U.S. patent application number 09/798755 was filed with the patent office on 2001-08-16 for directly compressible high load acetaminophen formulations.
Invention is credited to Hunter, Edward A., Sherwood, Bob E., Zeleznik, Joseph A..
Application Number | 20010014353 09/798755 |
Document ID | / |
Family ID | 27502003 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014353 |
Kind Code |
A1 |
Hunter, Edward A. ; et
al. |
August 16, 2001 |
Directly compressible high load acetaminophen formulations
Abstract
Direct compressed solid pharmaceutical dosage forms containing:
a) from about 40 to about 95% by weight acetaminophen; b) from
about 1 to about 60% by weight of a direct compression vehicle
comprising microcrystalline cellulose; and c) from about 0.01 to
about 4.0% by weight of a pharmaceutically-acceptabl- e lubricant
are disclosed. The acetaminophen and direct compression vehicle are
combined under high shear conditions which are sufficient to
transform acetaminophen and direct compression vehicle into a
homogenous granulate without degradation. In preferred aspects of
the invention, the lubricant is also combined with the
acetaminophen and direct compression vehicle under high shear
conditions. Methods of preparing the directly compressed solid
pharmaceutical dosage forms and methods of treatment with the
dosage forms are also disclosed. The methods are particularly well
suited for preparing directly compressed dosage forms containing
high load (i.e., up to 80% or greater) amounts of acetaminophen
based on the weight of the total tablet.
Inventors: |
Hunter, Edward A.; (Glenham,
NY) ; Sherwood, Bob E.; (Amenia, NY) ;
Zeleznik, Joseph A.; (New Paltz, NY) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
27502003 |
Appl. No.: |
09/798755 |
Filed: |
March 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09798755 |
Mar 2, 2001 |
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09331210 |
Jul 29, 1999 |
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09331210 |
Jul 29, 1999 |
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08964917 |
Nov 5, 1997 |
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5965166 |
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08964917 |
Nov 5, 1997 |
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08558335 |
Nov 15, 1995 |
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5733578 |
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Current U.S.
Class: |
424/464 ;
424/468; 424/489 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2095 20130101; A61K 31/167 20130101; A61K 9/2009
20130101 |
Class at
Publication: |
424/464 ;
424/489; 424/468 |
International
Class: |
A61K 009/20; A61K
009/22; A61K 009/14 |
Claims
What is claimed is:
1. A direct compressed solid pharmaceutical dosage form,
comprising: a) from about 40 to about 95% by weight acetaminophen;
b) from about 1 to about 60% by weight of a direct compression
vehicle comprising microcrystalline cellulose; and c) from about
0.01 to about 4.0% by weight of a pharmaceutically-acceptable
lubricant; said acetaminophen and said direct compression vehicle
being combined under shear conditions sufficient to transform said
acetaminophen and said direct compression vehicle into a homogenous
granulate without degradation, and which has been directly
compressed into a solid pharmaceutical dosage form.
2. The solid dosage form of claim 1, wherein said pharmaceutical
dosage form comprises from about 60% to about 85% by weight
acetaminophen.
3. The solid dosage form of claim 1, wherein said acetaminophen is
in granular form.
4. The solid dosage form of claim 1, wherein said microcrystalline
cellulose has been coprocessed with from about 0.1 to about 20% by
weight silicon dioxide, whereby said microcrystalline cellulose and
said silicon dioxide are in intimate association with each
other.
5. The solid dosage form of claim 4, wherein said silicon dioxide
has an average primary particle size of from 1 nm to about 100
.mu.m.
6. The solid dosage form of claim 5, wherein said silicon dioxide
has an average primary particle size of from about 5 nm to about 40
.mu.m.
7. The solid dosage form of claim 6, wherein said silicon dioxide
is derived from colloidal silicon dioxide.
8. The solid dosage form of claim 7, wherein said silicon dioxide
is present in an amount of from about 0.5 to about 10% by weight,
based on the weight of said microcrystalline cellulose.
9. The solid dosage form of claim 8, wherein said silicon dioxide
is present in an amount of from about 1.25 to about 5% by weight,
based on the weight of said microcrystalline cellulose.
10. The solid dosage form of claim 1, wherein said lubricant is
sodium stearyl fumarate.
11. The solid dosage form of claim 1, wherein said lubricant is
present in an amount of from about 0.1 to about 1.0% by weight.
12. The solid dosage form of claim 11, wherein said lubricant is
present in an amount of from about 0.2 to about 0.45% by
weight.
13. The solid dosage form of claim 1, wherein said homogeneous
granulate further comprises silicon dioxide.
14. The solid dosage form of claim 13, wherein said silicon dioxide
has been combined with said acetaminophen and said direct
compression vehicle under said high shear conditions.
15. The solid dosage form of claim 13, wherein said silicon dioxide
is colloidal silicon dioxide.
16. The solid dosage form of claim 13, wherein said amount of
silicon dioxide is from about 0.1 to about 5% by weight of said
dosage form.
17. The solid dosage form of claim 16, wherein said amount of
silicon dioxide is from about 0.15 to about 0.9% by weight of said
pharmaceutical dosage form.
18. The solid dosage form of claim 17, wherein said amount of
silicon dioxide is from about 0.4 to about 0.75% by weight of said
pharmaceutical dosage form.
19. The solid dosage form of claim 1, further comprising a
disintegrant.
20. The solid dosage form of claim 19, wherein said disintegrant
has been combined with said acetaminophen and said direct
compression vehicle under said high shear conditions.
21. The solid dosage form of claim 19, wherein said disintegrant is
sodium starch glycolate.
22. The solid dosage form of claim 19, wherein said direct
compression vehicle is present in an amount of from about 2 to
about 25% by weight of said solid dosage form.
23. The solid dosage form of claim 22, wherein said direct
compression vehicle is present in an amount of from about 5 to
about 20% by weight of said solid dosage form.
24. The solid dosage form of claim 15, wherein said silicon dioxide
is combined with said acetaminophen and said direct compression
vehicle to form a first high shear mixture and thereafter combining
said first high shear mixture with said lubricant under said shear
conditions to form said homogenous granulate.
25. The solid dosage form of claim 1, wherein said acetaminophen
comprises at least about 75% by weight of said solid dosage form
and said solid dosage form has an average tablet hardness of about
6.5 kP when said homogeneous granulate is direct compressed at a
compression force of about 25 kN.
