U.S. patent application number 10/457270 was filed with the patent office on 2004-04-29 for hydrolyzed cellulose granulations of partial salts of drugs.
Invention is credited to Erkoboni, David F., Favara, Andrew J., Sweriduk, Christopher A., Vladyka, Ronald S. JR..
Application Number | 20040081701 10/457270 |
Document ID | / |
Family ID | 26853293 |
Filed Date | 2004-04-29 |
United States Patent
Application |
20040081701 |
Kind Code |
A1 |
Erkoboni, David F. ; et
al. |
April 29, 2004 |
Hydrolyzed cellulose granulations of partial salts of drugs
Abstract
The present invention provides a method for preparing a
spray-dried, compressible granular formulation for preparing
pharmaceutical tablets in which essentially water-insoluble,
acidic, amphoteric, and basic pharmaceutically active agents are
converted to more water-soluble salts which are granulated with
hydrolyzed cellulose, drug-containing slurries, the resulting
granulations, capsules containing granulations, and pharmaceutical
tablets compressed from such granules. In these formulations there
is employed from 1% to 85% by weight of the pharmaceutically active
agent in its salt form, from 5% to 99% of hydrolyzed cellulose,
based on the dry weight of the granulation, and optionally,
conventional granulation and/or tableting additives such as
surfactants, disintegrants, and antiadherents/flow aids. Said
tablets have significantly increased dissolution of the
pharmaceutically active agent at the pH of the gastrointestinal
tract in comparison with the unconverted free pharmaceutically
active agent.
Inventors: |
Erkoboni, David F.;
(Pennington, NJ) ; Vladyka, Ronald S. JR.;
(Somerset, NJ) ; Sweriduk, Christopher A.;
(Chalfont, PA) ; Favara, Andrew J.; (New Egypt,
NJ) |
Correspondence
Address: |
Donald O. Nickey
Cardinal Health, Inc.
7000 Cardinal Place
Dublin
OH
43017
US
|
Family ID: |
26853293 |
Appl. No.: |
10/457270 |
Filed: |
June 9, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10457270 |
Jun 9, 2003 |
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09669533 |
Sep 26, 2000 |
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6596312 |
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60156547 |
Sep 29, 1999 |
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Current U.S.
Class: |
424/499 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/1652 20130101 |
Class at
Publication: |
424/499 |
International
Class: |
A61K 009/50 |
Claims
We claim:
1. A method of improving dissolution of a relatively
water-insoluble pharmaceutically active agent comprising the steps
of: a) mixing hydrolyzed cellulose with a water of hydration of 30
to 90% with at least one relatively water-insoluble
pharmaceutically active agent, and an acid or base that is capable
of reacting with said relatively water-insoluble pharmaceutically
active agent in an aqueous solvent to form a salt, the amount of
said acid or base being sufficient to convert at least 5% but less
than 100% of said relatively water-insoluble pharmaceutically
active agent to said salt, to form a mixture; and b) drying the
mixture to form granules.
2. A dry granular composition comprising hydrolyzed cellulose in
immixture with at least one relatively water-insoluble
pharmaceutically active agent in its more water-soluble form
wherein said pharmaceutically active agent in its more
water-soluble salt form comprises about 30% to about 80% of said
composition and comprises a mixture of ibuprofen and its potassium
salt in a ratio of about 3:1 to 1:1; said hydrolyzed cellulose
comprises about 20% to about 70% of said composition; said
composition additionally comprising about 1% to about 10% of
croscarmellose sodium, about 0.5% to about 5% of colloidial silicon
dioxide, and about 0.05% to about 0.4% sodium lauryl sulfate; all
percentages being by weight of the dry granules.
3. The method according to claim 1 wherein said relatively
water-insoluble active agent is ibuprofen, ketoprofen, or
naproxen.
4. The method according to claim 3 wherein said relatively
water-insoluble pharmaceutically active agent is ibuprofen.
5. The method according to claim 1 wherein said mixture comprises
at least about 10% to about 60% solids by weight.
6. The method according to claim 1 wherein said granules comprise
at least about 97.5% solids by weight.
7. The product of the method of claim 1.
8. A product according to claim 7 that comprises more than 97.5%
solids by weight.
9. A product according to claim 7 wherein said granules comprise:
a) about 1% to about 95% by weight of said salt; and b) about 5% to
about 99% by weight of said hydrolyzed cellulose.
10. A product according to claim 9 wherein said granules are
substantially porous and substantially spherical.
11. A compressed pharmaceutical tablet comprising the product
according to claim 10.
12. The method of improving dissolution of a relatively
water-insoluble pharmaceutically active agent comprising the steps
of: a) mixing hydrolyzed cellulose with a water of hydration of
30-90% with at least one relatively water-insoluble
pharmaceutically active agent, and an acid or base that is capable
of reacting with said relative water-insoluble pharmaceutically
active agent to form a salt, the amount of said acid or base being
insufficient to convert 100% of said relatively water-insoluble
pharmaceutically active agent to said salt, to form a mixture; and
b) drying the mixture to form granules.
13. The method according to claim 12 wherein said relatively
water-insoluble pharmaceutically active agent is ibuprofen,
ketoprofen, or naproxen.
14. The method according to claim 12 wherein said mixture comprises
at least about 10% to about 60% solids by weight.
15. The method according to claim 12 wherein said granules comprise
at least about 97.5% solids by weight.
16. The product of the method of claim 12.
17. A product according to claim 16 that comprises more than 97.5%
solids by weight.
