U.S. patent application number 11/174839 was filed with the patent office on 2006-01-12 for pharmaceutical excipient having improved compressibility.
This patent application is currently assigned to J. Rettenmaier & Soehne GmbH + Co. KG. Invention is credited to Edward A. Hunter, Bob E. Sherwood, John N. Staniforth.
Application Number | 20060008522 11/174839 |
Document ID | / |
Family ID | 34891458 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060008522 |
Kind Code |
A1 |
Staniforth; John N. ; et
al. |
January 12, 2006 |
Pharmaceutical excipient having improved compressibility
Abstract
A method of preparing an excipient composition includes forming
an aqueous slurry containing a mixture of microcrystalline
cellulose in the form of a wet cake and a surfactant, said
surfactant being present in an amount from about 0.1% to about 0.5%
by weight of the wet-cake microcrystalline cellulose; and drying
said slurry to obtain an excipient comprising a plurality of
agglomerated particles of microcrystalline cellulose in intimiate
association with said surfactant. The excipient may be mixed with a
therapeutically active agent to form a dosage form. The surfactant
provides a hydrophobic boundary at cellulose surfaces, and improves
absorptivity of the therapeutically active agent.
Inventors: |
Staniforth; John N.; (Bath,
GB) ; Hunter; Edward A.; (Cadosia, NY) ;
Sherwood; Bob E.; (Amenia, NY) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
J. Rettenmaier & Soehne GmbH +
Co. KG
Rosenberg
DE
|
Family ID: |
34891458 |
Appl. No.: |
11/174839 |
Filed: |
July 5, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10145563 |
May 14, 2002 |
6936277 |
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11174839 |
Jul 5, 2005 |
|
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09384829 |
Aug 27, 1999 |
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|
10145563 |
May 14, 2002 |
|
|
|
09037841 |
Mar 10, 1998 |
6106865 |
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09384829 |
Aug 27, 1999 |
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|
08660553 |
Jun 10, 1996 |
5866166 |
|
|
09037841 |
Mar 10, 1998 |
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08486183 |
Jun 7, 1995 |
5725883 |
|
|
08660553 |
Jun 10, 1996 |
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08370576 |
Jan 9, 1995 |
5585115 |
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08486183 |
Jun 7, 1995 |
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08868745 |
Jun 4, 1997 |
6395303 |
|
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09384829 |
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60019546 |
Jun 10, 1996 |
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Current U.S.
Class: |
424/464 ;
264/109 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61K 9/2013 20130101; A61K 9/2009 20130101; A61K 9/2054 20130101;
A61K 9/2036 20130101; A61K 9/2031 20130101; A61K 9/205 20130101;
A61K 9/2018 20130101 |
Class at
Publication: |
424/464 ;
264/109 |
International
Class: |
A61K 9/20 20060101
A61K009/20; B27N 3/00 20060101 B27N003/00 |
Claims
1. A method of preparing an excipient composition, comprising
forming an aqueous slurry containing a mixture of microcrystalline
cellulose in the form of a wet cake and a surfactant, and drying
said slurry to obtain an excipient comprising a plurality of
agglomerated particles of microcrystalline cellulose in intimate
association with said surfactant, said surfactant being present in
an amount sufficient to augment the compressibility of the
microcrystalline cellulose, wherein said amount is from about 0.1%
to about 0.5% by weight of the microcrystalline cellulose.
2. The method of claim 1, wherein said surfactant is an ionic
surfactant.
3. The method of claim 2, wherein said ionic surfactant is an
anionic surfactant.
4. The method of claim 3, wherein said anionic surfactant is sodium
lauryl sulfate.
5. The method of claim 3, wherein said anionic surfactant is
docusate sodium.
6. The method of claim 1, wherein said surfactant is included in an
amount of from about 0.15% to about 0.4%, based on the weight of
said microcrystalline cellulose.
7. The method of claim 1, wherein said surfactant is included in an
amount of from about 0.2% to about 0.3%, based on the weight of
said microcrystalline cellulose.
8. The method of claim 1, wherein said excipient composition
comprises particles having an average particle size of from about
10 .mu.m to about 1,000 .mu.m.
9. The method of claim 1, wherein said excipient particles have an
average particle size of from about 10 .mu.m to about 500
.mu.m.
10. The method of claim 1, wherein said excipient particles have an
average particle size of from about 30 .mu.m to about 250
.mu.m.
11. The method of claim 1, wherein said excipient particles have an
average particle size of from about 40 .mu.m to about 200
.mu.m.
12. The method of claim 1, wherein said excipient composition has a
moisture content from about 0.5% to about 15%.
13. The method of claim 1, wherein said excipient composition
further comprises from about 0.1 to about 20% by weight silicon
dioxide, based on the weight of the microcrystalline cellulose.
14. The method of claim 1, wherein said excipient composition
further comprises from about 0.5 to about 10% by weight silicon
dioxide, based on the weight of the microcrystalline cellulose.
15. The method of claim 1, wherein said excipient composition
further comprises from about 1.25 to about 5% by weight silicon
dioxide, based on the weight of the microcrystalline cellulose.
16. The method of claim 14, wherein said silicon dioxide is derived
from colloidal silicon dioxide.
17. The method of claim 1, wherein said excipient has a bulk
density from about 0.2 g/ml to about 0.5 g/ml.
18. The method of claim 15, wherein said excipient has a bulk
density from about 0.22 g/ml to about 0.35 g/ml.
19. The method of claim 1, wherein said excipient particles further
comprise a member selected from the group consisting of non-silicon
metal oxides, starches, starch derivatives, polyalkylene oxides,
celluloses, cellulose ethers, cellulose esters and mixtures
thereof.
20-34. (canceled)
Description
[0001] This is a continuation-in-part of U.S. application Ser. No.
09/037,841 filed Mar. 10, 1998, which is a continuation-in-part of
U.S. application Ser. No. 08/660,553 filed Jun. 10, 1996, now U.S.
Pat. No. 5,866,166, which is a continuation in part of U.S.
application Ser. No. 08/486,183, filed Jun. 7, 1995, now U.S. Pat.
No. 5,725,883, which is a continuation-in-part of U.S. application
Ser. No. 08/370,576, filed Jan. 9, 1995, now U.S. Pat. No.
5,585,115. This application is also a continuation-in-part of U.S.
application Ser. No. 08/868,745 filed Jun. 4, 1997, which in turn,
claims priority from U.S. Provisional Application Ser. No.
60/019,547 filed Jun. 10, 1996. The entire disclosures of U.S.
application Ser. Nos. 09/037,841, 08/660,553, 08/486,183,
08/370,576, 09/037,841, 08/868,745, and 60/019,547 are hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a novel excipient for use
in the manufacture of pharmaceuticals, and in particular, solid
dosage forms such as tablets which include one or more active
ingredients.
[0003] In order to prepare a solid dosage form containing one or
more active ingredients (such as drugs), it is necessary that the
material to be compressed into the dosage form possess certain
physical characteristics which lend themselves to processing in
such a manner. Among other things, the material to be compressed
must be free-flowing, must be lubricated, and, importantly, must
possess sufficient cohesiveness to insure that the solid dosage
form remains intact after compression.
[0004] In the case of tablets, the tablet is formed by pressure
being applied to the material to be tableted on a tablet press. A
tablet press includes a lower punch which fits into a die from the
bottom and a upper punch having a corresponding shape and dimension
which enters the die cavity from the top after the tableting
material fills the die cavity. The tablet is formed by pressure
applied on the lower and upper punches. The ability of the material
to flow freely into the die is important in order to insure that
there is a uniform filling of the die and a continuous movement of
the material from the source of the material, e.g. a feeder hopper.
The lubricity of the material is crucial in the preparation of the
solid dosage forms since the compressed material must be readily
ejected from the punch faces.
[0005] Since most drugs have none or only some of these properties,
methods of tablet formulation have been developed in order to
impart these desirable characteristics to the material(s) which is
to be compressed into a solid dosage form. Typically, the material
to be compressed into a solid dosage form includes one or more
excipients which impart the free-flowing, lubrication, and cohesive
properties to the drug(s) which is being formulated into a dosage
form.
[0006] Lubricants are typically added to avoid the material(s)
being tableted from sticking to the punches. Commonly used
lubricants include magnesium stearate and calcium stearate. Such
lubricants are commonly included in the final tableted product in
amounts of less than 1% by weight.
[0007] In addition to lubricants, solid dosage forms often contain
diluents. Diluents are frequently added in order to increase the
bulk weight of the material to be tableted in order to make the
tablet a practical size for compression. This is often necessary
where the dose of the drug is relatively small.
[0008] Another commonly used class of excipients in solid dosage
forms are binders. Binders are agents which impart cohesive
qualities to the powdered material(s). Commonly used binders
include starch, and sugars such as sucrose, glucose, dextrose, and
lactose.
[0009] Disintegrants are often included in order to ensure that the
ultimately prepared compressed solid dosage form has an acceptable
disintegration rate in an environment of use (such as the
gastrointestinal tract). Typical disintegrants include starch
derivatives and salts of carboxymethyl cellulose.
[0010] There are three general methods of preparation of the
materials to be included in the solid dosage form prior to
compression: (1) dry granulation; (2) direct compression; and (3)
wet granulation.
[0011] Dry granulation procedures may be utilized where one of the
constituents, either the drug or the diluent, has sufficient
cohesive properties to be tableted. The method includes mixing the
ingredients, slugging the ingredients, dry screening, lubricating
and finally compressing the ingredients.
[0012] In direct compression, the powdered material(s) to be
included in the solid dosage form is compressed directly without
modifying the physical nature of the material itself.
[0013] The wet granulation procedure includes mixing the powders to
be incorporated into the dosage form in, e.g., a twin shell blender
or double-cone blender and thereafter adding solutions of a binding
agent to the mixed powders to obtain a granulation. Thereafter, the
damp mass is screened, e.g., in a 6- or 8-mesh screen and then
dried, e.g., via tray drying, the use of a fluid-bed dryer,
spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red
dryer.
[0014] The use of direct compression is limited to those situations
where the drug or active ingredient has a requisite crystalline
structure and physical characteristics required for formation of a
pharmaceutically acceptable tablet. On the other hand, it is well
known in the art to include one or more excipients which make the
direct compression method applicable to drugs or active ingredients
which do not possess the requisite physical properties. For solid
dosage forms wherein the drug itself is to be administered in a
relatively high dose (e.g., the drug itself comprises a substantial
portion of the total tablet weight), it is necessary that the
drug(s) itself have sufficient physical characteristics (e.g.,
cohesiveness) for the ingredients to be directly compressed.
[0015] Typically, however, excipients are added to the formulation
which impart good flow and compression characteristics to the
material as a whole which is to be compressed. Such properties are
typically imparted to these excipients via a pre-processing step
such as wet granulation, slugging, spray drying, spheronization, or
crystallization. Useful direct compression excipients include
processed forms of cellulose, sugars, and dicalcium phosphate
dihydrate, among others.
[0016] A processed cellulose, microcrystalline cellulose, has been
utilized extensively in the pharmaceutical industry as a direct
compression vehicle for solid dosage forms. Microcrystalline
cellulose is commercially available under the tradename
EMCOCEL.RTM. from Edward Mendell Co., Inc. and as Avicel.RTM. from
FMC Corp. Compared to other directly compressible excipients,
microcrystalline cellulose is generally considered to exhibit
superior compressibility and disintegration properties.
[0017] Another limitation of direct compression as a method of
tablet manufacture is the size of the tablet. If the amount of
active ingredient is high, a pharmaceutical formulator may choose
to wet granulate the active with other excipients to attain an
acceptably sized tablet with the desired compact strength. Usually
the amount of filler/binder or excipients needed in wet granulation
is less than that required for direct compression since the process
of wet granulation contributes to some extent toward the desired
physical properties of a tablet. Thus, despite the advantages of
direct compression (such as reduced processing times and costs),
wet granulation is widely used in the industry in the preparation
of solid dosage forms. Many of those skilled in the art prefer wet
granulation as compared to direct compression because this method
has a greater probability of overcoming any problems associated
with the physical characteristics of the various ingredients in the
formulation, thereby providing a material which has the requisite
flow and cohesive characteristics necessary to obtain an acceptable
solid dosage form.
[0018] The popularity of the wet granulation process as compared to
the direct compression process is based on at least three
advantages. First, wet granulation provides the material to be
compressed with better wetting properties, particularly in the case
of hydrophobic drug substances. The addition of a hydrophilic
excipient makes the surface of a hydrophobic drug more hydrophilic,
easing disintegration and dissolution. Second, the content
uniformity of the solid dosage forms is generally improved. Via the
wet granulation method, all of the granules thereby obtained should
contain approximately the same amount of drug. Thus, segregation of
the different ingredients of the material to be compressed (due to
different physical characteristics such as density) is avoided.
Segregation is a potential problem with the direct compression
method. Finally, the particle size and shape of the particles
comprising the granulate to be compressed are optimized via the wet
granulation process. This is due to the fact that when a dry solid
is wet granulated, the binder "glues" particles together, so that
they agglomerate in the granules which are more or less
spherical.
[0019] Due to the popularity of microcrystalline cellulose,
pharmaceutical formulators have deemed it desirable to include this
excipient in a formulation which is wet granulated prior to
tableting. Unfortunately, currently-available microcrystalline
cellulose does not hold to the typical principle that the amount of
filler/binder needed in wet granulation is less than that in direct
compression. It is known that the exposure of the microcrystalline
cellulose to moisture in the wet granulation process severely
reduces the compressibility of this excipient. The loss of
compressibility of microcrystalline cellulose is particularly
problematic where the formulation dictates that the final product
will be relatively large in the environment of use. For example, if
a pharmaceutical formulator desires to prepare a solid oral dosage
form of a high dose drug, and the use of the wet granulation
technique is deemed necessary, the loss of compressibility of the
microcrystalline cellulose dictates that a larger amount of this
material may be needed to obtain an acceptably compressed final
product. The additional amount of microcrystalline cellulose needed
adds cost to the preparation, but more importantly adds bulk,
making the product more difficult to swallow.
[0020] The loss of compressibility of microcrystalline cellulose
when exposed to wet granulation has long been considered a problem
in the art for which there has been no satisfactory solution.
