U.S. patent application number 12/558813 was filed with the patent office on 2010-01-21 for flashmelt oral dosage formulation.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to DIVYAKANT S. DESAI, SANJEEV KOTHARI.
Application Number | 20100016448 12/558813 |
Document ID | / |
Family ID | 24186805 |
Filed Date | 2010-01-21 |
United States Patent
Application |
20100016448 |
Kind Code |
A1 |
KOTHARI; SANJEEV ; et
al. |
January 21, 2010 |
FLASHMELT ORAL DOSAGE FORMULATION
Abstract
There is provided granules for the production of flash-melt
pharmaceutical oral dosage forms. In addition to one or more
medicaments, the granules are composed of an excipient combination
consisting of a superdisintegrant, a dispersing agent, a
distributing agent, and a binder and may also include other
conventional ingredients such as sweetening and flavoring agents.
The subject granules are advantageous in that they are stable and
can be prepared without the aid of solvents and without the need
for special environments or handling. Dosage forms, especially
tablets, prepared therefrom on conventional equipment disintegrate
in the mouth in under about twenty five seconds.
Inventors: |
KOTHARI; SANJEEV;
(Princeton, NJ) ; DESAI; DIVYAKANT S.; (West
Windsor, NJ) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT, P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
24186805 |
Appl. No.: |
12/558813 |
Filed: |
September 14, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12056410 |
Mar 27, 2008 |
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12558813 |
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10979556 |
Nov 2, 2004 |
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12056410 |
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10920851 |
Aug 18, 2004 |
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10979556 |
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09973226 |
Oct 9, 2001 |
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10920851 |
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09589340 |
Jun 7, 2000 |
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09973226 |
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09547948 |
Apr 12, 2000 |
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09589340 |
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Current U.S.
Class: |
514/770 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 9/2009 20130101; A61K 9/2059 20130101; A61P 43/00 20180101;
A61K 9/2054 20130101; A61P 31/04 20180101; A61K 9/0056 20130101;
A61K 31/496 20130101; A61K 9/2018 20130101 |
Class at
Publication: |
514/770 |
International
Class: |
A61K 47/00 20060101
A61K047/00 |
Claims
1. A formed pharmaceutical product comprising: (a) a
pharmaceutically active ingredient; and (b) a calcium metasilicate
excipient having an aspect ratio of average major axial
diameter/average minor axial diameter of from about 1.3:1 to about
2.6:1, and an oil absorption of from about 36 ml/100 g to about 51
ml/100 g.
2. The formed pharmaceutical product of claim 1, wherein the
pharmaceutical product is in tablet form.
3. The formed pharmaceutical product of claim 1, wherein the
pharmaceutical product is in granular form.
4. The formed pharmaceutical product according to claim 1, further
comprising a disintegrant selected from the group consisting of
starch, modified starch, pregelatinized starch, cellulose,
chemically-modified cellulose, sugars, crospovidone and
croscarmellose.
5. A formed pharmaceutical product comprising: (a) a
pharmaceutically active ingredient; and (b) a calcium metasilicate
excipient having an aspect ratio (average major axial
diameter/average minor axial diameter), and an oil absorption range
defined by the aspect ratio and oil absorption range defined by the
aspect ratio and oil absorption of: (i) crystalline alpha triclinic
CaSiO.sub.3 from Aldrich Chemical Company; and (ii) crystalline
meta CaSiO.sub.3 from Alfa Aesar.
6. The formed pharmaceutical product according of claim 5, wherein
the crystalline alpha triclinic CaSiO.sub.3 from Aldrich Chemical
Company, and the crystalline meta CaSiO.sub.3 from Alfa Aesar, each
has about the specifications for surface area, bulk density, true
density and volatiles set forth in Table 1 for those materials.
7. The formed pharmaceutical product of claim 5 or claim 6, wherein
the pharmaceutical product is in tablet form.
8. The formed pharmaceutical product of claim 5 or claim 6, wherein
the pharmaceutical product is in tablet form.
9. The formed pharmaceutical product of claim 5 or claim 6, further
comprising a disintegrant selected from the group consisting of
starch, modified starch, pregelatinized starch, cellulose,
chemically-modified cellulose, sugars, crospovidone and
croscarmellose.
10. The formed pharmaceutical product comprising: (a) a
pharmaceutically active ingredient; and (b) a calcium metasilicate
excipient selected from the group consisting of; (i) crystalline
alpha triclinic CaSiO.sub.3 from Aldrich Chemical Company; and (ii)
crystalline meta CaSiO.sub.3 from Alfa Aesar.
11. The formed pharmaceutical product according of claim 10,
wherein the crystalline alpha triclinic CaSiO.sub.3 from Aldrich
Chemical Company, and the crystalline meta CaSiO.sub.3 from Alfa
Aesar, each has about the specifications for surface area, bulk
density, true density and volatiles set forth in Table 1 for those
materials.
12. The formed pharmaceutical product of claim 10 or 11, wherein
the pharmaceutical product is in tablet form.
13. The formed pharmaceutical product of claim 10 or 11, wherein
the pharmaceutical product is in granular form.
14. The formed pharmaceutical product of claim 10 or claim 11,
further comprising a disintegrant selected from the group
consisting of starch, modified starch, pregelatinized starch,
cellulose, chemically-modified cellulose, sugars, crospovidone and
croscarmellose.
15. A formed product comprising: (a) a disintegrant; and (b) a
dehydrated calcium metasilicate excipient having an aspect ratio
(average major axial diameter/average minor axial diameter) of from
about 1.3:1 to about 2.6:1, and an oil absorption of 36 ml/100 g to
about 51 ml/100 g. wherein the formed product disintegrates in
about 10 seconds or less when immersed in water.
