Oral modified release delivery technologies(procise and ring cap)

Oral Modified Release
Delivery Technologies
By
Vishesh Rodrigues
1st Year M.Pharm
Pharmaceutics
1KLEU's College of Pharmacy Belgavi

Introduction
• The oral route of drug delivery is typically
considered the preferred and most patient-
convenient means of drug administration.
• During drug discovery a lot of effort is put into
identifying and orally active candidate that will
be reproducible and have effective plasma
concentrations in vivo.

• Many orally active compounds are either
incompletely or ineffectively absorbed after oral
administration (i.e., bioavailability is an issue), or
that the required dosing frequency is too short to
enable once- or twice-daily administration (i.e.,
pharmacokinetic half-life is an issue).
• Modiﬁed-release formulation technologies offer
an effective means to optimize the bioavailability
and resulting blood concentration-time proﬁles of
drugs that otherwise suffer from such limitations.

Procise: Drug Delivery Systems
Based on Geometric Configuration
• Procise was developed by Glaxo Canada Inc.1 in 1991.
• Procise is an oral modified-release drug delivery system
comprised of a compression-coated core whose geometric
configuration controls the release profile of drugs.
• By varying the geometry of the core, the profile of the drug
release can be adjusted to follow zero order, first order, or a
combination of these orders.
• The system can also be designed to deliver two drugs at the
same time, each having a different release profile.
1-Current name and address: Glaxo SmithKline, 7333 Mississauga Road, Mississauga, ON,
L5N,6L4, Canada
KLEU's College of Pharmacy Belgavi 4

Description Of The Technology
• The system consists of a core that contains uniformly
dispersed drug and has a hole in the middle.
• A slowly permeable inactive coat surrounds all of the
surface of the core except the surface of the
cylindrical face.
• The drug release occurs only from the cylindrical
face, whose surface area dictates the rate of release
of drug.

Mechanism of Release
The mechanism of release of drug from this
uniquely designed dosage form can be
diffusion based or dissolution based.
A. Theory of Procise System Based on Dissolution Mechanism
B. Theory of Procise Based on Diffusion Mechanism

Theory of Procise System Based on
Dissolution Mechanism
• The release rate, dm/dt, of a drug from a compressed
soluble disc, when governed by dissolution, can be
expressed as
dm/dt =A(dx/dt)C
• where A is the surface area, C is the concentration of the
drug in the core, and dx/dt is the mass erosion rate. The
above equation predicts a constant dissolution rate if the
surface area is kept constant, active substance is uniformly
distributed within the tablet, and the mass erosion rate is
uniform.

Conﬁguration of the zero-order release active core used in Procise: (1) cylindrical face,
(2) cylindrical bore, (3) outer wall of cylinder, (4) inert coat. Dt-diameter of the core;
Dc-diameter of the cylinder; Ht-thickness at the cylinder; Hp-thickness at the
cylindrical face.

Theory of Procise Based on Diffusion
Mechanism
• The release of drug from a solid matrix by diffusion can be
represented by the following equation:
dq/dt= - D A dc/dr
• where q is the mass of drug being transferred, t is the time,
c is the drug concentration, r is the diffusion path length, A
is the area for the mass transport, and D is the diffusion
coefficient of the drug. According to the above equation,
the drug release rate decreases as the diffusion path
length, r, increases. As r cannot be kept constant, one way
to keep the release rate constant is to increase the area of
available diffusion source to compensate for the increase in
diffusion distance of drug transport.

Schematic cross-sectional views at various stages of dissolution testing of a Procise
formulation designed to release drug at a constant rate: (1) coat, (2) active soluble
core, (3) cylindrical face, (4) central pillar attached to the upper and lower face of the
coat, (5) core/coat interface. Dt-diameter of the tablet core; Hp-thickness of the
cylindrical face.

Manufacturing Process
• Manufacturing processes for the diffusion- and the
dissolution-based systems are very similar.
• However, the diffusion-based cores are composed of
soluble and insoluble components whereas dissolution-
based cores are composed of soluble components only.
• Granules for the cores are prepared using conventional, dry
or wet granulation methods and cores are compressed on a
conventional press ﬁtted with core-rod punches.
• The precompressed cores are compression-coated using a
core coater ﬁtted with a set of specially designed tooling
for placing cores precisely in the dyes.

Sequence of compression coating process: (1) coating granules for upper face of
the tablet, (2) core, (3) coating granules for lower face of the tablet.

Development And Optimization Of
Technology
• During the early development trials, it became clear that
erosion of the dissolution cores must occur only from the
exposed surface, which is the cylindrical face, and the
erosion must be uniform to achieve drug release proﬁles as
per theoretical predictions.

Dissolution proﬁle of Tablet A(Dissolution based procise) and
Tablet B(Reformulated Tablet A) in simulated ﬂuid (USP) without
enzyme.

NMR images of dissolution-based Procise tablet(Tablet A ) at
various stages of dissolution: (A) 15 min, (B) 1 h, (C) 2 h, (D) 3 h,
(E) 5 h, (F) 6 h, (G) 7 h, (H) 14 h.