Description
PRIOR APPLICATION DATA
[0001] The present application is a continuation-in-part of U.S.
patent application Ser. No. 09/669,533, filed Sep. 26, 2000, which
has been allowed and claims priority to U.S. Provisional Patent
Application Serial No. 60/156,547, filed Sep. 29, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to a method for granulation of
relatively water-insoluble pharmaceutically active agents capable
of forming a salt, to granular formulations thereof, and to
pharmaceutical tablets made from such granular formulations. More
specifically, the invention relates to drying an aqueous slurry of
hydrolyzed cellulose or microcrystalline cellulose and one or more
relatively water-insoluble pharmaceutically active agents which
have at least partially been converted, but not completely
converted, to more water-soluble salts to form granular
formulations for use in the manufacture of pharmaceutical tablets
and in filling capsules. The methods and compositions of this
invention are particularly useful for relatively water-insoluble
pharmaceutically active agents, such as ibuprofen, which are is
readily compressible into tablets after being dry blended with
excipients. Compressible compositions containing salts of these
relatively water-insoluble pharmaceutically active agents according
to the present invention have greatly increased rates of
dissolution.
BACKGROUND OF THE INVENTION
[0003] Certain pharmaceutically active agents present challenges to
dosage formulation. Ibuprofen, for example, is difficult to
compress into tablets from a dry mix of excipients as heretofore
practiced in the art. This lack of compressibility was overcome by
a spray drying granulation technique described in U.S. Pat. No.
5,858,409. In the process described in this patent, hydrolyzed
cellulose and the salt of the pharmaceutically active agent are
mixed in a slurry, optionally with other excipients. This slurry is
then spray dried to produce a granular composition which
advantageously is comprised of granules, 90% of which are larger
than 50 microns and smaller than about 500 microns. The median
granule size is typically in the range of about 150 to 300 microns.
Granules that are produced by this method are relatively porous,
free flowing, substantially spherical, and readily compressible
into pharmaceutical tablets having improved hardness, decreased
friability, and excellent dissolution characteristics.
[0004] Grassano et al. (U.S. Pat. No. 6,197,336) discloses an
analgesic composition comprising a composition resulting from
combining: a) ibuprofen, b) from 1.1 to 1.5 moles arginine per mole
of ibuprofen, c) from 0.5 to 10 weight percent of linear PVP based
on weight of ibuprofen, and d) from 5 to 10 weight percent of a
bicarbonate based on weight of ibuprofen. This patent clearly
teaches the conversion of all the ibuprofen to the salt form. This
is in contrast to one aspect of the present invention, that being,
improved composition can be obtained if at least 5 but less than
100 percent of the relatively water-insoluble pharmaceutically
active agent is converted to the salt prior to the preparation of
the granules.
[0005] Karetny et al. (U.S. Pat. No. 5,858,409) is directed to
granulations of pharmaceuticals. Karetny et al. discloses a method
for preparing spray-dried compressible granular formulations for
preparing pharmaceutical tablets in which hydrolyzed cellulose is
used as a granulation aid. Karetny et al. also discloses that the
substantially porous spherical granular compositions are useful for
compression into pharmaceutical tablets consisting of essentially 1
percent to 97 percent by weight of the pharmaceutically active
agent and 3 to 99 percent by weight of hydrolyzed cellulose. There
is no teaching nor suggestion in Karetny et al. regarding partially
converting the pharmaceutically active agent to its salt prior to
the formulation of granules with the hydrolyzed cellulose.
[0006] U.S. Pat. No. 4,859,704 to Haas is directed to water-soluble
ibuprofen compositions and methods for their preparation. The Haas
reference does disclose the use of water-soluble alkaline metal
salts of ibuprofen, which are prepared by reacting ibuprofen with
alkaline metal bicarbonate. This reference fails to make any
suggestion or disclosure of combining the alkaline metal salt of
ibuprofen with hydrolyzed cellulose. Most importantly, Haas makes
no suggestion nor disclosure of partially converting the ibuprofen
to the alkaline metal salt and then combining it with hydrolyzed
cellulose to form granules.
[0007] The Haas reference does recognize that ibuprofen salts may
be problematic. As discussed below, the potassium salt of ibuprofen
has a lower melting point than the free acid form and is more
hygroscopic. One aspect of the present invention is that incomplete
conversion to the salt results in formulations that are less sticky
and present fewer problems during compression, blending and
granulation. These benefits are not suggested nor even contemplated
by the prior art.
[0008] Through the incomplete conversion of the pharmaceutically
active agent to its salt form, the present inventors have turned
something relatively bad or difficult to work with into something
relatively easy to handle. This factor, combined with the discovery
that the use of hydrolyzed cellulose, as opposed to
microcrystalline cellulose, provides benefits in the dissolution
characteristics of the final product tablet, forms an additional
aspect of the present invention.
SUMMARY OF THE INVENTION
[0009] The present invention provides methods for granulating
pharmaceutically active agents that have been at least partially
converted into salts that are more water-soluble. These methods
comprise mixing hydrolyzed cellulose, an aqueous solvent, and a
relatively water-insoluble pharmaceutically active agent that has
been at least partially, but not completely, converted into a more
water-soluble salt form. In certain preferred embodiments, the
methods of the invention comprise the steps of preparing a slurry
that includes hydrolyzed cellulose, an aqueous solution of the salt
form of a pharmaceutically active agent, and optionally, other
excipients, and then drying the slurry.
