BURST DRUG RELEASE COMPOSITIONS
BACKGROUND
Burst dmg release from extended release hydrophilic matrix tablets is an
evolving area of pharmaceutics. The pharmaceutical industry employs various methods
for compounding pharmaceutical agents in tablet formulations. In addition to active
Ingredients, fonnulations include other excipients such as controlled release agents,
diluents, binders, disintegrants, surface active agents, glidants, lubricants, colorants,
coating substances, surfactants and many other raw materials that impart different
properties to the final solid dosage product.
Further, certain processing steps are utilized to formulate and accurately
formulate and/or manufacture solid dose products. The most common processing steps
associated with preparing solid dose formulations are summarized below:
"Wet Granulation" methods can be used where the flow properties of a
compound such as an active pharmaceutical ingredient ("API") are poor which result in
content unifonnity issues when fomriulated as a dry blend. Wet granulation is commonly
used to improve the processing characteristics of a powder blend, including improved
flowability, content unifonnity and more uniform particle size.
Wet granulation is used to improve flow, compressibility, bio-availability,
homogeneity, electrostatic properties, and stability of solid dosage forms. Granulation
is often required to improve the flow of powder mixtures and mechanical properties of
tablets. Granules are usually obtained by adding liquids (binder or solvent solutions).
Larger quantities of granulating liquid produce a narrower particle size range and
coarser and harder granules, i.e. the proportion of fine granulate particles decreases.
The particle size of the granulate is determined by the quantity and feeding rate of
granulating liquid.
1
Wet granulation methods can be used where the flow properties of a compound
such as an active phannaceutical ingredient ("API") are poor which result in content
uniformity issues when formulated as a dry blend. Wet granulation is commonly used to
improve the processing characteristics of a powder blend, including improved
flowability, content unifomiity and more uniform particle size. The use of water and heat
in wet granulation may cause chemical degradation or physical fonn conversion.
The variables faced in the processing of the granules can lead to significant
tableting problems. Properties of granules formed can be affected by viscosity of
granulating solution, the rate of addition of granulating solution, type of mixer used and
duration of mixing, method and rate of dry and wet blending. The above variables can
change the density and the particle size of the resulting granules and may have a major
influence on fill weight and compaction qualities. Drying can lead to an unfavorable
separation as soluble API migrates to the surface of the drying granules.
"Direct Compression" is defined as the process by which tablets are compressed
directly from powder mixture of API and suitable exclpients. No pretreatment of the
powder blend by wet or dry granulation procedure is required. It involves only blending
and compression. This offers the advantage of speedy production because it requires
fewer unit operations, less machinery, and generally less processing time along with, in
some cases, increased product stability.
In case of directly compressed tablets after disintegration, each primary dmg
particle is liberated. While in the case of tablets prepared by compression of granules,
small drug particles with a larger surface area adhere together into larger agglomerates;
thus decreasing the'surface area available for dissolution.
While having all the benefits a granulation process can provide such as
improving material flow behavior and content uniformity, "Roller Compaction" offers
unique advantages over wet granulation for moisture, solvent or heat sensitive
compounds.
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In roller compaction, powder Is fed to two counter-rotating rolls wtiich draw ttie
powder between the rolls due to friction, which compacts the powder. Roller compaction
is seemingly a simple process but the fundamental mechanisms are complex due to a
number of material properties and machine variables involved such as material flow
properties, ftiction against roll surface, compressibility, compactibility, elastic properties,
air permeability, roll surface, roll dimension, roll pressure, roll gap, roll speed, feed
method and conditions.
There are generally three controllable parameters in the roller compaction
process: roll pressure, roll gap and roll speed. Because the consolidation of a powder
blend into ribbons is the result of mechanical stress (normal and shear stresses) within
the powder during roller compaction, all the parameters are studied by examining their
con^elation to the normal (compressive) stress and the shear sti^ess.
Viscosity is anotiier characteristic that is relevant to solid dosage pharmaceutical
compositions, Oiough viscosity is most commonly recognized as property which
characterizes the flow nature of a liquid. In tiie pharmaceutical arts, viscosity becomes
relevant with respect to solid dosage forms such as tablets and capsules once these are
taken orally and are exposed to the fluids in the digestive tract including tiie mouth,
throat, stomach and intestines.