16. A formed product comprising: (a) a disintegrant; and (b) a
dehydrated calcium metasilicate excipient having an aspect ratio
(average major axial diameter/average minor axial diameter), and an
oil absorption range about within the aspect ratio range and oil
absorption range defined by the aspect ratio and oil absorption of:
(i) crystalline alpha triclinic CaSiO.sub.3 from Aldrich Chemical
Company; and (ii) crystalline meta CaSiO.sub.3 from Alfa Aesar.
wherein the formed product disintegrates in about 10 seconds or
less when immersed in water.
17. The formed product of claim 16, wherein the crystalline alpha
triclinic CaSiO.sub.3 from Aldrich Chemical Company, and the
crystalline meta CaSiO.sub.3 from Alfa Aesar, each has about the
specifications for surface area, bulk density, true density and
volatiles set forth in Table 1 for those materials.
18. A formed product comprising: (a) a disintegrant; and (b) a
calcium silicate excipient selected from the group consisting of:
(i) crystalline alpha triclinic CaSiO.sub.3 from Aldrich Chemical
Company; (ii) crystalline meta CaSiO.sub.3 from Alfa Aesar; wherein
the formed product disintegrates in about 10 seconds or less when
immersed in water.
19. The formed product of claim 18, wherein the crystalline alpha
triclinic CaSiO.sub.3 from Aldrich Chemical Company, and the
crystalline meta CaSiO.sub.3 from Alfa Aesar, each has about the
specifications for surface area, bulk density, true density and
volatiles set forth in Table 1 for those materials.
20. A formed pharmaceutical product comprising: (a) a
pharmaceutically active ingredient; and (b) a calcium silicate
excipient selected from the group consisting of: (i) crystalline
alpha triclinic CaSiO.sub.3 from Aldrich Chemical Company; (ii)
crystalline meta CaSiO.sub.3 from Alfa Aesar; and (iii) crystalline
alpha triclinic calcium silicate from Tomita Pharmaceutical Co.
21. The formed product of claim 20, wherein the crystalline alpha
triclinic CaSiO.sub.3 from Aldrich Chemical Company, and the
crystalline meta CaSiO.sub.3 from Alfa Aesar, each has about the
specifications for surface area, bulk density, true density and
volatiles set forth in Table 1 for those materials, and the
crystalline alpha triclinic calcium silicate from Tomita
Pharmaceutical Co., meets the following specifications: 1 to 15
m.sup.2/gm surface area; 0.50 to 0.63 g/cc bulk density; 2.4 to 2.9
g/cc true density; and less than 1% w/w volatiles.
22. An oral dosage composition comprising a calcium metasilicate
having an aspect ratio (average major axial diameter/average minor
axial diameter) of from about 1.3:1 to about 2.6:1, and an oil
absorption of from about 36 ml/100 g to about 51 ml/100 g.
23. The oral dosage composition according to claim 22, wherein the
calcium metasilicate is dehydrated.
24. The oral dosage composition according to claim 22, wherein the
calcium metasilicate is wollastonite.
25. The oral dosage composition according to claim 22, further
comprising one or more ingredients selected from the group
consisting of organoleptic enhancing agents, abrasives,
disintegration aids, therapeutic agents and thickening agents.
26. The oral dosage composition according to claim 25, wherein the
organoleptic enhancing agent comprises one or more ingredients
selected from the group consisting of humectants, sweeteners,
flavorants and colorants.
27. An oral dosage composition comprising: a calcium metasilicate
having an aspect ratio (average major axial diameter/average minor
axial diameter) of from about 1.3:1 to about 2.6:1, and an oil
absorption of from about 36 ml/100 g to about 51 ml/100 g; a
disintegration aid; and an organoleptic agent.
28. The oral dosage composition of claim 27, further comprising one
or more ingredients selected from the group consisting of
thickening agents, therapeutic agents, sweeteners, and
abrasives.
29. The oral dosage composition of claim 27, wherein the
organoleptic enhancing agent comprises one or more ingredients
selected from the group consisting of humectants, sweeteners,
flavorants and colorants.
30. An oral dosage composition comprising a calcium metasilicate
having an aspect ratio (average major axial diameter/average minor
axial diameter) of from about 1.3:1 to about 2.6:1, and an oil
absorption of from about 36 ml/100 g to about 51 ml/100 g.
31. The oral tablet composition according to claim 30, wherein the
calcium metasilicate is dehydrated.
32. The oral tablet composition according to claim 30, wherein the
calcium metasilicate is wollastonite.
33. The oral dosage composition of claim 30, further comprising one
or more ingredients selected from the group consisting of
organoleptic enhancing agents, abrasives, disintegration aids,
therapeutic agents and thickening agents.
34. The oral tablet composition according to claim 33, wherein the
organoleptic enhancing agent comprises one or more ingredients
selected from the group consisting of humectants, sweeteners,
flavorants, and colorants.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/056,410 filed Mar. 27, 2008, now abandoned, which is a
continuation of U.S. application Ser. No. 10/979,556 filed Nov. 2,
2004, now abandoned, which is a continuation of U.S. application
Ser. No. 10/920,851 filed Aug. 18, 2004, now pending, which is a
continuation of U.S. application Ser. No. 09/973,226 filed Oct. 9,
2001, which is a continuation-in-part of U.S. application Ser. No.
09/589,340 filed Jun. 7, 2000, now abandoned, which is a
continuation in-part of U.S. application Ser. No. 09/547,948 filed
Apr. 12, 2000, now abandoned.
FIELD OF THE INVENTION
[0002] The present invention relates to a formulation for solid
pharmaceutical oral dosage forms that rapidly disperses in the
mouth.
BACKGROUND OF THE INVENTION
[0003] There are a variety of solid pharmaceutical dosage forms
that rapidly dissolve or disintegrate in a glass of water or in the
gastrointestinal tract. Such dosage forms have been known in the
art for many years. The obvious advantages of the convenience of
carrying dosage forms that will dissolve or effervesce in water to
release medicaments are well known. The therapeutic need of having
an oral dosage form that will rapidly dissolve or disintegrate in
the mouth for situations where immediate medication is necessary
and water is not available has long been recognized.
