Oral MUPS: Overcoming Challenges in Formulating Modified Release Multiple-Unit Particulate Systems
1. Oral Modified Release Multiple-Unit
Particulate Systems
( Version 7.0)
Introduction of MUPS
Challenges in Formulating MUPS
Marketed Products of MUPS
Extrusion & SPHERONIZATION
5 Appendix
Prepared by
Changbaek Lim
3. 3
A design principle of increasing importance for sustained, controlled, delayed, site specific or
pulsatile release preparations is the compaction of coated particles into disintegrating multiple
unit tablets
One challenge in the production of disintegrating multiple unit tablets is maintaining the
modified drug release after compaction, as the application of the compaction pressure can
lead to deformation of film coating and, consequently, altered drug release
To protect the coating from such changes, excipients with so-called cushioning or protective
properties are usually incorporated in the tablet formulation in addition to fillers
The compression-induced changes in the structure of a film coating may depend on
physical factors of pellets such as the size, shape, density, porosity and formulation factors
such as type and amount of coating, the properties and structure of the substrate pellets and
the incorporation of excipient particles
The demand for MUPS tablets has been increasing due to its greater advantage over
other dosage forms
Introduction
4. 4
Multi particulates are filled into hard-shell gelatin capsules, compressed into tablets, suspended in
liquids or packed in sachets
Compaction of single units results in disintegrating tablets
; becoming more and more important on the pharmaceutical market, as they provide several
advantages compared to single-unit dosage forms and pellet-filled capsules
COMPRESSION OF PELLETS TO TABLETS (MUPS)
5. 5
1. The compression of multiparticulates into tablets, unlike the hard gelatin capsule, is a
tamper-proof dosage form and has greater physicochemical and microbiological stability of
pellets as they are embedment in the inert matrix
2. Tablets have less difficulty in oesophageal transport than capsules
3. Tablets containing coated subunits can be prepared at a lower cost than these subunits filled
into hard gelatin capsules because of higher production rate of the tablet press
4. The expensive control of capsule integrity after filling is also eliminated
5. In addition, tablets containing multiparticulates without losing the controlled-release properties
could be scored, which allow a more flexible dosage regimen
ADVANTAGES of MUPS
6. Composing the tablet with equal or different kinds of particles can be combined and so that
very specific release profiles can be generated
7. Once the coated subunits have been developed different dose strengths can be prepared just by
varying the tablet size keeping the same composition – no additional development efforts
need to be taken
8. Another option for dose strength variation is the development of dividable multi-unit tablets
Since the release characteristics are related to the single subunits, dividing the tablet does not
affect the release characteristics as it is true for monolithic tablets
9. Rapid and uniform transit of subunits contained in tablets from the stomach into small intestine
owing to their small size, drug release is more uniform and possibility of dose dumping is
avoided with minimized tendency for intersubject variations
6. 6
RATIONALE OF FORMULATING MUPS
The rationale in formulating MUPS is to design chased on the release rates such as designing
controlled release, sustained release, delayed release and colon targeted drug delivery system
; oral disintegrating taste-masked dosage form
; combining drugs with different release characteristics in the same dosage form
The drug dose administered in modified release form can be increased as compared to that
possible with capsules and enhance the stability of dosage form as compared to its capsule
counterpart
It also helps in obviating the need for specialized packaging such as that required for
capsules making it a more cost effective dosage form
7. 7
IDEAL CHARACTERISTICS OF MUPS
1. Should maintain all the tablet properties
2. Pellets should not show any interaction like developing electrostatic charges; during
compression
3. The pellets should not show any deviation in its release even after compression
4. The coated pellets during the process of compression should not fuse into a nondisintegrating
matrix and should not lose its coating integrity either by breaking or cracking or rupturing
the coating layer(s) or pinholes and other imperfections
5. Like tablets, MUPS should have ease to withstand physical parameters, stability, packing
storage and transportation
6. The dosage form must disintegrate rapidly into individual pellets in gastrointestinal fluids.
9. 9
1. To ensure uniformity of content and weight
2. To compress the coated subunits to tablets with sufficient hardness and low friability
without damaging the film coatings
CHALLENGES IN FORMULATING MUPS
How to overcome of challenges ?