Controlled release agents are commonly included as excipients in
phamnaceutical fomriulations. Such sustained release agents, preferably a substituted
cellulose derivative, such as hydroxypropylmetiiyl cellulose (HPMC) facilitate the
delayed release of tiie phannaceutically active ingredients from tiie formulation such
that the fonmulation can be administered to a patient less often, such as once daily. It is
preferably present in an amount tiiat allows for the fonnation of a gel matiix from which
the active ingredient is gradually released. In addition, composition contemplated
herein may comprise further sustained release agents, preferably those that swell upon
contact with water such as polyvinylpyn-olidone, hydroxyethylcellulose,
hydroxypropylcellulose, other cellulose ethers and esters like methylcellulose,
methylethylcellulose, hydroxypropylmetiiylcellulose, carboxymethylcellulose, starch,
pregelatinized starch, polymethacrylate, polyvinylacetate, microcrystalline cellulose,
dextrans or mixtures thereof.
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SUMMARY OF THE INVENTION
The Inventors have found that certain kinds of processing on ingredients in
formulations that included pharmaceutical actives and controlled release agents with
certain apparent viscosities have marked effect on the dissolution of the active
ingredients. In the phannaceutical sciences, controlling the dissolution rate of active
ingredients can be critical to the desired release timing and functionality of the active
ingredient(s). As such, the discoveries and compositions disclosed herein offer novel
approaches to controlling the dissolution of active ingredients through unique
combinations of ingredients and using specifically processed active ingredient(s) in the
compositions.
DESCRIPTION OF THE INVENTION AND EXAMPLES
One specific observation and advantage of the inventions disclosed herein is that
the process of wet granulation of the mix of pharmaceutically active ingredients plus
controlled release agents gave surprising results in solid formulations with respect to the
burst characteristics of pharmaceutically active ingredients at certain viscosities.
Spedfically, higher viscosity formulations where the mix of pharmaceutically active
ingredients plus conti-olled release agents were processed using wet granulation had
consistently faster burst rates.
Conversely, anotiier specific observation and advantage of the inventions
disclosed herein is that the processes of direct compression and roller compaction
showed similar characteristics to each other with respect to burst characteristics of
phannaceutically active ingredients at certain viscosities. Specifically, higher viscosity
formulations where tiie mix of phannaceutically active ingredients plus controlled
release agents were processed using direct compression and roller compaction had
consistently slower burst rates tiian those processed using wet granulation.
The invention will allow the formulation of pharmaceuticals wherein release
profiles can be adjusted to create compositions with both Immediate Release (IR) and
Extended Release (ER) characteristics. As a prefen-ed embodiment, with respect to
pain management products, a critical need is to have an initial dose released up front to
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provide analgesia along with efficacious blood levels for sustained time periods.
Compositions, exemplified herein, offer such advantageous characteristics.
A further advantage to the compositions embodied by this invention is that IR/ER
formulations can be created in a single, monolithic design. Contrary to commonly used
multilayer approaches to IR/ER fomnulations, monolithic prototypes have significant
advantages from a manufacturing perspective. The tablet/capsule press can be mn
faster as the compression events that are occurring are less complicated. Additionally,
with tablet presses that are double sided, production rates can be doubled. Also, tablet
specifications are more straight fonvard as you are only dealing with a single layer. As
such, there is less concern with layers sticking to one another as can occur with
bilayers. Further, bilayer tablets may have higher friability.
With regard to active ingredients, the prefen^ed embodiment includes NSAIDs
present in an analgesia- inducing or pain-alleviating amounts. Of the cyclooxygenase-1
inhibitors useful in the practice of the present invention, including those that are
mentioned as being prefen-ed, ibuprofen may be present in the claimed compositions in
amounts ranging from about 50 to about 800 mg. Preferably it is present in amounts
ranging from about 200 to about 600 mg. Most preferably, it is present in an amount of
about 600 mg. The tenns "effective amount" or "therapeutically effective amount" of an
active agent as provided herein is defined as an amount of the agent at least sufficient
to provide the desired therapeutic effect. As noted above, the present invention is based
on the discovery that the effective dose of a decongestant and/or antihistamine can be
reduced if administered with a nonnal dose of a NSAID. The exact amount required will
vary from subject to subject, depending on age, general condition of the subject, the
severity of the condition being treated, and the particular active agent administered, and
the like.
