USA) (25).
Sensors are placed in advance of the laser firing point to detect the presence of a tablet in
the individual carrier slot. Should a misfire occur, additional sensors downstream activate
a reject mechanism that physically removes undrilled tablets from the batch. Throughputs
of up to 200,000 tablets per hour are now possible in commercial laser units (26).
Next, a drying step may be instituted to reduce the levels of process solvent in
the final product. Tablets can be placed into an environmentally controlled tray dryer
High-sheargranulator(collette)
Lubricant blending(tote tumbler)
Core compression(manesty D3B)
Membrane coating(vector hi-coater)
Humidity drying(hotpack oven)
Drug and/or color overcoating(vector hi-coater)
Printing(ackley printer)
Laser drilling(hartnett/coherent)
FIGURE 6 Example process flow diagram for manufacture of EOP. Abbreviation: EOP, elemen-
tary osmotic pump.
TABLE 2 Granulation Options for EOP Core Preparation
Technique Example Application
Equipment
Planetary mixing Hobart Aqueous or solvent wet granulation
High-shear mixing Collette Contained aqueous or solvent wet granulation
Roller compaction Chilsonator Dry granulation
Fluid bed Vector FBG One-step aqueous or solvent granulation
Abbreviation: EOP, elementary osmotic pump.
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[e.g., Hotpack (Warminster, PA, USA)] for a specified period, depending on the char-
acteristics of the core and membrane formulations.
In some instances, dried tablets may be returned to the coater for the application of
an aqueous-based color overcoat, before being sent on to a printing step [e.g., Ackley
Machine (Moorestown, NJ, USA)] for product identification.
The process applied to the manufacture of the Push-Pull osmotic system is, in
many ways, similar to that of the EOP (Fig. 7). There are some notable exceptions
though, particularly in the granulation and compression steps. In the former, as both the
push and drug formulations can contain a hydrophilic polymer, the use of an aqueous-
based, planetary granulation process is problematic, as the water applied can induce an
irreversible plasticization of the polymer, leaving the resultant granulation difficult to
process further.
In the compression step, because Push-Pull type formulations routinely comprise
two or more distinct compartments, a tablet press capable of producing bi-layer, tri-layer,
or core-within-a-core compacts is necessary. Equipment manufacturers such as Manesty
and Korsch (Berlin, Germany) supply machines for these applications. In fact, Korsch
systems can accommodate up to five layers in a single tablet (27).
The remaining unit operations, membrane coating, orifice drilling, drying, and, if
necessary, color overcoating and printing, are similar in the manufacture of the EOP and
Push-Pull osmotic systems. Slight variations are necessary in the drilling process, because
the equipment must distinguish the drug compartment side of the tablet from the non-
drug regions. Color sensors provide the necessary discrimination within the tablet, which
normally contains light-colored drug-containing compartments and dark-colored non-
drug compartments.
EXAMPLES OF ORAL OSMOTIC DELIVERY SYSTEMS
The desire to improve compliance and convenience is often cited as the rationale for
combining a new delivery system and an existing drug, and a number of commercially
successful products have been developed in response to this challenge. Oral osmotic
systems have been widely used with therapeutics for cardiovascular, endocrine, urologic,
and central nervous system (CNS) applications.
OROS Nifedipine (Procardia XL�)
The early success of OROS technology was realized with cardiovascular drugs such as
nifedipine (Procardia XL�) and verapramil hydrochloride (Covera HS�). Both agents are
calcium-channel blockers indicated for the treatment of hypertension. Procardia XL is
commonly used for the treatment of angina pectoris as well. Calcium-channel blockers
administered from IR dosage forms may be associated with vasodilatory side effects and
reflex activation of the sympathetic nervous system (28). Kleinbloesem and van
Brummelen (29) studied the effect of the rate of delivery on hemodynamic effects of
nifedipine. Two regimens of IV infusion were administered to evaluate hemodynamic
effects in six healthy volunteers. The first regimen resulted in steady-state blood plasma
concentrations over 5–7 hours, and the second regimen achieved the same results within
3 minutes; the concentrations were similar. During the gradual-rise infusion, heart rate
was unchanged, and diastolic blood pressure fell slowly by 10mmHg. With a faster
infusion rate, the heart rate increased immediately and remained elevated for the duration
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of the infusion. At the end of the gradual-rise regimen, a sudden increase in the infusion
rate for 10 minutes produced tachycardia and an unexpected increase in blood pressure.
The authors hypothesized these unexpected effects could be due to baroreceptor
activation.
Drug formulation Push formulation
Aqueous fluid bed granulation(Glatt FBG)
Lubricant blending(tote tumbler)
Core compression(manesty BB4)
Membrane coating (fluid-bed coater)
Laser drilling(hartnett/coherent)
Humidity drying(eurovent oven)
Drug and/or color overcoating(fluid-bed coater)
Printing(ackley printer)
Aqueous fluid bed granulation(Glatt FBG)
Lubricant blending(tote tumbler)
FIGURE 7 Sample process flow diagram for manufacture of Push-Pull system.