[0004] Initially, a distinction must be drawn between flash-melt
dosage forms and rapidly disintegrating dosage forms. The former
are intended to dissolve or disintegrate in the mouth of the
patient in less than one minute whereas the latter are intended for
primary dissolution or disintegration within 3 to 20 minutes in the
acidic medium of the stomach or a container of water. The
recognized test for rapidly disintegrating dosage forms is
disintegration time in 0.1 N hydrochloric acid. Those of ordinary
skill in the art will appreciate that the requirements for
formulating dosage forms to meet these criteria must necessarily be
different since the conditions, particularly pH, in the mouth and
the stomach are quite different. More importantly, the time in
which a dosage form must dissolve or disintegrate in the mouth is
necessarily much shorter than in the stomach with the obvious
exception of dosage forms, e.g. lozenges, that are specifically
formulated to slowly dissolve in the mouth.
[0005] Another consideration common to most if not all dosage form
formulations intended for flash-melt or rapid disintegration is the
need to take precautions in the preparation, packaging, handling
and storing of the finished dosage forms since they tend to be both
hygroscopic and friable. Dosage forms dependent on effervescence to
promote their disintegration are particularly susceptible to
moisture and must be packaged with special wrapping, stoppers,
packets of drying agent and the like.
[0006] Regardless of such potential problems, there is still an
acute need for dosage forms that can rapidly dissolve or
disintegrate for the obvious benefits of having a therapeutic
dosage of the medicament contained therein available for absorption
in a very short time. In addition to the benefits of rapid
availability, flash-melt dosage forms are advantageous for
administration of medicaments to patients such as the very young,
the elderly, the non-compliant and those with a physical impairment
that makes it difficult if not impossible to swallow an intact
dosage form. Flash-melt dosage forms are further a convenience for
situations where potable water may not be readily available or
desirable. Medicaments amenable to such dosage forms would include
sedatives, hypnotics, antipsychotics, motion sickness medication,
mild stimulants such as caffeine and the like.
[0007] Those of ordinary skill in the art are aware that there are
two basic compounding concepts recognized for the preparation of
rapidly dissolving/disintegrating dosage forms. The first of these,
particularly suited for the preparation of flash-melt dosage forms,
is freeze drying wherein a cake or wafer is prepared from a
freeze-dried solution or suspension of medicament and suitable
excipients in water or other solvents. Such wafers dissolve very
rapidly on the tongue, i.e. within about ten seconds, due to a
combination of a high affinity for moisture resulting from the
freeze drying process and a very high porosity, which promotes
rapid ingress of saliva. While such dosage forms are capable of
rapid disintegration/dissolution in the mouth, the freeze drying
process suffers from several disadvantages, primary among which is
the fact that a solution or a stable suspension of the medicament
must be formed before it can be freeze dried. While not always the
case, typically such solutions are aqueous and, therefore, not
suited to formulating medicaments sensitive to water. The process
itself is typically laborious and time-consuming. Finally, the
resultant dosage forms, in addition to being hygroscopic, tend to
be very soft and, therefore, require special moisture- and
impact-resistant packaging and require careful handling prior to
administration.
[0008] The second major technology utilized in the manufacture of
rapidly disintegrating dosage forms is based on special grades of
sugars such as mannitol, sorbitol and the like in combination with
superdisintegrants. The latter are excipients that are
characterized by a special wicking capacity to channel water into
the interior of the dosage form, or by rapid swelling in water,
both of which act to hasten disintegration. It is also known to
enhance dissolution of dosage forms by the inclusion of
effervescent combinations, typically sodium bicarbonate and a weak
acid, such as citric acid. As noted above, effervescent
formulations require special moisture resistant packaging as even
very small levels of moisture may be sufficient to initiate the
effervescent reaction. Techniques, such as fluidized bed
granulation, are recognized as being useful in the preparation of
such formulations. Too often, however, such technologies require a
specific, very costly plant including special handling equipment,
controlled-humidity environments and the like. In spite of such
measures, dosage forms produced by such techniques typically
require moisture resistant packaging, the need to include in the
packaging packets or capsules of moisture absorbing agents and the
like.
[0009] An example of a teaching of the incorporation of super
disintegrants in dosage form formulations to enhance dissolution is
WO 98/030640, FMC Corporation. It is disclosed therein that, for
cost considerations, up to 90% of a group of super disintegrants
including cross-linked cellulose, cross-linked carboxymethyl
cellulose, cross-linked starch, croscarmellose alkali metal salt,
crospovidone, alkali metal starch glycolate and the like can be
replaced by a co-disintegrant. Included among the latter group are
natural diatomaceous silica, a synthetic hydrous alkaline earth
metal calcium silicate and a porous hydrophilic zeolite. The weight
ratio of super disintegrant to co-disintegrant is stated as from
4:1 to 1:10, preferably 2-1:1. There is no indication of any
recognition of benefits to be derived from the formulation other
than the obvious consideration of cost savings since the
co-disintegrants are less expensive and the combination is stated
to accomplish the desired results.
[0010] In contrast, Japanese patent 10114655, Kyowa Hakko Kogyo KK
discloses a formulation intended for rapid dissolution in the
stomach that can contain up to 30% by weight of a
superdisintegrant, such as crospovidone or hydroxypropylcellulose,
croscarmellose and the like and up to 30% of a neutral or basic
ingredient including magnesium aluminum metasilicate, calcium
silicate, a phosphoric acid salt or a metal hydroxide. The dosage
form is intended for medicaments that produce a gel at acidic
pH.
[0011] There are numerous other examples of specific formulations
that utilize one or more of the techniques or mechanisms discussed
above. For the most part, however, they also possess one or more of
the enumerated disadvantages to some degree, e.g. it is difficult
or expensive to produce dosage forms by such techniques, the
resulting dosage forms are friable or are sensitive to
environmental factors such as moisture. There continues to be the
need for a formulation that mitigates or eliminates these
disadvantages, yet yields a flash-melt dosage form that will
disintegrate in the mouth within about 25 seconds. Such
formulations are provided in accordance with the present
invention.