The tenn "normal approved dose" of an active agent as provided herein is
defined as an amount of the agent that has been approved as safe and effective by the
United States Food and Dnjg Administration for administration in humans in a particular
dosage form. An approved dose is thus a dose found in a pharmaceutical product, an
amount of active agent per unit dosage form. In the present invention, reference to a
ratio of approved doses means doses approved for the same patient population (e.g.,
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adult to adult or pediatric to pediatric), and approved for the same dosage form (e.g.,
elixir, tablet, capsule, caplet, controlled release, etc.).
In the practice of the invention, one of ordinary skill in the art can take an
approved dosage form of any over-the-counter (OTC) or prescription decongestant
and/or antihistamine, reduce it by, e.g., 25% to 50% or more, and co-administer it with
an approved amount (dose) of a NSAID to achieve effective relief of rtiinitis with
reduced side effects. In one embodiment, the present invention contemplates the use of
less than or equal to about 75% and more that 1% of an amount present in an approved
dose of one or more of the decongestant, antitussitive or the antihistamine, relative to
an amount of the NSAID con-esponding to about 100% of the amount present in a
normal strength dosage form of the NSAID. An alternate range is from about 10% to
about 65%. Another range is from about 30% to about 55%. Ranges from about 35% to
about 50% are also possible.
The present invention contemplates compositions comprising either a single or
multiple pharmaceutically active ingredients (i.e., decongestant, antihistamine and
NSAID).
The non-steroidal anti-inflammatory drugs (NSAID's) for use in the
phamiaceutical compositions and methods of use of the present invention may be
selected from any of the following categories:
(1) The propionic acid derivatives;
(2) the acetic acid derivatives;
(3) The fenamic acid derivatives
(4) The biphenylcarboxylic acid derivatives;
(5) The oxicams, and
(6) Cox-2 inhibitors
Accordingly, the term "NSAID" as used herein is intended to mean any nonsteroidal
anti-inflammatory compound, including the pharmaceutically acceptable nontoxic
salts thereof, falling within one of the six structural categories above.
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The specific compounds falling within the foregoing definition of the non-steroidal
anti-inflammatory drugs for use in the present invention are well known to those skilled
in the art and reference may be found in various literature reference sources for their
chemical structures, pharmacological activities, side effects, nonnal dosage ranges, etc.
See, for example. Physician's Desk Reference, and The Merek Index.
Of the propionic acid derivatives for use herein, ibuprofen, naxproxen,
flurbiprofen, fenoprofen, ketoprofen, suprofen, fenbufen, and fluprofen are specifically
contemplated. Of the acetic acid derivatives, exemplary compounds include tolmetin
sodium, zomepirac, sulindac and indomethadn. Of the fenamic acid derivatives,
exemplary compounds include mefenamic acid and meclofenamate sodium. Exemplary
biphenylcarboxlic acid derivatives for use in the present invention include diflunisal and
flufenisal. Exemplary oxicams include piroxicam, sudoxicam and isoxicam. Exemplary
Cox-2 inhibitors include celecoxib, rofecoxib, meloxicam, and nimesulide. Of the
foregoing non-steroidal anti-inflammatory drugs, in the practice of the exemplified
embodiments of the present invention, ibuprofen is exemplified.
With respect to the dosage amount of the non-steroidal anti-inflammatory drugs
in the compositions of the invention, although the speciflc dose will vary depending
upon the age and weight of the patient, the severity of the symptoms, the incidence of
side effects and the like, for humans, typical effective analgesic arriounts of NSAID's are
about 200-1000 mg diflunisal, about 50-200 mg zomepirac sodium, about 100-800 mg
ibuprofen, more preferably 600 mg ibuprofen, about 250-1000 mg naproxen, about 50-
200 mg fluriDiprofen, about 100-400 mg fenoprogen, about 20-40 mg piroxicam, about
250-500 mg mefanaic acid, about 200-800 mg fenbufen or about 50-100 mg ketoprofen;
however, greater or lesser amounts may be employed if desired or necessary.