• The hydration of the core for Tablet A is clearly visible in the
15-min image. The sign of hydration of the core also
appears at the core coat interface as seen in the 1-h image
(B).
• It was observed that the whole core/coat interface on both
sides of the tablet had hydrated, suggesting that the
penetration of the medium occurred through the coat.
• The coat was reformulated to retard the rate of penetration
of the dissolution medium into the coat to prevent
hydration of cores from the sides.

NMR images of Tablet B(Reformulated tablet A) at various
stages of dissolution: (A) 20 min, (B) 1 h, (C) 2 h, (D) 3 h, (E) 5 h,
(F) 7 h, (G) 9 h, (H) 16 h.

• The dissolution plot of Tablet B indicates that the drug
release from this tablet with the modiﬁed coat formulation
was complete in 5h.
• The NMR images of Tablet B showed no sign of water along
the core/coat interface throughout the core dissolution
process.
• Careful inspection of the images of Tablet B reveals that the
water begins to penetrate the coat at some point earlier
than 1 h but at a much lower rate than in the case of Tablet
A.

In Vitro Studies
• Several in vitro studies have been carried out to
demonstrate that the drug release proﬁle from Procise
follows the theoretical predictions. Release proﬁles of two
Procise formulations, one based on the dissolution
mechanism and the other based on the diffusion
mechanism, are shown in the figures below.

Release proﬁle of the dissolution-based Procise formulation of labetalol hydrochloride in water
The plot in Figure shows a zero-order release proﬁle for a
dissolution- based Procise formulation of labetalol hydrochloride
over a 10-h period.

Release proﬁles of diffusion based Procise of salbutamol sulfate
in water.
The plot in Figure displays dissolution behavior of a diffusion-based
Procise formulation of salbutomol sulfate. All of the drug is
released in 6.5 h.

In Vivo Studies
• The in vivo drug release behavior of dissolution-based
Procise system has been evaluated using a gamma
scintigraphy technique in six healthy male subjects.
• Neutron-activated samarium-153 and ytterbium-175 were
used to label the core and the coat, respectively, of a
placebo tablet.
• The tablet showed no apparent physical changes after
neutron bombardment. In vitro core dissolution time of 4.5
h remained unchanged after neutron activation.

Advantage
• Procise has the competitive advantage over other oral
delivery systems as the drug release proﬁle can be easily
modulated in a predictable manner simply by changing the
geometric conﬁguration of its core. No other drug delivery
system currently on the market can claim this feature.

Conclusion
• A lag time is usually associated with osmotic systems,
coated diffusion matrices, and coated dissolution
matrices before the drug is released. There is no lag
with Procise systems.
• Salient features of Procise technology:-
 No intact residue is left in the body as opposed to many
diffusion-based matrices.
 Utilization of compression coating process, which does not
require solvents.
 No fear of dose dumping as the system’s core itself is slow
dissolving.
 The system can be easily manufactured on a commercial
scale.

Ring Cap Technology
• RingCap is a patented, oral controlled-release drug delivery system.
The dosage form is a capsule-shaped matrix tablet to which bands
of insoluble material are applied circumferentially to the surface of
the tablet.
• These bands modify the release of drug from the tablet through the
control of surface area
• the release of drug from RingCap tablets is proportional to the
surface area exposed to the dissolution media. This surface area
changes over time as the area around the bands becomes hydrated
and erodes creating new surface area
• This new surface area can decrease, remain constant, or even
increase with time. The exposed surface area is controlled by the
number, width, and placement of bands of insoluble material
applied to the tablets.

RingCap Tablets

Historical Development
• RingCap was developed to address the continuing need for
improved oral controlled-release drug delivery systems.
• The intent was to provide a delivery system with reliable and
reproducible drug release characteristics, but also a simple and
cost-effective system that could be manufactured with conventional
solids-processing equipment.

Description of The Technology
• Drug Release:-
 The RingCap system is based on the principle that the rate at which a drug
is released from an erodible matrix is proportional to the surface area
exposed to surrounding liquid over time.
 Shown schematically is the release rate of drug from a conventional matrix
tablet decreases proportionately over time Fig 1
 A typical release profile for acetaminophen formulated in a conventional
matrix tablet is shown in Fig 2
 The specific configuration of number, width, and placement of the bands
on the RingCap tablet determines the release profile. Figure 3 shows the
release profile for acetaminophen RingCap tablets with four 2-mm bands.
 A proprietary mathematical model, developed to predict the release of
drug from RingCap tablets, allows for the design of specific banding
configurations that target the desired release profile prior to laboratory
experimentation, thereby shortening development time.

Fig 1-Schematic erosion of
a conventional matrix
tablet.
Fig 2-Release from 750-mg
acetaminophen matrix tablets (no
bands.)

Schematic erosion of a RingCap
tablet.
Fig 3-Release from 750-mg
acetaminophen RingCap tablets
(four 2-mm bands).