26. The solid dosage form of claim 1, wherein said pharmaceutical
dosage form comprises from about 10 to about 1000 milligrams of
acetaminophen.
27. The solid dosage form of claim 26, wherein said pharmaceutical
dosage form comprises from about 80 to about 750 milligrams
acetaminophen.
28. The solid dosage form of claim 27, wherein said pharmaceutical
dosage form comprises from about 120 to about 600 milligrams of
acetaminophen.
29. A method of preparing a direct compressed solid pharmaceutical
dosage form, comprising: a) combining from about 40 to about 95% by
weight acetaminophen and from about 1 to about 60% by weight of a
direct compression vehicle comprising microcrystalline cellose
under shear conditions sufficient to transform said acetaminophen
and said direct compression vehicle into a first homogenous
granulate; b) combining said first homogenous granulate with from
about 0.01 to about 4.0% of a pharmaceutically-acceptable
lubricant; and c) compressing said homogenous granulate containing
said lubricant into a solid pharmaceutical dosage form.
30. The method of claim 29, wherein said pharmaceutical dosage form
comprises from about 60% to about 85% by weight acetaminophen.
31. The method of claim 29, wherein said acetaminophen is in
granular form.
32. The method of claim 29, wherein said microcrystalline cellulose
has been coprocessed with from about 0.1 to about 20% by weight
silicon dioxide, whereby said microcrystalline cellulose and said
silicon dioxide are in intimate association with each other.
33. The method of claim 32, wherein said silicon dioxide is
colloidal silicon dioxide and has an average primary particle size
of from 1 nm to about 100 .mu.m.
34. The method of claim 32, wherein said silicon dioxide is present
in an amount of from about 0.5 to about 10% by weight, based on the
weight of said microcrystalline cellulose.
35. The method of claim 29, wherein said lubricant is sodium
stearyl fumarate.
36. The method of claim 29, wherein said lubricant is present in an
amount of from about 0.01 to about 4.0% by weight.
37. The method of claim 1, wherein said first homogeneous granulate
further comprises silicon dioxide.
38. The method of claim 37, wherein said silicon dioxide has been
combined with said acetaminophen and said direct compression
vehicle under said high shear conditions.
39. The method of claim 37, wherein said silicon dioxide is
colloidal silicon dioxide.
40. The method of claim 37, wherein said amount of silicon dioxide
is from about 0.1 to about 5% by weight of said dosage form.
41. The method of claim 29, further comprising combining a
disintegrant with said acetaminophen and said direct compression
vehicle under said high shear conditions.
42. The method of claim 41, wherein said disintegrant is sodium
starch glycolate.
43. The method of claim 29, wherein said direct compression vehicle
is present in an amount of from about 2 to about 25% by weight of
said solid dosage form.
44. The method of claim 37, wherein said silicon dioxide is
combined with said acetaminophen and said direct compression
vehicle to form a first high shear mixture prior to said combining
of said lubricant.
45. The method of claim 29, wherein said lubricant is combined with
said first homogeneous granulate under high shear mixing
conditions.
46. The method of claim 45, wherein said high shear mixing
conditions used to combine said lubricant are less than said shear
conditions used to form said first homogeneous granulate.
47. A method of effecting analgesia in mammals, comprising
administering to a mammal in need of such analgesia a direct
compressed dosage form containing: a) from about 40 to about 95% by
weight acetaminophen; b) from about 1 to about 60% by weight of a
direct compression vehicle comprising microcrystalline cellulose;
and c) from about 0.01 to about 4.0% by weight of a
pharmaceutically-acceptable lubricant; said acetaminophen and said
direct compression vehicle being combined under shear conditions
sufficient to transform said acetaminophen and said direct
compression vehicle into a homogenous granulate without
degradation.
48. The method of claim 47, wherein said compressed dosage form
comprises from about 10 to about 1000 milligrams of
acetaminophen.
49. The method of claim 48, wherein said compressed dosage form
comprises from about 120 to about 750 milligrams of acetaminophen.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to methods of preparing solid
dosage forms using direct compression techniques. In particular,
the present invention relates to methods of directly compressing
tablets containing relatively high amounts of acetaminophen based
on the total tablet weight.
[0002] In order to prepare a solid dosage form containing one or
more active ingredients (such as drugs), it is necessary for the
materials to be compressed into the dosage form possess certain
physical characteristics which lend themselves to solid dosage form
processing. 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.
[0003] 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 tabletting
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.
[0004] Since most drugs have none or only some of these properties,
methods of tablet formulating have been developed to impart these
desirable characteristics to the material(s) which is to be
compressed into a solid dosage form. Typically, 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.
[0005] Lubricants are typically added to avoid the material(s)
being tabletted from sticking to the punches. Commonly used
lubricants include magnesium stearate and calcium stearate. Such
lubricants are commonly included in the final tabletted product in
amounts usually less than 1% by weight.
[0006] In addition, solid dosage forms often contain diluents.
Diluents are frequently added in order to increase the bulk weight
of the material to be tabletted in order to make the tablet a
practical size for compression. This is often necessary where the
dose of the drug is relatively small.
[0007] 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.
[0008] 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 carboxymethylcellulose.
[0009] There are three general methods of preparing the materials
to be included in the solid dosage form prior to compression: (1)
dry granulation; (2) wet granulation; and (3) direct
compression.
[0010] Dry granulation procedures may be utilized where one of the
constituents, either the drug or the diluent, has sufficient
cohesive properties to be tabletted. The method includes mixing the
ingredients with a lubricant, if required, slugging the
ingredients, dry screening, lubricating and finally compressing the
ingredients.
[0011] 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 under shear mixing conditions 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 or fluid-bed
drying. The wet granulating technique is rather time consuming due
to its process steps and can also be considered to be relatively
expensive. In addition, wet granulating has been known to reduce
the compressibility of some pharmaceutical ingredients including
microcrystalline cellulose.