The term "antihistamine", used in connection with treating nasal symptoms
associated with allergy or cold, generally refers to histamine Hi receptor antagonists.
Numerous chemical substances are known to have histamine Hi receptor antagonist
activity. Many useful compounds can be classified as ethanolamines, ethylenediamines,
alkylamines, phenothiazines or piperidines. Representative Hi receptor antagonists,
include, without limitation: astemizole, azatadine, azelastine, acrivastine,
brompheniramine, chlorpheniramine, clemastine, cyclizine, carebastine,
cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117),
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desloratadine doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine,
hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin,
noberastine, meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine,
tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily
be evaluated to detennine activity at Hi receptors by known methods, including specific
blockade of the contractile response to histamine of isolated guinea pig ileum.
Chlorpheniramine is specifically contemplated herein. The usual adult dosage of
chlorpheniramine is 4 mg orally every 4-6 hours as needed, up to a maximum of 24 mg
per day. The usual pediatric dosage of chlorpheniramine is 2 mg orally every 4-6 hours,
up to a maximum of 12 mg per day. The prefen-ed salt is chlorpheniramine maleate. In
accordance with the present invention, the usual adult dosage is thus reduced to 3 mg,
or further to 2 mg, orally every 4-6 hours as needed, up to a maximum of 12-18 mg per
day. Similarly, in an embodiment of the invention, the pediatric dosage is 1.5 mg, or 1
mg, orally every 4-6 hours, up to a maximum of 6-9 mg per day. In a further
embodiment, the invention permits combining a pediatric dosage of chlorpheniramine
with an adult dosage of an NSAID, such as ibuprofen.
The decongestants for use in the pharmaceutical compositions and methods of
use of the present invention include, but are not limited to, pseudoephedrine,
phenylephedrine, phenylpropanolamine. One of skill in the art would know of many
other appropriate decongestants and their approved dosages.
Pseudoephedrine and phenylephedrine are specifically contemplated herein. The
usual adult dose of pseudoephedrine is 60 mg every 4-6 hours, up to a maximum of 240
mg per day. The usual pediatric dose of pseudoephedrine is 15 mg every 6 hours, up to
a maximum of 60 mg per day for ages 2-5 and 30 mg every 6 hours, up to a maximum
of 120 mg per day for ages 6-12. Thus, in specific embodiments of the practice of the
present invention, the adult dose can be reduced to 45 or 30 mg every 4-6 hours, with a
maximum of 120 to 180 mg per day, and the pediatric dose can be reduced to about 11
or 7.5 mg every 6 hours, up to a maximum of 30-45 mg per day. From the foregoing it is
apparent that the invention contemplates administering a double pediatric dose with a
normal adult dose of an NSAID to an adult.
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Anti-tussitives act on the brain to suppress the cough reflex. Such cough
suppressants are used to relieve dry persistent coughs. The most commonly used
daigs are dextromethorphan (an NMDA receptor antagonist), codeine and pholcodine
(which are opioids. However, one skilled in the art would understand that there are
many other well known and common anti-tussitives that may be used. The present
invention is optionally direct to the use of anti-tussitives. The anti-tussitive may be used
in amounts of less than or equal to 75% of the approved approved dosage.
Compositions of the invention are fonnulated in a solid single dosage form such
as tablets, capsules, sachets, trochets and the like. Solid compounds will typically be
administered orally.
Exemplary compositions of the present invention are directed to solid dosage
forms such as bulk powders, tablets, caplets, pellets, capsules, sachets, granules, and
any other dosage form suitable for oral administration. For purposes of this specification
and the accompanying claims, the tenn "tablet" refers equally to a tablet, a caplet or any
other solid dosage fomn which is suitable for oral administration.