• Formulation and Manufacturing:-
 RingCap tablets are manufactured using a patented combination of readily
available manufacturing techniques and equipment.
 The matrix core tablet can be prepared by multiple techniques such as
low- or high-shear wet granulation, fluid-bed granulation, or dry blending.
 Capsule-shaped tablets are compressed using high-speed tabletting
equipment
 A film coat is applied to the matrix tablets to prepare the surface for the
application of bands.
 The banding material for Ring- Cap tablets is selected from a group of
polymers that are insoluble and impermeable. The banding formulation
may contain plasticizers, colorants, or other additives depending on the
specific application.
 Conventional capsule banding equipment (modified to apply multiple
bands) is employed to apply the bands around the circumference of the
matrix tablets.

Research And Development
• Technical Development:-
 Acetaminophen was selected as a model drug to challenge various
parameters of the RingCap system, particularly the number, width, and
placement of bands on the surface of tablets.
 Various band conﬁgurations were evaluated for in vitro release using a
USP Type III dissolution apparatus.
 A comparison of acetaminophen tablets with different numbers and
widths of bands indicated that the rate of release and total amount
released in 18 h decreased with increasing number of bands and width of
bands.
 The placement of bands on the surface of acetaminophen tablets also
affected the release rate.
 A comparison of RingCap tablets with two 5-mm bands separated by
either a 1- or 3-mm gap demonstrated that, although the tablets had the
same exposed surface area, the tablets had statistically different release
proﬁles.

 The combined effect of number, width, and placement of bands was
evaluated using two groups of RingCap tablets: tablets with two 4-mm
bands and tablets with four 2-mm bands.
 The results of this evaluation showed that the percent of acetaminophen
released in each hour (over 18 h). Hence it was concluded that the drug
release profiles from the RingCap system depend significantly on the
specific banding configuration.
 The proprietary mathematical model predicts drug release by using the
erosion rate of the matrix core tablet and the effect of the various
banding parameters, notably the number, width, and placement of bands.
 The mathematical model was challenged in numerous studies by
comparing the predicted release profilesto the actual in vitro dissolution
data. In each case, the profiles were significantly correlated ( p 0.001).
Figure 4 shows a representative correlation for 750-mg acetaminophen
tablets with two 4-mm bands.

Fig 4-In vitro dissolution versus model predicted for 750-
mg acetaminophen Ring- Cap tablets with two 4-mm
bands.

• Clinical Studies:-
 A critical aspect in the development of a novel drug delivery technology is
the demonstration of in vivo performance. For the RingCap system, a
randomized, single-dose, three-way, crossover study was conducted in 12
healthy adult human volunteers (eight males, four females) using
acetaminophen as a model drug.
 Acetaminophen meets the criteria as a highly soluble, highly permeable
Class I drug according to the Biopharmaceutics Classiﬁcation System
 The three acetaminophen dosing arms in the study included: a 750-mg
RingCap tablet (with two 4-mm bands), a 750-mg unbanded matrix tablet,
and a commercially available immediate-release dosage form (two 325-
mg tablets). A 1-week washout period was included between doses.
• The results of this human study showed highly signiﬁcant differences
among the three formulations for each of the nine pharmacokinetic
parameters examined. A comparison of the fraction released and fraction
absorbed for the RingCap tablets indicated a Level A in vitro–in vivo
correlation

 In addition, the mathematical-model-predicted release of acetaminophen
from the RingCap tablets was compared to the in vivo fraction absorbed.
 As shown in Figure 3, a signiﬁcant correlation was demonstrated. This
comparison demonstrates that once an in vitro–in vivo correlation is
established, the mathematical model can be used to predict in vitro
release proﬁles and the resulting in vivo plasma concentrations.
In vivo mean fraction absorbed versus model predicted
release for 750-mg acetaminophen RingCap tablets with two
4-mm bands

Competitive Advantage
• RingCap is differentiated from other oral-controlled release technologies
by the availability of a proprietary mathematical model used to predict the
release of drug and shorten development time, the use of conventional
materials and processes, the relative ease and cost-effectiveness of
manufacturing, and the distinctive appearance of the ﬁnal dosage form.
• The RingCap system uses conventional matrix tablet excipients and
formulation. It is adaptable to a wide range of drug concentrations and
solubilities. RingCap tablets are manufactured using a patented
combination of conventional tablet processing and capsule banding
technologies that can be easily integrated into existing manufacturing
lines.
• Since there is no need for specialty manufacturing, which often requires
outsourcing activities, RingCap offers a cost-effective technology that
allows an innovator company to maintain control of quality, cost of goods,
and market supply.

References
• Modified-Release Drug Delivery Technology
edited by Michael J. Rathbone1,Jonathan
Hadgraft2 ,Michael S.Roberts3
1. Inter Ag Hamilton, New Zealand.
2. Medway Sciences, NRI University of Greenwich Chatham, England.
3. Princess Alexandria Hospital and University of Queensland Brisbane,
Queensland, Australia.

Oral modified release delivery technologies(procise and ring cap)

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