[0021] Attempts have been made to provide an excipient having high
compressibility, a small bulk (high apparent density), and good
flowability, while being capable of providing satisfactory
disintegration of the solid dosage form, which is applicable to wet
granulation as well as to dry granulation and direct compression
methods for preparation of solid dosage forms.
[0022] For example, U.S. Pat. No. 4,159,345 (Takeo, et al.)
describes an excipient which consists essentially of a
microcrystalline cellulose having an average degree of
polymerization of 60 to 375 and obtained through acid hydrolysis or
alkaline oxidative degradation of a cellulosic substance selected
from linters, pulps and regenerated fibers. The microcrystalline
cellulose is said to be a white cellulosic powder having an
apparent specific volume of 1.6-3.1 cc/g, a repose angle of
35.degree. to 42.degree., a 200-mesh sieve residue of 2 to 80% by
weight and a tapping apparent specific volume of at least 1.4
cc/g.
[0023] In U.S. Pat. No. 4,744,987 (Mehra, et al.), a particulate
co-processed microcrystalline cellulose and calcium carbonate
composition is described wherein the respective components are
present in a weight ratio of 75:25 to 35:65. The co-processed
composition is said to be prepared by forming a well-dispersed
aqueous slurry of microcrystalline cellulose and calcium carbonate
and then drying the slurry to yield a particulate product. The
patent notes that "[t]he microcrystalline cellulose is preferably
wet cake from a conventional microcrystalline cellulose
manufacturing process. The wet cake is material which has not yet
been dried, sometimes termed `never dried` or hydrocellulose, to
yield a conventional microcrystalline cellulose free-flowing powder
product." Alternatively "[t]he microcrystalline cellulose source
may also be conventional product, which has already been dried."
The combination of microcrystalline cellulose and calcium carbonate
is said to provide a lower cost excipient which has tableting
characteristics similar to those of microcrystalline cellulose and
which would satisfy a need for an economical excipient with good
performance that is desired by the vitamin market.
[0024] European Patent Application EP 0609976A1 (assigned to Asahi
Kasei Kabushiki Kaisha) describes an excipient comprising white
powdery microcrystalline cellulose having an average degree of
polymerization of from 100 to 375, preferably from 190 to 210, and
an acetic acid holding capacity of 280% or more, preferably from
290 to 370%. The excipient is said to exhibit high compactability
and a high rate of disintegration and is said to be obtained by
heat-treating an aqueous dispersion of purified cellulose
particles, which has a solids content of 40% or less by weight, at
100.degree. C. or more, followed by drying, or by subjecting an
aqueous dispersion of purified cellulose particles having a solids
content of 23% or less by weight to thin film-forming treatment and
drying the resultant thin film. The excipient is said to possess a
high compressibility, and a good balance of compactability and rate
of disintegration.
[0025] There still remains a need in the industry for a
pharmaceutical excipient which possesses excellent compressibility
whether utilized in a direct compression or wet granulation
procedure.
OBJECTS AND SUMMARY OF THE INVENTION
[0026] It is an object of the present invention to provide an
excipient which is useful in a variety of applications, and which
may be utilized in direct compression or wet granulation
methods.
[0027] It is a further object of the present invention to provide
an excipient useful in direct compression methods which has
improved compressibility relative to microcrystalline
cellulose.
[0028] It is a further object of the present invention to provide
an excipient useful in wet granulation methods which has improved
compressibility relative to microcrystalline cellulose.
[0029] It is a further object of the present invention to provide a
free-flowing excipient which has excellent compressibility
properties when utilized in direct compression or wet granulation
methods, and which furthermore possesses pharmaceutically
acceptable disintegration properties.
[0030] It is a further object of the present invention to provide a
free-flowing excipient which has excellent compressibility
properties when utilized in direct compression or wet granulation
methods, and which furthermore possesses pharmaceutically
acceptable absorptive properties, e.g. enhanced bioavailability of
the active agent from the gastrointestinal tract.
[0031] It is a further object of the present invention to provide
an improved microcrystalline cellulose excipient in which the
microcrystalline cellulose has not been chemically altered, and
which has improved compressibility relative to "off-the-shelf"
commercially available microcrystalline cellulose.
[0032] It is a further object of the present invention to provide a
solid dosage form which includes one or more active agents and the
improved microcrystalline cellulose excipient of the present
invention.
[0033] It is a further object of the present invention to provide
an oral solid dosage form for one or more drugs which is economical
to manufacture, which maintains its integrity during storage, and
which possesses excellent disintegration and dissolution properties
when exposed, e.g., to gastrointestinal fluid.
[0034] In accordance with the above objects and others which will
be obvious to those skilled in the art, the present invention is
directed to an excipient comprising a particulate agglomerate of
coprocessed microcrystalline cellulose and a compressibility
augmenting agent. The novel agglomerated excipient preferably
possesses compressibility at least equal to that of commercial
grade microcrystalline cellulose, and preferably superior to that
of commercial grade microcrystalline cellulose, when dry mixed or
wet granulated with an active agent, other optional pharmaceutical
additives and compressed into solid dosage forms.
[0035] The relative amount of compressibility augmenting agent
coprocessed with the microcrystalline cellulose is dependent, in
part, upon the type of compressibility augmenting agent selected.
For purposes of the present invention, the amount is generally
described as an effective amount, i.e. an amount which enhances or
augments the compressibility of the microcrystalline cellulose.
However, one skilled in the art will appreciate that in certain
embodiments of the invention where improved or equal
compressibility is not crucial to the preparation of the final
solid dosage form, the agglomerated excipient may include an amount
of augmenting agent which may not favorably affect compressibility
but may instead impart a different beneficial result to the final
product.
[0036] The present invention is further directed to an agglomerated
excipient which is derived from the aqueous slurry. The
agglomerated excipient, which includes microcrystalline cellulose
in the form of a wet cake (i.e. hydrocellulose or hydrolyzed
cellulose), at least one compressibility augmenting agent, and
other optional ingredients, is dried in a manner which inhibits the
formation of hydrogen bonds in the microcrystalline cellulose
(intra-molecular and/or inter-molecular bonding). In other words,
the compressibility augmenting agent is capable, during the drying
of the aqueous slurry, of restricting the close approach of
cellulose surfaces to each other by physically preventing these
surfaces from approaching each other; or by changing the
environment between these surfaces from an environment which tends
to promote surface-to-surface interactions (such as
hydrogen-bonding) to an environment which tends to inhibit such
surface-to-surface interactions between surfaces of the
microcrystalline cellulose. In certain embodiments, the
compressibility of the microcrystalline cellulose is improved by
utilizing one or more agents which are capable of both of these
interactions with the microcrystalline cellulose.
[0037] Compressibility augmenting agents which create physical
barriers between microcrystalline cellulose surfaces include
silicon dioxide having a very fine particle size, e.g., from about
1 nm to about 100 .mu.m. A most preferred silicon dioxide is
colloidal silicon dioxide. Other materials of similar size may also
be used instead of silicon dioxide to create the aforementioned
physical barrier. In certain preferred embodiments, such other
physically-acting compressibility augmenting agents will have at
least some physical characteristics similar to that of silicon
dioxide.
[0038] Compressibility augmenting agents which inhibit
surface-to-surface interactions between surfaces of the
microcrystalline cellulose include any material which has the
ability, via a portion of the molecule, to bind or interact with
the surface of the microcrystalline cellulose and at the same time,
via another portion of the molecule, to inhibit the attraction of
the cellulose surfaces, e.g., via a hydrophobic portion or "tail".
Suitable compressibility augmenting agents will have an HLB value
of at least 10, preferably at least about 15, and more preferably
from about 15 to about 40 or greater. To date, compressibility
augmenting agents which have shown the greatest effect have had
relatively high HLB values, and therefore an HLB value from about
30 to about 40 or greater is most preferred. Agents which exhibit
these properties include certain surfactants such as sodium lauryl
sulfate and polysorbate 40, and highly polar compounds, including
pharmaceutically acceptable dyes such as congo red.
[0039] The present invention is further directed to an aqueous
slurry useful in the preparation of a compressible excipient useful
in dry and wet granulation formulation methods, comprising a
mixture of microcrystalline cellulose in the form of a wet cake
(i.e. hydrocellulose or hydrolyzed cellulose) and a compressibility
augmenting agent. The solids content of the aqueous slurry is from
about 0.5% to about 25%, by weight, preferably from about 15% to
about 20% by weight, and most preferably from about 17% to about
19% by weight.
[0040] The present invention is further directed to a mixture of an
active ingredient(s) and an excipient comprising a particulate
agglomerate of coprocessed microcrystalline cellulose and a
compressibility augmenting agent. The microcrystalline cellulose
and compressibility augmenting agent are in intimate association
with each other and the ratio of active ingredient to excipient is
from about 1:99 to about 99:1, by Weight.
[0041] The present invention is further directed to a granulate of
an active agent and the novel excipient described herein, wherein
the active agent and excipient have been subjected to a wet
granulation procedure.
[0042] The present invention is also directed to a compressed solid
dosage form comprising an active ingredient(s) and the novel
excipient described herein, wherein the active agent and excipient
have been directly compressed into the solid dosage form or have
been subjected to a wet granulation procedure and thereafter
compressed into the solid dosage form. The compressed solid dosage
form provides a suitable release dissolution profile of the active
ingredient(s) when exposed to aqueous solutions during in-vitro
dissolution testing, and provides a release of drug in an
environment of use which is considered bioavailable. In one
embodiment of the invention, the dissolution profile of the solid
dosage form is suitable for immediate release of the active agent.
In further embodiments of the invention, the dissolution profile of
the solid dosage form is modified to provide a controlled or
sustained release dissolution profile.
[0043] The present invention is further directed to a method of
maintaining and/or enhancing the compressibility of
microcrystalline cellulose. The method includes forming an aqueous
slurry containing a mixture of microcrystalline cellulose in the
form of a wet cake (i.e. hydrocellulose or hydrolyzed cellulose)
and a compressibility augmenting agent, and drying the slurry to
obtain microcrystalline cellulose-based excipient particles in
which the compressibility augmenting agent has been integrated with
the microcrystalline cellulose particles. Within this aspect of the
invention, the slurry contains from about 0.5% to about 25% by
weight microcrystalline cellulose in the form of a wet cake, with
amounts of from about 15% to about 20% being preferred. The novel
excipient described herein is free-flowing, possesses excellent
disintegration and/or absorptive properties, and importantly, in
certain embodiments possesses improved compressibility relative to
normal "off-the-shelf" commercially available microcrystalline
cellulose when directly compressed. The advantages of the novel
excipient described herein are especially realized in
pharmaceutical formulations prepared using wet granulation
techniques. When utilized in wet granulation techniques, the novel
excipient surprisingly provides a compressibility which is
substantially improved in preferred embodiments in comparison to
the compressibility of normal "off-the-shelf" commercially
available microcrystalline cellulose used in wet granulation and is
even comparable to "off-the-shelf" microcrystalline cellulose used
in direct compression techniques. In other embodiments, the novel
excipient surprisingly provides a compressibility which is
substantially superior to the compressibility of normal
"off-the-shelf" commercially available microcrystalline cellulose
used in direct compression techniques.
[0044] Accordingly, the novel agglomerated of the invention
provides enhanced material flow properties and direct compression
compactibility compared to regular microcrystalline cellulose. The
enhanced compactibility has been shown to allow for the production
of satisfactory tablets, even with poorly compactible drugs,
reduction in tablet size for various high dose drug formulations,
and, in general, enhancement of the drug content uniformity of
tableted dosage forms, especially in high speed tableting.
[0045] The term "environmental fluid" is meant for purposes of the
invention to encompass, e.g., an aqueous solution, or
gastrointestinal fluid.
[0046] By "bioavailable" it is meant for purposes of the invention
that the therapeutically active medicament is absorbed from the
solid dosage form which includes the novel agglomerated excipient
of the invention, and becomes available in the body at the intended
site of drug action.
[0047] By "surfactant" it is meant for purposes of the present
invention that the material is a surface active agent which
displays wetting, detergent or soap-like qualities as those agents
are understood by those of ordinary skill in the art.
[0048] As one of ordinary skill in the art will appreciate, the
terms "microcrystalline cellulose in the form of a wet cake",
"hydrocellulose", and "hydrolyzed cellulose" are synonymous, and
refer to the precursor of the (dried) microcrystalline cellulose
product.
[0049] The benefits of the novel agglomerated microcrystalline
cellulose excipients of the invention include higher direct
compression compactibility (which in turn provides harder, less
friable tablets, reduces binder usage/cost, reduces tablet size,
and accommodates poorly compactible active ingredients), and
enhanced material flow (which in turn provides better content
uniformity, allows higher speed tableting, and accommodates poorly
flowing drugs); and preservation of compactibility in a wet
granulation (which in turn reduces formulation development time and
cost, reduces binder usage/cost, avoids extra-granular
processing/cost, and reduces tablet size).
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0051] FIG. 1 graphically shows a comparison of the tensile
strength of tablets prepared in accordance with the invention
(compressibility augmenting agent silicon dioxide) and prior art
tablets.
[0052] FIG. 2 graphically shows a comparison of the tensile
strength of APAP containing tablets prepared in accordance with the
invention and prior art APAP containing tablets.
[0053] FIG. 3 graphically shows a comparison of the tensile
strength of tablets prepared in accordance with the invention to
contain microcrystalline cellulose coprocessed with diatomaceous
earth, tablets containing microcrystalline cellulose coprocessed
with 2% w/w SiO.sub.2 and prior art tablets prepared to contain
only unmodified microcrystalline cellulose.
[0054] FIG. 4 graphically illustrates a comparison of the tensile
strength of tablets prepared using microcrystalline cellulose
coprocessed with silica gel, tablets prepared with coprocessed
microcrystalline cellulose and tablets prepared with
microcrystalline cellulose alone.
[0055] FIG. 5 graphically illustrates a comparison of the tensile
strength of tablets prepared using microcrystalline cellulose
coprocessed with HS 5 grade SiO.sub.2, tablets prepared using
coprocessed microcrystalline cellulose-SiO.sub.2 and prior art
tablets prepared to contain only unmodified microcrystalline
cellulose.
[0056] FIG. 6 graphically shows a comparison of the tensile
strength of tablets prepared in accordance with the invention
(compressibility augmenting agent=surfactant) and prior art
tablets.