Also contemplated are the inclusion of one or more non-pharmaceutically active
excipients in the compositions of the present invention. These include, but are not
limited to, controlled release agents, diluents, binders, disintegrants, surface active
agents, glidants, lubricants, colorants, coating substances, surfactants and many other
raw materials that impart different properties to the final solid dosage product.
Controlled release agents are commonly included as excipients in
pharmaceutical formulations. Such sustained release agents, preferably a substituted
cellulose derivative, such as hydroxypropylmethyl cellulose (HPMC) facilitate the
delayed release of the pharmaceutically active ingredients from the formulation such
that the formulation can be administered to a patient less often, such as once daily. It is
preferably present in an amount that allows for the formation of a gel matrix from which
the active ingredient is gradually released. In addition, composition contemplated
herein may comprise further sustained release agents, preferably those that swell upon
contact with water such as polyvinylpyrrolidone, hydroxyethylcellulose,
hydroxypropylcellulose, other cellulose ethers and esters like methylcellulose,
methylethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, starch,
9
pregelatinized starch, polymethacrylate, polyvinylacetate, microcrystalline cellulose,
dextrans or mixtures thereof. Generally, controlled release agents are present in an
amount from about 0.5% to about 50% of the weight of the final composition and more
specifically from about 10% to about 30% of the weight of the final composition.
Binders are agents used to impart cohesive qualities to the powdered material.
Binders impart cohesiveness to the tablet formulation which insures the tablet remaining
intact after compression, as well as improving the free-flowing qualities by the
formulation of granules of desired hardness and size. Suitable binder materials include,
but are not limited to, starch (including com starch and pregelatinzed starch), gelatin,
sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol,
waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, celluloses
such as Microcrystalline Cellulose and synthetic polymers such as polymethacrylates
and polyvinylpyrrolidone.
Lubricants have a number of functions in tablet manufacture. They prevent
adhesion of the tablet material to the surface of the dies and punches, reduce
interparticle friction, facilitate the ejection of the tablets from the die cavity and may
improve the rate of flow of the tablet granulation. Examples of suitable lubricants
include, but are not limited to, magnesium stearate, calcium stearate, stearic acid,
glyceryl behenate, talc, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene
glycol or mixtures thereof. Generally, the lubricant is present in an amount from about
0.25% to about 5% of the weight of the final composition and more specifically from
about 0.5 to about 1.5% of the weight of the final composition.
A disintegrant is a substance, or a mixture of substances, added to a tablet to
facilitate its breakup or disintegration after administration. Materials serving as
disintegrants have been classified chemically as starches, clay, celluloses, aligns, gums
and cross-linked polymers. Examples of suitable disintegrants include, but are not
limited to, crosscarmelose sodium, sodium starch glycolate, starch, magnesium
aluminum silicate, colloidal silicon dioxide, methylcellulose, agar, bentonite, alginic acid,
guar gum, citrus pulp, carboxymethyl cellulose, microcrystalline cellulose, or mixtures
thereof. Generally, the disintegrant is present in an amount from 0% to about 30% of the
weight of the final composition and more specifically from about 0% to about 15% of the
weight of the final composition.
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Glidants are substances which improve the flow characteristics of a powder
mixture. Examples of glidants include, but are not limited to colloidal silicon dioxide, talc
or mixtures thereof. Generally, the glidant is present in an amount of from about 0.1 % to
about 10% of the weight of the final composition and more specifically from 5 about
0.1 % to about 5% of the weight of the final composition.
The adsort>ent may be, for example colloidal silicon dioxide, microcrystalline
cellulose, calcium silicate or mixtures thereof. Generally, the adsorbent is present in an
amount from about 0.05% to about 42% of the weight of the final composition and more
specifically from about 0.05% to about 37% of the weight of the final composition.
If desired, other ingredients, such as diluents, stabilizers and anti-adherents,
conventionally used for pharmaceutical formulations may b>e included in the present
formulations. Optional ingredients include coloring and flavoring agents which are well
known in the art.
The pharmaceutical composition described in the present invention may be
formulated to release the active ingredients in a sustained release manner. Various
formulations are contemplated for dosage forms of these components.