SUMMARY OF THE INVENTION
[0012] According to a first embodiment of the present invention is
provided a flash-melt pharmaceutical dosage form comprising a
medicament, a superdisintegrant, a dispersing agent and a binder
wherein said medicament is aripiprazole, entecavir, cefprozil,
pravastatin, captopril, gatifloxacin, desquinolone, omapatrilat or
irbesartan and wherein said dispersing agent is calcium silicate,
magnesium trisilicate or silicic acid.
[0013] According to a first series of embodiments of the present
invention are provided flash-melt pharmaceutical dosage forms as
described herein wherein greater than 50% of said dispersing agent
by weight is comprised of calcium silicate.
[0014] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein greater than 80% of said dispersing agent by weight is
comprised of calcium silicate.
[0015] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said dispersing agent is calcium silicate.
[0016] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said dispersing agent comprises from about 20 to about 70
percent by weight of said dispersing agent based on the total
weight of said dosage form.
[0017] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said dispersing agent comprises from about 35 to about 45
percent by weight of said dispersing agent based on the total
weight of said dosage form.
[0018] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is crystalline.
[0019] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is amorphous.
[0020] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is ortho-, meta- or alpha
triclinic-calcium silicate.
[0021] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is alpha triclinic-calcium
silicate.
[0022] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is comprised of a combination of
alpha triclinic-calcium silicate and at least one other
pharmaceutical grade of calcium silicate wherein said alpha
triclinic-calcium silicate comprises from about 10% to about 90% by
weight of said combination.
[0023] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate has a surface area of 1.0 m.sup.2/gm
to 210 m.sup.2/gm, bulk density of 0.075 g/cc to 0.90 g/cc, true
density of 1.70 g/cc to 2.90 g/cc and volatile content of less than
1% to 14% w/w.
[0024] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is alpha triclinic calcium silicate
that has a surface area of about 1.3 m.sup.2/gm, bulk density of
about 0.63 g/cc, true density of about 2.90 g/cc and volatile
content of less than 1% w/w.
[0025] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is ortho crystalline calcium silicate
that has a surface area of about 0.98 m.sup.2/gm, bulk density of
about 0.492 g/cc, true density of about 3.252 g/cc and volatile
content of less than 1% w/w.
[0026] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is meta crystalline calcium silicate
that has a surface area of about 2.5 m.sup.2/gm, bulk density of
about 0.867 g/cc, true density of about 2.940 g/cc and volatile
content of less than 1% w/w.
[0027] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is crystalline calcium silicate that
has a surface area of about 90.4 m.sup.2/gm, bulk density of about
0.094 g/cc, true density of about 2.596 g/cc and volatile content
of less than 1% w/w.
[0028] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is amorphous calcium silicate that
has a surface area of about 191.3 m.sup.2/gm, bulk density of about
0.120 g/cc, true density of about 2.314 g/cc and volatile content
of about less than 14% w/w.
[0029] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is amorphous calcium silicate that
has a surface area of about 103.0 m.sup.2/gm, bulk density of about
0.130 g/cc, true density of about 1.702 g/cc and volatile content
of about less than 14% w/w.
[0030] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said calcium silicate is amorphous calcium silicate that
has a surface area of about 209 m.sup.2/gm, bulk density of about
0.075 g/cc, true density of about 2.035 g/cc and volatile content
of about less than 14% w/w.
[0031] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said medicament comprises not more than about 30 percent by
weight of said medicament based on the total weight of said dosage
form.
[0032] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said medicament comprises not more than about 15 percent by
weight of said medicament based on the total weight of said dosage
form.
[0033] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said medicament is selected from the group consisting of
aripiprazole, entecavir, cefprozil, pravastatin, captopril,
gatifloxacin, desquinolone, omapatrilat and irbesartan.
[0034] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said medicament is aripiprazole.
[0035] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 3 to
about 15 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0036] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 4 to
about 10 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0037] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 4 to
about 8 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0038] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 5 to
about 7 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0039] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 8 to
about 12 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0040] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent comprises from about 9 to
about 10 percent by weight of said superdisintegrant agent based on
the total weight of said dosage form.
[0041] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent is crospovidone,
croscarmellose sodium, sodium starch glycolate, low-substituted
hydroxypropyl cellulose or pregelatinized starch.
[0042] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent is crospovidone or
croscarmellose sodium.
[0043] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said superdisintegrant agent is crospovidone and
croscarmellose sodium.
[0044] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described
herein, wherein based on the total weight of said dosage form, said
crospovidone comprises from about 6 to about 8 percent by weight of
said crospovidone and said croscarmellose sodium comprises from
about 2 to about 4 percent by weight of said croscarmellose
sodium.
[0045] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said distributing agent comprises from about 1 to about 10
percent by weight of said distributing agent based on the total
weight of said dosage form.
[0046] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said distributing agent comprises from about 1.5 to about 3
percent by weight of said distributing agent based on the total
weight of said dosage form.
[0047] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said distributing agent is amorphous silica, fumed silica,
diatomaceous earth, talc, kaolin or magnesium aluminum
trisilicate.
[0048] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said distributing agent comprises from about 10 to about 50
percent by weight of said binder based on the total weight of said
dosage form.
[0049] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said distributing agent comprises from about 12 to about 20
percent by weight of said binder based on the total weight of said
dosage form.
[0050] According to other embodiments of the present invention are
provided flash-melt pharmaceutical dosage forms as described herein
wherein said binder is microcrystalline cellulose, hydroxypropyl
cellulose, ethyl cellulose, lactose, mannitol or calcium
phosphate.
[0051] Yet other embodiments or aspects of the present invention
reside in the combination of one or more of the embodiments or
aspects described herein.
[0052] Yet other embodiments or aspects of the present invention
are described below.