[0057] FIG. 7 graphically shows a comparison of the tensile
strength of tablets prepared in accordance with the invention to
contain microcrystalline cellulose coprocessed with sodium lauryl
sulfate, tablets containing microcrystalline cellulose coprocessed
with docusate sodium and prior art tablets prepared to contain only
unmodified microcrystalline cellulose.
[0058] FIG. 8 graphically illustrates a comparison of the tensile
strength of tablets prepared using microcrystalline cellulose
coprocessed with polysorbate 40, tablets prepared sodium lauryl
sulfate coprocessed microcrystalline cellulose, and tablets
prepared with microcrystalline cellulose alone.
[0059] FIG. 9 graphically illustrates a comparison of the tensile
strength of tablets prepared using microcrystalline cellulose
coprocessed with polydimethyl siloxane (simethicone), tablets
prepared using coprocessed microcrystalline cellulose-sodium lauryl
sulfate and prior art tablets prepared to contain only unmodified
microcrystalline cellulose.
DETAILED DESCRIPTION OF THE INVENTION
[0060] Excipients of the present invention comprise
Microcrystalline Cellulose (MCC) and augmenting agents.
Microcrystalline cellulose is a well-known tablet diluent, binder
and disintegrant. Its chief advantage over other excipients is that
it can be directly compressed into self-binding tablets which
disintegrate rapidly when placed into water. This widely-used
ingredient is prepared by partially depolymerizing cellulose
obtained as a pulp from fibrous plant material with dilute mineral
acid solutions. Following hydrolysis, the hydrocellulose thereby
obtained is purified via filtration and an aqueous slurry is spray
dried to form dry, white odorless, tasteless crystalline powder of
porous particles of various sizes. In this regard, one of ordinary
skill in the art will appreciate that the term "microcrystalline
cellulose in the form of a wet cake", hydrocellulose and hydrolyzed
cellulose, are synonymous and encompass materials prepared by
partially depolymerizing cellulose obtained as a pulp. Another
method of preparing microcrystalline cellulose is disclosed in U.S.
Pat. No. 3,141,875. This reference discloses subjecting cellulose
to the hydrolytic action of hydrochloric acid at boiling
temperatures so that amorphous cellulosic material can be removed
and aggregates of crystalline cellulose are formed. The aggregates
are collected by filtration, washed with water and aqueous ammonia
and disintegrated into small fragments, often called cellulose
crystallites by vigorous mechanical means such as a blender.
Microcrystalline cellulose is commercially available in several
grades which range in average particle size from 20 to 200
microns.
[0061] Microcrystalline cellulose is water-insoluble, but the
material has the ability to draw fluid into a tablet by capillary
action. The tablets then swell on contact and the microcrystalline
cellulose thus acts as a disintegrating agent. The material has
sufficient self-lubricating qualities so as to allow a lower level
of lubricant as compared to other excipients.
[0062] Typically, microcrystalline cellulose has an apparent
density of about 0.28 g/cm.sup.3 and a tap density of about 0.43
g/cm.sup.3. Handbook of Pharmaceutical Excipients, pages 53-55.
[0063] When utilized in pharmaceutical applications,
microcrystalline cellulose is typically used as a tablet
binder/diluent in wet granulation and direct compression
formulations in amounts of 3-30% of the formulation, or more.
However, it is known to use more or less microcrystalline cellulose
in pharmaceutical products, depending upon the requirements of the
formulation.
[0064] The novel excipients of the present invention also include
one or more compressibility augmenting agents. The compressibility
augmenting agent(s) is present in amounts ranging from about 0.1%
to about 50% by weight of microcrystalline cellulose.
[0065] Direct compression tablet manufacturing is preferred for
many products in the pharmaceutical industry. It is a simple
process involving less extensive equipment, operating time and
cost. Microcrystalline cellulose is a good excipient for direct
compression processing. Microcrystalline cellulose has inherently
high compactibility due to its plastic deformation and limited
elastic recovery. Microcrystalline cellulose usually provides for
good drug dispersion, even ordered mixing with some drugs and
particular grades of microcrystalline cellulose. However, the
material flow properties are relatively poor for most grades of
microcrystalline cellulose. Intermittent and non-uniform flow can
occur as the formulation moves from the hopper to the die on a
tablet press. This non-uniform flow can lead to drug content
variations in the finished tableted dosage form.
[0066] The popularity of the wet granulation process as compared to
the direct compression process is based on at least three potential
advantages. First, wet granulation may provide the material to be
compacted with a more hydrophilic nature, in order to improve the
wetting, disintegration and dissolution characteristics of some
hydrophobic drugs or ingredients. Second, the content uniformity
and drug segregation-resistance can be enhanced using a granulation
step to lock drug and excipient components together during
blending. Finally, the micrometric characteristics of the component
powders can be optimized prior to compaction, which is often aided
by incorporation of a polymeric binder. It is normally considered
that this last property imbued by wet granulation will yield a
significantly more compactible product and consequently stronger,
more robust tablets. However, it has been found that the most
compactable tableting excipient, microcrystalline cellulose, can
lose between 30 and 50% of its tablet strength enhancing
characteristics, following wet granulation. Microcrystalline
cellulose tablet weakening caused by wet granulation is observed in
all cases where water is added, although the magnitude of loss of
compactibility is directed related to the concentration of water
used, as well as granulation and drying energetics. This loss of
compactibility can result in a very significant loss of
functionality, generally leading to a requirement for a larger
binder concentration in the formulation and consequently less
efficient and more costly tablet production as well as larger
tablets.
[0067] We have found that the reduction in compactibility of
microcrystalline cellulose which has been wet granulated is
generally accompanied by a decrease in particle porosity, specific
surface area available to adsorb nitrogen and also an increase in
granule bulk density and friability. However, granule particle size
distribution was found to have a relatively minor effect on granule
compactibility. Wet granulation has been found to have only a minor
effect on the solubility parameters of microcrystalline cellulose.
Further, wet granulation does not alter the X-ray diffraction
pattern and the Raman and 13C-NMR spectra of microcrystalline
cellulose. However, as a result of granulation, the infrared
spectra of microcrystalline cellulose obtained using the techniques
of attenuated total reflectance (ATRIR) and optical IR spectroscopy
were altered slightly. This is hypothesized to indicate that only
the near-surface molecular layers may be significantly involved in
interactions with water. Granule properties, including
compactibility, have also been found to be influenced by the amount
of granulating fluid employed, the duration and rate of wet mass
agitation, wet mass storage time before drying, and granule drying
technique. Further, granule dewatering by solvent exchange was
found to have a beneficial effect on granule compactibility.
[0068] It is hypothesized that the granulation-reduced
microcrystalline cellulose compactibility is caused at least in
significant part by increasing intraparticle and/or interparticle
hydrogen bonding. For purposes of the present invention, this
phenomenon is termed "quasi-hornification" since, unlike
hornification of cellulose fibers described in the literature
elsewhere, quasi-hornification of microcrystalline cellulose has
not been observed by us to reduce the ability of microcrystalline
cellulose to absorb water vapor. Furthermore, quasi-hornified
microcrystalline cellulose was found to be fully reversible, unlike
the hornification which occurs when cellulose is wetted.
Microcalorimetry indicates that during adsorption of water vapor by
granulated microcrystalline cellulose, the extent of intraparticle
bond disruption is greater than occurring during water vapor
adsorption by ungranulated microcrystalline cellulose. This
provides evidence to support the theory that granulation results in
increased intraparticle hydrogen bonding, some of which is
reversible on adsorption of water vapor.
[0069] The present invention is directed in part to a novel
agglomerated microcrystalline cellulose excipient which comprises a
combination of microcrystalline cellulose as described above
together in intimate association with a compressibility augmenting
agent. The novel agglomerated microcrystalline cellulose excipient
is prepared in a manner which significantly reduces the hydrogen
bonding between inter- and/or intra-molecular
cellulose-to-cellulose bonding which occurs when regular,
commercial grade microcrystalline cellulose is exposed to moisture
(water). This can be accomplished, e.g., by preparing an aqueous
slurry of microcrystalline cellulose in the form of a wet cake
(i.e. hydrocellulose or hydrolyzed cellulose), compressibility
augmenting agent(s), and other optional ingredients, and drying the
mixture in a manner which inhibits quasi-hornification.
[0070] The novel agglomerated microcrystalline cellulose excipient
utilizes a compressibility augmenting agent which [0071] (i)
physically restricts the proximity of the interface between
adjacent cellulose surfaces; [0072] (ii) inhibits interactions
between adjacent cellulose surfaces, for example, via the creation
of a hydrophobic boundary at cellulose surfaces; or [0073] (iii)
accomplishes both (i) and (ii) above.
[0074] In one preferred embodiment of the invention, the
compressibility augmenting agent which provides a physical barrier
between adjacent cellulose surfaces is a silicon dioxide. Silicon
dioxide is obtained by insolubilizing dissolved silica in sodium
silicate solution. When obtained by the addition of sodium silicate
to a mineral acid, the product is termed silica gel. When obtained
by the destabilization of a solution of sodium silicate in such a
manner as to yield very fine particles, the product is termed
precipitated silica. Silicon dioxide is insoluble in water. Prior
to the present invention, silicon dioxide, and in particular
colloidal silicon dioxide, was used mainly as a glidant and
anti-adherent in tableting processes and encapsulation, promoting
the flowability of the granulation. The amount of silicon dioxide
included in such tablets for those applications is very limited,
0.1-0.5% by weight. Handbook of Pharmaceutical Excipients,
.COPYRGT.1986 American Pharmaceutical Association, page 255. This
is due in part to the fact that increasing the amount of silicon
dioxide in the mixture to be tableted causes the mixture to flow
too well, causing a phenomena known to those skilled in the
tableting art as "flooding". If the mixture flows too well, a
varying tablet weight with uneven content uniformity can
result.
[0075] Those skilled in the art will appreciate that the name
and/or method of preparation of the silicon dioxide utilized in the
present invention is not determinative of the usefulness of the
product. Rather, as previously mentioned, it has been surprisingly
discovered that it is the physical characteristics of the silicon
dioxide that are critical. In particular, it has been discovered
that silicon dioxide having a relatively large particle size (and
correspondingly small surface area), such as silica gel, is not
useful in the preparation of the improved microcrystalline
cellulose products of the invention. The appended claims are deemed
to encompass all forms of silicon dioxide having an average primary
particle size from about 1 nm to about 100 .mu.m, and/or a surface
area from about 10 m.sup.2/g to about 500 m.sup.2/g.
[0076] The silicon dioxide utilized in the invention is of the very
fine particle size variety. In the more preferred embodiments of
the invention, the silicon dioxide utilized is a colloidal silicon
dioxide. Colloidal silicon dioxide is a submicron fumed silica
prepared by the vapor-phase hydrolysis (e.g., at 1110.degree. C.)
of a silicon compound, such as silicon tetrachloride. The product
itself is a submicron, fluffy, light, loose, bluish-white, odorless
and tasteless amorphous powder which is commercially available from
a number of sources, including Cabot Corporation (under the
tradename Cab-O-Sil); Degussa, Inc. (under the tradename Aerosil);
E.I. DuPont & Co.; and W.R. Grace & Co. Colloidal silicon
dioxide is also known as colloidal silica, fumed silica, light
anhydrous silicic acid, silicic anhydride, and silicon dioxide
fumed, among others. A variety of commercial grades of colloidal
silicon dioxide are produced by varying the manufacturing process.
These modifications do not affect the silica content, specific
gravity, refractive index, color or amorphous form. However, these
modifications are known to change the particle size, surface areas,
and bulk densities of the colloidal silicon dioxide products.
[0077] The surface area of the preferred class of silicon dioxides
utilized in the invention ranges from about 50 m.sup.2/gm to about
500 m.sup.2/gm. The average primary particle diameter of the
preferred class of silicon dioxides utilized in the invention
ranges from about 5 nm to about 50 nm. However, in commercial
colloidal silicon dioxide products, these particles are
agglomerated or aggregated to varying extents. The bulk density of
the preferred class of silicon dioxides utilized in the invention
ranges from about 20 g/l to about 100 g/l.
[0078] Commercially available colloidal silicon dioxide products
have, for example, a BET surface area ranging from about 50.+-.15
m.sup.2/gm (Aerosil OX50) to about 400.+-.20 (Cab-O-Sil S-17) or
390.+-.40 m.sup.2/gm (Cab-O-Sil EH-5). Commercially available
particle sizes range from a nominal particle diameter of 7 nm
(e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average primary
particle size of 40 nm (Aerosil OX50). The density of these
products range from 72.0.+-.8 g/l (Cab-O-Sil S-17) to 36.8 g/l
(e.g., Cab-O-Sil M-5). The pH of the these products at 4% aqueous
dispersion ranges from pH 3.5-4.5. These commercially available
products are described for exemplification purposes of acceptable
properties of the preferred class of silicon dioxides only, and
this description is not meant to limit the scope of the invention
in any manner whatsoever.
[0079] When the novel excipient of the invention utilizes a
colloidal silicon dioxide, it has been found that the resultant
excipient product surprisingly provides a compressibility which is
substantially improved in preferred embodiments even in comparison
to the compressibility of normal "off-the-shelf" commercially
available microcrystalline cellulose used in direct compression
techniques.
[0080] In other embodiments of the present invention, it has been
discovered that the compressibility of microcrystalline cellulose
which is wet granulated is significantly improved by a wider range
of silicon dioxide products. Thus, in embodiments of the present
invention where an improvement in overall compressibility of the
microcrystalline cellulose (whether utilized in wet granulation or
dry granulation) is not important, and the microcrystalline
cellulose product is to be subjected to wet granulation, it has
been discovered that the surface area of the silicon dioxide can be
as low as about 50 m.sup.2/gm and the average primary particle
diameter can be as large as about 100 .mu.m. Such silicon dioxide
products are also deemed to be encompassed within the scope of the
invention.