The invention is further described by means of the following examples, which are
not intended to limit the scope of the claimed invention in any manner.
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EXAMPLES
The following embodiments demonstrate the advantages of the inventions.
To investigate process effects, small scale lab batches of monolithic prototypes
were manufactured by wet granulation (WG), roller compaction (RC), and direct
compression (DC). To investigate polymer effects, a matrix of different viscosity grades
(K100LV and K4M) and levels of hydroxypropyl methylcellulose (20 and 25% HPMC)
was evaluated. See Table 1 for the premix preparations used in the specific Examples
below.
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Table 1: Premix preparations used in the examples
Premix Batch A: 20% HPMC (100:0 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen USP 90 Grade (BASF) 67.26 600.00
MCC, NF(AvicelpH102) 12.56 112.00
HPMC, USP K100LV Premium CR 20.18 18000
HPMC, USP K4M Premium CR 0.00 000
TOTAL I 100.00 I 89200
Premix Batch B: 20% HPMC (67:33 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen USP 90 Grade (BASF) 67.26 600.00
MCC, NF(AvicelpH102) 12.56 112.00
HPMC, USP K100LV Premium CR 13.45 120.00
HPMC, USP K4M Premium CR 6.73 60.00
TOTAL 100.00 892.00
13
Premix Batch C: 20% HPMC (33:67 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen USP 90 Grade (BASF) 67.26 600.00
MCC, NF(AvicelpH102) 12.56 112.00
HPMC, USP K100LV Premium CR 6.73 60.00
HPMC, USP K4M Premium CR 13.45 120.00
TOTAL I 100.00 I 892.00
Premix Batch D: 20% HPMC (0:100 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen USP 90 Grade (BASF) 67.26 600.00
MCC. NF(AvicelpH102) 12.56 112.00
HPMC, USP K100LV Premium CR 0.00 0.00
HPMC, USP K4M Premium CR 20.18 180
TOTAL 100.00 I 892.00
Premix Batch E: 25% HPMC (100:0 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen USP 90 Grade (BASF) 63.06 600.00
MCC, NF(AvicelpH102) 11.72 111.50
HPMC, USP K100LV Premium CR 25.22 240.00
HPMC, USP K4M Premium CR 0.00 0.00
TOTAL 100.00 I 951.50
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Premix Batch F: 25% HPMC (67:33 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen USP 90 Grade (BASF) 63.06 600.00
MCC, NF(AvicelpH102) 11.72 111.50
HPMC, USP K100LV Premium CR 16.82 160.00
HPMC. USP K4M Premium CR 8.41 80.00
TOTAL 100.00 951.50
Premix Batch G: 25% HPMC (33:67 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen USP 90 Grade (BASF) 63.06 600.00
MCC. NF(AvicelpH102) 11.72 111.50
HPMC. USP K100LV Premium CR 8.41 80.00
HPMC. USP K4M Premium CR 16.82 160.00
TOTAL I 100.00 I 951.50
Premix Batch H: 25% HPMC (0:100 K100LV:K4M)
~ Batch Size 4 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen USP 90 Grade (BASF) " 63.06 600.00
MCC. NF(AvicelpH102) 11.72 111.50
HPMC. USP K100LV Premium CR 0.00 0.00
HPMC. USP K4M Premium CR 25.22 240
TOTAL I 100.00 I 951.50
15
The following compositions were then formulated. The premixes A - H (in Table I)
were blended and portions of each premix were distributed to the three manufacturing
processes. The direct compression premix was blended with silicon dioxide and stearic
acid and compressed (as described below). The roller compaction premixes were
granulated and milled on lab scale equipment and then blended with the extragranular
silicon dioxide and stearic and compressed. The wet granulation premixes were
granulated, dried and milled on lab scale equipment and then blended with the
extragranular silicon dioxide and stearic and compressed.