[0010] The present invention also provides compositions comprising
hydrolyzed cellulose in immixture with an aqueous solution that
includes at least one relatively water-insoluble pharmaceutically
active agent that has been at least partially, but not completely,
converted into its more water-soluble salt form. Such compositions
preferably are prepared either by adding a solution containing the
salt form of the pharmaceutically active agent to a slurry of
hydrolyzed cellulose in an aqueous solvent, or by adding the
pharmaceutically active agent to the slurry and then at least
partially converting it to its salt form in situ by reacting it
with a suitable acid and/or base. Accordingly, one aspect of the
present invention relates to compositions comprising hydrolyzed
cellulose, water, at least one relatively water-insoluble
pharmaceutically active agent, and an acid or base that is capable
of reacting with said relatively water-insoluble pharmaceutically
active agent and thereby converting it at least partially, but not
completely, into its more water-soluble salt form.
[0011] In another aspect, the invention provides granular
compositions that are produced by a spray drying process. These
compositions contain about 1 percent to about 95 percent by weight
of the relatively water-insoluble pharmaceutically active agent
which has been at least partially converted into its more
water-soluble salt and about 5 percent to about 99 percent by
weight of hydrolyzed cellulose. In yet another aspect, the
invention provides pharmaceutical tablets manufactured by
compression of the granular composition of this invention, which
provide unexpectedly superior dissolution of the pharmaceutically
active agent.
[0012] Dissolution of relatively insoluble pharmaceutically active
agents, which can be converted to a salt, is significantly improved
by conversion of at least a portion of the pharmaceutically active
agent to its more water-soluble salt form and then forming granules
with hydrolyzed cellulose.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 shows a comparison of the solubility of unprocessed
ibuprofen, free acid ibuprofen which has been spray dried with
hydrolyzed cellulose (FAI), and ibuprofen which has been partially
converted into the potassium salt and has been spray dried with
hydrolyzed cellulose (PI).
[0014] FIG. 2 shows dissolution profiles of free acid ibuprofen
spray dried with hydrolyzed cellulose (FAI), and ibuprofen which
had been at least partially converted into the potassium salt and
spray dried with hydrolyzed cellulose (PI).
[0015] FIG. 3 shows dissolution profiles of free acid ibuprofen
spray dried with hydrolyzed cellulose and formed into tablets
(FAI), and ibuprofen which had been at least partially converted
into the potassium salt, spray dried with hydrolyzed cellulose and
formed into tablets (PI) at low pH for 60 minutes before adjusting
pH to >6.0.
DETAILED DESCRIPTION OF THE INVENTION
[0016] It has been discovered that certain difficulties typically
encountered in preparing solid dosage forms containing relatively
water-insoluble pharmaceutically active agents can be overcome by
placing the free acid or free base of the pharmaceutically active
agent in solution, together with a compound that provides a
counter-ion (e.g., an acid or base), so as to form a solution
containing a salt of the pharmaceutically active agent.
Alternatively, the free acid or free base of the pharmaceutically
active agent may be mixed with all of the ingredients of the dosage
form, including the compound that provides the counter-ion, at
once, thus allowing the partial conversion of the relatively
water-insoluble pharmaceutically active agent to its more
water-soluble salt in situ. The salt-containing solutions of the
invention optionally can be mixed with other ingredients of the
dosage form before they are dried down to produce generally porous
and spherical granules suitable for compression into tablets.
[0017] As used herein, the term "relatively water-insoluble" refers
to compounds and compositions that are either insoluble or
practically insoluble (greater than or equal to 10,000 parts of
solvent required for 1 part of solute), very slightly soluble (from
1,000 to 10,000 parts of solvent required for 1 part of solute),
slightly soluble (from 100 to 1,000 parts of solvent required for 1
part of solute), or sparingly soluble (from 30 to 100 parts of
solvent required for 1 part of solute) in water, as defined in the
U.S. Pharmacopeia, Remington: Pharmaceutical Science, 18.sup.th
Edition, Mack Publishing Co., and as used in the industry by those
of ordinary skill in the art, irrespective of dose.
[0018] As used herein "converted" refers to partial or incomplete
conversion. That is, when referring to a relatively water-insoluble
pharmaceutically active agent that has been converted to its more
water-soluble salt, it is meant that at least some amount of the
relatively water-insoluble pharmaceutically active agent has been
converted to its more water-soluble salt, but not 100%.
[0019] As an example, and not by way of limitation, ibuprofen, in
its free acid form, is relatively water-insoluble and has a melting
point of about 70.degree. C. When converted to its potassium salt,
however, the melting point of ibuprofen decreases to about
50-55.degree. C. This decrease in melting point presents a
formulation problem in that the frictional forces generated during
tableting of ibuprofen typically result in temperatures that are
higher than the melting point of the ibuprofen salt. Thus, if one
tableted formulations containing ibuprofen salts in a conventional
method, this would tend to result in adherence of the formulation
to the tableting equipment and produce inferior tablets.
Furthermore, as the ibuprofen salt is more hygroscopic than the
free acid, it is not practical to dry the salt to make tablets by
conventional means.
[0020] In the process aspect of this invention, an aqueous slurry
of hydrolyzed cellulose may be employed, which is in large measure
responsible for the improved properties of the granular
formulations of U.S. Pat. No. 5,858,409 and for the improved
tablets made therefrom. The compositions of this invention have
dissolution characteristics that are directly traceable to the use
of the salt of the relatively water-insoluble pharmaceutically
active agents in combination with hydrolyzed cellulose. In this
aspect, the invention thus provides a process for preparing a
granular composition for filling capsules or preparation of
tableted pharmaceutical dosage forms comprising the steps of (a)
intimately mixing the pharmaceutically active agent, converted
partially (at least 5 but less than 100%) to its salt form, with a
smooth, uniform aqueous slurry of hydrolyzed cellulose to form a
smooth, uniform aqueous slurry comprising hydrolyzed cellulose and
the pharmaceutically active agent; and (b) drying the resulting
slurry at a temperature below the charring temperature of the
hydrolyzed cellulose. The advantages and benefits of this invention
are most readily achieved when spray drying is selected as the
method of drying, and the conditions for spray drying are selected
to produce spray-dried particles which are relatively porous and
substantially spherical, in which about 90% of the particles are
larger than about 50 microns and smaller than about 1000 microns,
and the median particle size is between about 150 microns and about
500 microns. It is a further advantage of the present invention to
include in the slurry additional granulation and tableting
additives (i.e., excipients) such as binders, fillers,
disintegrants, flow aids, antiadherents, and/or surfactants, so
that the resulting granules may be directly compressed into tablets
with the addition of nothing more than a lubricant.