[0081] The coprocessed product consists of microcrystalline
cellulose and silicon dioxide in intimate association with each
other. Magnifications of the resultant particles indicate that the
silicon dioxide is integrated with, or partially coats, the
surfaces of the microcrystalline cellulose particles. When the
amount of silicon dioxide included in the excipient is greater than
about 20% by weight relative to the microcrystalline cellulose, the
silicon dioxide appears to substantially coat the surfaces of the
microcrystalline cellulose particles. The exact relationship of the
two ingredients of the excipients after coprocessing is not
presently understood; however, for purposes of description the
coprocessed particles are described herein as including an
agglomerate of microcrystalline cellulose and silicon dioxide in
intimate association with each other. The coprocessed particles are
not necessarily uniform or homogeneous. Rather, under
magnification, e.g., scanning electron microscope at 500.times.,
the silicon dioxide at the preferred percent inclusion appears to
be an "edge-coating".
[0082] Depending upon the amount and type of drying, the
concentration of the microcrystalline cellulose in the form of a
wet cake (i.e. hydrocellulose or hydrolyzed cellulose) and silicon
dioxide in the suspension, the novel compressible particles will
have different particle sizes, densities, pH, moisture content,
etc.
[0083] The particulate coprocessed product of this aspect of the
present invention possesses desirable performance attributes that
are not present when the combination of microcrystalline cellulose
and silicon dioxide are combined as a dry mixture. It is believed
that the beneficial result obtained by the combination of these two
materials is due to the fact that the two materials are intimately
associated with each other.
[0084] One skilled in the art will appreciate that other classes of
compounds having size, surface area, and other similar physical
characteristics to silicon dioxide may be useful in physically
forming a barrier which may reduce the surface-to-surface
interactions (including hydrogen-bonding) between cellulose
surfaces. Such materials include (but are not limited to)
non-silicon metal oxides, preferably colloidal. Such obvious
modifications of the present invention are deemed to be within the
contemplated scope of the appended claims.
[0085] In addition to the benefits described above, it has been
surprisingly discovered that the use of a material such as silicon
dioxide which physically restricts the proximity of the interface
between adjacent cellulose surfaces provides the further benefit of
enhancing the disintegration time of the final compressed solid
dosage form (e.g., tablet). This in turn will allow pharmaceutical
formulators to prepare oral solid dosage forms which comply with
pharmacopeial requirements for dissolution/disintegration for
particular therapeutically active ingredients (e.g., drugs), and
preferably allows for the preparation of an oral solid dosage form
of a particular drug which possesses an improved disintegration as
compared to other commercially available formulations of the same
drug.
[0086] Examples of therapeutically active agents for which improved
disintegration results can be obtained include ibuprofen, aldoril,
and gemfebrozil, which are relatively high dose (greater than 200
mg/dose) and water-insoluble; veraparnil, maxzide, diclofenac and
metrolol, which are moderate-dose drug (25-200 mg/dose) and
water-soluble; maproltiline, which is moderate dose (25-200
mg/dose) and water-insoluble; triazolam and minoxidil, which are
relatively low dose (less than 25 mg/dose) and water-soluble. These
examples are provided for discussion purposes only, and are
intended to demonstrate the broad scope of applicability of the
invention to a wide variety of durgs. It is not meant to limit the
scope of the invention in any way.
[0087] In other preferred embodiments of the invention, the
compressibility augmenting agent is a material which inhibits
interactions between adjacent cellulose surfaces, for example, via
the creation of a hydrophobic boundary or barrier at cellulose
surfaces. As previously mentioned, compressibility augmenting
agents which inhibit surface-to-surface interactions between
surfaces of the microcrystalline cellulose include any material
which has the ability, via a portion of the molecule, to bind or
interact with the surface of the microcrystalline cellulose and at
the same time, via another portion of the molecule, to inhibit the
attraction of the cellulose surfaces, e.g., via a hydrophobic
portion or "tail". Suitable compressibility augmenting agents will
have an HLB value of at least 10, preferably at least about 15, and
more preferably from about 15 to about 40 or greater.
Compressibility augmenting agents having an HLB value from about 30
to about 40 or greater is most preferred.
[0088] Surfactants which may be used in the present invention as a
compressibility augmenting agent generally include all
pharmaceutically-acceptable surfactants, with the proviso that the
surfactant have an HLB value of at least 10, and preferably at
least about 15.
[0089] In certain preferred embodiments, the HLB value of the
surfactant is from about 15 to 50, and in further embodiments is
most preferably from about 15.6 to about 40. Suitable
pharmaceutically-acceptable anionic surfactants include, for
example, those containing carboxylate, sulfonate, and sulfate ions.
Those containing carboxylate ions are sometimes referred to as
soaps and are generally prepared by saponification of natural fatty
acid glycerides in alkaline solutions. The most common cations
associated with these surfactants are sodium, potassium, ammonium
and triethanolamine. The chain length of the fatty acids range from
12 to 18. Although a large number of alkyl sulfates are available
as surfactants, one particularly preferred surfactant is sodium
lauryl sulfate, which has an HLB value of about 40.
[0090] In the pharmaceutical arts, sodium lauryl sulfate has been
used as an emulsifying agent in amounts of up to about 0.1% by
weight of the formulation. However, surfactants such as sodium
lauryl sulfate have been included in coprocessed microcrystalline
cellulose compositions. Moreover, surfactants have been used in the
amounts described herein to improve the compressibility of
microcrystalline cellulose especially in wet granulations. Sodium
lauryl sulfate is a water-soluble salt, produced as a white or
cream powder, crystals, or flakes and is used as a wetting agent
and detergent. Also known as dodecyl sodium sulfate, sodium lauryl
sulfate is actually a mixture of sodium alkyl sulfates consisting
chiefly of sodium lauryl sulfate. Sodium lauryl sulfate is also
known as sulfuric acid monododecyl ester sodium salt. Furthermore,
sodium lauryl sulfate is readily available from commercial sources
such as Sigma or Aldrich in both solid form and as a solution. The
solubility of sodium lauryl sulfate is about 1 gm per 10 ml/water.
The fatty acids of coconut oil, consisting chiefly of lauric acid,
are catalytically hydrogenated to form the corresponding alcohols.
The alcohols are then esterified with sulfuric acid (sulfated) and
the resulting mixture of alkyl bisulfates (alkyl sulfuric acids) is
converted into sodium salts by reacting with alkali under
controlled conditions of pH.
[0091] Alternative anionic surfactants include docusate salts such
as the sodium salt thereof. Other suitable anionic surfactants
include, without limitation, alkyl carboxylates, acyl lactylates,
alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl
carbonates, N-acyl glutamates, fatty acid, polypeptide condensates
and sulfuric acid esters.
[0092] In other aspects of the invention amphoteric
(amphipathic/amphiphilic surfactants), non-ionic surfactants and/or
cationic surfactants are included in the coprocessed compositions
of the invention. Suitable pharmaceutically-acceptable non-ionic
surfactants such as, for example, polyoxyethylene compounds,
lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated
amides, polyoxypropylene compounds, propoxylated alcohols,
ethoxylated/propoxylated block polymers, propoxylated esters,
alkanolamides, amine oxides, fatty acid esters of polyhydric
alcohols, ethylene glycol esters, diethylene glycol esters,
propylene glycol esters, glycerol esters, polyglycerol fatty acid
esters, SPAN's (e.g., sorbitan esters), TWEEN's (i.e., sucrose
esters), glucose (dextrose) esters and simethicone. The HLB for one
acceptable non-ionic surfactant, polysorbate 40, is about 15.6.
[0093] Other suitable pharmaceutically-acceptable surfactants
include acacia, benzalkonium chloride, cholesterol, emulsifying
wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer,
polyoxy ethylene, and castor oil derivatives.
[0094] Those skilled in the art will further appreciate that the
name and/or method of preparation of the surfactant utilized in the
present invention is not determinative of the usefulness of the
product. Rather, as previously mentioned, it has been surprisingly
discovered that it is the physical characteristics of surfactants,
especially those of the anionic class such as sodium lauryl
sulfate, which are critical. In particular, it has been discovered
that when an anionic surfactant such as sodium lauryl sulfate is
coprocessed with microcrystalline cellulose in the amounts
described herein, improved microcrystalline cellulose products of
the invention result.
[0095] When the novel excipient of the invention utilizes an
anionic surfactant, it has been found that the resultant excipient
product surprisingly provides a compressibility which is
substantially improved in preferred embodiments even in comparison
to the compressibility of normal "off-the-shelf" commercially
available microcrystalline cellulose used in direct compression
techniques. In other embodiments of the present invention, it has
been discovered that the compressibility of microcrystalline
cellulose which is wet granulated is significantly improved by
coprocessing the microcrystalline cellulose with an anionic
surfactant such as sodium lauryl sulfate.
[0096] Since microcrystalline cellulose in the form of a wet cake
is substantially water insoluble, the particle size of this
ingredient in the well-dispersed aqueous slurry is directly related
to its particle size as it was introduced into the aqueous
solution. Most surfactants, on the other hand, tend to be water
soluble. Sodium lauryl sulfate, for example, is relatively soluble
in water (1 g/10 ml) and, therefore, dissolves in the aqueous
slurry. It should be understood, however, that the coprocessed
products of the present invention are not solely limited to those
which contain a dissolved surfactant. The contemplated compositions
can also be prepared from slurries which contain a dispersion of
the surfactant as well as the microcrystalline cellulose in the
form of a wet cake (i.e. hydrocellulose or hydrolyzed
cellulose).
[0097] Highly polar molecules having the requisite HLB value range
set forth above may also be utilized as the compressibility
augmenting agent. Such highly polar molecules include certain dyes,
particular those which may be capable of binding to the cellulose
surface while thereafter creating a relatively hydrophobic
environment due to the presence of a hydrophobic portion of the
molecule (e.g., a hydrophobic tail) which "points away" from the
cellulose surface and discourages hydrophilic surface-to-surface
cellulose interactions, such as hydrogen-bonding. Preferably, the
dye is one which is pharmaceutically acceptable for inclusion in
sold dosage forms.
[0098] Examples of suitable dyes include Congo Red (chemical name:
3,3'-[[1,1'Biphenyl]-4,4'-diylbis-(azo)]bis[4-amino-1-naphthalenesulfonic
acid] disodium salt; FD&C Red No. 40 (also known as "Allura
Red") (chemical name: Disodium salt of
6-hydroxy-5[(2-methyl-4-sulfophenyl) azo]-2-naphthalenesulfonic
acid); FD&C Yellow No. 5 (common name: tartrazine) (chemical
name:
5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxylic
acid, trisodium salt); FD&C Yellow No. 6 (common name: Sunset
Yellow FCF) (chemical name: Disodium salt of
1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); Ponceau 4R
(chemical name: Trisodium-2-hydroxy-1-(4-sulfonato-1-naphthylazo)
naphthalene-6,8-disulfonate); Brown HT (chemical name: Disodium
4,4'-(2,4-dihydroxy-5-hydroxymethyl-3,3-phenylene
bisazo)di(napthalene-1-sulfonate)); Brilliant Black BN (Chemical
name: Tetrasodium
4-acetamido-5-hyroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylaz-
o]naphthalene-1,7-disulfonate); Carmoisine (chemical name: Disodium
4-hydroxy-3-(4-sulfanato-1-naphythylazo) Naphthalene-1-sulfonate);
Amaranth (chemical name: Trisodium
2-hydroxy-1-(4-sulfonato-1-naphthylazo)
naphthalene-3,6-disulfonate); and mixtures thereof.
[0099] Other highly polar molecules having the requisite HLB value
range set forth above which may be utilized as the compressibility
augmenting agent include the active agents themselves. For example,
it is well-known to those skilled in the art that certain classes
of pharmaceuticals, such as anti-pyschotic drugs, are highly polar
in nature and may be utilized as a compressibility augmenting agent
in accordance with this invention.
[0100] One skilled in the art will appreciate that other classes of
highly polar compounds may be useful in reducing the
surface-to-surface interactions (including hydrogen-bonding)
between cellulose surfaces. Such obvious modifications of the
present invention are deemed to be within the contemplated scope of
the appended claims.
[0101] It is preferred in the present invention that the
microcrystalline cellulose and compressibility augmenting agent are
coprocessed, resulting in an intimate association of these
ingredients, rather than being combined, e.g., as a dry mixture. In
preferred embodiments of the present invention, an aqueous slurry
of the microcrystalline cellulose in the form of a wet cake (i.e.
hydrocellulose or hydrolyzed cellulose), the compressibility
augmenting agent(s) and other optional ingredients is prepared in
order to obtain (after a drying step) agglomerated particles
wherein these components are intimately associated. The aqueous
slurry of the microcrystalline cellulose in the form of wet cake
(i.e. hydrocellulose or hydrolyzed cellulose) and compressibility
augmenting agent are introduced into the spray dryer as a single
aqueous medium. However, it is possible to separately introduce
each ingredient into separate aqueous medium which are then
combined. Other procedures for combining these materials with or
without other optional ingredients known to those skilled in the
art are deemed to be equivalent to the spray-drying technique
described above, and are further deemed to be encompassed by the
appended claims.
[0102] In preferred embodiments of the present invention, the
coprocessing of the microcrystalline cellulose and compressibility
augmenting agent is accomplished by forming a well-dispersed
aqueous slurry of microcrystalline cellulose in the form of a wet
cake (i.e. hydrocellulose or hydrolyzed cellulose) into which the
compressibility augmenting agent has been dissolved, and thereafter
drying the slurry and forming a plurality of microcrystalline
cellulose-based excipient particles. Typically, microcrystalline
cellulose in the form of a wet cake (i.e. hydrocellulose or
hydrolyzed cellulose) is first added to an aqueous solution so that
a slurry or suspension containing from about 0.5% to about 25%
hydrocellulose in the form of solids is obtained. Preferably, the
slurry or suspension contains from about 15% to 20% hydrocellulose
and most preferably from about 17% to about 19% hydrocellulose. At
this stage, it is optionally desirable to adjust the pH of the
slurry to about neutral with ammonium hydroxide, sodium hydroxide,
and mixtures thereof or the like. The suspension is kept under
constant agitation for a sufficient time to assure a uniform
distribution of the solids prior to being combined with the
compressibility augmenting agent.
[0103] For example, silicon dioxide is added to the suspension or
slurry in amounts ranging from 0.1% to about 20% by weight, based
on the amount of microcrystalline cellulose, amounts from about
0.5% to about 10% are preferred while amounts of from about 1.25%
to about 5% by weight are especially preferred. There is no
appreciable dissolution of either ingredient (microcrystalline
cellulose in the form of a wet cake or silicon dioxide), since both
are relatively water insoluble. The microcrystalline cellulose in
the form of a wet cake and silicon dioxide are well-dispersed in
the slurry or suspension prior to drying and forming the novel
particles.