Example 1: Direct Compression Batch A
~ Batch Size 2 Kilograms
~API Dose 60000 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend A 98.67 892.00
Silicon Dioxide Colloidal NF nerosol 200 088 8.00
Stearic Acid, NF Powder Food Grade 0^44 4.00
TOTAL I 100.00 904.00
Example 2: Direct Compression Batch B
~ Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend B 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 0^88 8.00
Stearic Add, NF Powder Food Grade 044 4.00
TOTAL I 100.00 I 904.00
Example 3: Direct Compression Batch C
- Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend C 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 088 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
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Example 4: Direct Compression Batch D
~ Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend D 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 0.88 8.00
Stearic Acid, NF Powder Food Grade 0^44 4.00
TOTAL I 100.00 904.00
Example 5: Direct Compression Batch E
- Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen Pre-Mix Blend E 98.67 951.50
Silicon Dioxide Colloidal NF Derosol 200 0^88 8.53
Stearic Acid. NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Example 6: Direct Compression Batch F
~ Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend F 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 088 8.53
Stearic Acid. NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
17
Example 7: Direct Compression Batch G
~ Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend G 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 088 8.53
Stearic Acid, NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Example 8: Direct Compression Batch H
~ Batch Size 2 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Pre-Mix Blend H 98.67 951.50
Silicon Dioxide Colloidal NF nerosol 200 088 8.53
Stearic Acid, NF Powder Food Grade 044 4.27
TOTAL I 100.00 I 964.30
Example 9: Roller Compaction Batch A
~ Batch Size 09 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC A 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 088 8.00
Stearic Acid, NF Powder Food Grade 044 4.00
TOTAL I 100.00 I 904.00
Example 10: Roller Compaction Batch B
~ Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen Milled RC B 98.67 892.00
Silicon Dioxide Colloidal NF nerosol 200 088 8.00
Stearic Acid, NF Powder Food Grade 044 4.00
TOTAL I 100.00 I 904.00
18
Example 11: Roller Compaction Batch C
~ Batch Size 0^9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC C 98.67 ~ 892.00
Silicon Dioxide Colloidal NF Aerosil 200 0.88 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
Example 12: Roller Compaction Batch D
~ Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC D 98.67 892.00
Silicon Dioxide Colloidal NF nerosol 200 0^88 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
Example 13: Roller Compaction Batch E
~ Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC E 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 088 8.53
Stearic Acid, NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Example 14: Roller Compaction Batch F
~ Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w% mg/dose
Ibuprofen Milled RC F 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 0.88 8.53
Stearic Acid, NF Powder Food Grade 0.44 4.27
TOTAL I 100.00 I 964.30
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Example 15: Roller Compaction Batch G
" Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC G 98.67 951.50
Silicon Dioxide Colloidal NF Derosol 200 0^88 8.53
Stearic Acid, NF Powder Food Grade 0.44 4.27
TOTAL I 100.00 964.30
Example 16: Roller Compaction Batch H
~ Batch Size 0.9 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled RC H 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 088 8.53
Stearic Acid, NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Example 17: Wet Granulation Batch A
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG A 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 0.88 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
Example 18: Wet Granulation Batch B
- Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG B 98.67 892.00
Silicon Dioxide Colloidal NF Derosol 200 088 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
20
Example 19: Wet Granulation Batch C
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG C 98.67 892.00
Silicon Dioxide Colloidal NF Aerosil 200 088 8.00
Stearic Acid, NF Powder Food Grade 0.44 4.00
TOTAL I 100.00 I 904.00
Example 20: Wet Granulation Batch D
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG D 98.67 892.00
Silicon Dioxide Colloidal NF Derosol 200 088 8.00
Stearic Acid, NF Powder Food Grade 044 4.00
TOTAL I 100.00 I 904.00
Example 21: Wet Granulation Batch E
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG E 98.67 951.50
Silicon Dioxide Colloidal NF Derosol 200 088 8.53
Stearic Acid, NF Powder Food Grade 044 4.27
TOTAL I 100.00 I 964.30
Example 22: Wet Granulation Batch F
~ Batch Size 1 Kilograms
~ API Dose [ 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG F 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 0.88 8.53
Stearic Acid, NF Powder Food Grade 044 4.27
TOTAL I 100.00 I 964.30
21
Example 23: Wet Granulation Batch G
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG G 98.67 ~ 951.50
Silicon Dioxide Colloidal NF Derosol 200 0.88 8.53
Stearic Acid, NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Example 24: Wet Granulation Batch H
~ Batch Size 1 Kilograms
~ API Dose 600.00 mgs
Ingredient w/w % mg/dose
Ibuprofen Milled WG H 98.67 951.50
Silicon Dioxide Colloidal NF Aerosil 200 0J8 8.53
Stearic Acid, NF Powder Food Grade 0^44 4.27
TOTAL I 100.00 I 964.30
Viscosity* of the specific Examples was determined and summarized in Table 2 below.