[0021] As used in this specification and claims, the term
"hydrolyzed cellulose" means a cellulosic material prepared by acid
hydrolysis of cellulose, and includes hydrolyzed cellulose that has
been dried (e.g. microcrystalline cellulose) as well as hydrolyzed
cellulose that has been maintained in an at least partially
hydrated form. Thus, in some embodiments, the composition may
comprise hydrolyzed cellulose that was previously dried to form
microcrystalline cellulose, or, in other embodiments, the
composition may comprise hydrolyzed cellulose that has been
maintained in a hydrated state. In preferred embodiments, the
hydrolyzed cellulose includes water of hydration from about 30-90%,
typically from about 50-80%, and more preferably from about 55-65%.
Although there are different ways of effecting hydrolysis of
cellulose, a typical method for preparing hydrolyzed cellulose
comprises the treatment of original cellulosic material, for
example, wood-derived pulp, with an inorganic acid such as 2.5N
hydrochloric acid solution for 15 minutes at the boiling
temperature. This treatment has the effect of reducing the degree
of polymerization (DP) to a relatively constant level. A DP of 125
means that the chain of cellulose is composed of 125 anhydroglucose
units. Higher DP values represent longer chain lengths of
cellulose, and lower values represent shorter chain lengths. The
hydrolyzed cellulose in the slurries utilized herein should have a
minimum of 85% of the material with a DP of not less than 50 nor
more than 550. More preferably, 90% of this material should have a
DP within the range of 75 to 500. Even more preferably, 95% of the
material should have a DP of 75 to 450. The level-off average DP,
that is, the average of the total hydrolyzed cellulose sample,
which is consistently approached for a particular type of pulp,
should be in the range of 200 to 300. The source of the pulp being
hydrolyzed results in variations of the level of DP. Hydrolyzed
cellulose as used in this invention is a known composition more
fully described as level-off DP in U.S. Pat. Nos. 2,978,446 and
3,111,513.
[0022] The hydrolysis step described above effectively destroys
non-cellulosic components of the starting material as well as the
fibrous, amorphous structure of the cellulose, leaving the
crystallite material that is described above. Heretofore, the usual
practice has been to dry this material after it has been washed
with water to remove the acid and all soluble residues from the
hydrolysis. A common method of drying is spray drying. Spray drying
is the method in general use for the preparation of
microcrystalline cellulose which may also be used beneficially with
pharmaceutically active agents which have at least partially been
converted to a salt. It has been found that spray drying the
crystallites prior to granulation with pharmaceutically active
agents can make the cellulose particles more dense and less
compressible and thereby less useful.
[0023] The use of hydrolyzed cellulose that has not been previously
dried results in improved compressibility of the granular
composition when it is dried. Drying slurries of hydrolyzed
cellulose and pharmaceutically active agents that have been
partially, but not completely converted to their more water-soluble
salts (and, optionally, other excipients) provides advantageous
formulations.
[0024] The process to prepare the granulations of this invention
typically begins with a slurry of hydrolyzed cellulose in water.
The term "slurry," as used herein, is intended to mean an aqueous
suspension of hydrolyzed cellulose particles which have not been
previously dried through application of heat or other evaporative
means, as well as an aqueous suspension of microcrystalline
cellulose reconstituted in an aqueous solvent. It is, however,
intended to include a slurry of hydrolyzed cellulose from which a
significant amount of water has been removed by mechanical means
such as filtration. The water content may be reduced from about 90%
to 55-65% to produce a suitable, dewatered starting material for
use in the present invention. Reconstitution for use in this
process is accomplished by the simple addition of water to the
material, followed by thorough mixing. Preferably, the
reconstituted slurry used as the starting material in the process
will contain about 15% to about 25% by weight solids. In certain
embodiments, it is preferred to use a form of hydrolyzed cellulose
that has been maintained in at least a partially hydrated form.
[0025] As used in this specification, the phrase "at least
partially converted to a more water-soluble salt" means that the
conversion to a salt has proceeded to a point that at least some
amount of the relatively water-insoluble pharmaceutically active
agent is in its more water-soluble salt form. As a practical
matter, at least about 5% of the pharmaceutically active agent
should be converted to the salt, and usually greater than about 20%
is converted to the salt to cause this change in solubility.
Therefore, in still a more preferred embodiment, about 50% is
converted to the salt with the understanding that less than 100% of
the conversion, preferably less than 95% of the pharmaceutically
active agent should be converted to the salt form.