10. 10
Pellet shape
The shape of the pellets should be spherical or nearly spherical for good rhombohedral
packing
A more deviation in spherical shape does not result in compacts of characteristic release due
to flaws and cracks during compression
Pellet size
The size of the coated pellets can be maximum up to 2 mm to withstand compression pressure
Large sized pellets cause rupture to the coating of pellets due to segregation with tabletting
excipients and there by direct exposure of the transmitted force by the upper punch to lower
punch
Pellet Density
Pellets of density about 1.5 g/cm3 shows faster gastric emptying than pellets with higher
density of > 2 g/cm3
Pellets with < 2 mm in diameter and < 2 g/cm3 density can pass through pyloric sphincter both
in fasted and fed state which is similar to liquids in terms of gastric emptying
OVERCOME OF CHALLENGES I
In order to ensure undamaged film coatings and thus reproducible drug release after tablet
compression, various impact factors need to be considered:
11. 11
Pellet core and Core material
Pellets should have low surface to volume ratio; which might result in a decreased area of
contact between the particles as they consolidate
In favor of this, pellet core should have some degree of plasticity to have deformation in shape
during compression without any damage to the coated film
An extensive study was carried out on microcrystalline cellulose (MCC) by many researchers
both as powdered and granulated forms, and revealed that MCC shows plastic deformation
during compression and offers better protection to the coated particles as powder and
granules
Studies done with different concentrations of MCC and starch 155 confirmed that starch
strong compacts were formed by increasing concentrations of MCC while compaction with
MCC and starch 1500 results in decreased strength of compacts
Core material should not be too hard
※ DCP pellets, which obstructs the flow of pellets
In such case, compression force shows impact on the surface and results in deformation of
the surface and alters the release characteristics
OVERCOME OF CHALLENGES II
12. 12
Porosity
Porosity of pellets plays a major role in compression thereby relates to deformation
A study conducted by Nicklsson on compression of pellets with low, medium and high porosity
with extragranular materials MCC, PEG and dicalcium phosphate, the deformation of pellets
was much in favor of medium and high porous pellets
The fact found was that structures with high porous nature become denser due to the applied
compression force and forms as deformed coherent units due to the non interfering excipients
In case of compaction of reservoir pellets with high porous nature, compression force indicates
more densification and deformation with no marked difference in the drug release profiles
Conversely compaction of less porous pellets results in significant increase in the release rates of
the drug which is due to comparatively low densification and deformation
During compaction of porous pellets the entrapped air escapes out due to the compaction
pressure applied and surrounds the densifying pellets
☞ Pellets are subjected structural deformation to greater extent due to the rearrangement of
bonds; can be visualized by SEM analysis, and form coherent tablets
The formation of coherent units is attributed by the polymer coating used and the extragranular
material
The excipients used should not interfere with the pellets which alter the drug release profile
The extragranular material must form closest packing with the deformed pellets
OVERCOME OF CHALLENGES III
13. 13
Polymer coating and Film flexibility
Polymers widely used in attaining specific release profiles are cellulose derivatives and polyacryls
Cellulose and its derivatives like HPMC, HPMCP has elongation < 5% forms hard and brittle
films that fractures during compression whereas polyacryls and copolymers of acrylics form
flexible film deforms easily on compression
Plasticizers like triethyl citrate (TEC), triacetin and PEG also helps in the formation of flexible
films
Among them TEC was found efficient
During compression a highly flexible film ensures elastic properties and prevents cracking of
coating
Polymers like Eudragit along with plasticizers triethyl citrate provide greater flexibility to the
film in sufficient/required quantity
Retardation characteristics occur at higher percentages
OVERCOME OF CHALLENGES IV
14. 14
Mechanical resistance
Film flexibility provides mechanical stability to pellets during compaction
During compression, high mechanical resistance support film integrity by preventing deformation
of pellets
High mechanical stability is given by a dense structure like that provided by mini-tablets,
extrusion pellets or roller compaction granules
Furthermore, a bigger particle size supports mechanical stability and in addition leads to less
interparticle contacts which also support less film damages
OVERCOME OF CHALLENGES V
Coating thickness
The thickness of coating layer is related to mechanical resistance of pellets during compaction
Greater thicknesses support elastic properties, whereas below a certain thickness even highly
flexible films will break
The manner in which deformation of the coated pellets occurs during compaction alters the
thickness of the coating layer which has an impact on the release profile of the drug
If the deformation of the substrate pellet may stretch out the coating, making it thinner or more
permeable, faster drug release was observed
Whereas the densification of the substrate pellet may compress the coating, making it thicker or
less permeable, and consequently results in prolonged drug release
15. 15
Extra-granular material and cushioning agents
Film stability is influenced by extra-granular material during compression
Sharp-edged and abrasive crystalline materials may damage the coating as compression force
increases
his alters the drug release characteristics after compaction into tablets
Type and amount of the coating agent, selection of additives like plasticizers, use of cushioning
excipients and rate of pressure applied must be monitored carefully to maintain the drug release
properties of the sub units helps in the protection of the film
Soft materials or conventional powder excipients with plastic or elastic behavior like micro
crystalline cellulose or lactose can be used to protect film coating
The quantity of extagranular to be compressed along with pellets is 30-70% w/w
A threshold of atleast 30% (w/w) of extra-granular material should be added as it provides