[0104] On the other hand, the surfactant is added to the suspension
or slurry in amounts ranging from about 0.1% to about 20% by
weight, preferably from about 0.1 to about 5% by weight, based on
the amount of microcrystalline cellulose, and in certain
embodiments preferably from about 0.15% to about 0.4%, by weight.
When the surfactant is sodium lauryl sulfate, the amount is most
preferably from about 0.2 to about 0.3%, by weight. The surfactant
can be added to the suspension as either a solid or in solution
form. The microcrystalline cellulose in the form of a wet cake
(i.e. hydrocellulose or hydrolyzed cellulose) is thus
well-dispersed in the slurry or suspension and the surfactant is
dissolved therein prior drying and forming the novel particles. It
will be understood that other useful surfactants can be used in
like amounts or even greater amounts, i.e. up to 20% by weight or
even more. The usable concentration range for the selected
surfactant depends in part upon not only its molecular weight but
also its degree of foaming, particularly when present in agitated
slurries which will be spray dried to form the desired particulate.
Thus, in those aspects of the invention where surfactants other
than sodium lauryl sulfate are coprocessed with the
microcrystalline cellulose, it is to be understood that the
surfactant will be present in an amount which enhances the
compressibility of the microcrystalline cellulose and yet does not
have a degree of foaming which would substantially inhibit spray
drying.
[0105] Other compressibility augmenting agents (including highly
polar dyes, highly polar drugs, and other useful materials having a
HLB from about 15 to about 50) may be included in the aqueous
slurry in amounts ranging from about 0.1% to about 20%, by weight,
and more preferably from about 0.5 to about 10%, by weight.
[0106] After a uniform mixture of the ingredients is obtained in
the suspension, the suspension is dried to provide a plurality of
microcrystalline cellulose-based excipient particles having
enhanced compressibility (e.g., dried in a manner which inhibits
quasi-hornification).
[0107] In the (preferred) spray-drying process, the aqueous
dispersion of microcrystalline cellulose in the form of a wet cake
(i.e. hydrocellulose or hydrolyzed cellulose) and a compressibility
augmenting agent (for example, a surfactant or silicon dioxide) is
brought together with a sufficient volume of hot air to produce
evaporation and drying of the liquid droplets. The highly dispersed
slurry of microcrystalline cellulose in the form of a wet cake
(i.e. hydrocellulose or hydrolyzed cellulose) and compressibility
augmenting agent is pumpable and capable of being atomized. It is
sprayed into a current of warm filtered air, which supplies the
heat for evaporation and conveys a dried product to a collecting
device. The air is then exhausted with the removed moisture. The
resultant spray-dried powder particles are approximately spherical
in shape and are relatively uniform in size, thereby possessing
excellent flowability. The coprocessed product consists of
microcrystalline cellulose and compressibility augmenting agent in
intimate association with each other. The exact relationship of the
two ingredients of the excipients after coprocessing is not
presently understood; however, for purposes of description the
coprocessed particles are described herein as including an
agglomerate of microcrystalline cellulose and compressibility
augmenting agent in intimate association with each other. By
"intimate associate", it is meant that the compressibility
augmenting agent has in some manner been integrated with the
microcrystalline cellulose particles, e.g., via a partial coating
of the microcrystalline particles, as opposed to a chemical
interaction of the two ingredients. The term "intimate association"
is therefore deemed for purposes of the present description as
being synonymous with "integrated" or "united". The coprocessed
particles are not necessarily uniform or homogeneous.
[0108] It is preferred that the suspension be dried using
spray-drying techniques, as they are known in the art. Other drying
techniques, however, such as flash drying, ring drying, micron
drying, tray drying, vacuum drying, radio-frequency drying, and
possibly microwave drying, may also be used, although spray drying
is preferred.
[0109] Depending upon the amount and type of drying, the
concentration of the microcrystalline cellulose in the form of a
wet cake (i.e. hydrocellulose or hydrolyzed cellulose) and
compressibility augmenting agent in the suspension, the novel
compressible particles will have different particle sizes,
densities, pH, moisture content, etc.
[0110] The particulate coprocessed product of the present invention
possesses desirable performance attributes that are not present
when the combination of microcrystalline cellulose and
compressibility augmenting agent are combined as a dry mixture. It
is believed that the beneficial result obtained by the combination
of these two materials is due to the fact that the two materials
are intimately associated with each other. It has also been found
that intimate association of microcrystalline cellulose and other
detergent-like materials such as simethicone, even when they are
dissolved/dispersed in the aqueous solutions which form the wet
cake--microcrystalline cellulose slurry, fail to provide
microcrystalline cellulose with enhanced compressibility.
[0111] The average particle size of the agglomerated
microcrystalline cellulose excipient of the present invention
ranges from about 10 microns to about 1000 microns. Particle sizes
of about 10-500 microns are preferred, particle sizes of about
30-250 microns are more preferred and particle sizes of about
40-200 microns are most preferred. It will be appreciated by those
of ordinary skill in the art that the drying of the aqueous
suspension results in a random size distribution of the novel
excipient particles being produced. For example, if spray drying
techniques are used, droplet size, temperatures, agitation,
dispersion, air flow, atomizer wheel speed, etc. will effect final
particle size. Furthermore, it is within the scope of the invention
to sort or mechanically alter the dried particles according to
ranges of particle sizes depending upon end uses. The particle size
of the integrated excipient is not narrowly critical, the important
parameter being that the average size of the particle must permit
the formation of a directly compressible excipient which forms
pharmaceutically acceptable tablets.
[0112] The novel agglomerated microcrystalline cellulose excipient
has a bulk (loose) density ranging from about 0.2 g/ml to about 0.6
g/ml, and most preferably from about 0.22 g/ml to about 0.55 g/ml.
The novel excipient has a tapped density ranging from about 0.20
g/ml to about 0.70 g/ml, and most preferably from about 0.35 g/ml
to about 0.60 g/ml. The pH of the particles is most preferably
about neutral, although granulates having a pH of from about 3.0 to
about 8.5 are possible. The moisture content of the excipient
particles will broadly range from about 0.5% to about 15%,
preferably from about 2.5% to about 6%, and most preferably from
about 3.0% to about 5% by weight.
[0113] The angle of repose is a measurement used to determine the
flow characteristics of a powder. The angle of repose is subject to
experiment and experimenter, but in a comparative test, the novel
excipient is superior.
[0114] The novel agglomerated microcrystalline cellulose excipient
of the invention is free-flowing and directly compressible.
Accordingly, the excipient may be mixed in the desired proportion
with an active agent and optional lubricant (dry granulation), and
then directly compressed into solid dosage forms. In preferred
embodiments of the present invention wherein the surfactant is
sodium lauryl sulfate, the novel excipient represents an augmented
microcrystalline cellulose having improved compressibility as
compared to standard commercially available grades of
microcrystalline cellulose.
[0115] Alternatively, all or part of the excipient may be subjected
to a wet granulation with the active ingredient. A representative
wet granulation includes loading the novel excipient particles into
a suitable granulator, such as those available from Baker-Perkins,
and granulating the particles together with the active ingredient,
preferably using an aqueous granulating liquid. The granulating
liquid is added to the mixture with stirring until the powdery mass
has the consistency of damp snow and then wet screened through a
desired mesh screen, for example, having a mesh from about 12 to
about 16. The screened granulate is then dried, using standard
drying apparatus such as a convection oven before undergoing a
final screening. Additional dry screening of this material is
possible, such as by using screens of from about 40 to about 200
mesh. Those materials flowing through 40 and 60 mesh screens may be
further ground prior to ultimate tablet formulation. The thus
obtained granulate containing the novel excipient is now capable of
undergoing tableting or otherwise placed into a unit dosage
form.
[0116] In certain preferred embodiments, a portion of the total
amount of the novel excipient is wet granulated with the active
ingredient, and thereafter the additional portion of the novel
excipient is added to the granulate. In yet other embodiments, the
additional portion of the novel excipient to be added to the
excipient/active ingredient granulate may be substituted with
conventional microcrystalline cellulose, or other excipients
commonly used by those skilled in the art, depending of course upon
the requirements of the particular formulation.
[0117] By virtue of the novel excipient of the present invention,
the amount of the novel excipient compared to the amount of
microcrystalline cellulose which must be used in a wet granulation
technique to obtain an acceptable solid dosage form is
substantially reduced.
[0118] In other embodiments of the invention, a further material is
added to the aqueous slurry of microcrystalline cellulose in the
form of a wet cake (i.e. hydrocellulose or hydrolyzed cellulose)
and compressibility augmenting agent. Such additional materials
include silicon dioxides, non-silicon metal oxides, starches,
starch derivatives, surfactants, polyalkylene oxides, cellulose
ethers, celluloses esters, mixtures thereof, and the like. Specific
further materials which may be included in the aqueous slurry (and
consequently in the resultant agglomerated microcrystalline
cellulose excipient) are aluminum oxide, stearic acid, kaolin,
polydimethylsiloxane, silica gel, titanium dioxide, diatomaceous
earth, corn starch, high amylose corn starch, high amylopectin corn
starch, sodium starch glycolate, hydroxylated starch, modified
potato starch, mixtures thereof, and the like. These additives may
be included in desired amounts which will be apparent to those
skilled in the art.
[0119] In addition to one or more active ingredients, additional
pharmaceutically acceptable excipients (in the case of
pharmaceuticals) or other additives known to those skilled in the
art (for non-pharmaceutical applications) can be added to the novel
excipient prior to preparation of the final product. For example,
if desired, any generally accepted soluble or insoluble inert
pharmaceutical filler (diluent) material can be included in the
final product (e.g., a solid dosage form). Preferably, the inert
pharmaceutical filler comprises a monosaccharide, a disaccharide, a
polyhydric alcohol, inorganic phosphates, sulfates or carbonates,
and/or mixtures thereof. Examples of suitable inert pharmaceutical
fillers include sucrose, dextrose, lactose, xylitol, fructose,
sorbitol, calcium phosphate, calcium sulfate, calcium carbonate,
"off-the-shelf" microcrystalline cellulose, mixtures thereof, and
the like.
[0120] An effective amount of any generally accepted pharmaceutical
lubricant, including the calcium or magnesium soaps may optionally
be added to the novel excipient at the time the medicament is
added, or in any event prior to compression into a solid-dosage
form. The lubricant may comprise, for example, magnesium stearate
in any amount of about 0.5-3% by weight of the solid dosage form.
In embodiments where a surfactant is included as part or all of the
compressibility augmenting agent, an additional inclusion lubricant
may not be necessary.
[0121] The complete mixture, in an amount sufficient to make a
uniform batch of tablets, may then subjected to tableting in a
conventional production scale tableting machine at normal
compression pressures for that machine, e.g., about 1500-10,000
lbs/sq in. The mixture should not be compressed to such a degree
that there is subsequent difficulty in its hydration when exposed
to gastric fluid.
[0122] The average tablet size for round tablets is preferably
about 50 mg to 500 mg and for capsule-shaped tablets about 200 mg
to 2000 mg. However, other formulations prepared in accordance with
the present invention may be suitably shaped for other uses or
locations, such as other body cavities, e.g., periodontal pockets,
surgical wounds, vaginally. It is contemplated that for certain
uses, e.g., antacid tablets, vaginal tablets and possibly implants,
that the tablet will be larger.
[0123] The active agent(s) which may be incorporated with the novel
excipient described herein into solid dosage forms invention
include systemically active therapeutic agents, locally active
therapeutic agents, disinfecting agents, chemical impregnants,
cleansing agents, deodorants, fragrances, dyes, animal repellents,
insect repellents, fertilizing agents, pesticides, herbicides;
fungicides, and plant growth stimulants, and the like.
[0124] A wide variety of therapeutically active agents can be used
in conjunction with the present invention. The therapeutically
active agents (e.g. pharmaceutical agents) which may be used in the
compositions of the present invention include both water soluble
and water insoluble drugs. Examples of such therapeutically active
agents include antihistamines (e.g., dimenhydrinate,
diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate),
analgesics (e.g., aspirin, codeine, morphine, dihydromorphone,
oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g.,
naproxyn, diclofenac, indomethacin, ibuprofen, sulindac),
anti-emetics (e.g., metoclopramide), anti-epileptics (e.g.,
phenyloin, meprobamate and nitrazepam), vasodilators (e.g.,
nifedipine, papaverine, diltiazem and nicardirine), anti-tussive
agents and expectorants (e.g., codeine phosphate), anti-asthmatics
(e.g. theophylline), antacids, anti-spasmodics (e.g. atropine,
scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,
ethacrynic acid, bendrofluazide), anti-hypotensives (e.g.,
propranolol, clonidine), antihypertensives (e.g., clonidine,
methyldopa), bronchodilators (e.g., albuterol), steroids (e.g.,
hydrocortisone, triamcinolone, prednisone), antibiotics (e.g.,
tetracycline), antihemorrhoidals, hypnotics, psychotropics,
antidiarrheals, mucolytics, sedatives, decongestants, laxatives,
vitamins, stimulants (including appetite suppressants such as
phenylpropanolamine). The above list is not meant to be
exclusive.
[0125] A wide variety of locally active agents can be used in
conjunction with the novel excipient described herein, and include
both water soluble and water insoluble agents. The locally active
agent(s) which may be included in the controlled release
formulation of the present invention is intended to exert its
effect in the environment of use, e.g., the oral cavity, although
in some instances the active agent may also have systemic activity
via absorption into the blood via the surrounding mucosa.