[0026] The pharmaceutically active agent can be added to this
hydrolyzed cellulose slurry, and the resulting slurry mixed
thoroughly. Depending upon the pharmaceutically active agent, the
pharmaceutically active agent may be partially converted to its
more water-soluble salt prior to addition to the slurry;
alternatively, the conversion can take place in the slurry after
the addition of the pharmaceutically active agent has been
completed. The choice of the method of operation may be influenced
by the handling characteristics of both the pharmaceutically active
agent and its salt form. For example, and not by way of limitation,
ibuprofen does not require complete conversion to its potassium
salt for complete dissolution of the ibuprofen in an aqueous
environment. Rather, the presence of about 10% up to about 75% of
the salt in an aqueous environment is sufficient to cause complete
dissolution of the acidic ibuprofen. Thus, it may be preferable to
prepare a solution of ibuprofen and its potassium salt (about 3:1
to about 1:1) in water before adding it to the slurry. This is not
to say that ibuprofen cannot be added to the slurry prior to salt
formation. In certain embodiments, when the pharmaceutically active
agent is combined in solution with the compound that provides the
counter ion (e.g., an acid or base) before either is added to the
slurry of hydrolyzed cellulose, the resulting salt preferably does
not precipitate out of solution. The salt solution can then be
added to the aqueous slurry of hydrolyzed cellulose and any other
excipients desired. The resulting slurry is then dried.
Alternatively, the pharmaceutically active agent may be added to
the aqueous slurry of hydrolyzed cellulose simultaneously with the
compound that provides the counter ion, or before the compound that
provides the counter ion and any other excipients desired. For some
pharmaceutically active agents, it is preferred that the
pharmaceutically active agent is converted into its salt form in
situ, i.e., with the salt conversion taking place in the presence
of the aqueous slurry of hydrolyzed cellulose.
[0027] The ratio of pharmaceutically active agent to cellulosic
solids in the slurry is directly proportional to the ratio of these
components in the finished granular formulation and ultimately in
the tableted pharmaceutical product. As indicated below this may
extend over a wide range in that the finished granule may contain
from about 1 to 95% of the pharmaceutically active agent and from
about 5 to 99% of cellulosic solids, the balance, if any, being
conventional granulation and tableting aids, such as binders,
fillers, disintegrants, flow aid, antiadherents, surfactants,
lubricants, and/or any other excipients used in the art.
[0028] Sufficient water is added, if necessary, to provide a slurry
having the maximum amount of solids that will permit the slurry to
be pumped to a dryer. Maximizing the solids content minimizes the
energy required for granulation and also has a beneficial effect on
particle size and size distribution of the resulting granules. It
is also advantageous to homogenize the slurry to provide a smooth,
homogeneous suspension prior to drying.
[0029] The solids content of the drug-containing slurry is
advantageously between about 10 and about 70 weight percent of the
slurry, preferably about 20 to about 60 weight percent, even more
preferably about 30 to about 60 weight percent. It is well
recognized that the viscosity of a slurry is dependent on the
percentage of the solids in the slurry, and the use of the more
water-soluble salts does not contribute significantly to the slurry
viscosity. Consequently, the use of more water-soluble salts of
relatively water-insoluble pharmaceutically active agents enables
one to employ a higher solids content than would be possible if the
unconverted, relatively water-insoluble pharmaceutically active
agent were to be used in the slurry when it is dried. This increase
in the solids content represents a significant improvement over
processes in which lower solids content must necessarily be used
with a concomitant increase in water to be removed in the drying
step.
[0030] The drug-containing slurry of the invention is dried such
that slurries of various concentrations are obtained. Depending on
the method of drying employed and the rate of dehydration, such
composition contain greater than about 10-60% solids, more
preferably the slurry is dried to contain greater than about 60-95%
solids, more preferably, the slurry is dried to contain greater
than about 97.5% solids.
[0031] As will be understood by those skilled in the art, the
specific type of dryer employed is not critical to the success of
this invention. Drying may be done in a spray dryer, for example, a
disk dryer or a tower dryer, a fluid bed dryer, by vacuum drying,
freeze drying, or by flash drying. Spray drying is the preferred
method of drying. If a disk spray dryer is utilized, a large
diameter dryer, such as the one in Example 1, is preferred to avoid
producing smaller, denser granules, which are useful, but are not
preferred. In spray drying, it will also be appreciated that the
method of atomization is important to the production of granules
having the correct size and characteristics. In these regards some
experimentation may be required to optimize the process for a
particular blend of hydrolyzed cellulose and the more water-soluble
salt of a relatively water-insoluble pharmaceutically active
agent.
[0032] In spray drying, an important aspect of the process is the
control of temperature within the spray dryer. The outlet
temperature must be carefully controlled to avoid charring the
hydrolyzed cellulose. The use of the salt of a pharmaceutically
active agent, however, may obviate a requirement that the
temperature also be below the melting point of the pharmaceutically
active agent unless the conversion to the salt is partial, thus
leaving a significant amount of unconverted pharmaceutically active
agent as in Example 1 below. An outlet temperature above about
120.degree. C. will char the cellulose, making it a requirement
that the outlet temperature not exceed this temperature. Lower
temperatures, even those below the melting temperature of the
unmodified pharmaceutically active agent may still be preferred,
and may be selected for each pharmaceutically active agent as
appropriate. Temperatures within the range of about 40.degree. C.
to about 115.degree. C. are advantageous, and preferred
temperatures are in the range of about 40.degree. C. to about
105.degree. C.
[0033] The spray-dried granular product of this invention will
normally contain less than 10% by weight moisture. To obtain
granular materials having the preferred 5% moisture content or the
most preferred moisture content of 2.5% or less, it may be
advantageous to place a fluid bed dryer in series with the spray
dryer. This final step does not alter the granule size, but merely
removes additional water from the granules.
[0034] In accordance with the second aspect of this invention, the
resulting granular composition comprises (a) from about 1 percent
to about 95 percent by weight of a mixture of the pharmaceutically
active agent and its salt and (b) from about 5 percent to about 99
percent by weight of hydrolyzed cellulose. The optimum ratio of
pharmaceutically active agent to hydrolyzed cellulose may be
obtained through routine experimentation. Even though the
conversion of the relatively water-insoluble pharmaceutically
active agents into salts contained in the granular formulation of
the invention can significantly improve the handling
characteristics of the pharmaceutically active agents, there are
residual effects that, when the granulations are compressed into
tablets, can, for example, cause sticking to the tooling, thereby
producing defective tablets. As a rule, these problems can be
readily and routinely counteracted by altering the amount of
hydrolyzed cellulose in the granulation, such as, for example, by
increasing the amount of hydrolyzed cellulose.