DETAILED DESCRIPTION OF THE INVENTION
[0053] As used herein the terms "a medicament", "a
superdisintegrant", "a dispersing agent", "a distributing agent" or
"a binder" means that one or more of agents belonging to each class
may be suitably employed in the present invention unless otherwise
specified. Furthermore, if agents belonging to a particular class
are referred to in the alternative, it is understood that one or
more of said agents may be suitably employed. Thus for example, two
or more superdisintegrants may be employed unless otherwise
specified. The flash-melt pharmaceutical dosage forms the present
invention may be prepared by dry granulation of the excipients with
the medicament and suitable conventional ingredients, such as
flavoring and sweetening agents, without the use of any solvent, to
form stable granules that can be readily compressed into dosage
forms on conventional equipment without the need for special
handling techniques.
[0054] The active medicament may comprise up to about 30% by
weight, particularly up to about 15% by weight, of the formulation,
depending on the amount required for a therapeutically effective
dosage and factors such as its capacity to be directly granulated,
the amount of flavoring/sweetening agents required to mask the
taste or bitterness thereof and the like. It is within the scope of
the present invention to utilize medicaments that are coated for
taste or other reason in the subject formulations provided that the
coatings do not interfere with either the compounding or the
disintegration of the tablets.
[0055] Suitable superdisintegrants include crospovidone,
croscarmellose sodium, sodium starch glycolate, low-substituted
hydroxypropylcellulose, pregelatinized starch and the like.
Crospovidone can be utilized in large amounts without causing a
formulation containing it to have a propensity to gel.
[0056] Suitable dispersing agents, also sometimes referred to in
the art as anticaking agents, include calcium silicate-ortho, meta
and alpha triclinic forms thereof, magnesium trisilicate-ortho and
meta forms thereof and silicic acid. Calcium silicate is the
preferred dispersing agent. Particularly preferred is a crystalline
alpha triclinic calcium silicate, commercially available from
Aldrich Chemical Company which meets the following specifications:
1.3 m.sup.2/gm surface area; 0.63 g/cc bulk density; 2.90 g/cc true
density; and <1% w/w volatiles. Also particularly preferred is a
crystalline alpha triclinic calcium silicate, commercially
available from J.M. Huber Inc., Tomita Pharmaceutical Co., Aldrich
Chemical Company which meets the following specifications: 1.0 to
15 m.sup.2/gm surface area; 0.50 to 0.63 g/cc bulk density; 2.40 to
2.90 g/cc true density; and <1% w/w volatiles. A variety of
pharmaceutical grades of calcium silicate available from other
vendors, as shown in Table 1, have also been found to produce
satisfactory flash-melt dosage forms as well. These include ortho
and meta forms of calcium silicate available from Alfa-Aesar,
synthetic calcium silicates Micro-cel C and Micro-cel E, available
from Celite Corp, Hubersorb 600 NF and Hubersorb 250 NF available
from J. M. Huber Corp, and combinations of various grades thereof.
These products have been found to cover the following range of
specifications for calcium silicate: 1.0 m.sup.2/gm to 210
m.sup.2/gm surface area; 0.075 g/cc to 0.90 g/cc bulk density; 1.70
g/cc to 2.90 g/cc true density; and <1% to 14% w/w volatiles.
Table 1 lists the individual specifications for each of the
materials obtained from the vendors listed above.
TABLE-US-00001 TABLE 1 Surface True Volatiles area Bulk Density
Density (% Source Description m.sup.2/gm g/cc (.+-.s.d.) g/cc w/w)
Aldrich CaSiO3 < 1.3 0.627 (0.020) 2.934 0.50 200 mesh
(crystalline, alpha triclinic) Alfa 2CaO.cndot.SiO2 0.98 0.492
(0.003) 3.252 0.02 Aesar (crystalline, ortho) Alfa CaSiO3 2.5 0.867
(0.009) 2.940 0.50 Aesar (crystalline, meta) Celcite Micro-cel E
90.4 0.094 (0.006) 2.596 0.94 (crystalline) Celcite Micro-cel C
191.3 0.120 (0.006) 2.314 5.11 (amorphous) JM Hubersorb 103.0 0.130
(0.008) 1.702 9.90 Huber 250NF (amorphous) JM Hubersorb 209 0.075
2.035 13.8 Huber 600NF (<0.001) (amorphous)
[0057] Alpha triclinic calcium silicate is advantageously combined
in the subject formulations with at least one other pharmaceutical
grade of calcium silicate wherein the alpha triclinic form would
comprise from about 10% to about 90% by weight of the combination.
In contrast to its use in conventional tabletting formulations, it
is considered unexpected that the dispersing agent, i.e. calcium
silicate, is the primary constituent of the excipient combination
of the subject formulations since it is generally recognized by
those of ordinary skill in the art as being poorly
compressible.
[0058] Examples of suitable distributing agents for the excipient
combination of the subject formulations include amorphous silica,
fumed silica, diatomaceous earth, talc, kaolin, magnesium aluminum
trisilicate and the like.
[0059] Suitable binders are those that also function as a wicking
or distributing agent in that they act to promote water intake into
dosage forms made therefrom. Suitable binders include carbohydrates
such as, microcrystalline cellulose, hydroxypropyl cellulose, ethyl
cellulose, starch, lactose, and also, mannitol and calcium
phosphate. Microcrystalline cellulose is commercially available as
Avicel.RTM. PH (pharmaceutical grade) from FMC Corporation,
Philadelphia, Pa., particularly Avicel.RTM. PH 101, PH 102, PH 103,
PH 112, PH 200, PH 301, PH 302 and Ceolus. Microcrystalline
cellulose is also available from Mendell, Penwest Company,
Patterson, N.Y., as Emcocel.RTM. 90M and Emcocel.RTM. 50M, which
could be used satisfactorily.