support and cushioning
; hence the coated subunits embed freely in the matrix without segregation and form a coherent
tablet
With use of higher amount of pellets of at least 50%w/w
; variation may reduce, but the tendency for damage to coating increases
OVERCOME OF CHALLENGES VI
16. 16
Extra-granular material and cushioning agents
Generally suggested fillers are combination of different grades of fillers with different particle
size like Avicel PH 200 and Avicel PH 101
Cushioning agents are waxy in nature take up the pressures of compaction by re-arranging
themselves within the tablet structure or by preferentially getting deformed and/or fractured
thereby provides protection to the coated pellets
They also enhance deformation of pellets when used as extra-granular material in addition to
diluents
The best choice of cushioning agent is PEG preferably PEG 6000
Cushioning pellets are normally more porous and soft compared to coated drug pellets and
normally made of excipients which are used
The drug pellets-to-cushioning excipient(s) ratio is very critical in preventing coating film damage
– a ratio of 1:3 or 1:4 is considered most suitable
OVERCOME OF CHALLENGES VI
17. 17
Electrostatic Charges
Development of an electrostatic charge on the pellet surfaces can interfere with their flow during
tablet compression cycle
This problem is usually solved by adding talc, which acts as a glident. During development of
multiparticulate tablets comparative dissolution tests should be conducted to identify the possible
differences between the release rates of the uncompressed tabletting mixture versus the tablets
In order to ensure reproducible drug releases the difference between the two dissolution profiles
should not exceed 10%
OVERCOME OF CHALLENGES VII
18. 18
Tablet press designed MUPS have a modification in the hopper, feed frame and forced feeders
compared to normal tablet press
The hopper for feed consists of a butterfly valve to modulate the flow of blend to feed frame
The feed frame designed is continuous to ensure uniform clearance from the turret and prevent
attrition/ segregation of pellets from extra-granular material and also crushing of coated pellets
throughout the compression process, which is not possible with the regular rotary tablet press
The forced feeder used is gravity feeder, designed to prevent abrasion or grinding of pellets
TABLET PRESS FOR PREPARING MUPS
19. 19
MUPS Compression force
To a greater extent leads to damage of polymeric functional coating and alters dissolution profile
based of the designed type of formulation
In case of delayed release formulation rupture of polymer coat leads to release of drug in
acidic media and thereby, degradation of the drug
Compression speed
Probably be optimum for the formulation
High speed may cause improper die fill
Capping and lamination can be prevented by increasing the contact between punch heads and
compression rollers
PROCESS VARIABLES IN FORMULATING
21. 21
Spheronization is the process where extrudates (the output from an
extruder) are shaped into small rounded or spherical granules
In practice these usually vary in size from 0.4 to about 3.0 mm
The use of these spheroids can be relevant for a wide variety of industries
WHAT IS SPHERONIZATION?
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22. 22
The products produced from this process can be useful in several ways:
Product performance and functionality can be improved or changed to
meet a wide range of requirements
Plant procedures can be simplified, to reduce costs or enhance security of
operation
The process is well known and widely used in the pharmaceutical,
neutraceutical, catalyst, petrochemical, materials science and other
industries
Its use is becoming increasingly recognized in other areas of industrial
material handling
WHY CONSIDER SPHERONIZATION?
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The main uses and advantages of
spheronization ( I )
Possibility Potential benefit...
Agglomerates of
material with a
uniform and controlled
size
Spheronization provides an efficient method of producing uniform
discrete particles of various sizes (size can be controlled, according
to user needs between a wide range of diameters)
As an example, where spheres would allow a better dispersion of
ingredients is especially useful in the pharmaceutical, biotechnology
(such as bone filler and regeneration) and nutraceutical industries
Producing small
particles with a high
surface area to volume
ratio
This can offer advantages in catalyst applications where
maximization of surface area can be useful
In other industries this allows for the most optimum product
for coating where this is required or desirable
The optimization of
flow characteristics
The excellent flow properties of spheres is well known
This allows the use of automated processes or use where exact
dosing is required such as tableting, mold filling, capsule filling and
other forms of packaging
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The main uses and advantages of
spheronization ( II )
Possibility Potential benefit...
Producing the
optimum shape for
coating
Granules and spheres can require coating for a variety of reasons such as
the stabilization of the active ingredients or the controlled release of the
active ingredients
The most widespread use of coated spheroids is the controlled
release of medicine in the pharmaceutical industry
The easiest and most economical shape to coat is a small sphere, as no
additional material is required to coat or fill irregularities in the surface of
the particles
To facilitate the
mixing of non-
compatible Products
Filling of two incompatible active products into capsules can be easily and
cheaply done using spheronized products.
To improve
appearance of
powder or granulated
materials
Having spheres of a uniform and controlled size can significantly improve
the physical appearance of products
In markets where product differentiation is necessary to assist marketing
success, spheronization is a rapid and inexpensive way of separating your
products from the competition
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The main uses and advantages of
spheronization ( III )
Possibility Potential benefit...
To improve the ability
to reproduce the same
physical properties of
packing beds
In several industrial applications columns or porous beds are used as
chemical reactors
The use of small spheres rather than irregular granules allow for easier
calculations, predictions and reproducibility.