[0012] Direct compression, on the other hand, is regarded as a
relatively quick process wherein the powdered materials included in
the solid dosage form are compressed directly without modifying
their physical nature. Usually, the active ingredient, direct
compression vehicle and other ancillary substances, such as a
glidant to improve the rate of flow of the tablet granulation and
lubricant to prevent adhesion of the tablet material to the surface
of the dies and punches of the tablet press, are blended in a twin
shell blender or similar low shear apparatus before being
compressed into tablets. This type of mixing of the ingredients was
believed to be essential in order to prepare pharmaceutically
acceptable dosage forms. For example, Remington's Pharmaceutical
Sciences, 16th Edition (1980), Arthur Osol, Ed., cautions artisans
that the manner in which a lubricant is added to a formulation must
be carefully controlled. Consequently, lubricants are usually added
to a granulation by gentle mixing. At page 1556, Remington's,
warns: "Prolonged blending of a lubricant with a granulation can
materially affect the hardness and disintegration time for the
resulting tablets." Further, those of ordinary skill in the art
have long believed that excessive mixing of a lubricant with the
granulate ingredients overcoats the granules and reduces the tablet
hardness or tablet strength of the compressed tablets. Thus, for at
least these reasons, high shear mixing conditions have not been
used to prepare direct compression dosage forms.
[0013] Pharmaceutical manufacturers would often prefer to use
direct compression techniques over wet or dry granulation
techniques because of its processing time and cost advantages.
Direct compression, however, is usually limited to those situations
where the drug or active ingredient has a requisite crystalline
structure and the physical characteristics required for formation
of a pharmaceutically acceptable tablet. Often, however, one or
more excipients must be combined with the active ingredient before
the direct compression method can be used since many active
ingredients do not have the necessary properties. Since each
excipient added to formulation necessarily increases the tablet
size of the final product, artisans were often limited to using
direct compression techniques in formulations containing a rather
low load of active ingredient per compressed tablet. Solid dosage
forms containing the drug to be administered in a relatively high
load or dose (e.g., the drug itself comprises a substantial portion
of the total compressed tablet weight), could only be directly
compressed if the drug itself had sufficient physical
characteristics (e.g., cohesiveness) for the ingredients to be
directly compressed.
[0014] For example, acetaminophen, a widely used analgesic, is
considered to be a high load active ingredient. Most commercial
compressed tablet formulations include anywhere from 70 to 85% by
weight acetaminophen per finished tablet. This high load of active
ingredient combined with its rather poor physical characteristics
for direct compression have not allowed pharmaceutical
manufacturers to use direct compression techniques to prepare the
final tablets. Previous attempts to directly compress acetaminophen
with microcrystalline cellulose have failed to provide an
acceptable product. The final products tend to be soft, prone to
capping and otherwise not commercially desirable, i.e., difficult
to swallow because of the large size. Consequently, the more time
consuming and expensive wet granulation techniques must be
used.
[0015] Thus, another limitation of direct compression as a method
of tablet manufacturing is the potential size of the compressed
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 amount of acetaminophen. 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.
[0016] Microcrystalline cellulose, a processed 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 as long as
it is not wet granulated prior to compression.
[0017] Thus, despite the advantages of direct compression such as
reduced processing times and costs, wet granulation is widely used
in the industry to prepare solid dosage forms. Currently, many
skilled in the art also prefer wet granulation over direct
compression because wet granulating 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 with the
wet granulation method because all of the granules obtained thereby
usually 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] In spite of the advantages afforded by wet granulation
methods, many manufacturers would nonetheless welcome the
opportunity to directly compress tablets containing acetaminophen,
especially those containing high loads of acetaminophen and/or
microcrystalline cellulose.
[0020] Thus, there still remains a need in the industry for
techniques and pharmaceutical excipients which would allow artisans
to prepare direct compressed dosage forms containing relatively
high amounts of acetaminophen by weight and thereby avoid the time
and expense of wet granulations.
OBJECTS AND SUMMARY OF THE INVENTION
[0021] It is an object of the present invention to provide
improvements in direct compression techniques.
[0022] It is a further object of the present invention to provide a
cost effective alternative to wet granulating acetaminophen
formulations in order to prepare solid dosage forms containing a
relatively high proportion of the drug when compared to the total
weight of the dosage form.
[0023] It is a further object of the present invention to provide
direct compressed acetaminophen oral solid dosage forms which
disintegrate rapidly in vivo and in vitro.
[0024] A further object of the present invention is to provide
direct compressed dosage forms which provide controlled release of
acetaminophen without relying on fluidized bed or wet granulating
techniques.
[0025] Another object of the present invention is to provide solid
dosage forms which include acetaminophen and which are prepared
according to the methods described herein.
[0026] In accordance with the above objects and others which will
be obvious to those skilled in the art, the present invention
includes a direct compressed solid pharmaceutical dosage form
containing:
[0027] a) from about 40 to about 95% by weight acetaminophen;
[0028] b) from about 1 to about 60% by weight of a direct
compression vehicle comprising microcrystalline cellulose; and
[0029] c) from about 0.01 to about 4.0% by weight of a
pharmaceutically-acceptable lubricant.
[0030] The acetaminophen and direct compression vehicle included in
the direct compressed dosage form are combined under shear mixing
conditions which are sufficient to transform the acetaminophen and
direct compression vehicle into a homogenous granulate without
degradation.
[0031] In preferred embodiments of this aspect of the invention,
the solid dosage form comprises from about 60% to about 85% by
weight acetaminophen and the acetaminophen is in granular form. The
solid dosage forms accordingly can contain from about 10 to about
1000 milligrams of acetaminophen. In a particularly preferred
embodiment, the direct compression vehicle includes
microcrystalline cellulose which has been coprocessed with from
about 0.1 to about 20% by weight silicon dioxide so that the
microcrystalline cellulose and silicon dioxide are in intimate
association with each other and provide enhanced compressibility
properties for the direct compressed dosage forms. An additional
preferred embodiment includes preparing the direct compressed solid
pharmaceutical dosage form to include from about 0.1 to about 1% by
weight of a pharmaceutically acceptable lubricant such as sodium
stearyl fumarate. The lubricant is included as part of the
homogeneous mixture containing the acetaminophen and direct
compression vehicle and is preferably admixed with these
ingredients under the same or similar high shear conditions used to
form the homogeneous mixture.
[0032] In another embodiment, the direct compressed dosage forms of
the present invention include from about 0.1 to about 5.0% by
weight silicon dioxide. The silicon dioxide is preferably combined
with the homogeneous mixture containing the acetaminophen and
direct compression vehicle during the same high shear mixing
conditions used to transform the ingredients into the homogeneous
mixture.
[0033] In another embodiment of the invention, the direct
compressed dosage forms include a disintegrant which has preferably
been high shear mixed with the aforementioned acetaminophen, direct
compression vehicle and lubricant.