[0060] The formulations of the present invention may contain other
conventional ingredients found in similar preparations known in the
art and recognized as approved for use in preparations to be taken
into the body. These would include, for example, natural and
artificial flavors, polyols such as mannitol, sorbitol, maltitol
and xylitol, artificial sweetening agents such as,
N-.alpha.-L-Aspartyl-L-phenylalanine 1-methyl ester (aspartame) and
6-methyl-3,4-dihydro-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide,
particularly the potassium salt thereof (acesulfame K), flavor
adjuncts such as tartaric acid, tabletting lubricants, such as
magnesium stearate, and the like. Those skilled in the art of
pharmaceutical compounding will appreciate that the amount of
flavoring and sweetening agents, if any, present in the
formulations of the present invention will be directly proportional
to the taste or bitterness of the medicament. The flavoring and
sweetening agents do not serve to coat the medicament, but are
adequate to mask the objectionable taste of the medicaments in
homogeneous admixture therewith. In general, the total of such
conventional ingredients will not exceed about 32 percent,
preferably from about 25 to about 30 percent by weight based on the
total weight of the formulation.
[0061] The medicament in the formulations of the present invention
typically will not exceed about 30 percent by weight, preferably
from about 1 to about 15 percent by weight of the formulation.
Those of ordinary skill in the art will appreciate that the
physical characteristics of the medicament itself, i.e. its
particle size and morphology, will directly influence its limiting
content in the subject formulations. Clearly, there has to be
sufficient medicament in the dosage form produced form the subject
formulations to provide a therapeutically effective dosage. While
solid dosage forms can be prepared from the formulations of the
present invention by any recognized technique, including wet
granulation, it is a particular advantage that the formulations can
be dry granulated without the use of specialized equipment and
conditions, thereby making them suitable for the formulation of
medicaments that are sensitive to moisture and high
temperatures.
[0062] Examples of medicaments that can be formulated into
flash-melt tablets in accordance with the present invention
include, without intended limitation, antihistamines, anti-motion
sickness agents, analgesics, anti-inflammatory agents, antibiotics,
cholesterol lowering agents, anti-anxiety agents,
anti-hypertensives, anti-cancer agents, hypnotics, anti-ulcer
agents, coronary dilators, antivirals, anti-psychotics,
anti-depressants, neuromuscular agents, anti-diarrheals,
hypoglycemic agents, thyroid suppressors, anabolic agents,
antisposmodics, antimigraine agents, diuretics, stimulants,
decongestants, uterine relaxants, anti-arrhythmics, male erectile
dysfunction compounds, Maxi-K channel openers or neuroprotective
agents for the treatment of stroke or Alzheimer's disease and
therapeutically appropriate combinations thereof. Specific
therapeutic agents falling into the foregoing categories include,
again without intended limitation, aripiprazole, ibuprofen,
aspirin, acetaminophen, chlorpheniramine maleate, psuedoephedrine,
diphenhydramine HCl, ranitidine, phenylpropanolamine, cimetidine,
loperamide, meclizine, caffeine, entecavir, cefprozil, melatonergic
agonists, pravastatin, captopril, fosinopril, irbesartan,
omapatrilat, gatifloxacin and desquinolone and therapeutically
appropriate combinations thereof.
[0063] As stated above, a decided advantage of the formulation of
the present invention is that it can be dry-granulated into stable,
fine granules that can be directly compressed into pharmaceutically
elegant flash-melt oral dosage forms, e.g. tablets, caplets, wafers
and the like. Preferably, the granules for flash-melt dosage forms
in accordance with the present invention are formed in two steps.
The process comprises initially forming granules, referred to
herein as the intragranulation, by blending all of the medicament,
the dispersing agent, (distributing agent), other conventional
ingredients as described above and a portion of each of the
superdisintegrant, binder and tabletting lubricant together in a
suitable mixer to assure uniform distribution throughout. A
conventional V-blender is a preferred apparatus for this step.
While a minor portion of the dispersing agent may be omitted from
the intragranulation, it is preferred that all be incorporated
therein. The blended mixture is then compacted in a conventional
roller compactor having an orifice such that the compacts thereof
are in the form of ribbons. Alternately, a slugging process can be
used. The compacts from the roller compactor or the slugs from the
slugger are passed through a fine screen, e.g. a 30 mesh (600
microns) screen, thereby breaking them into granules between about
150 and 400 microns in size. The intragranulation granules
thus-prepared are thereafter blended in a suitable mixer with the
remaining ingredients, i.e., superdisintegrant, binder and
lubricant, referred to herein as the extragranulation ingredients,
to form a final blend that can be directly compressed into
pharmaceutical dosage forms utilizing conventional equipment such
as a tablet press. Rather than directly compress the final blend
upon formation, since it is stable, it can be stored and
subsequently pressed into dosage forms at a later time. It is a
decided advantage of particular aspects of the subject invention
that these operations are carried out without the need to resort to
special handling such as taking precautions against any moisture
coming in contact with the ingredients or the granules, and without
the use of specially controlled temperature and humidity
conditions.
[0064] The intragranulation comprises from about 80 to 99,
preferably from about 85 to 95, most preferably about 90, percent
by weight of the final blend. Based on the weight of the final
blend, the intragranulation preferably comprises up to about 30
percent by weight, preferably from about 6 to 20 percent by weight,
of the binder, up to about 5 percent by weight, preferably from
about 2 to 4 percent by weight, of the superdisintegrant, and all
of the dispersing agent and the distributing agent. The binder and
superdisintegrant are divided between the intragranulation and the
extragranulation ingredients in weight ratios of approximately 2:1
to 4:1 for the binder and 0.5:2.0 to 2.0:0.5 for the
superdisintegrant. The conventional tabletting lubricant is divided
approximately equally between the intragranulation and the
extragranulation ingredients.
[0065] The final blend is formed by mixing the intragranulation and
the extragranulation components of the excipient combination,
adding the remaining tabletting lubricant thereto and blending
until uniform. Alternatively, a direct compression approach can be
utilized in which all of the ingredients with the exception of the
tabletting lubricant are mixed in a suitable blender, such as a
conventional V-blender, by geometrically building the entire mass
of the formulation via sequential blending for three minutes after
each addition, and finally adding the lubricant to the mixture
after all other ingredients have been blended.