[0126] The locally active agent(s) include antifungal agents (e.g.,
amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol,
etc.), antibiotic agents (penicillins, cephalosporins,
erythromycin, tetracycline, aminoglycosides, etc.), antiviral
agents (e.g, acyclovir, idoxuridine, etc.), breath fresheners (e.g.
chlorophyll), antitussive agents (e.g., dextromethorphan
hydrochloride), anti-cariogenic compounds (e.g., metallic salts of
fluoride, sodium monofluorophosphate, stannous fluoride, amine
fluorides), analgesic agents (e.g., methylsalicylate, salicylic
acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics
(e.g., chlorhexidine and salts thereof, hexylresorcinol,
dequalinium, chloride, cetylpyridinium chloride), anti-inflammatory
agents (e.g., dexamethasone, betamethasone, prednisone,
prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents
(oestriol), antiplaque agents (e.g, chlorhexidine and salts
thereof, octenidine, and mixtures of thymol, menthol,
methysalicylate, eucalyptol), acidity reducing agents (e.g.,
buffering agents such as potassium phosphate dibasic, calcium
carbonate, sodium bicarbonate, sodium and potassium hydroxide,
etc.), and tooth desensitizers (e.g., potassium nitrate). This list
is not meant to be exclusive. The solid formulations of the
invention may also include other locally active agents, such as
flavorants and sweeteners. Generally any flavoring or food additive
such as those described in Chemicals Used in Food Processing, pub
1274 by the National Academy of Sciences, pages 63-258 may be used.
Generally, the final product may include from about 0.1% to about
5% by weight flavorant.
[0127] The tablets of the present invention may also contain
effective amounts of coloring agents, (e.g., titanium dioxide, F.D.
& C. and D. & C. dyes; see the Kirk-Othmer Encyclopedia of
Chemical Technology, Vol. 5, pp. 857-884, hereby incorporated by
reference), stabilizers, binders, odor controlling agents, and
preservatives.
[0128] Alternatively, the novel excipient can be utilized in other
applications wherein it is not compressed. For example, the
granulate can be admixed with an active ingredient and the mixture
then filled into capsules. The granulate can further be molded into
shapes other than those typically associated with tablets. For
example, the granulate together with active ingredient can be
molded to "fit" into a particular area in an environment of use
(e.g., an implant). All such uses would be contemplated by those
skilled in the art and are deemed to be encompassed within the
scope of the appended claims.
[0129] In further embodiments of the invention, more than one
compressibility augmenting agent is used. Thus, for example, it is
possible to use two or more agents which act as physical barriers
(e.g., physically restricting the proximity of the interface
between adjacent cellulose surfaces); or to use two or more agents
which inhibit interactions between adjacent cellulose surfaces, for
example, via the creation of a hydrophobic boundary at cellulose
surfaces (e.g., surfactants having the requisite HLB value, and/or
highly polar materials such as the previously mentioned dyes).
[0130] In certain preferred embodiments, two or more
compressibility enhancing agents are used which provide an effect
by different mechanisms, such as one agent which acts as a physical
barrier (such as colloidal silicon dioxide), and another agent
which inhibit interactions between adjacent cellulose surfaces (for
example, sodium lauryl sulfate). In such embodiments, it is
preferred that both agents are incorporated into the aqueous slurry
and dried (e.g., via spray drying) to form agglomerated particles
in which the microcrystalline cellulose, colloidal silicon dioxide
and sodium lauryl sulfate are in intimate association. Such
preferred embodiments are capable of providing a synergistically
improved microcrystalline cellulose excipient which has properties
described above which are at least as good, and preferably
improved, as compared to the properties of the novel
microcrystalline cellulose excipients which include only one class
of these compressibility augmenting agents.
[0131] In addition to the improved formulation properties described
above, it has been surprisingly discovered that the use of a
surfactant as an augmenting agent for microcrystalline cellulose
has the added benefit of providing a final formulation which has
enhanced performance characteristics with respect to absorptivity
of the therapeutically active agent in the gastrointestional tract,
and along with this enhanced absorptivity, enhanced
bioavailability. This is a particularly beneficial result when the
therapeutically active agent is substantially water insoluble.
Examples of therapeutically active agents for which improved
absorptivity results can be obtained include acetaminophen
nabumetone, and griseofulvin, which are relatively high dose
(greater than 200 mg/dose) and water-insoluble; cefaclor, which is
high dose (greater than 200 mg/dose) and water-soluble); maxzide,
which is a moderate-dose drug (25-200 mg/dose) and water-soluble;
and piroxicam, which is relatively low dose (less than 25 mg/dose)
and water-insoluble. These examples are provided for discussion
purposes only, and are intended to demonstrate the broad scope of
applicability of the invention to a wide variety of durgs. It is
not meant to limit the scope of the invention in any way.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0132] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
[0133] The examples set forth the preparation of various
microcrystalline cellulose/silicon dioxide compositions. Tablets
were prepared using each of the compositions and each of tablet
preparations was tested for tensile strength.
EXAMPLES 1-3
Preparation of Coprocessed Microcrystalline Cellulose-SiO.sub.2
Compositions and Granulations Thereof
EXAMPLE 1
MCC-SiO.sub.2 Product--5% w/w SiO.sub.2
A. Excipient Particles
[0134] In this example, about 6.2 kilograms of microcrystalline
cellulose (MCC), (Mendell Co., Inc. Patterson, N.Y.) in the form of
a wet cake (i.e., hydrocellulose or hydrolyzed cellulose) was
combined with 5.2 kilograms of water in a mix tank to form a slurry
containing about 15% solids. The pH was adjusted to about neutral
with about 3 ml of ammonium hydroxide. The slurry was allowed to
mix for about 15 minutes before being combined with 5% w/w silicon
dioxide (SiO.sub.2), 200 m.sup.2/g (CaboSil, PTG grade, available
from Cabot Corp., Tuscola, Ill.) After allowing the materials to
become intimately combined, the slurry was spray dried using a Niro
Production Minor (Niro, Columbia, Md.), inlet
temperature--215.degree. C., outlet temperature--125.degree. C.,
atomizer wheel speed 22,300 rpm, to provide microcrystalline
cellulose-SiO.sub.2 having an average particle size of 40-60
microns.
B. Granulation of Excipient Particles
[0135] The microcrystalline cellulose-SiO.sub.2 particles obtained
as a result of Example 1A. were wet granulated in a Baker-Perkins
10 liter high-sheer granulator for 3 minutes using water as the
granulating fluid. The resultant product was wet screened through a
12 mesh screen, tray dried in a convection oven for about 2-3 hours
until a moisture content of less than 5% was obtained, dry screened
and sieved to obtain an average particle size of from about 55 to
about 70 microns.
EXAMPLE 2
MCC-SiO.sub.2 Product--20% w/w SiO.sub.2
[0136] The processes of Example 1A and B were repeated except that
20% w/w silicon dioxide was used to form the product.
EXAMPLE 3
MCC-SiO.sub.2 Product--2% w/w SiO.sub.2
[0137] In this example, the processes of Example 1A and B were
repeated except that 2% w/w silicon dioxide was used to form the
product.
EXAMPLE 4
Dry Blend Mix of MCC and SiO.sub.2 (5% w/w)--Comparative
[0138] As a control, EMCOCEL.RTM. grade 50 M microcrystalline
cellulose (Mendell Co., Inc.) and 5% w/w silicon dioxide, 200
m.sup.2/g (CaboSil, PTG grade) were dry blended. No spray drying or
other treatment of the mixture was undertaken. The method of
Example 1B, however, was repeated.
EXAMPLE 5
Processed MCC without SiO.sub.2
[0139] As a second control, the process described in Example 1B was
repeated except that no SiO.sub.2 was added.
EXAMPLE 6
[0140] In this example, batches of compressed tablets were prepared
using each of the products obtained as a result of Examples 1-5.
The tablets were prepared using a Korsch tablet press having a
punch size of 3/8'' and an aim weight of about 245 mg. The
granulations were included in five separate tabletting runs using
compression forces of 6, 12, 18, 24 and 30 kN respectively. Ten
tablets from each run were weighed, measured for diameter and
tested for thickness and hardness on the Erweka TBH 30 tablet
hardness tester to determine the compressibility of the
microcrystalline cellulose as measured by tensile strength. The
results of the analysis are graphically illustrated in FIG. 1 as a
comparison of tensile strength versus compression force.
[0141] As can be seen from the graph, substantial benefits are
obtained by coprocessing microcrystalline cellulose with SiO.sub.2.
The tablets prepared using the products of comparative examples 4
and 5 demonstrated poor tensile strength. The novel excipient is
superior and demonstrates approximately the same relative
improvement across the entire range of compression forces.
Furthermore, the graph also illustrates that tablets prepared with
a mere dry admixture of microcrystalline cellulose and SiO.sub.2
(example 4 formulation) failed to demonstrate acceptable tensile
strengths. Thus, the coprocessed microcrystalline
cellulose-SiO.sub.2 described herein provides significant retention
of microcrystalline cellulose compressibility.
EXAMPLES 7-12
[0142] In these examples, compressed tablet products containing 70%
by weight microcrystalline cellulose and 30% acetaminophen (APAP
herein) were prepared. The products of examples 7-9 were controls
and prepared without the coprocessed microcrystalline
cellulose-SiO.sub.2 of the present invention. The products of
examples 10-12, on the other hand, included 70% by weight of the
novel coprocessed microcrystalline cellulose-SiO.sub.2 and 30%
APAP. Details concerning the preparation of each granulation
product is set forth below. A graphical comparison of the tensile
strength versus compression force for each tabletted product is
provided in FIG. 2.
EXAMPLE 7
Intragranulation and Extragranulation of APAP with Microcrystalline
Cellulose
[0143] In this example, tablets were prepared using off-the-shelf
microcrystalline cellulose (EMCOCEL.RTM. 50 M) according to the
following formula: TABLE-US-00001 INGREDIENTS WEIGHT (GRAMS)
Microcrystalline cellulose 267.9 APAP 114.8 Deionized water
165.8
[0144] One half of the microcrystalline cellulose was added to a
Baker-Perkins 10 liter blender and combined with all of the APAP.
The blender impeller was adjusted to 200 rpm and the chopper was
set at 1000 rpm. After one minute, the water was added over 90
seconds using a rinse bottle. Thereafter, mixing was continued for
an additional 90 seconds. The granulation was removed from the
blender, wet screened through a 12 screen-mesh and dried in a
convection oven for 2-3 hours at 60.degree. C. until a moisture
content of less than 5% was obtained. The granulation was then dry
screened through a 16 mesh screen before being blended for 10
minutes with the remaining portion of the microcrystalline
cellulose in a two quart V-blender. The granulation was removed
from the blender and tabletted in accordance with the method
described below.
Tablet Strength Testing
[0145] In order to prepare tablets for the formulations of examples
7, 8, 10 and 11, the following procedure was used: [0146] the wet
granulation products were weighed and mixed in a 2 quart V-blender
for 5 minutes with 0.2% Pruv.TM. (sodium stearyl fumarate,
available from Mendell Co., Inc.).
[0147] Five separate tabletting runs were undertaken with
compression forces of 5, 10, 15, 20 and 25 kN respectively using a
Korsch tablet press having a punch size of 3/8'' and an aim weight
of about 245 mg. Ten tablets from each compression force were
selected and used in the experiment set forth in Example 13.
EXAMPLE 8
Wet Granulation of APAP with MCC
[0148] In this example, only wet granulation or the
intragranulation step as described above was undertaken. The
formulation was prepared according to the following formula using
off-the-shelf EMCOCEL.RTM. 50 M microcrystalline cellulose:
TABLE-US-00002 INGREDIENTS WEIGHT (GRAMS) Microcrystalline
cellulose 178.6 APAP 76.5 Deionized water 170.1
[0149] The microcrystalline cellulose was added to a Baker-Perkins
10 liter blender and combined with the APAP. The blender impeller
was adjusted to 200 rpm and the chopper was set at 1000 rpm. After
one minute, the water was added over 90 seconds using a rinse
bottle. Thereafter, mixing was continued for an additional 90
seconds. The granulation was removed from the blender, wet screened
through a 12 screen mesh and then dried in a convection oven at
60.degree. C. for 2-3 hours, until a moisture content of less than
5% was achieved. The granulation was then dry screened through a 16
mesh screen and tabletted in accordance with the method described
in example 7.
EXAMPLE 9
Direct Compression Formulation of APAP with MCC
[0150] A direct compression formulation for tablets was prepared to
contain 70% off-the-shelf EMCOCEL.RTM. 50 M microcrystalline
cellulose and 30% APAP by weight. The tablets were prepared
according to the following formula: TABLE-US-00003 INGREDIENTS
WEIGHT (GRAMS) Microcrystalline cellulose 175.0 APAP 74.5 PRUV
0.5
[0151] The microcrystalline cellulose and APAP were combined in a
V-blender and mixed for 15 minutes. Thereafter, the Pruv.RTM.
(stearyl fumarate, commercially available from Edward Mendell Co.,
Inc.) was added and mixing was continued for another 5 minutes. The
granulation was removed and five separate tabletting runs were
undertaken using compression forces of 5, 10, 15, 20 and 25 kN
respectively on a Korsch tablet press. The tablet press had a punch
size of 3/8'' and an aim weight of about 245 mg. Ten tablets from
each compression force were used in the experiment set forth in
Example 13.
EXAMPLE 10
Wet Granulation of APAP with Coprocessed Microcrystalline
Cellulose-SiO.sub.2 (5% w/w)
[0152] In this example, tablets were prepared by wet granulation
with the coprocessed microcrystalline cellulose (5% w/w SiO.sub.2)
of Example 1A. The tablet granulation was prepared according to the
following formula: TABLE-US-00004 INGREDIENTS WEIGHT (GRAMS)
Microcrystalline Cellulose-SiO.sub.2 178.6 APAP 76.5 Deionized
water 170.1
[0153] The microcrystalline cellulose-SiO.sub.2 was added to a
Baker-Perkins 10 liter blender and combined with the APAP. The
blender impeller was adjusted to 200 rpm and the chopper was set at
1000 rpm. After one minute, the water was added over 90 seconds
using a rinse bottle. Thereafter, mixing was continued for an
additional 90 seconds. The granulation was removed from the
blender, wet screened through a 12 screen mesh and then dried in a
convection oven for 2-3 hours at 60.degree. C. until a moisture
content of less than 5% was achieved. The granulation was then dry
screened through a 16 mesh screen and tabletted according to the
method set forth in Example 7.