[0034] One particularly preferred solid dosage form of the present
invention includes at least about 75% by weight acetaminophen and
has an average tablet hardness of about 6.5 kP when the homogeneous
granulate containing the acetaminophen and microcrystalline
cellulose is direct compressed at a compression force of about 25
kN.
[0035] The tablets of the present invention also have a relatively
rapid disintegration rate which compares favorably with
acetaminophen tablets prepared using wet granulation techniques. In
certain preferred embodiments, the disintegration rate for the
tablets of the present invention meets the requirements set forth
in the USP 23 .COPYRGT. 1994 United States Pharmacopeial
Convention, Inc. Furthermore, the dissolution rate of the inventive
tablets is also believed to compare favorably, and in certain
embodiments, even exceed that of wet granulated APAP products. In
certain preferred embodiments, the inventive tablets also meet the
dissolution requirements for acetaminophen tablets as set forth in
the USP 23 official monograph. For example, the direct compressed
APAP tablets will preferably dissolve in 900 ml of pH 5.8 phosphate
buffer in 30 minutes. The "dissolution requirements" and
"disintegration requirements" referred to herein are conducted
using the equipment and tests specified in the aforementioned USP
23.
[0036] In another aspect of the present invention, there are
provided methods of preparing direct compressed solid
pharmaceutical dosage forms containing acetaminophen. This aspect
of the invention includes first combining an effective amount of
acetaminophen and a direct compression vehicle which comprises
microcrystalline cellulose under shear conditions which are
sufficient to transform the acetaminophen and direct compression
vehicle into a first homogenous granulate without degradation.
Next, the homogeneous granulate is combined with a
pharmaceutically-acceptable lubricant, either by similar high shear
or other dry mixing conditions, and thereafter compressing the
resultant homogenous granulate containing the lubricant into solid
pharmaceutical dosage forms.
[0037] Alternative aspects of the inventive methods described
herein include forming a high shear mixture which includes silicon
dioxide, preferably in the form of colloidal silicon dioxide. One
particularly preferred method includes forming a first high shear
mixture containing acetaminophen and a direct compression vehicle
which includes microcrystalline cellulose and silicon dioxide
before adding the lubricant under high shear conditions.
[0038] A still further aspect of the inventive method includes
preparing direct compression solid pharmaceutical dosage forms by
preparing a first high shear mixture by combining the
acetaminophen, direct compression vehicle and, optional silicon
dioxide and/or disintegrant. Next, the first high shear mixture is
combined with a lubricant in a separate shear mixing step to form
the final homogenous granulate. In this aspect of the invention,
however, the second shear mixing step is carried out under
conditions which are milder than those used to carry out the first
shear mixing step.
[0039] For purposes of the present invention, the term "high-load"
is meant to indicate that the acetaminophen comprises a substantial
portion of the solid oral dosage form on a weight basis. Those of
ordinary skill in the art recognize that compressed tablets
containing at least about 40% by weight of acetaminophen are
"high-load" tablets.
[0040] The term "granular" for purposes of the present invention is
meant to connote particles having an average cross-sectional
diameter of from about 50 to about 500 microns. The granular
particles are to be distinguished from powdered particles having a
particle size of less than about 50 microns and more likely in the
range of 10-20 microns.
[0041] The term "environmental fluid" is meant for purposes of the
invention to encompass, e.g., an aqueous solution, or
gastrointestinal fluid.
[0042] "Sustained release" is meant for purposes of the invention
to mean that the acetaminophen is released from the solid dosage
form at a controlled rate such that therapeutically beneficial
blood levels (but below toxic levels) of the active ingredient are
maintained over an extended period of time, e.g., providing a 12
hour or a 24 hour dosage form.
[0043] "Controlled release" is meant for purposes of the invention
to mean that the acetaminophen is released from the solid dosage
form at a predetermined rate such that therapeutically beneficial
blood levels are maintained over a period of time.
[0044] By "bioavailable" it is meant for purposes of the invention
that the acetaminophen is absorbed from the dosage form and becomes
available in the body at the intended site of action.
[0045] By "primary particle size" it is meant for purposes of the
invention that the particles are not agglomerated. Agglomeration is
common with respect to silicon dioxide particles, resulting in a
comparatively average large agglomerated particle size.
[0046] The methods and compositions of the present invention
provide several advantages to pharmaceutical formulators with
regard to direct compression techniques. For example, the methods
provide artisans with the ability to include high-load amounts of
acetaminophen in direct compression dosage forms. In the past,
high-load oral solid dosage forms containing acetaminophen could
only be prepared using wet granulation techniques because the
amount of additional excipients required to impart the necessary
physical characteristics, such as hardness and size, rendered the
final dosage forms unacceptable for both manufacturers and
consumers.
[0047] A further advantage of the present invention is that it is
now possible to increase the tablet hardness of
acetaminophen-containing solid dosage forms by subjecting the
formulation to high shear blending. This technique is especially
advantageous in situations where one or more of the formulation
ingredients, such as an additional active ingredient, is incapable
of undergoing wet granulation.
[0048] For a better understanding of the present invention,
together with other and further objects, reference is made to the
following description, taken together with the accompanying
figures, and the scope of the invention will be pointed out in the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0049] 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.
[0050] FIG. 1 graphically illustrates the tensile strengths of high
load APAP tablets prepared in accordance with Examples 3-5, 7, 8, a
control high load APAP tablets made in accordance with Example 6
and a second control prepared using prior art techniques.
[0051] FIG. 2 graphically illustrates a comparison of the tensile
strength of tablets prepared in accordance with Examples 8 and 9-11
and that obtained for a control high load APAP formulation.
[0052] FIG. 3 is a graphic illustration of the differences in the
disintegration time for a batch of tablets prepared in accordance
with the present invention and commercially available APAP
tablets.
DETAILED DESCRIPTION OF THE INVENTION
[0053] In one aspect of the invention, there are provided direct
compressed solid pharmaceutical dosage forms comprising:
[0054] a) from about 40 to about 95% by weight acetaminophen;
[0055] b) from about 1 to about 60% by weight of a direct
compression vehicle comprising microcrystalline cellulose; and
[0056] c) from about 0.01 to about 4.0% by weight of a
pharmaceutically-acceptable lubricant.