To improve the
hardness and friability
of granules
The hardness of any tablet or sphere depends partly upon the internal
cohesive forces and partly on the surface characteristics of the product.
Spheronization increases the hardness and reduces the friability of the
materials being treated
This will reduce the amount of fines or dust during transportation or
subsequent handling
To increase the density
of granules
With spheronization both the true and the bulk density of the products
are increased
The amount of the increase depends upon the formulations being
processed
This gives the opportunity to improve both the processing and
packaging of products
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The main uses and advantages of
spheronization ( IV )
Possibility Potential benefit...
To improve
accuracy in dosage
control
Improved flow characteristics facilitate accurate dosing
control
To improve the high
speed handling of
materials
Spheres have excellent flow properties. This allows the
increased ease of automated processes
To remove dust
hazard
Operations involving powders can produce dust. This
unwanted aspect of production can be a hazard to personal
safety and to the purity of the end product
The management of this is important in many industries
Spheronization will minimize the amount of dust thereby
reducing risk,keeping processes clean and preventing cross
contamination of processes and products during exposed
operations
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The main uses and advantages of
spheronization ( V )
Possibility Potential benefit...
To simplify the
handling of difficult
material
Materials that are difficult to handle such as hygroscopic
materials, flavors, dyestuffs etc. can benefit from
spheronization
Once spheronized they can increase in stability and be less
affected by surrounding conditions
To simplify and
increase speed of
processing
Products that have been spheronized and dried have “fast flow”
characteristics
Problems due to blockage in transfer or valve mechanisms, or
bridging when the material is in hoppers, and losses due to
handling are reduced to a minimum
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WHAT IS THE BASIC EQUIPMENT FOR
THE PROCESS OF SPHERONIZATION?
The process of spheronization consists of four key steps:
Mixing or granulation - a mixer or granulator is required
Extrusion - an extruder is required
Spheronization - a spheronizer is required
Drying and possibly coating - a coater and drier may be required
All of these steps are important and all can have a considerable influence
on the final product performance
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The influence of different mixing/granulating parameters should not be
underestimated
It is true that in many cases mixing can have little or no effect on the
process or final product performance but this should never be assumed
When doing development work, it is important to keep the mixing
/granulation parameters constant (to remove a potential source of
variation) or to make systematic trials and demonstrate the effect (or lack
of effect) of changes in the mixing parameters
Mixing and/or Granulation:
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The extrusion of the materials is a required step prior to spheronization
The final size of the pellets is principally determined by the diameter of
the extrudate used for the spheronization process
For example in order to obtain spheres with a diameter of about 1 mm, a 1
mm diameter hole is used on the extruder die or screen, although
dies and screens with slighter larger hole diameters will sometimes be
used to allow for shrinkage on drying
In a spheronizer, it is possible to obtain spheres with a diameter ranging
from about 0.4 mm to about 8 mm
Extrusion
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A Twin Screw Variable Density production
extruder from Caleva
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Modern spheronizers have several additions and adaptations depending
upon the needs of the particular product and process
The design principle of the spheronizer is relatively simple but the detailed
development of auxiliary equipment and the specifics of the design have
widened the range of applications and greatly improved the flexibility of
the machines
In principle the basic machine consists of a round disc with rotating drive
shaft, spinning at high speed at the bottom of a stationary cylindrical bowl
The spinning friction plate has a carefully designed groove pattern to the
base
This is most often cross-hatched, but several sizes and other types are
available
These discs are designed to increase the friction with the product
Spheronization I
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Extrudates are added to the spheronizer and they fall onto the spinning
plate
During the early contacts of the cylindrical granules with the friction plate,
the extrudates are cut into segments with a length ranging from 1 to 1.2
times their diameter
These segments then collide with the bowl wall and they are thrown back
to the inside of the friction plate. Centrifugal force sends the material to
the outside of the disc
The action of the material being moved causes the extrudate to be
broken down into pieces of approximately equal length relative to the
diameter of the extrudate
Spheronization II
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These cylindrical segments are gradually rounded by the collisions with the
bowl wall, the plate and each other
The ongoing action of particles colliding with the wall and being thrown
back to the inside of the plate creates a “rope movement” of product along
the bowl wall
The continuous collision of the particles with the wall and with the friction
plate will gradually turn the cylindrical segments into spheres, provided
that the granules are pliable enough to allow the deformation without
being destroyed
It is essential that this rope movement is present for an optimal
spheronization
Spheronization III
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These cylindrical segments are gradually rounded by the collisions with the
bowl wall, the plate and each other
The ongoing action of particles colliding with the wall and being thrown
back to the inside of the plate creates a “rope movement” of product along
the bowl wall
The continuous collision of the particles with the wall and with the friction
plate will gradually turn the cylindrical segments into spheres, provided
that the granules are pliable enough to allow the deformation without
being destroyed