[0035] In exceptional cases this may be insufficient to overcome
these problems. Although the granulation may already contain
optional ingredients, including disintegrants, flow aids,
surfactants, lubricants, fillers, binders, and/or antiadherents,
etc., it will be possible to overcome the problem by mixing
microcrystalline cellulose, lubricant, and additional disintegrant,
flow aid, and filler with the granules before tableting is
performed.
[0036] A preferred formulation for granules containing a mixture of
ibuprofen and its potassium salt (in a ratio of about 3:1 to about
1:1) would contain from about 30% to about 80% by weight of the
pharmaceutically active agent and its salt, from about 20% to about
70% of hydrolyzed cellulose, from about 1% to about 10% of a
disintegrant, preferably croscarmellose sodium, from about 0.5% to
about 5% flow aid, e.g., colloidal silicon dioxide, and 0.05% to
about 0.40% surfactant, preferably sodium lauryl sulfate. All
percentages are by weight of the finished (i.e., dry) granules.
[0037] This process is applicable to all pharmaceutically active
agents, preferably those which, in their unmodified state, are
relatively water-insoluble, as that term is used herein with
reference to the U.S. Pharmacopeia and known to those of skill in
the art. This includes acidic, amphoteric, and basic
pharmaceutically active agents. In many cases, pharmaceutically
active agents belonging to these categories may be easier to handle
in their unconverted state and then converted to the appropriate
salt during the granulation process, either in aqueous solution
apart from the hydrolyzed cellulose slurry, or in situ (i.e, in the
presence of the hydrolyzed cellulose). Conversely, in some
situations it may be preferable to handle the salt rather than the
unconverted pharmaceutically active agent. As a consequence, this
is a very versatile process which, in addition to the significantly
improved dissolution characteristics provided by the salts of
pharmaceutically active agents, provides an improved method of
processing difficult-to-handle pharmaceutically active agents.
[0038] For conversion to a more water-soluble salt, an acidic
pharmaceutically active agent has, for example, a labile hydrogen
atom, which can be neutralized with a base. Appropriate bases
include, but are not limited to, sodium, potassium, ammonium,
quaternary ammonium, magnesium, and calcium hydroxides. The cations
appropriate for the salts of pharmaceutically active agents are
limited to those that produce more water-soluble salts and do not
contribute physiological effects such as lithium ions would. The
choice of the cation may be different for different
pharmaceutically active agents because of the physical properties
imparted by the cation to the salt.
[0039] Basic pharmaceutically active agents are converted to their
salt by partial neutralization (e.g., of amine functionality
therein) with an inorganic or organic acid. Appropriate acids
include, but are not limited to, hydrochloric acid, sulfuric acid,
phosphoric acid, citric acid, maleic acid, gluconic acid, fumaric
acid, glycolic acid, and the like.
[0040] Amphoteric pharmaceutically active agents may be converted
to a salt by either treatment with a base or an acid such as those
listed above. The choice of which method of conversion to a salt
for a specific amphoteric pharmaceutically active agent may be
dictated by the characteristics of the anionic and cationic salts
of that pharmaceutically active agent and further by the choice of
the counter-ion from the numerous possibilities already mentioned
above.
[0041] The granular compositions of the invention can be formed
from essentially all relatively water-insoluble pharmaceutically
active agents which may be converted to a salt, including
combinations of them. Typical of such pharmaceutically active
agents are: analgesics, anti-inflammatories, antibiotics,
anti-epileptics, antitussives, expectorants, antihistamines,
decongestants, antifungals, cardiovascular drugs, gastrointestinal
drugs, and respiratory drugs, ibuprofen, ketoprofen, diclofenac,
naproxen, chlorpromazine, and nifedipine are representative,
non-limiting examples of pharmaceutically active agents that derive
the benefits of increased dissolution and bioavailability by
processing them using the improved methods of this invention.
[0042] The drug-containing granulated material of the invention may
be compressed into tablets or used to fill capsules.
[0043] The following examples are illustrative of the methods of
this invention, but are not intended to be limiting. Those skilled
in the art will readily understand the benefits of the process
described herein, and will appreciate the applications to which it
can be applied. All percentages in the following example are by
weight unless otherwise clearly indicated.
EXAMPLE 1
[0044] In a large, portable tank was placed 39.2 kg of distilled
water which was stirred with a Lightnin.TM. mixer. To this water
was added 29.6 kg of hydrolyzed cellulose wetcake, and the mixture
was stirred for approximately 10 minutes after addition was
complete, forming a smooth slurry containing 17% by weight of
hydrolyzed cellulose solids. The pH of this slurry was 3.5. A
solution of 30 grams of potassium hydroxide pellets (87%) in 100
grams of distilled water was prepared. Portionwise, this potassium
hydroxide was added to the hydrolyzed cellulose slurry, and, after
each addition, the pH of the slurry was measured. A total of 46.0
grams of the potassium hydroxide solution was added, raising the pH
to 8.6. Next, 400 grams of colloidal silicon dioxide
(Cab-O-Sil.RTM. M-5) was added to the slurry with continued
stirring. After the addition of 600 grams of croscarmellose sodium
to the slurry, mixing was continued for approximately 10 minutes.