[0057] The acetaminophen and direct compression vehicle are
combined under shear mixing conditions which are sufficient to
transform the acetaminophen and direct compression vehicle into a
homogenous granulate without degradation. The lubricant included in
the dosage forms is also combined with the homogeneous granulate.
In this regard, high shear conditions are preferred although not
required.
[0058] ACETAMINOPHEN
[0059] The acetaminophen, hereinafter APAP, used in the direct
compressed dosage forms of the present invention is preferably in
granular form and has an average cross-sectional diameter of from
about 50 to about 500 microns. More preferably, however, the
granular APAP has a cross sectional diameter of from about 250-300
microns. Acetaminophen having these physical characteristics is
available, for example from Mallinkrodt, St. Louis, Mo. USA. An
alternative acetaminophen, also available from Mallinkrodt is
DC-90. It is to be understood that the present invention is not
limited to these types of granular APAP. Other sources of APAP are
also contemplated so long as the APAP has the granular
characteristics set forth above.
[0060] The granular APAP preferably used in the dosage forms of the
present invention is to be contrasted with powdered forms of the
active ingredient. Such powdered forms of APAP have a cross
sectional diameter of from about 10-20 microns and are not
contemplated for use herein. While applicants are not bound by
theory, it is believed that a critical particle size is required to
successfully withstand the high shear mixing conditions which
transform the APAP, in high load amounts, and direct compression
vehicle into a flowable granulate which is capable of being direct
compressed into solid dosage forms having sufficient hardness and
other physical qualities associated with an acceptable dosage
form.
[0061] In a preferred aspect of the invention, the solid dosage
forms contain from about 60 to about 85% by weight acetaminophen.
Of course, the exact amount of acetaminophen included in the dosage
forms of the present invention will depend upon the size of tablet
and dosage amount contemplated by the artisan. Currently, APAP
tablets are frequently formulated to contain from about 160 to
about 650 milligrams of the drug. Tablets containing about 325 and
about 500 milligrams are also commonly found. Several other APAP
formulations are also commercially available. The tablets of the
present invention contain from about 10 to about 1000 milligrams of
APAP, preferably from about 80 to about 750 milligrams of APAP and
most preferably from about 120 to about 650 milligrams of APAP.
[0062] In an alternative aspect of the invention the direct
compressed acetaminophen tablets are prepared to contain an
additional active ingredient such as those commonly found in APAP
products. A non-limiting list of suitable ingredients which may be
combined with the APAP includes narcotic analgesics such as codeine
phosphate, oxycodone and hydromorphone, sinus and/or nasal
decongestant ingredients such pseudoephedrine and antihistamines
such as diphenhydramine.
[0063] DIRECT COMPRESSION VEHICLES
[0064] The direct compression vehicles used in the solid dosage
forms of the present invention represent from about 1 to about 60%
by weight of the solid dosage form and include microcrystalline
cellulose (MCC). Preferably, the solid dosage forms contain from
about 2 to about 25 and most preferably about 5 to about 20% by
weight direct compression vehicle.
[0065] Microcrystalline cellulose is a well-known tablet diluent
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 the aqueous slurry is spray
dried to form dry, white odorless, tasteless crystalline powder of
porous particles of a broad size distribution. 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.
[0066] 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.
[0067] Typically, microcrystalline cellulose bulk powder 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.
[0068] 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 5-30% 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. In spite of it being known to include MCC in direct
compression formulations, mere twin shell blending of APAP and MCC
has not provided a mixture which could be direct compressed into an
acceptable solid dosage form.
[0069] In one preferred embodiment of the invention, the direct
compression vehicle includes a microcrystalline cellulose which has
been coprocessed with from about 0.1 to about 20% silicon dioxide.
This coprocessed, direct compression vehicle is an agglomerate of
microcrystalline cellulose and silicon dioxide in which the
microcrystalline cellulose and silicon dioxide are in intimate
association with each other such as that described in
commonly-assigned U.S. patent application Ser. No. 08/370,576, the
disclosure of which is incorporated by reference herein.
Magnifications of these coprocessed particles indicate that the
silicon dioxide is integrated with, or partially coats, the
surfaces of the microcrystalline cellulose particles.
[0070] The exact relationship of the two ingredients in the
excipient 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. By "intimate association", it is meant that the silicon
dioxide 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. 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".
[0071] The compressed excipient has a bulk (loose) density ranging
from about 0.2 g/ml to about 0.6 g/ml, and most preferably from
about 0.35 g/ml to about 0.55 g/ml. The coprocessed excipient has a
tapped density ranging from about 0.25 g/ml to about 0.65 g/ml, and
most preferably from about 0.35 g/ml to about 0.55 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 1.5% to about 7%,
and most preferably from about 3.0% to about 5% by weight.
[0072] The coprocessed excipient can be used alone or in
combination with "off-the-shelf" MCC in any desired proportion to
form the direct compression vehicle included in the novel dosage
forms.
[0073] The silicon dioxide coprocessed with microcrystalline in
this aspect of the invention preferably has an average primary
particle size of from about 1 nm to 1,000 .mu.m. More preferably,
however, the silicon dioxide has an average primary size of from
about 5 nm to 40 .mu.m.
[0074] The silicon dioxide coprocessed with the MCC is preferably
derived from colloidal silicon dioxide and, preferably comprises
from about 0.5 to 10% by weight of the coprocessed material based
on the weight of the microcrystalline cellulose and, more
preferably, comprises from about 1.25 to about 5% by weight of the
agglomerate based on the weight of the microcrystalline
cellulose.
[0075] LUBRICANTS
[0076] The solid dosage forms of the present invention also include
a sufficient amount of a lubricant. In preferred aspects of the
invention, the lubricant selected is sodium stearyl fumarate.
Alternatives, however, include magnesium stearate, hydrogenated
vegetable oil, LUBRITAB.RTM. (Edward Mendell Co., Inc.), stearic
acid, PEG, and other lubricants known to those of ordinary skill in
the art.
[0077] In this regard, the lubricant will be present in amounts
ranging from about 0.01 to about 4.0% by weight of the dosage form.
Amounts of from about 0.1 to about 1.0% by weight are preferred and
amounts of from about 0.2 to about 0.45% are most preferred.