It is essential that this rope movement is present for an optimal
spheronization
Spheronization III
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As processing continues, the shape of the pieces gradually changes as
shown below
Spheronization III
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When the particles have reached the desired shape (usually in about 2 to 10
minutes) then the spheroids can be removed
When the particles have obtained the desired spherical shape, the discharge
valve of the spheronization chamber is opened and the granules are
discharged by the centrifugal force
Spheronization IV
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Friction plate pattern
The most common groove pattern used for spheronizer discs is the “waffle-
iron” design, where the friction plate is like a chessboard of chopped-off
pyramids
The choice of which plate to use is not always clear
As a guideline extrudates up to 0.8 mm in diameter are normally processed
on a 2 mm pitch plate
A 3 mm pitch plate is used for extrudates up to 3 mm in diameter
Discs with a radial design are also used, as these are considered gentler on
the material being spheronized
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Friction plate speed
The typical rotation speed of a production size (700 mm diameter) disc
ranges from 200 to 450 rpm
The higher the speed, the more energy is put into the particle during a
collision
The optimum speed depends on the characteristics of the product being
used and the particle size
The smaller the diameter of the disc the higher the speed required
The important parameter is the speed at the outer edge of the disc
In practice the optimum speed can be determined with a little experience
For some products it may be recommended to start at a high speed and to
lower the speed in the final stage of the process
This can be determined by simple practical tests
The process allows a high degree of flexibility for good formulations
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Retention time (The length of time the product is
spheronized in the spheronizer)
Typical spheronization retention times to obtain spheres range from 3 to 8
minutes
This is relatively easy to determine and best obtained by simple trials with
specific products
For some products, the strong cohesive forces in the extrudates prevent
the extrudates from breaking up into smaller pieces
If the objective is to reduce dust and not necessarily obtain perfect spheres
then the short contact with the friction plate is sufficient to break the long
extrudates into small segments and round the edges
The edges of cylindrical granules are the most fragile part and they will
generate dust during handling and transportation
Spheronization with a short retention time can help to reduce the amount
of dust significantly.
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The charge volume or weight (The quantity of
product loaded into the spheronizer)
The optimum level depends upon the machine size and the product
characteristics;
there is an optimum quantity of product to be charged per batch into the
spheronizer chamber that will produce the most narrow particle
distribution and the best spheres
A typical charge volume for a machine with a 380 mm diameter disc is 4
kg depending upon the density of the material
Increasing the load per batch increases the hardness of the spheres and
smooths the granule surface
With the larger 700 spheronizer a load of from 2 kg to about 12 kg is
normal
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Rheology I
The rheology of the product can be changed by using binders or
lubricants, or by changing the mixing time and by altering the liquid
content of the mix
Although the examination of the rheology of the product seems complex
and potentially time consuming to perfect, with a Caleva Mixer Torque
Rheometer (MTR) the ideal formulation can be determined very quickly
and easily
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Rheology II
Binders can be used to increase the strength of the granules and reduce the
amount of fine dust generated during spheronization
If too much binder is added and the granules become too hard, it will be
difficult to obtain good spheres
Lubricants will increase the plasticity but may also increase the amount of
fine dust generated during spheronization
Water can also be used as a lubricant
If too much water is used, sticking can occur on the friction plate and bowl
wall
It can also happen that the granules will stick together, forming big lumps
If the extrudates are too dry, a high amount of fine dust will be generated
The optimum moisture content for spheronization is slightly less than for
extrusion only
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Mixer Torque Rheometer can be used to optimize rheology of your formulation
Rheology III
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Drum Heating/Cooling Jacket
Heating or cooling water can be introduced in a jacket around the
spheronizer bowl
Warm water can be particularly useful on the chamber wall to drive off
moisture that would cause product to stick to the wall
Cooling the wall will avoid temperature rises in heat sensitive products,
although the average temperature rise in a spheronizer is generally rather
small (approximately 2 to 3 °C)
Air introduction (Fines air)
A slight flow of air can be introduced in the chamber from under the
friction plate
This not only prevents dust from getting between the rotating plate and
the wall of the chamber but also can help to remove moisture from the
granule’s surface, improving the friction forces and process efficiency
Auxiliary beneficial options for
spheronizer configuration I
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Automatic timer
It is useful but not essential to have an automatic timer on a spheronizer
Spheronization is a batch process and not a continuous process
Proper timing of the spheronization run time for each batch will help to
maintain standard operating procedures and enhance performance
standardization and product quality
Non-Stick Coatings
For some products, the chamber wall and the plate can be coated with
non-stick materials if this is necessary for ease of use with sticky
materials or cleaning
Auxiliary beneficial options for
spheronizer configuration II
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Twin Dome Granulator
Twin Dome Granulator
Applicable to the fine-granule with a pilot scale production and the low-
volume high-mix production
GMP design
Dome Die and Screw Case are easily disassembled so that the powder-
contacting parts can be cleaned by a water.