504 Davar et al.
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A slowly rising and consistent 24-hour drug release from OROS nifedipine has been
shown to improve the safety profile and efficacy compared to an (IR) formulation (30). In a
study that switched patients from an IR to OROS treatment, the latter resulted in reduction
in angina and nitroglycerin usage. Furthermore, based on questionnaires that asked about
frequency of symptoms, activity, work performance, and energy level, 87% of the patients
reported stable or improved quality of life after switching to OROS nifedipine.
Another calcium-channel blocker, COER verapramil hydrochloride (Covera HS),
uses a unique modification of the basic OROS technology to establish a drug-release
profile that manages circadian changes in blood pressure.
Hypertensive patients have been shown to have higher blood pressure and heart
rate readings in the morning hours than compared with when they are asleep, and car-
diovascular events frequently occur within 4 hours after awakening. As such, drug release
from Covera HS is delayed for 4–5 hours so that peak concentrations are achieved
8–12 hours after bedtime administration to reduce early morning blood pressure (31).
OROS� Oxybutynin (Ditropan XL�)
The anticholinergic, antispasmodic agent, oxybutynin hydrochloride, is indicated for the
treatment of overactive bladder and urge-urinary incontinence. Oxybutynin binds to the
muscarinic receptors on the detrusor muscle of the bladder, inhibiting involuntary bladder
contractions. Unfortunately, IR formulations have been associated with systemic chol-
inergic side effects, such as dry mouth, which may limit compliance with dosing
regimens.
OROS oxybutynin was designed to release drug in a constant zero-order manner
over 24 hours. By design, no appreciable quantity of the drug is delivered in the first
2–3 hours after a patient ingests the system. In fact, most of the drug is released when the
system reaches the colonic portion of the GIT some 3–5 hours following dosing.
OROS controlled-release delivery of oxybutynin improved bioavailability and
reduced dry mouth compared with IR formulations. In one study, bioavailability with
OROS was 153% (32) and peak and trough plasma concentrations were 66–81% lower
with OROS system. These values may be the result of delivering drug primarily to the
lower part of the GI tract, which reduces gut-wall first-pass metabolism and avoids
cytochrome-P450-mediated metabolism in the upper part of the GI tract. Dry mouth
severity and saliva output indicated dry mouth severity correlated with the concentration
of the metabolite, desethyloxybutynin. Levels of metabolite and dry mouth severity were
lower with the OROS formulation, and saliva output was higher. Another single-day,
healthy-volunteer, placebo-controlled study compared both OROS oxybutynin and
controlled-release tolterodine (Detrol� LA) with IR oxybutynin and showed saliva output
was higher with the controlled-release formulations (33).
OROS� Methylphenidate (Concerta�)
Concerta� is indicated for treatment of attention deficit/hyperactivity disorder (ADHD)
and contains methylphenidate, a CNS stimulant long used in IR and conventional SR
formulations for ADHD. Concerta has an ascending-release profile that allows a fast
onset of action followed by a sustained effect for an additional 12 hours and is designed
for a single morning dose that allows controlled release of drug over school day and late
afternoon. The system is tri-layer, membrane-coated tablet core surrounded with a drug
overcoat layer. The overcoat contains approximately 20% of the dose, and the core and
middle layers contain increasing concentrations of drug. The OROS design successfully
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overcomes the deficiencies of the existing IR and SR methylphenidate products. IR
formulations need to be taken several times a day for effective treatment and the SR
product [Ritalin SR�, Novartis, E. Hanover, NJ, USA] lacks a fast onset of action and
yields a flat plasma profile that may encourage the development of tolerance to the
drug (34).
A study of the pharmacodynamic effects of methylphenidate delivered by
Concerta showed drug plasma concentrations increased over the first 2 hours following
release from the drug overcoat layer, and a further increase was achieved as drug from the
first layer of the tablet core was released. Peak plasma concentrations were achieved
6–8 hours after administration following release from the second layer of the tablet core.
In clinical trials in children between 6 and 12 years of age, Concerta was
significantly more effective than placebo. The efficacy of Concerta was similar to IR
methylphenidate administered three times a day and demonstrated similar onset of
action (35).
Methylphenidate is a controlled substance and is subjected to abuse. The Drug
Abuse and Warning Network mentions OROS methylphenidate 50 times compared with
588 mentions of all other methylphenidate brands between years 2000 and 2002; of
the 548 citations for abuse of oral methylphenidate, only 49 concerned the OROS
formulation. There was no mention of any abuse of the OROS formulation via other
routes, (sniffing or snorting and injecting). The OROS market share is estimated at
5–48% of the total, and abuse of OROS formulation has been significantly less than that
of other methylphenidate products (36).
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