[0078] In accordance with the present invention, the lubricant is
combined with the homogeneous mixture containing the APAP and
direct compression vehicle. It has been surprisingly found that
high shear blending of the lubricant with the homogeneous granulate
does not adversely affect the tablet hardness of direct compressed
dosage forms. While Applicants are not bound by theory, it is
proposed that the high shear mixing conditions convey physical
properties on the lubricant-containing granulate which are
completely contrary to what was expected and which are desirable
for direct compression of the granulation.
[0079] ADDITIONAL INGREDIENTS
[0080] A. Silicon Dioxide
[0081] In certain preferred aspects of the invention, the direct
compressed pharmaceutical dosage forms include silicon dioxide in
an amount which is separate from and in addition to the silicon
dioxide included with the coprocessed MCC (if used). In this
regard, the silicon dioxide is preferably colloidal silicon dioxide
and is present in an amount of from about 0.1 to about 5% by weight
of the dosage form. Preferably, however, the silicon dioxide is
present in an amount of from about 0.15 to about 0.9% by weight and
most preferably in an amount of from about 0.4 to about 0.75% by
weight of the dosage form.
[0082] 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 de-stabilization 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. Silicon dioxide, and in particular colloidal silicon
dioxide, is mainly used as a glidant and anti-adherent in tableting
processes and encapsulation to promote the flowability of the
granulation. 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.
[0083] 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, it has been surprisingly discovered that high
shear mixing of SiO.sub.2 with other formulation ingredients
unexpectedly enhances tablet hardness in direct compression dosage
forms.
[0084] The present invention encompasses 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.
[0085] The silicon dioxide utilized in the invention is of the very
fine particle size variety. In the most 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.
[0086] 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.
[0087] 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.
[0088] In those aspects of the invention where the silicon dioxide
is a part of the pharmaceutical dosage form, it is preferred that
the silicon dioxide be combined with the acetaminophen, direct
compression vehicle and lubricant under the same high shear
conditions used to create the homogenous mixture of the solid
dosage form ingredients. Alternatively, the silicon dioxide can be
high shear blended with the acetaminophen and direct compression
vehicle before the lubricant is combined therewith.
[0089] B. DISINTEGRANT
[0090] A disintegrant may also be included with the other solid
dosage form ingredients and subjected to the high shear mixing and,
therefore, become part of the homogenous mixture. In one preferred
aspect of the invention, the disintegrant is sodium starch
glycolate and will be present in amounts ranging from 0.01 to about
4.0% by weight of the dosage form, preferably from about 0.1 to
about 2.0% and most preferably in amounts ranging from about 1.00
to about 1.50% by weight of the dosage form. One particularly
useful disintegrant is available under the trademark Explotab.TM.
available from Edward Mendell Co., Inc. Alternative disintegrants
include, for example, carboxymethylcellulose, cross-linked
polyvinyl pyrrolidones in amounts similar to that set forth above
or starches, in amounts of from around 4 to about 5%.
[0091] C. ANCILLARY PHARMACEUTICAL INGREDIENTS
[0092] The solid dosage form can also include an inert
pharmaceutical filler such as 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,
mixtures thereof, and the like. The amount of inert filler, if
included, will be an amount which does not detract from the
enhanced tablet hardness achieved by the novel process described
herein. In this regard, the amount will be less than 10% by weight
of the tablet.
[0093] SHEAR MIXING CONDITIONS
[0094] The present invention includes transforming acetaminophen, a
direct compression vehicle and optionally, a
pharmaceutically-acceptable lubricant into a homogenous granulate
under shear conditions which do not degrade the ingredients. For
purposes of the present invention, the shear conditions under which
the ingredients are combined can generally be described as a set of
conditions including a combination of temperature and mechanical
forces which permit the formation of the homogenous granulate but
do not break down the materials undergoing the processing. For
purposes of the present invention, the conditions are described as
high shear to distinguish them from the standard blending achieved
by twin shell mixing or tumbling. Suitable apparatus for carrying
out the high shear mixing contemplated herein can include high
speed mixers having an impeller or mixing blade rotating about a
central shaft close to the bottom of the mixing bowl and a chopper
or series of choppers which consist of fast rotating arms or knives
which are inserted into the mixing bowl. This combination of mixing
and chopping confers a mechanical influence or force on the APAP
and MCC which transforms them into a homogeneous mixture which can
be direct compressed even if the APAP constitutes the majority of
the granulate on a weight basis. One high shear granulator having
an impeller and high shear chopper is available from Baker-Perkins.
While such apparatus is usually used to prepare wet granulations,
it has been found that when the apparatus is operating under dry
mixing conditions, it is capable of transforming the solid dosage
form ingredients under shear conditions into the homogenous
mixture. In this particular apparatus, the operation of the
impeller in combination with the chopper creates the shear mixing
environment. One useful set of parameters with this apparatus for
rendering the necessary high shear conditions includes operating
the impeller at about 100 to 300 rpm and the chopper from about 200
to about 1,200 rpm. It will be understood, however, that the speeds
of the impeller and chopper can extend beyond the ranges provided
with regard to the illustrative device and that optimum operating
conditions for alternative shear mixing apparatus will be apparent
to those of ordinary skill without undue experimentation. The
simultaneous action of the impeller and chopper have been found to
uniquely transform the solid dosage form ingredients into a mixture
which can be directly compressed into solid pharmaceutical dosage
forms having sufficient hardness and size characteristics suitable
for oral delivery of even high load-containing tablets. It is to be
understood, however, that the Baker-Perkins apparatus described
above is merely illustrative of the type of apparatus useful in
transforming the dosage form ingredients. Those of ordinary skill
in the art will realize that other high shear mixing devices can be
used, such as a Patterson-Kelly twin shell mixing apparatus
equipped with an intensifier bar to facilitate mixing, chopping,
shear forces and counter rotating of the ingredients. The Gral high
shear mixer available from Machines Collette, Inc. Totowa, N.J.
operating under dry conditions can also be used.
[0095] In another aspect of the invention, the shear mixing
conditions used to transform the APAP and direct compression
vehicle are expressed as a measurement of the vigorousness of the
mechanical processing. One such measurement is the relative swept
volume, a ratio of the volume through which the impeller travels
every second to the volume of the bowl. The size of the swept
volume is calculated by dividing the area of each impeller blade
into vertical segments and on the impeller velocity, calculating
the volume the impeller blades travel through per second.