Particle diameter: 0.3 mm to 2 mm in diameter
Product shape: Cylindrical
Application examples
Pharmaceutical products
Seasonings
Granulated sugar
Health food products
Agrochemical products
Fish Feed
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Extruder Twin Screw type EXD
(Radial Extrusion)
Extruder Twin Screw type EXD (Radial Extrusion)
The pioneer of wet extrusion granulator in the world.
All powder-contact parts to the product can be easily disassembled and
re-assembled.
Available in Heating/ Cooling Jacket
GMP design is available
Particle diameter: 0.5 mm to 3.0 mm in diameter
Product shape: Cylindrical
Application examples
Pharmaceutical products
Seasonings
Granulated sugar
Health food products
Agrochemical products
Fish Feed
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Spheronizer/ Marumerizer
Converting the cylindrical shaped granule into the spherical shaped
granule by the friction force, the driving force and the centrifugal force.
Also different length of cylindrical granules are converted into uniform
length in a short operation time
Spherical granules can be produced with narrow/sharp particle size
distribution with high yield
All powder-contact parts to the product can be easily disassembled and re-
assembled.
GMP design is available
Particle diameter: 0.4 mm to 10 mm in diameter
Product shape: Spherical granule
Application examples
Pharmaceutical products (Coating for the Drug Delivery System of
pharmacy)
Agrochemical products (Coating for the sustained release of WDG)
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Combined Granulation System
Multiple devices are combined from the product feeding to spheronization
By reducing the human intervention in the process, it contributes to the
stable product quality and the labor cost reduction
Each device is redesigned so that its structure is suitable for integration
Granulator can be chosen to meet the desired capacity, granule size
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76. 왜 에스라졸은 넥시움과 용출패턴이 달라야 하나
76
1.넥시움은 장용성코팅을 한 소형 pellet1000개를 압축하여 정제로 만든 제형
(외부는 일반 코팅)
→ 정제는 위에서 붕해되지만 장용pellet은 소장에서 개별적으로 붕해되고 약물용출
2.에스라졸은 정제내부에 알카리화제와 안정화제를 홉한한후 나정을 장용코팅한 코팅정
→ 정제는 위에서 붕해되지 않고 소장에서 정제가 붕해되고 약물이 용출
☞ 위에서 붕해된 넥시움이 소장 상부에서 흡수가 되는 방면 에스라졸은 소장에서 정제가
붕해되고 용출되므로 넥시움에 비해 상대적으로 천천히 흡수된다
☞ 흡수의 시간 차이를 극복하기 위해 에스라졸이 넥시움 보다 용출이 빨라야 흡수차이를
상쇄할수 있음
80. 80
TOPROL-XL uses a patented extended-release technology
TOPROL-XL (metoprolol succinate) is available in extended-release tablets
with oral administration, providing 24-hour hypertension treatment with 1 dose daily
TOPROL-XL
81. 81
Mean steady-state plasma concentrations
TOPROL-XL maintained consistent plasma levels vs immediate-release metoprolol
and immediate-release atenolol over 24 hours
TOPROL-XL
83. 태평약 제약 자체 기술 독사조신 서방성 제제
MSCR (multi-stage controlled release )기술
OROS 특허 회피 전략으로 매트릭스 시스템으로 서방성 제제 개발
한미약품 H-matrix 기술 회피 전략으로 3중 방출 제어 모델 설정
프조신 XL
2023-07-10 83
121. Elan사의 대표적인 서방성 제제기술
입상백당(Nonparel) 같은 불활성 core에 약물을 코팅한 후 방출조절이 가능한
폴리머를 적절한 비율로 코팅한 미세한 구형입자
(spherical bead, 직경 1∼2 mm )
적용하는 폴리머의 조성변경 -> 다양한 방출 양상을 나타내는 제제 개발 가능
SODAS (Spheroid oral drug absorption system)
SODAS : Technology overview
2023-07-10 121
122. Sodas® multilayer tablet technology is a multilayer drug delivery system
which focuses on the production of controlled release beads
The Sodas® technology is characterized by its inherent flexibility that
enables the production of customized dosage forms that respond directly
to individual needs such as pain and blood pressure
The technology essentially leads a pursatile drug release where the drug is
released in pulses that are separated by defined time intervals
Examples of this technology include Ritalin® LA and Focalin® XR
They are both used to treat Attention Deficit Hyperativity Disorder
(ADHD)
They provide a once-daily pulsed profile that offers the patient
efficacy throughout the day negating the need for taking the dose during
working hours unlike the twice-daily dosing of the conventional
immediate release tablet
A schematic representation of Sodas®
multilayer tablet technology
2023-07-10 122
123. Benefits offered by the SODAS® technology include
Controlled absorption with resultant reduction in peak to trough ratios,
targeted release of the drug to specific areas within the gastrointestinal
tract, absorption independent of the feeding state, suitability for use with