Simultaneously, a solution of 40 grams of sodium lauryl sulfate in
500 grams of distilled water was prepared in a separate container.
This solution was then added to the hydrolyzed cellulose slurry
with mixing for 10 minutes. To a mixing tank containing 26.0 kg of
distilled water was added slowly 3.74 kg of potassium hydroxide
pellets (87%). This solution was continuously stirred with a
Lightnin.TM. mixer fitted with a high energy blade. Then 24.0 kg of
ibuprofen was added to it. Mixing was continued for at least 15
minutes and until all of the ibuprofen had dissolved. This amounted
to a 50% conversion of the ibuprofen free acid to the potassium
salt. The ibuprofen solution was then pumped into the tank
containing the hydrolyzed cellulose slurry. To completely empty the
tank that had contained the ibuprofen solution, 2.0 kg of distilled
water was used to rinse the tank, and this water was then pumped
into the slurry. The slurry was mixed for 10 minutes before the
Lightnin.TM. mixer was replaced by a Greeco rotor stator type
mixer. After 10 additional minutes of mixing, the entire slurry was
transferred to Groen jacketed mixing tank where it was mixed for 10
minutes at a setting of 3 using both the paddle blade and the
impeller mixing blade. The slurry was spray dried using a disk
dryer having a diameter of approximately 5 meters at an inlet
temperature of 100.degree. C. and an outlet temperature of
48.degree. C. The air flow was approximately 48.14 cubic
meters/minute (1700 standard cubic feet/minute), and the feed rate
was 1.50 kg/minute. The time required to dry the entire slurry was
135 minutes. The material collected at the dryer discharge weighed
25.2 kg, and an additional 3.5 grams of product was recovered from
the cyclone, making a total of 28.7 kilograms of product having a
moisture content of 1.92%. The particle size distribution was
determined using a stack of sieves in which the top sieve has the
largest size openings and each sieve below has smaller size
openings than the next higher sieve. The material that was retained
on each sieve was weighed. The particle size distribution was
determined in this way to be: >50 mesh (>297 microns), 30.8%;
50-60 mesh (297-250 microns), 8.4%; 60-80 mesh (250-177 microns),
19.6%; 80-100 mesh (177-149 microns), 8.6%; 100-120 mesh (149-125
microns), 6.9%; 120-170 mesh (125-88 microns), 11.6%; and <170
mesh (<88 microns), 14.3%. The median particle size thus falls
between 177 microns and 250 microns.
[0045] A portion (49.25 parts) of this product was dry blended in a
twin shell blender with 42.0 parts of Avicel.RTM. PH-101
microcrystalline cellulose, 2.5 parts of croscarmellose sodium
(Ac-Di-Sol.RTM.), 5.0 parts of colloidal silicon dioxide
(Cab-O-Sil.RTM.), 1.0 part of talc, and 0.25 part of magnesium
stearate. This mixture was tableted using a two station Stokes B-2
press fitted with 0.5 inch bevel edge tooling. Each tablet
contained 131.95 mg of ibuprofen and had an initial average
hardness of 7.2 Kp. These tablets were tested for dissolution of
the pharmaceutically active agent under two sets of conditions and
were directly compared with commercial Advil.RTM. Liqui-gels.RTM.
comprising solubilized (partial conversion to the potassium salt)
ibuprofen (200 mg ibuprofen/capsule, Whitehall Laboratories Inc.).
In the first comparative test using a USP apparatus 2 (paddle) at
50 rpm in 900 mL of 0.05 M phosphate buffer at pH 7.2, after 5
minutes 97.+-.1.5% of the ibuprofen in the experimental tablets had
dissolved whereas the commercial product had released 1% of the
ibuprofen contained therein. The commercial product required 15
minutes to release 65% of the ibuprofen, and one hour to completely
release the pharmaceutically active agent. The second test method
used the same equipment, but substituted a 0.1 N hydrochloric acid
solution for the phosphate buffer. Under these conditions
29.+-.0.6% of the ibuprofen was released from the tablets of this
invention after five minutes whereas the commercial liqui-gels
released 1% of the pharmaceutically active agent. After one hour
these values were 39.+-.1.2% and 11%, respectively. At the
conclusion of the hour, the pH of the solution was adjusted to
greater than 6.0 by the addition of 5.3M sodium hydroxide. The
dissolution measured five minutes after the pH adjustment showed
that 84.+-.10.1% of the ibuprofen had dissolved from the
experimental tablets, but 15.+-.4.2% of it had dissolved from the
Liqui-gels. Two additional sets of ibuprofen-containing tablets
(each containing 200 mg of the pharmaceutically active agent) were
prepared using the method described above. One set of tablets used
the spray-dried formulation of Example 1, and the other set of
tablets was prepared using the free ibuprofen acid as formulated by
the method of U.S. Pat. No. 5,858,409. Both were tested in 0.5M
phosphate buffer at pH 7.2 and at pH 5.8. After 5 minutes at pH
7.2, 95-97% of the ibuprofen had dissolved, indicating little
difference in the rate of dissolution of both tablets; however,
after 5 minutes at pH 5.8, which is more representative of early
intestinal pH, the tablets of this invention had released 82% of
the pharmaceutically active agent whereas 39% of the free acid was
released. After 30 minutes, 97% of the pharmaceutically active
agent in the tablets of this invention had dissolved as compared
with 85% of the free acid from the tablets of the prior art
formulation.