[0096] In preferred aspects of the invention, the solid dosage
forms of the present invention are prepared from a homogenous
granulate prepared as a result of a two step, high shear mixing
technique. In the first step, the acetaminophen, direct compression
vehicle, and, optionally, disintegrant and/or silicon dioxide, are
combined under high shear conditions to form a first high shear
mixture which preferably contains the ingredients in a homogenous
distribution. The second step includes combining the first high
shear mixture with the lubricant under high shear conditions to
form the final homogenous granulate. In preferred aspects of this
embodiment, the shear force used to combine the lubricant with the
first high shear mixture is less than that used to combine the
ingredients of the first high shear mixture.
[0097] DIRECT COMPRESSION OF APAP GRANULATE
[0098] The present invention also includes methods of preparing
solid pharmaceutical dosage forms containing APAP via direct
compression. As pointed out above, direct compression techniques
include compressing tablet ingredients directly without modifying
the physical nature of any of the ingredients. In this regard,
therefore, the methods include:
[0099] a) combining from about 40 to about 95% by weight
acetaminophen and from about 1 to about 60% by weight of a direct
compression vehicle comprising microcrystalline cellose under shear
conditions which are sufficient to transform the acetaminophen and
direct compression vehicle into a first homogenous granulate;
[0100] b) combining the first homogenous granulate with from about
0.01 to about 4.0% of a pharmaceutically-acceptable lubricant;
and
[0101] c) compressing the homogenous granulate containing the
lubricant into a solid pharmaceutical dosage form.
[0102] It is to be understood that the combining steps described
above are preferably carried out in the high shear mixing apparatus
described above.
[0103] In preferred embodiments of the present invention, the APAP
is in granular form having a particle size of from about 250 to
about 500 microns and the direct compression vehicle includes
co-processed MCC.
[0104] An alternative method in accordance with the present
invention includes combining from about 0.1 to about 5% by weight
silicon dioxide with the APAP and direct compression vehicle and
subjecting this mixture to the shear mixing conditions described
herein. A disintegrant can also be included in this high shear
mixture designated herein as a first homogeneous granulate. The
lubricant can be combined with the first homogeneous granulate
either by additional high shear mixing or by other blending
techniques such as twin shell blending. It is preferred, however,
that the lubricant be combined with the first homogeneous granulate
by additional high shear mixing. In this regard, it is preferred
that the high shear blending used to incorporate the lubricant be
carried out under shear conditions which are less than those used
to prepare the first homogeneous granulate. Thus, the lubricant
will preferably be added under shear conditions which include one
or more reductions in the mixing parameters i.e. lower mixing or
chopping rpm's and/or shorter mixing times.
[0105] The complete homogeneous high shear mixture, in an amount
sufficient to make a uniform batch of tablets, is then subjected to
tableting in a conventional production scale direct compression
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.
[0106] As pointed out above, the solid dosage forms of the present
invention will contain from 10 to about 1000 milligrams of APAP.
The average tablet size for the direct compressed tablets will
therefore range from about 50 mg to 2000 mg. 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.
[0107] One particularly preferred solid dosage form of the present
invention contains at least about 75% by weight APAP and has an
average tablet hardness of about 6.5 kP when the homogeneous
granulate is direct compressed at a compression force of about 25
kN.
[0108] In certain embodiments of the invention, the tablet is
coated with a sufficient amount of a hydrophobic polymer to render
the formulation capable of providing a release of the medicament
such that a 12 or 24 hour formulation is obtained. The hydrophobic
polymer can be selected from materials well known to those of
ordinary skill in the art such as acrylic acid derivatives. In
other embodiments of the present invention, the tablet coating may
comprise an enteric coating material in addition to or instead or
the hydrophobic polymer coating. Examples of suitable enteric
polymers include cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate,
methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose
succinate, cellulose acetate trimellitate, and mixtures of any of
the foregoing. An example of a suitable commercially available
enteric material is available under the trade name Eudragit.TM.
100-555.
[0109] In further embodiments, the dosage form may be coated with a
hydrophilic coating in addition to or instead of the
above-mentioned coatings. An example of a suitable material which
may be used for such a hydrophilic coating is
hydroxypropylmethylcellulose (e.g., Opadry.RTM., commercially
available from Colorcon, West Point, Pa.).
[0110] The coatings may be applied in any pharmaceutically
acceptable manner known to those skilled in the art. For example,
in one embodiment, the coating is applied via a fluidized bed or in
a coating pan. For example, the coated tablets may be dried, e.g.,
at about 60-70.degree. C. for about 3-4 hours in a coating pan. The
solvent for the hydrophobic polymer or enteric coating may be
organic, aqueous, or a mixture of an organic and an aqueous
solvent. The organic solvents may be, e.g., isopropyl alcohol,
ethanol, and the like, with or without water.
[0111] The coatings which may be optionally applied to the
compressed solid dosage form of the invention may comprise from
about 0.5% to about 30% by weight of the final solid dosage
form.
[0112] In additional embodiments of the present invention, a
support platform is applied to the tablets manufactured in
accordance with the present invention. Suitable support platforms
are well known to those skilled in the art. An example of suitable
support platforms is set forth, e.g., in U.S. Pat. No. 4,839,177,
hereby incorporated by reference. In that patent, the support
platform partially coats the tablet, and consists of a polymeric
material insoluble in aqueous liquids. The support platform may,
for example, be designed to maintain its impermeability
characteristics during the transfer of the therapeutically active
medicament. The support platform may be applied to the tablets,
e.g., via compression coating onto part of the tablet surface, by
spray coating the polymeric materials comprising the support
platform onto all or part of the tablet surface, or by immersing
the tablets in a solution of the polymeric materials.
[0113] The support platform may have a thickness of, e.g., about 2
mm if applied by compression, and about 10 .mu.m if applied via
spray-coating or immersion-coating. Generally, in embodiments of
the invention wherein a hydrophobic polymer or enteric coating is
applied to the tablets, the tablets are coated to a weight gain
from about 1% to about 20%, and in certain embodiments preferably
from about 5% to about 10%.
[0114] Materials useful in the hydrophobic coatings and support
platforms of the present invention include derivatives of acrylic
acid (such as esters of acrylic acid, methacrylic acid, and
copolymers thereof) celluloses and derivatives thereof (such as
ethylcellulose), polyvinylalcohols, and the like.