EXAMPLE 11
Intra- and Extragranulation of APAP with Microcrystalline
Cellulose-SiO.sub.2 (5% w/w)
[0154] A granulation for compressed tablets was prepared according
to the following formula: TABLE-US-00005 INGREDIENTS WEIGHT (GRAMS)
Microcrystalline Cellulose-SiO.sub.2 267.9 APAP 114.8 Deionized
water 165.8
[0155] One half of the coprocessed Microcrystalline
cellulose-SiO.sub.2 (prepared as in Example 1A) was added to a
Baker-Perkins 10 liter blender and combined with all of the APAP.
The blender impeller was adjusted to 200 rpm and the chopper was
set at 1000 rpm. After one minute, the water was added over 90
seconds using a rinse bottle. Thereafter, mixing was continued for
an additional 90 seconds. The granulation was removed from the
blender, wet screened through a 12 screen mesh and then dried in a
convection oven for 2-3 hours at 60.degree. C. until a moisture
content of less than 5% was achieved. The granulation was then dry
screened through a 16 mesh screen before being blended for 10
minutes with the remaining portion of the coprocessed
Microcrystalline cellulose-SiO.sub.2 in a 2 quart V-blender,
removed from the blender, and tableted according to the method of
Example 7.
EXAMPLE 12
Direct Compression Formulation of APAP with Microcrystalline
Cellulose-SiO.sub.2 (5% w/w)
[0156] A direct compression formulation similar to that set forth
in example 9 was undertaken except that the tablets were prepared
to contain the coprocessed Microcrystalline cellulose-SiO.sub.2 of
Example 1A. The tablet granulation was prepared according to the
following formula: TABLE-US-00006 INGREDIENTS WEIGHT (GRAMS)
Microcrystalline cellulose-SiO.sub.2 175.0 APAP 74.5 PRUV 0.5
[0157] As was the case in example 9, five separate tabletting runs
were undertaken using compression forces of 5, 10, 15, 20 and 25 kN
respectively on a Korsch tablet press, (punch size: 3/8'' and aim
weight--about 245 mg). Ten tablets from each compression force were
used to carry out the experiment set forth in Example 13.
EXAMPLE 13
Tablet Strength Testing
[0158] Ten tablets from each compression force run for each
formulation prepared in Examples 7-12 were weighed, measured for
diameter and tested for thickness and hardness on the Erweka TBH 30
tablet hardness tester to determine the compressibility of the
microcrystalline cellulose. The results are graphically illustrated
in FIG. 2 as a comparison of tensile strength versus compression
force.
[0159] Referring now to FIG. 2, it can be seen that compressed
tablets made with the inventive coprocessed Microcrystalline
cellulose-SiO.sub.2 have relatively high tensile strengths when
compared to those made with off-the-shelf Microcrystalline
cellulose. The advantages of the coprocessed Microcrystalline
cellulose-SiO.sub.2 are clearly seen in both direct compression and
wet granulation formulations and especially in wet granulation
products.
EXAMPLES 14-16
Diatomaceous Earth
[0160] In these examples, the coprocessing method described in
Example 1A was repeated except that diatomaceous earth of about 40
micron particle size (J. T. Baker, Phillipsburg, N.J. was used as
the source of SiO.sub.2). TABLE-US-00007 Diatomaceous Example Earth
(wt %) 14 2.0 15 1.0 16 0.5
[0161] The resultant granulates prepared according to Example 1B
were tabletted according to the same method described in Example 6
and evaluated for tensile strength. The products of inventive
Example 3 (Microcrystalline cellulose-SiO.sub.2 2% w/w) and Example
5 (Microcrystalline cellulose alone) were included in FIG. 3 for
comparison purposes.
[0162] Referring now to FIG. 3, it can be seen that although the
retention of compressibility afforded by coprocessing diatomaceous
earth is not as great as that provided by colloidal SiO.sub.2
having surface areas of about 200 m.sup.2/g, the coprocessed
Microcrystalline cellulose-diatomaceous earth nonetheless
demonstrates improved compressibility in wet granulation
formulations.
EXAMPLES 17-19
Silica Gel
[0163] In these examples, the coprocessing method described in
Example 1A was repeated using silica gel 200 micron particle size
(VWR Corp., Piscataway, N.J. as the source of SiO.sub.2).
TABLE-US-00008 Example Silica Gel (wt %) 17 1 18 2 19 5
[0164] The resultant granulates prepared according to Example 1B
were tabletted according to the same method described in Example 6
and evaluated for tensile strength. The products of inventive
Example 3 (Microcrystalline cellulose-SiO.sub.2 2% w/w) and Example
5 (Microcrystalline cellulose alone) were included in FIG. 4 for
comparison purposes.
[0165] Referring now to FIG. 4, it can be seen that the retention
of compressibility afforded by coprocessing with silica gel is well
below that provided by colloidal SiO.sub.2 having surface areas of
about 200 m.sup.2/g. In fact, Microcrystalline cellulose
coprocessed with silica gel demonstrates compressibility properties
about the same as off-the-shelf Microcrystalline cellulose in wet
granulation formulations.
EXAMPLES 20-22
HS-5 Grade Silicon Dioxide
[0166] In these examples, the coprocessing method described in
example 1 was repeated using HS-5 grade SiO.sub.2 surface area--325
m.sup.2/g (Cabot Corp., Tuscola, Ill.). TABLE-US-00009 Example
Silica Gel (wt %) 20 2 21 1 22 0.5
[0167] The resultant granulates prepared according to Example 1B
were tabletted according to the same method described in Example 6
and evaluated for tensile strength. The products of inventive
Example 3 (Microcrystalline cellulose-SiO.sub.2 2% w/w) and Example
5 (off-the-shelf Microcrystalline cellulose) were included in FIG.
5 for comparison purposes.
[0168] Referring now to FIG. 5, the retention of compressibility
afforded by coprocessing with HS-5 is comparable to that obtained
using SiO.sub.2 having surface areas of about 200 m.sup.2/g.
[0169] While there have been described what are presently believed
to be the preferred embodiments of the invention, those skilled in
the art will realize that changes and modifications may be made
thereto without departing from the spirit of the invention. It is
intended to claim all such changes and modifications that fall
within the true scope of the invention.
EXAMPLES 23-25
Preparation of Coprocessed Microcrystalline Cellulose-SLS
Compositions and Granulations Thereof
EXAMPLE 23
Microcrystalline Cellulose-SLS Product--0.25% w/w SLS
A. Excipient Particles
[0170] In this example, about 6.2 kilograms of microcrystalline
cellulose (Microcrystalline cellulose), (Mendell Co., Inc.
Patterson, N.Y.) in the form of a wet cake (i.e hydrocellulose or
hydrolyzed cellulose) was combined with 5.2 kilograms of water in a
mix tank to form a slurry containing about 15% solids. The pH was
adjusted to about neutral with about 3 ml of ammonium hydroxide.
The slurry was allowed to mix for about 15 minutes before being
combined with 0.25% w/w sodium lauryl sulfate (SLS) powder
(available from Spectrum Chemical, Gardena, Calif.) After allowing
the materials to become intimately combined, the slurry was spray
dried using a Niro Production Minor (Niro, Columbia, Md.), inlet
temperature--215.degree. C., outlet temperature--125.degree. C.,
atomizer wheel speed 22,300 rpm, to provide Microcrystalline
cellulose-SLS having an average particle size of 40-60 microns.
B. Granulation of Excipient Particles
[0171] The Microcrystalline cellulose-SLS particles obtained as a
result of Example 23A. were wet granulated in a Baker-Perkins 10
liter high-sheer granulator for 3 minutes using water as the
granulating fluid. The resultant product was wet screened through a
12 mesh screen, tray dried in a convection oven for about 2-3 hours
until a moisture content of less than 5% was obtained, dry screened
and sieved to obtain an average particle size of from about 55 to
about 70 microns.
EXAMPLES 24-27
Microcrystalline Cellulose-SLS Products
[0172] The processes of Example 23A and B were repeated except that
0.5% w/w sodium lauryl sulfate was used to form the product of
Example 24; 0.1% w/w SLS was used to form the product of Example
25; 0.2% w/w SLS was used to form the product of Example 26; and
0.3% w/w SLS was used to form the product of Example 27.
EXAMPLE 28
Dry Blend Mix of Microcrystalline Cellulose and SLS (0.25%
w/w)--Comparative
[0173] As a control, EMCOCEL.RTM. grade 50 M microcrystalline
cellulose (Mendell Co., Inc.) and 0.25% w/w SLS powder were dry
blended. No spray drying or other treatment of the mixture was
undertaken. The method of Example 23B, however, was repeated.
EXAMPLE 29
Processed Microcrystalline Cellulose without SLS
[0174] As a second control, the process described in Example 23B
was repeated except that no SLS was added.
EXAMPLE 30
[0175] In this example, batches of compressed tablets were prepared
using each of the products obtained as a result of Examples 23-29.
The tablets were prepared using a Korsch tablet press having a
punch size of 3/8'' and an aim weight of about 245 mg. The
granulations were included in five separate tabletting runs using
compression forces of 6, 12, 18, 24 and 30 kN respectively. Ten
tablets from each run were weighed, measured for diameter and
tested for thickness and hardness on the Erweka TBH 30 tablet
hardness tester to determine the compressibility of the
microcrystalline cellulose as measured by tensile strength. The
results of the analysis for the products of Examples 23, 25-29 are
graphically illustrated in FIG. 6 as a comparison of tensile
strength versus compression force. The results obtained using the
product of Example 24 were determined to be comparable to that
obtained for the product of Example 25 (0.1% SLS).
[0176] As can be seen from the graph, substantial benefits are
obtained by coprocessing Microcrystalline cellulose with SLS. The
tablets prepared using the products of comparative examples 28 and
29 demonstrated poor tensile strength. The novel excipient is
superior and demonstrates approximately the same relative
improvement across the entire range of compression forces.
Furthermore, the graph also illustrates that tablets prepared with
a mere dry admixture of Microcrystalline cellulose and SLS (Example
28 formulation) failed to demonstrate acceptable tensile strengths.
Thus, the coprocessed microcrystalline cellulose-SLS described
herein provides significant retention of Microcrystalline cellulose
compressibility.
EXAMPLES 31-32
Docusate Sodium
[0177] In these examples, the coprocessing method described in
Example 23A was repeated except that docusate sodium (Spectrum
Chemical) was used as the coprocessing agent). TABLE-US-00010
Docusate Example Sodium (wt %) 31 0.25 32 0.50
[0178] The resultant granulates prepared according to Example 23B
were tabletted according to the same method described in Example 30
and evaluated for tensile strength. The products of inventive
Example 26 (Microcrystalline cellulose-SLS 0.20% w/w) and Example
29 (microcrystalline cellulose alone) were included in FIG. 7 for
comparison purposes.
[0179] Referring now to FIG. 7, it can be seen that coprocessing
microcrystalline cellulose with docusate sodium also affords the
retention of microcrystalline cellulose compressibility.
EXAMPLES 33-36
Polysorbate 40
[0180] In these examples, the coprocessing method described in
Example 23A was repeated using the non-ionic surfactant polysorbate
40 (Spectrum Chemical) as the coprocessing agent. TABLE-US-00011
Example Polysorbate 40 (wt %) 33 0.25 34 0.50 35 1.0 36 2.0
[0181] The resultant granulates prepared according to Example 23B
were tabletted according to the same method described in Example 30
and evaluated for tensile strength. The products of inventive
Example 26 (Microcrystalline cellulose-SLS 0.2% w/w) and Example 29
(microcrystalline cellulose alone) were included in FIG. 8 for
comparison purposes.
[0182] Referring now to FIG. 8, it can be seen that the retention
of compressibility afforded by coprocessing with polysorbate 40 is
well below that provided by sodium lauryl sulfate. In fact,
microcrystalline cellulose coprocessed with polysorbate 40
demonstrates compressibility properties about the same as
off-the-shelf Microcrystalline cellulose in wet granulation
formulations.
EXAMPLES 37-39
Simethicone
[0183] In these examples, the coprocessing method described in
example 23 was repeated using simethicone (Dow Corning, Midland.
Mich.) as the surfactant coprocessing agent. TABLE-US-00012 Example
Simethicone (wt %) 37 0.5 38 1.0 39 2.0
[0184] The resultant granulates prepared according to Example 23B
were tabletted according to the same method described in Example 30
and evaluated for tensile strength. The products of inventive
Example 29 (Microcrystalline cellulose-SLS 0.2% w/w) and Example 29
(off-the-shelf microcrystalline cellulose) were included in FIG. 9
for comparison purposes.
[0185] Referring now to FIG. 9, it can be seen that this surfactant
provides little, if any, improvement in the retention of
microcrystalline cellulose compressibility. It can, therefore, be
seen that mere addition of any lubricant in any amount is not
sufficient to allow microcrystalline cellulose to retain its
compressibility in wet granulations, Rather, selected surfactants,
present within the claimed ranges, provide the desirable
compressibility characteristics to the microcrystalline
cellulose.
EXAMPLE 40
MCC-SiO.sub.2 Product--2% w/w SiO.sub.2
[0186] In this example, the process of Example 1A was repeated
except that 2% w/w colloidal silicon dioxide was used to form the
product.
EXAMPLES 41-49
[0187] In these examples, batches of compressed tablets containing
granular acetaminophen (APAP) in high load (80% wt.) were prepared
using the techniques described herein and compared to a high load
(80% by weight) APAP formulation described above wherein all
ingredients were V-blended before being compressed into
tablets.
[0188] In each case, the tablets were prepared using a Korsch
tablet press having a punch size of 3/8'' and an aim weight of
about 245 mg.+-.5 mg. Each of the foregoing granulations was
included in five separate tableting runs using compression forces
of 6, 12, 18, 24 and 30 kN, respectively. Ten tablets from each run
were weighed, measured for diameter and tested for thickness and
hardness on the Erweka TBH 30 tablet hardness tester to determine
tensile strength of the final product.
[0189] The batch formula for the comparative control tablets is set
forth below: TABLE-US-00013 COMPARATIVE BATCH GRAMS PER INGREDIENT
BATCH % BATCH Microcrystalline cellulose (MCC) 17.80% 44.50 APAP
80.00% 200.00 Sodium starch glycolate (SSG) 2.00% 5.00 Mg. Stearate
0.20% 0.50 TOTAL 100.00% 250.00
[0190] The MCC, APAP and SSG were added to a two quart V-blender
and mixed for 15 minutes. Thereafter, the Mg stearate was added to
the blender and mixing was continued for an additional 5 minutes.