[0066] Tablets compressed on a conventional tablet press from the
final blend obtained from either a one-step granulation or a direct
compression blend, were pharmaceutically elegant and disintegrated
in water within ten seconds. A tablet is considered as
disintegrated when it has totally broken down to granules and there
are no discernible lumps remaining. Since the medicament is not
intimately bound to any of the ingredients of the formulation, it
is released within the same time period. Another advantage of
particular aspects of the subject formulations is that dosage forms
can be manufactured therefrom which are robust and, hence, avoid
the need for specialized unit dose packaging and careful handling
during manufacture or use as is often the case with present dosage
forms. The dosage forms prepared from formulations of particular
aspects of the present invention can be packaged in conventional
blister packs or in HDPE bottles.
[0067] It is understood that various other embodiments and
modifications in the practice of the invention will be apparent to,
and can be readily made by, those of ordinary skill in the art
without departing form the scope and spirit of the invention as
described above. Accordingly, it is not intended that the scope of
the claims appended hereto be limited to the exact description set
forth above, but rather that the claims be construed as
encompassing all of the features of patentable novelty that reside
in the present invention, including all the features and
embodiments that would be treated as equivalents thereof by those
skilled in the art to which the invention pertains. The invention
is further described with reference to the following experimental
work.
[0068] Means of manufacturing aripiprazole drug substance for
formulating according to the present flashmelt invention may be
performed as follows.
[0069] Aripiprazole Hydrate
[0070] The aripiprazole hydrate (grains) of the present invention
have the physicochemical properties given in (1)-(5) below. This
aripiprazole hydrate is described hereinafter as "Aripiprazole
Hydrate A".
[0071] (1) It has an endothermic curve which is substantially the
same as the thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min) endothermic curve shown in FIG. 1.
Specifically, it is characterized by the appearance of a small peak
at about 71.degree. C. and a gradual endothermic peak around
60.degree. C. to 120.degree. C.
[0072] (2) It has an .sup.1H-NMR spectrum which is substantially
the same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 2. Specifically, it has characteristic peaks at 1.55-1.63 ppm
(m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56
ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6
Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),
6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H).
[0073] (3) It has a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 3. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
[0074] (4) It has clear infrared absorption bands at 2951, 2822,
1692, 1577, 1447, 1378, 1187, 963 and 784 cm.sup.-1 on the IR (KBr)
spectrum.
[0075] (5) It has a mean grain size of 50 .mu.m or less.
[0076] Method of Manufacturing Aripiprazole Hydrate A
[0077] Aripiprazole Hydrate A is manufactured by milling
conventional aripiprazole hydrate.
[0078] Conventional milling methods can be used to mill the
aripiprazole hydrate. For example, the aripiprazole hydrate can be
milled in a milling machine. A widely used milling machine can be
used, such as an atomizer, pin mill, jet mill or ball mill. Of
these, the atomizer is preferred.
[0079] Regarding the specific milling conditions when using an
atomizer, a rotational speed of 5000-15000 rpm could be used for
the main axis, for example, with a feed rotation of 10-30 rpm and a
screen hole size of 1-5 mm.
[0080] The mean grain size of the Aripiprazole Hydrate A obtained
by milling should normally be 50 .mu.m or less, preferably 30 .mu.m
or less. Mean grain size can be ascertained by the grain size
measurement method described hereinafter.
[0081] Grain Size Measurement: 0.1 g of the grains to be measured
were suspended in a 20 ml n-hexane solution of 0.5 g soy lecithin,
and grain size was measured using a size distribution meter
(Microtrack HRA, Microtrack Co.).
[0082] Aripiprazole Anhydride Crystals
[0083] The aripiprazole anhydride crystals of the present invention
have the physicochemical properties given in (6)-(10) below. These
aripiprazole anhydride crystals are referred to hereinafter as
"Aripiprazole Anhydride Crystals B".
[0084] (6) They have an .sup.1H-NMR spectrum which is substantially
the same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in
FIG. 4. Specifically, they have characteristic peaks at 1.55-1.63
ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),
2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm
(brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4
Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1
Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm
(s, 1H).
[0085] (7) They have a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 5. Specifically, they have characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
[0086] (8) They have clear infrared absorption bands at 2945, 2812,
1678, 1627, 1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
[0087] (9) They exhibit an endothermic peak near about
141.5.degree. C. in thermogravimetric/differential thermal analysis
(heating rate 5.degree. C./min).
[0088] (10) They exhibit an endothermic peak near about
140.7.degree. C. in differential scanning calorimetry (heating rate
5.degree. C./min).
[0089] Aripiprazole Anhydride Crystals B of the present invention
have low hygroscopicity. For example, Aripiprazole Anhydride
Crystals B of the present invention maintain a water content of
0.4% or less after 24 hours inside a dessicator set at a
temperature of 60.degree. C. and a humidity of 100%.
[0090] Well-known methods of measuring water content can be used as
long as they are methods commonly used for measuring the water
content of crystals. For example, a method such as the Karl Fischer
method can be used.
[0091] Method of Manufacturing Aripiprazole Anhydride Crystals
B
[0092] The Aripiprazole Anhydride Crystals B of the present
invention are prepared for example by heating the aforementioned
Aripiprazole Hydrate A at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally
since it differs depending on heating temperature. The heating time
and heating temperature are inversely related, so that for example
the heating time will be longer the lower the heating temperature,
and shorter the higher the heating temperature. Specifically, if
the heating temperature of Aripiprazole Hydrate A is 100.degree.
C., the heating time should normally be 18 hours or more or
preferably about 24 hours. If the heating temperature of
Aripiprazole Hydrate A is 120.degree. C., on the other hand, the
heating time can be about 3 hours. The Aripiprazole Anhydride
Crystals B of the present invention can be prepared with certainty
by heating Aripiprazole Hydrate A for about 18 hours at 100.degree.