[0115] In certain embodiments of the present invention, the tablet
core includes an additional dose of a medicament, i.e. APAP,
included in either the hydrophobic or enteric coating, or in an
additional overcoating coated on the outer surface of the tablet
core (without the hydrophobic or enteric coating) or as a second
coating layer coated on the surface of the base coating comprising
the hydrophobic or enteric coating material. This may be desired
when, for example, a loading dose of APAP is needed to provide
therapeutically effective blood levels when the formulation is
first exposed to gastric fluid. The loading dose of medicament
included in the coating layer may be, e.g., from about 10% to about
40% of the total amount of medicament included in the
formulation.
[0116] 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.
[0117] 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.
[0118] Alternatively, the novel homogenous high shear granulate can
be utilized in other applications wherein it is not compressed. For
example, the granulate can be filled into capsules. The granulate
can further be molded into shapes other than those typically
associated with tablets. For example, the granulate together with
acetaminophen 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.
[0119] A still further embodiment of the present invention is
directed to a method of effecting analgesia in mammals. This method
includes administering a dosage form described herein containing an
effective amount of APAP to a mammal in need of such treatment. In
preferred aspects of this embodiment, the dosage forms contain from
about 10 to about 1000 milligrams of APAP and more preferably, from
about 120 to about 750 milligrams of APAP. For purposes of the
present invention, the term "effective amount" shall be understood
to include a generally accepted amount of APAP for purposes of
effecting analgesia for mild to moderate pain. The method of
treatment can also include administering the effective amount as a
single dose or as multiple doses administered every four to six
hours as needed.
[0120] A still further aspect of the invention includes homogeneous
high-shear granulates which are useful as pharmaceutical
intermediates. The granulates include:
[0121] a) from about 94 to about 99.99% by weight of a direct
compression vehicle comprising microcrystalline cellulose; and
[0122] b) from about 0.01 to about 6.0% by weight of a
pharmaceutically-acceptable lubricant.
[0123] The direct compression vehicle and
pharmaceutically-acceptable lubricant are combined under shear
conditions which are sufficient to transform the direct compression
vehicle and pharmaceutically-acceptable lubricant into a homogenous
granulate without degradation. The intermediates are thus suitable
for admixture with one or more active ingredients such as by
additional high shear mixing and thereafter direct compression into
a solid pharmaceutical dosage form.
[0124] The shear conditions under which the intermediate
ingredients are combined are similar to that used for the APAP
formulations described above. In addition, all other direct
compression ingredients, such as disintegrants, etc., can also be
included in the intermediate product as well.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0125] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
[0126] The examples set forth the preparation of pharmaceutical
compositions containing a high load of the active ingredient
acetaminophen (APAP) in combination with microcrystalline cellulose
based excipients. Tablets were prepared using each of the
compositions and each of tablet preparations was tested for tensile
strength.
EXAMPLES 1-2
Preparation of Coprocessed MCC--SiO.sub.2 Compositions and
Granulations Thereof
Example 1
MCC--SiO.sub.2 Product--5% w/w SiO.sub.2
[0127] In this example, about 6.2 kilograms of microcrystalline
cellulose (MCC), (Mendell Co., Inc. Patterson, N.Y.) in the form of
a wet cake 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 colloidal silicon dioxide (CSD), 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 MCC--SiO.sub.2 having
an average particle size of 40-60 microns.
Example 2
MCC--SiO.sub.2 Product--2% w/w SiO.sub.2
[0128] In this example, the process of Example 1 was repeated
except that 2% w/w colloidal silicon dioxide was used to form the
product.
Examples 3-11
[0129] 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.
[0130] 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. The results of the analyses are graphically
illustrated in FIGS. 1-2 as a comparison of tensile strength versus
compression force.
[0131] The batch formula for the comparative control tablets is set
forth below:
1 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
[0132] 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 3
[0133] 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 1.
2 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
[0134] The tablets were prepared according to the following
procedure:
[0135] The coprocessed MCC was added to a Baker-Perkins 10L 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 4
[0136] In this example, the procedure of Example 3 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 1. The tablets were prepared using
the following batch formula:
3 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 5
[0137] In this example, the procedure of Example 3 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.
4 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 6
[0138] 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:
5 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 7
[0139] In this example, the procedure of Example 3 was followed. In
this batch, however, the MCC used was the coprocessed product of
Example 2 which contained 2.0% SiO.sub.2. The batch also did not
include a separate amount of added CSD in the high shear
mixture.
6 GRAMS PER INGREDIENT BATCH % BATCH MCC coprocessed w/2% CSD
18.10% 90.50 APAP 80.00% 400.00 Sodium starch glycolate (SSG) 1.50%
7.55 Sodium stearyl fumarate (SSF) 0.40% 2.00 TOTAL 100.00%
500.00
Example 8
[0140] In this example, the directly compressed tablets containing
APAP were prepared using the procedure of Example 3 except that the
MCC used was the coprocessed microcrystalline cellulose of Example
2. The batch formula set forth below was used.
7 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
[0141] Referring now to FIG. 1, 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.
[0142] 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 6, 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 point up the fact that those high load
tablets prepared with MCC coprocessed with SiO.sub.2, i.e. Examples
3 and 8 as well as those containing a separately added amount of
SiO.sub.2, i.e. Example 4, have a particularly desirable tablet
hardness profile.
[0143] 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 9
[0144] In this example, the tablets were prepared according to the
following batch formula:
8 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
[0145] 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 4 (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 10
[0146] The procedure of Example 11 was repeated except that an
equal amount of magnesium stearate was substituted for the sodium
stearyl fumarate used in Example 11 for the V-blending step prior
to the direct compression of the tablets.
9 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 11
[0147] In this example, the two step high shear blending procedure
of Example 4 was repeated except that magnesium stearate was
substituted for the originally described sodium stearyl fumarate.
As was the case in Example 4, high shear mixing was used for both
performing both the initial and final blends.
10 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
[0148] FIG. 2 graphically provides the results for the comparison
of the two step high shear mixed, direct compressed tablets of
Example 8 with the high shear, then low shear mixed formulations of
Examples 9 and 10 and the V-blended control formulation. The graph
also provides the results for the two step high shear formulation
of Example 11, which included magnesium stearate instead of sodium
stearyl fumarate in the second high shear mixing step.
[0149] 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 12
[0150] In this example, the average disintegration time for tablets
prepared in accordance with Example 8 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 8 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 and illustrated as a graph which
is set forth as FIG. 3.
[0151] As can be seen from the graph, 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.
[0152] 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.
* * * * *