All mixing of the ingredients was carried out in a room having a
relative humidity of about 10%. The mixture was then removed from
the blender and tableted in the same manner as that used to prepare
the tablets of the invention.
EXAMPLE 41
[0191] In this example, compressed tablets containing APAP were
prepared according to the batch formula set forth below. The
microcrystalline cellulose used was the MCC coprocessed with 5.0%
SiO.sub.2 as described in Example 1A. TABLE-US-00014 GRAMS PER
INGREDIENT BATCH % BATCH MCC coprocessed w/5% CSD 17.60% 88.00 APAP
80.00% 400.00 Colloidal silicon dioxide (CSD) 0.50% 2.50 Sodium
starch glycolate (SSG) 1.50% 7.50 Sodium stearyl fumarate (SSF)
0.40% 2.00 TOTAL 100.00% 500.00
[0192] The tablets were prepared according to the following
procedure:
[0193] The coprocessed MCC was added to a Baker-Perkins 10 L high
shear granulator along with the APAP, CSD and SSG. The CSD added
was in addition to that included in the coprocessed MCC. The
ingredients are mixed under dry, high shear conditions for 3
minutes with the impeller set at 200 rpm and the chopper at 1,000
rpm. Thereafter, the sodium stearyl fumarate, PRUV.TM., Edward
Mendell Co., Inc., was added to the high shear granulator and
mixing was continued for an additional 25 seconds with the impeller
at 200 rpm and the chopper at 500 rpm. At the conclusion of this
mixing step, the dry granulate was removed and directly compressed
into tablets using the aforementioned Korsch PH-100 tablet press
and compression forces.
EXAMPLE 42
[0194] In this example, the procedure of Example 41 was repeated
except that the MCC used was "off-the-shelf" MCC (EMCOCEL.RTM.,
Edward Mendell Co., Inc.) rather than the silicon dioxide
coprocessed material of Example 1A. The tablets were prepared using
the following batch formula: TABLE-US-00015 GRAMS PER INGREDIENT
BATCH % BATCH MCC (off-the-shelf) 17.60% 88.00 APAP 80.00% 400.00
Colloidal silicon dioxide (CSD) 0.50% 2.50 Sodium starch glycolate
(SSG) 1.50% 7.50 Sodium stearyl fumarate (SSF) 0.40% 2.00 TOTAL
100.00% 500.00
EXAMPLE 43
[0195] In this example, the procedure of Example 41 was repeated
except that additional CSD was not included in the high shear
mixing of the ingredients. The batch formula set forth below was
used. TABLE-US-00016 GRAMS PER INGREDIENT BATCH % BATCH MCC
coprocessed w/5% CSD 18.10% 90.50 APAP 80.00% 400.00 Sodium starch
glycolate (SSG) 1.50% 7.50 Sodium stearyl fumarate (SSF) 0.40% 2.00
TOTAL 100.00% 500.00
EXAMPLE 44
[0196] In this example an additional control granulation was
prepared by V-blending mixing off-the-shelf MCC with the other
ingredients in a controlled environment having a relative humidity
of about 40%. The granulation also did not include any added
silicon dioxide. The formulation was prepared according to the
following batch formula: TABLE-US-00017 GRAMS PER INGREDIENT BATCH
% BATCH MCC 18.10% 90.50 APAP 80.00% 400.00 Sodium starch glycolate
(SSG) 1.50% 7.50 Sodium stearyl fumarate (SSF) 0.40% 2.00 TOTAL
100.00% 500.00
EXAMPLE 45
[0197] In this example, the procedure of Example 41 was followed.
In this batch, however, the MCC used was the coprocessed product of
Example 40 which contained 2.0% SiO.sub.2. The batch also did not
include a separate amount of added CSD in the high shear mixture.
TABLE-US-00018 GRAMS PER INGREDIENT BATCH % BATCH MCC coprocessed
w/2% CSD 18.10% 90.50 APAP 80.00% 400.50 Sodium starch glycolate
(SSG) 1.50% 7.55 Sodium stearyl fumarate (SSF) 0.40% 2.00 TOTAL
100.00% 500.00
EXAMPLE 46
[0198] In this example, the directly compressed tablets containing
APAP were prepared using the procedure of Example 41 except that
the MCC used was the coprocessed microcrystalline cellulose of
Example 40. The batch formula set forth below was used.
TABLE-US-00019 GRAMS PER INGREDIENT BATCH % BATCH MCC coprocessed
w/2% CSD 17.60% 88.00 APAP 80.00% 400.00 Colloidal silicon dioxide
(CSD) 0.50% 2.50 Sodium starch glycolate (SSG) 1.50% 7.50 Sodium
stearyl fumarate (SSF) 0.40% 2.00 TOTAL 100.00% 500.00
Discussion
[0199] The results of the tensile strength tests for the
directly-compressed high load tablets are discussed. Each of the
high load-containing APAP tablets made in accordance with the
present invention had a desirable tablet hardness profile when
compared to that of the V-blended comparative example.
[0200] It can also be seen that mere dry blending of the
ingredients prior to direct compression did not provide acceptable
tensile strength. Even in the case of Example 44, where humidity
was increased to about 40%, the results failed to match that
obtained by the high shear mixing of the present invention.
Furthermore, the advantages of high shear blending the APAP and
MCC-based compression vehicle is especially apparent at higher
compression forces. The results also demonstrate fact that those
high load tablets prepared with MCC coprocessed with SiO.sub.2,
i.e. Examples 41 and 46 as well as those containing a separately
added amount of SiO.sub.2, i.e. Example 42, have a particularly
desirable tablet hardness profile.
[0201] In general, the results obtained for the inventive
compositions were completely unexpected since those of ordinary
skill in the art are well aware of the problems associated with
combining tablet lubricants such as sodium stearyl fumarate with
the other tablet ingredients under high shear conditions. Contrary
to what was expected, the directly compressed high load tablets had
higher rather than lower tensile strength. Further, the overcoating
of the granules with the lubricant which was expected and which
would have significantly reduced the tablet hardness was not
observed. In addition, it was also unexpected that granular forms
of APAP would provide the necessary physical characteristics to a
formulation to allow formation of direct compressed high load
tablets having acceptable levels of hardness. Thus, it can be seen
that the high shear mixing of MCC-based excipients as described
herein directly addresses a shortcoming of the prior art
techniques.
EXAMPLE 47
[0202] In this example, the tablets were prepared according to the
following batch formula: TABLE-US-00020 GRAMS PER INGREDIENT BATCH
% BATCH MCC (coprocessed w/2% CSD) 17.60% 88.00 APAP 80.00% 400.0
Colloidal silicon dioxide (CSD) 0.50% 2.50 Sodium starch glycolate
(SSG) 1.50% 7.50 Sodium stearyl fumarate (SSF) 0.40% 2.00 TOTAL
100.00% 500.00
[0203] In this example, the initial high shear mixing of the MCC,
APAP, CSD, and SSG was carried out in the same manner as described
above with regard to Example 42 (i.e., using the high shear blender
for 3 minutes at 200 rpm for impeller and 1,000 rpm for chopper).
However, after this first high shear mixing step, all ingredients
were removed and transferred to a 2 quart V-blender. No further
high shear mixing was undertaken. Instead, the sodium stearyl
fumarate was added to the mixture and V-blender mixing was carried
out for 5 minutes. The tablets were then made following the
procedures described above.
EXAMPLE 48
[0204] The procedure of Example 47 was repeated except that an
equal amount of magnesium stearate was substituted for the sodium
stearyl fumarate used in Example 47 for the V-blending step prior
to the direct compression of the tablets. TABLE-US-00021 GRAMS PER
INGREDIENT BATCH % BATCH MCC (coprocessed w/2% CSD) 17.60% 88.00
APAP 80.00% 400.0 Colloidal silicon dioxide (CSD) 0.50% 2.50 Sodium
starch glycolate (SSG) 1.50% 7.50 Magnesium stearate 0.40% 2.00
TOTAL 100.00% 500.00
EXAMPLE 49
[0205] In this example, the two step high shear blending procedure
of Example 42 was repeated except that magnesium stearate was
substituted for the originally described sodium stearyl fumarate.
As was the case in Example 42, high shear mixing was used for both
performing both the initial and final blends. TABLE-US-00022 GRAMS
PER INGREDIENT BATCH % BATCH MCC (off-the-shelf) 17.60% 88.00 APAP
80.00% 400.00 CSD 0.50% 2.50 SSG 1.50% 7.50 Magnesium stearate
0.40% 2.00 TOTAL 100.00% 500.00
Discussion
[0206] In each case, it can be seen that improvements in tablet
hardness can be realized even if the lubricant is combined under
low shear conditions. In all cases, the tablets prepared from
granulations which were prepared using at least one high shear
mixing step out-performed the completely V-blended control.
EXAMPLE 50
[0207] In this example, the average disintegration time for tablets
prepared in accordance with Example 46 was determined and compared
to that of commercially available APAP tablets sold under the
Tylenol.RTM. brand. The test was carried out according to the
U.S.P. guidelines using a Van-Kel disintegration apparatus. In
particular, six tablets prepared according to the procedure of
Example 46 as well as six Tylenol tablets were individually
evaluated in the apparatus to determine disintegration time in
deionized water at 37.degree. C. without using the basket disk of
the apparatus. The average disintegration time for the six tablets
in each group was then calculated. The tablets prepared in
accordance with the present invention had an average disintegration
time of less than half of that required for the commercially sold
formulation. This rapid disintegration feature illustrates an
additional advantage of the formulations of the present
invention.
EXAMPLE 51
[0208] In this example, compressed tablets containing APAP are
prepared according to the batch formula set forth below. The
microcrystalline cellulose used is the MCC coprocessed with 5.0%
SiO.sub.2 as described in Example 1A. TABLE-US-00023 Ingredient
Batch % MCC coprocessed w/5% SiO.sub.2 19.6% APAP 80.00% Sodium
stearyl fumarate 0.40% Total 100.00%
[0209] The tablets are prepared according to the following
procedure:
[0210] The coprocessed MCC is mixed together with the APAP and the
sodium stearyl fumarate in a V-blender. A sufficient quantity of
water is added to the mixture to form a wet mass. The wet mass is
dried in a fluid bed dryer to produce a dried granulate. The dried
granulate is compressed to form tablets containing 80 mg APAP.
EXAMPLE 52
[0211] In this example, tablets according to Example 51 are
prepared except that "off the shelf" microcrystalline cellulose is
used. The tablet formulation is shown in the table below:
TABLE-US-00024 Ingredient Batch % MCC 19.6% APAP 80.00% Sodium
stearyl fumarate 0.40% Total 100.00%
Discussion
[0212] The tablets of Example 51 exhibit improved disintegration
properties when compared to the tablets of example 52 due to
inclusion of the coprocessed MCC/SiO.sub.2 excipient.
EXAMPLE 53
[0213] In this example, compressed tablets containing APAP are
prepared according to the batch formula set forth below. The
microcrystalline cellulose used is the MCC coprocessed with 2%
SiO.sub.2 as described in Example 1A. TABLE-US-00025 INGREDIENT
BATCH % MCC coprocessed w/2% SiO.sub.2 19.60% APAP 80.00% Sodium
stearyl fumarate (SSF) 0.40% TOTAL 100.00%
[0214] The tablets are prepared according to the following
procedure described in Example 51.
EXAMPLE 54
[0215] In this example, tablets according to Example 53 are
prepared except that "off the shelf" microcrystalline cellulose is
used. The tablet formulation is shown in the table below:
TABLE-US-00026 INGREDIENT BATCH % MCC 19.60% APAP 80.00% Sodium
stearyl fumarate (SSF) 0.40% TOTAL 100.00%
Discussion
[0216] The tablets of Example 53 exhibit improved disintegration
(e.g. bioavalability of APAP) properties when compared to the
tablets of Example 54 due to inclusion of the coprocessed MCC/CSD
excipient.
EXAMPLE 55
[0217] In this example, compressed tablets containing APAP are
prepared according to the batch formula set forth below. The
microcrystalline cellulose used is the MCC coprocessed with a
surfactant (SLS). TABLE-US-00027 INGREDIENT BATCH % MCC coprocessed
w/0.1% SLS 19.60% APAP 80.00% Sodium stearyl fumarate (SSF) 0.40%
TOTAL 100.00%
[0218] The tablets are prepared according to the procedure of
Example 51.
EXAMPLE 56
[0219] In this example, tablets according to Example 55 are
prepared except that "off the shelf" microcrystalline cellulose is
used. The tablet formulation is shown in the table below:
TABLE-US-00028 INGREDIENT BATCH % MCC 19.60% APAP 80.00% Sodium
stearyl fumarate (SSF) 0.40% TOTAL 100.00%
Discussion
[0220] The tablets of Example 55 exhibit improved absorption
properties when compared to the tablets of Example 56 due to
inclusion of the coprocessed MCC/SLS excipient.
EXAMPLE 57
[0221] In this example, compressed tablets containing APAP are
prepared according to the batch formula set forth below. The
microcrystalline cellulose used is the MCC coprocessed with LSD and
SLS. TABLE-US-00029 INGREDIENT BATCH % MCC coprocessed w/0.1% SLS
and 5% SiO.sub.2 19.60% APAP 80.00% Sodium stearyl fumarate (SSF)
0.40% TOTAL 100.00%
[0222] The tablets are prepared according to the procedure set
forth in Example 51.
EXAMPLE 58
[0223] In this example, tablets according to Example 57 are
prepared except that "off the shelf" microcrystalline cellulose is
used. The tablet formulation is shown in the table below:
TABLE-US-00030 INGREDIENT BATCH % MCC 19.60% APAP 80.00% Sodium
stearyl fumarate (SSF) 0.40% TOTAL 100.00%
Discussion
[0224] The tablets of Example 57 exhibit improved disintegration
and absorption properties when compared to the tablets of Example
58 due to inclusion of the coprocessed MCC/SiO.sub.2/SLS
excipient.
[0225] While there have been described what are presently believed
to be the preferred embodiments of the invention, those skilled in
the art will realize that changes and modifications may be made
thereto without departing from the spirit of the invention. It is
intended to claim all such changes and modifications that fall
within the true scope of the invention.
* * * * *