one or more active drug candidate, facility to produce combination dosage
forms, “sprinkle dosing” by administrating the capsule contents with soft
food, once or twice daily dose resembling multiple daily dose profiles
A schematic representation of Sodas®
multilayer tablet technology
2023-07-10 123
126. SODAS : Technology overview
The SODAS® delivery system continues to be an accepted and approved system by regulatory
authorities with five products approved and launched in the U.S. since 2002 including once daily
oral dosage forms of Avinza®, Ritalin® LA, Focalin® XR and Luvox® CR
2023-07-10 126
127. SODAS continues to be an accepted and approved system by regulatory authorities with the
most recent regulatory approvals for a SODAS based system occurring since US in 2002 with
the launch of once daily oral dosage forms of Avinza®, Ritalin® LA and Focalin® XR
A number of other compounds are in late stage development utilizing Elan’s SODAS technology
Avinza : Morphine Sulfate Extended release capsule[Norvatis]
Ritalin LA : Methylphenidate HCl , Extended release capsule[Ligand]
Focalin XR : Dexmethylphenidate (Norvatis)
SODAS : 시판제품
2023-07-10 127
142. Verelan® PM represents a commercialized product using the CODAS technology
The Verelan PM formulation was designed to begin releasing Verapamil approximately four
to five hours post ingestion
This delay in release is introduced by the level of release controlling polymer applied to the
drug loaded beads
The release controlling polymer is a combination of water soluble and water insoluble
polymers
As water from the gastrointestinal tract comes in contact with the polymer coat beads, the
water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in
the coating
The water insoluble polymer continues to act as a barrier, maintaining controlled release of
the drug
When taken at bedtime, this controlled onset extended release delivery system enables a
maximum plasma concentration of Verapamil in the morning hours, when blood pressure
normally rises from its overnight low
CODAS : Technology overview
2023-07-10 142
146. PRODAS involves direct compression of an immediate release granulate to
produce individual minitablets.
These minitablets are subsequently packaged into hard gelatin capsules,
which represent the final dosage form
A more beneficial use of the technology, however, is in the production of
controlled release formulations.
In this case the incorporation of various polymer combinations within the
granulate delays the release rate of drug from each of the individual
minitablets.
These minitablets may subsequently be coated with controlled release
polymer solutions to provide additional delayed release properties
PRODAS : Technology overview
2023-07-10 146
158. 2023-07-10 158
보유기술 III
( TaPe Capsule Technology )
복합제 제조시 주성분간의 물리화학적 상호작용을 극복 복합제
내부 : 고형정제 및 펠렛을 함유하는 캡슐형 제형
안정성 및 물리화학적 상호작용문제로 단일제제화 하기 어려운 다수의 성분 복합
내부에 포함된 정제 및 펠렛 : 장용코팅, 서방화 등 다양한 제제특성
159. 2023-07-10 159
보유기술 IV
( Double SODAS Technology )
시판제품 (클라빅신듀오 캡슐)
2010년 유럽에서 발매된 사노피-아벤티스사와 BMS사가 공동으로 개발한 복합제
DuoPlavin’(DuoCover)‘과 비교해 장기복용에 따른 아스피린의 위점막 자극 등의 부작용 최소화
성분 간의 약물상호작용을 방지
→ 안정성을 높일 수 있도록 double SODAS (spheroidal oral drug absorption) 제제기술을 적용
→ 장용성펠렛(enteric coating pellet)
Double SODAS
클로피도그렐(속방성 펠렛) + 아스피린(장용성 펠렛)
→캡슐에 충진해 주성분 간의 물리적 접촉을 차단함으로써 안정성 강화
단일제 병용투여와의 비교임상시험
→클로피도그렐, 아스피린 뿐만 아니라 각각의 활성대사체에 대해서도 동등한 약물동태학적 특성
169. 169
대원 '업타파' 약 20억 독주체제 시동…동광·한림도 10억원 돌파
피타바스타틴 + 페노피브레이트 복합제 시장: 1년만에 두 배 가량 확대
피타바스타틴의 오리지널 의약품 : JW중외제약(리바로정)
한림제약 등 8개 제약사
-파타바스타틴 + 페노피브레이트 복합제국내 허가→2019.07 시판
특장점
-피파바스타틴 : LDL 콜레스테롤 감소
-페노피브레이트 : 중성지방 감소 / HDL 콜레스테롤 증가
적응증
-관상동맥심질환(CHD) 고위험이 있는 성인환자에서 피타바스타틴 2mg 단일치료
요법시 LDL-콜레스테롤 수치는 적절히 조절되지만 트리글리세라이드 수치는 높고
HDL-콜레스테롤 수치는 낮은 복합형 이상지질혈증의 치료
복합제 특장점
174. 174
에소메졸 DR
청구항 1
에스오메프라졸(esomeprazole)염을 함유하는
; 코어, 상기 코어 상에 형성된 내피 코팅층
; 상기 내피 코팅층 상에 형성된 제 1 장용성 코팅층을 포함하는 제1용출부
; 상기 내피 코팅층 상에 형성된 제 2 장용성 코팅층을 포함하는 제2용출부
; 복합 캡슐
; 상기 제1장용성 코팅층은 코팅기제로서 메타크릴산 코폴리머 LD를 내피 코팅층이 형성된
코어의 5 내지 50%(w/w)로 포함
; 상기 제2장용성 코팅층은 코팅기제로서 메타크릴산 코폴리머 S및 메타크릴산 코폴리머 L의
1.5:1 내지 3.5:1(w/w) 혼합물을 내피 코팅층이 형성된 코어의 15 내지 40 %(w/w)로 포함
; 제1용출부 및 제2용출부의 코어는 모두 미니정제인 복합 캡슐제
182. Introduction
General administration methods for the sprinkle drug products in various dosage forms including
tablets, powder, granules, immediate-release (IR) capsules, extended-release (ER) capsules, delayed-
release (DR) capsules, and multiarticulate drug delivery system (MDDS).