EXAMPLE 2
[0046] A dried, 50/50 mixture of potassium ibuprofen and ibuprofen
was prepared as set forth in Example 1 for granulating with
excipients for subsequent tablet formation. 666.60 g of ibuprofen
(BASF) was combined with 100.42 g potassium hydroxide pellets
(Baker) and 490.47 g DI water. As the potassium hydroxide pellets
contain about 10% water, there is actually about 90.89 g potassium
hydroxide and 500 g DI water. A Lightnin.TM. mixer was used to mix
the water and potassium hydroxide pellets until the potassium
hydroxide dissolved. The ibuprofen was slowly added until all of
the ibuprofen went into solution. The solution was then dried in a
vacuum oven (VWR table top model) for 8 days at 25 psi at a
temperature of about 50.degree. C. The dried potassium ibuprofen
was screened by hand through a 30 mesh sieve.
[0047] Cab-O-Sil.RTM. fumed silica was screened by hand through a
30 mesh sieve. The following ingredients were then dry mixed for 10
minutes in the smallest PK: potassium ibuprofen (50/50 potassium
ibuprofen/ibuprofen, dried)(32.29 g), Avicel.RTM. microcrystalline
cellulose PH-103 (55.42 g), Ac-Di-Sol.RTM. croscarmellose (3.85 g),
screened Cab-O-Sil.RTM. fumed silica (5.37 g), and sodium laurel
sulfate (SLS) (0.07 g). Talc (1.0 g) was hand screened through a 30
mesh sieve, charged into the PK mixer, and the ingredients were
mixed for an additional 5 minutes. Sterotex (hydrogenated vegetable
oil) (2.0 g) was hand screened with a 30 mesh sieve and charged
into the mixer. The formulation was then mixed for another 5
minutes. The formulation was then discharged into a polybag.
[0048] The mixture was tableted using a Stokes 512 press fitted
with .+-.2 standard concave round tooling using two stations. Each
tablet had a weight of 676.6 mg and a hardness between 4-12 kp.
[0049] The tablets capped at all hardness levels tested (4-12 kp)
with severe edge wear evident. The tablets caused filming of the
punches, and sticking of the formulation to the center of the upper
punches was evident after compression of about 100 g of the
formulation. Disintegration was in the 45 second range at 4 kp and
in the 1.5 minute range at 12 kp.
EXAMPLE 3
[0050] A granular preparation of ibuprofen (which had been
converted at least partially into potassium ibuprofen) was
spray-dried with hydrolyzed cellulose and was designated PI.
Separately, free acid ibuprofen was spray-dried with hydrolyzed
cellulose and designated FAI. In order to neutralize the hydrolyzed
cellulose, some ammonia was added to the FAI mixture before drying.
The addition of ammonia does not appreciably cause formation of
ibuprofen salt. The dissolution profiles of the two formulations
were examined in 900 ml phosphate buffer (pH=4.5) at 50 rpm using
the paddle method as described in Example 1.
[0051] As shown in FIG. 2, at 5 minutes, 55% of the potassium
ibuprofen had dissolved compared with 12% of the ibuprofen free
acid. At 30 minutes, 65% of the potassium ibuprofen had dissolved
as compared with 32% of the ibuprofen free acid. At 60 minutes, 67%
of the potassium ibuprofen had dissolved compared with 41% of the
ibuprofen free acid.
EXAMPLE 4
[0052] A granular preparation of ibuprofen (which had been
converted at least partially into potassium ibuprofen, as per
Example 1) was spray-dried with hydrolyzed cellulose, was formed
into tablets, film-coated, and designated PI. Separately, free acid
ibuprofen was spray-dried with hydrolyzed cellulose, formed into
tablets, film-coated and designated FAI. As in Example 3, FAI was
prepared with the addition of a small amount of ammonia to
neutralize the hydrolyzed cellulose mixture. The tablets were
subjected to dissolution profile analysis in 900 ml of 0.1N HCl at
50 rpm using the paddle method as described in Example 1.
[0053] As shown in FIG. 3, at 5 minutes at low pH (below the pKa of
ibuprofen) 25% of the potassium ibuprofen had dissolved compared
with 5% of the ibuprofen free acid. At 30 minutes, 31% of the
potassium ibuprofen had dissolved compared with 18% of the
ibuprofen free acid. At 60 minutes, the pH of the solution was
adjusted to greater than 6.0 with 5.3M NaOH. At the higher pH, the
remainder of each tablet rapidly dissolved. The increased
solubility of potassium ibuprofen at low pH may have the advantage
of rapid uptake of drug into the circulation while still in the
acidic environment of the stomach as compared to ibuprofen free
acid and conventional ibuprofen preparations.
[0054] As shown in FIG. 1, there is no appreciable dissolution of
ibuprofen in the unprocessed, free acid form or the free acid form
processed with the hydrolyzed cellulose when the pH is below about
6.0. At a pH of about 6.0, the solubility of the free acid
formulated with the hydrolyzed cellulose was 0.134 mg/ml as
compared to the solubility of the spray dried potassium ibuprofen,
which was 2.42 mg/ml (18 fold greater solubility). Even more
striking is the fact that at low pH (less than about 2) the
solubility of the potassium ibuprofen is slightly greater than the
solubility of the unprocessed ibuprofen or the ibuprofen free acid
spray-dried with hydrolyzed cellulose at a pH of about 6.0.
INDUSTRIAL APPLICABILITY
[0055] The pharmaceutical industry is constantly in search of new
preparations of pharmaceutically active compounds that overcome
certain limitations of those pharmaceutically active compounds. The
present invention advances the state of the art by partially
converting relatively water-insoluble pharmaceutically active
agents to the salt form and thereafter preparing granular
formulations with hydrolyzed cellulose.
[0056] The prior art fails to suggest or disclose such an
improvement. Those skilled in the art will readily appreciate the
various modifications that can be made to the invention as
described, without departing from the spirit and scope of the
invention as recited in the claims.
* * * * *