* Viscosity of a 2% w/w HPMC solution in water, cps
Table 2: Viscosity Results for HPMC Examples
Examples K100LV wt % K4M Wt% 3^0In Vise
1,5,9,13,17,21 100 1 4000 0 100
2.6.10.14.18.22 100 0.67 4000 0.33 411
3.7.11.15.19.23 100 0.33 4000 0.67 1414
4,8, 12, 16,20,24 100 0 4000 1 4000
The amount of burst release was expressed as a ratio as shown below, where the
denominator is calculated from the linear release rate in the region from 60 to 720 mins.
Figures 2-9 show the profiles and comparisons of wet granulation, roller compaction and
direct compression processed compositions.
22
Figure 1 summarizes the comparison API Release and composition viscosity in
compositions processed with wet granulation, roller compaction and direct compression
processes.
Results: Higher polymer levels were associated with lower release rates and lower
levels of burst drug release. As the polymer level increases, the API release rate and burst
rate decreases as this creates a more robust gel matrix.
Polymer viscosity also has a strong correlation with burst levels. Increasing the
proportion of higher viscosity polymer increases the amount of burst release, which is a
function the hydration rates of the HPMC. This reduced hydration level of the polymer
allows release of API before the gel matrix develops.
Process factors had the most dramatic effect on burst release. Dry processes had
lower levels of burst release vs. wet granulation. These results suggest that the
hydration/dehydration steps of the wet granulation process increase the amount of burst
release.
Conclusions: This set of BCS Class II, high drug load prototypes showed that burst
release can be minimized by using higher levels of HPMC, selecting lower viscosity
polymer grades, and using dry processing methods.
23

CLAIMS
We claim,
1. A solid dose composition comprising at least one pharmaceutically active ingredient
and at least one controlled release agent wherein the burst profile of at least one
pharmaceutically active ingredient is regulated by the apparent viscosity of the
controlled release agent and wherein at least one pharmaceutically active ingredient
is processed by wet granulation.
2. A method of manufacturing a solid dose composition comprising at least one
pharmaceutically active ingredient and at least one controlled release agent wherein
the burst profile of at least one pharmaceutically active ingredient is regulated by the
apparent viscosity of the controlled release agent and wherein at least one
pharmaceutically active ingredient is processed by wet granulation.
3. A solid dose composition comprising at least one pharmaceutically active ingredient
and at least one controlled release agent wherein the apparent viscosity of the
controlled release agent is between 100 and 100,000 centipoise and wherein at
least one pharmaceutically active ingredient is processed by wet granulation.
4. A solid dose composition of claim 3 wherein at least one of the pharmaceutically
active ingredients is ibuprofen.
5. A solid dose composition of claim 3 wherein at least one of the controlled release
agents is hydroxypropylmethylcellulose.
6. A solid dose composition of claim 3 wherein at least one of the controlled release
agents is hydroxypropylmethylcellulose and wherein at least one of the
pharmaceutically active ingredients is ibuprofen.
7. A method of manufacturing a solid dose composition of claim 2 wherein at least one
of the pharmaceutically active ingredients is ibuprofen.
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8. A method of manufacturing a solid dose composition of claim 2 wherein at least one
of the controlled release agents is hydroxypropylmethylcellulose.
9. A method of manufacturing a solid dose composition of claim 2 wherein at least one
of the controlled release agents is hydroxypropylmethylcellulose and wherein at least one
of the pharmaceutically active ingredients is ibuprofen.
Dated this 1 1 * day of November 2011 \r\0^\/^
Of Airana and Aifand Advocates
Agents for the Applicant
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