2023-07-10 182
183. Pentasa
The number of approved New Drug Applications (NDAs) for sprinkle drug products since 1941
A total of sixty-five original sprinkle products are available on the US pharmaceutical market
2023-07-10 183
206. 206
Diclofenac sodium 75 mg biphasic-release capsules comprising
DR pellets (magenta beads) and XR pellets (yellow beads)
Concepts of MUPS
207. 207
SEM micrographs of cross-sections of diclofenac sodium DR and XR pellets ( 500×) and Raman maps of XR pellets (spatial
resolution of 10 µm and high resolution of 3 µm)
Rocation of diclofenac sodium marked with red color, core material with different shades of blue, hypromellose—green to
yellow, and polymethacrylate-based coating—pink
Concepts of MUPS
217. 217
Pellets prepared by conventional and innovative technologies III
Schematic illustration of drug layering process of the active substance
from solution/suspension and polymer coating
218. 218
Pellets prepared by conventional and innovative technologies IV
Schematic illustration of dry powder layering of starter core and polymer coating
234. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Capsule Filling with
JRS Pharma‘s
NON-PAREIL SEEDS
Sacchari spheri Ph.Eur.,
Sugar Spheres USP / NF
235. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
4 names for one dosage form:
Globuli
Pellets
Spheres
Non-Pareils
JRS Pharma‘s
NON-PAREIL SEEDS
Sacchari spheri Ph.Eur.,
Sugar Spheres USP / NF
236. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Capsule Filling
With Powder With Non-Pareils
Functions as carrier for
controlled or sustained
release drug delivery
technologies
No active function
Sugar based
MCC based
Lets talk about this!
237. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Tablets are cheap – why to use capsules filled
with spheres?
High Content Uniformity
Consistent and controlled drug release
Multiple drug can be combined in one unit
High drug stability
Many different ways to coat the active
Easy Manufacturing Process
Risk of drug dumping is reduced
238. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Easy Manufacturing Process:
Active + (...) + Solvent:
1. Coating of NON-PAREIL SEEDS with an Active Solution
2. Drying of the pellets
For Sustained Release Formulations:
1. Coating of the Active-Spheres with coating material, e.g.
HPMC Solution, in different thickness
2. Drying of the pellets
Single Units Cores in different sizes
Active in the same concentration
Film in different thickness
239. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Multiple Units
core
active
film
Single Units
Body
Disintegration with
different
release profiles
Easy Manufacturing Process:
240. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Sustained Release Systems
Film coating systems: Limits
Working with spheres
(multiple dosage):
No problem !
Working with tablets
(single unit):
High risk !
241. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Benefits of sustained release formulations?
Homogenous blood concentration levels due to
their consistent distribution in the GI-tract
Improved patient compliance by reducing
dose frequency
Therefore reduced side effects
Resistance of API to stomach acid
242. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Characteristics of NON-PAREIL SEEDS?
specially designed spherical particles
of uniform diameter within different grades
white, uniform granules
Remainder is chiefly starch
243. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Important properties of NON-PAREIL SEEDS
Sweet taste
Practically inert and odorless
Not sensitive against heat (up to 30°C)
High breaking hardness – uniform surface
Nearly no abrasion –
no dust development – therefore
easy to coat
High surface area for the active coating
244. LEADING THE WORLD IN EXCIPIENTS JRS PHARMA
Monograph Specifications: Sugar Spheres NF
1. Appearance White, hard, brittle, free-flowing, spherical masses
2. Identification The insoluble portion of a slurry gives a reddish-violet
to deep blue color with iodine
3. Specific rotation + 41° - + 61°
4. Loss on drying not more than 4.0 %
5. Sucrose 62.5 – 91.5 % on dried basis
6. Residue on ignition not more than 0.25 %
7. Particle size (by RoTap)
not less than 90.0 % passes the coarser sieve
sieze stated in the labelling; 100 % passes the
next coarser sieve size listed in the labelling.
Not more than 10.0 % passes the finer sieve
size stated in the labeling.