C., and then heating it for about 3 hours at 120.degree. C. The
Aripiprazole Anhydride Crystals B of the present invention can also
be obtained if the heating time is extended still further, but this
is not economical.
[0093] Furthermore, the Aripiprazole Anhydride Crystals B of the
present invention are prepared for example by heating conventional
aripiprazole anhydride crystals at 90-125.degree. C. The heating
time is generally about 3-50 hours, but cannot be stated
unconditionally since it differs depending on heating temperature.
The heating time and heating temperature are inversely related, so
that for example the heating time will be longer the lower the
heating temperature, and shorter the higher the heating
temperature. Specifically, if the heating temperature of the
aripiprazole anhydride crystals is 100.degree. C., the heating time
can be about 4 hours, and if the heating temperature is 120.degree.
C. the heating time can be about 3 hours.
[0094] The aripiprazole anhydride crystals which are the raw
material for preparing the Aripiprazole Anhydride Crystals B of the
present invention are prepared for example by Method a or b
below.
[0095] Method a:
[0096] Aripiprazole anhydride crystals are prepared by well-known
methods, as by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril
with 1-(2,3-dichlorophenyl)piperadine and recrystallizing the
resulting raw aripiprazole crystals with ethanol as described in
Example 1 of Japanese Unexamined Patent Publication No.
191256/1990.
[0097] Method b:
[0098] Aripirazole anhydride crystals are prepared by heating
conventional aripiprazole hydrate at a temperature of at least
60.degree. C. and less than 90.degree. C. The heating time is
generally about 1-30 hours, but cannot be stated unconditionally
since it differs depending on heating temperature. The heating time
and heating temperature are inversely related, so that for example
the heating time will be longer the lower the heating temperature,
and shorter the higher the heating temperature. Specifically, if
the heating temperature of the aripiprazole hydrate is about
60.degree. C., the heating time can be about 8 hours, while if the
heating temperature is 80.degree. C., the heating time can be about
4 hours.
[0099] The Method b is described in the Proceedings of the 4th
Japanese-Korean Symposium on Separation Technology (Oct. 6-8,
1996).
[0100] Furthermore, the Aripiprazole Anhydride Crystals B of the
present invention are prepared for example by heating conventional
aripiprazole hydrate at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally
since it differs depending on heating temperature. The heating time
and heating temperature are inversely related, so that for example
the heating time will be longer the lower the heating temperature,
and shorter the higher the heating temperature. Specifically, if
the heating temperature of the aripiprazole hydrate is 100.degree.
C., the heating time can be about 24 hours, while if the heating
temperature is 120.degree. C., the heating time can be about 3
hours.
[0101] The aripiprazole hydrate which is the raw material for
preparing the Aripiprazole Anhydride Crystals B of the present
invention is prepared for example by Method c below.
[0102] Method c:
[0103] Aripiprazole hydrate is easily obtained by dissolving the
aripiprazole anhydride crystals obtained by Method a above in a
hydrous solvent, and heating and then cooling the resulting
solution. Using this method, aripiprazole hydrate is precipitated
as crystals in the hydrous solvent.
[0104] An organic solvent containing water is usually used as the
hydrous solvent. The organic solvent should be one which is
miscible with water, such as for example an alcohol such as
methanol, ethanol, propanol or isopropanol, a ketone such as
acetone, an ether such as tetrahydrofuran, dimethylformamide, or a
mixture thereof, with ethanol being particularly desirable. The
amount of water in the hydrous solvent can be 10-25% by weight of
the solvent, or preferably close to 20% by weight.
[0105] As mentioned above, the Aripiprazole Anhydride Crystals B of
the present invention are prepared by heating at 90-125.degree. C.
of said Aripiprazole Hydrate A, conventional aripiprazole anhydride
crystals or conventional aripiprazole hydrate, and said
Aripiprazole Hydrate A, conventional aripiprazole anhydride
crystals or conventional aripiprazole hydrate may be used either
individually or in combination.
[0106] The following examples used aripiprazole drug substance made
by first milling the conventional hydrate of aripiprazole and then
heating it to form the anhydrous form (anhydride B).
Example 1
[0107] Flash-melt tablets were prepared as follows:
Intragranulation:
TABLE-US-00002 [0108] Ingredient Percent w/w Mg. per tablet Xylitol
(300) Xylisorb 26 52 Avicel .RTM. PH 102 12 24 Calcium Silicate
43.35 86.7 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild
cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium
stearate 0.25 0.5 Total weight 92.75 185.5
[0109] The ingredients except for the magnesium stearate were
blended in a commercial V-blender in geometric proportions for 5
minutes each until all were added. The magnesium stearate was then
added and the mixture blended for an additional three minutes. The
blended formulation was compacted at a pressure of 30-35
kgF/cm.sup.2 in a commercial compactor equipped with an orifice
such that the compacts therefrom are in the form of ribbons. The
ribbons were passed through a 30 mesh (600 microns) screen to form
stable granules of about 150 to 400 microns.
Extragranulation Ingredients:
TABLE-US-00003 [0110] Ingredient Percent w/w Mg. per tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
[0111] The intragranulation was placed in the blender and the
Avicel.RTM. PH 200 and crospovidone added thereto and blended for
five minutes. The magnesium stearate was then added and the mixture
blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.3 kP (3.5
SCU) and disintegrated in 10 seconds in 5 ml of water. The final
blend formulation demonstrated excellent flow and was free of other
problems such as chipping, capping and sticking. It has been found
that utilizing Avicel.RTM. PH 102 for the intragranulation and
Avicel.RTM. PH 200 for the extragranulation ingredient enhanced the
quality of the resultant tablets.
Example 2
[0112] Flash-melt tablets containing a combination of two grades of
calcium silicate were prepared as follows:
Intragranulation:
TABLE-US-00004 [0113] Ingredient Percent w/w Mg. per tablet Xylitol
(300) Xylisorb 26 52 Avicel .RTM. PH 102 12 24 Calcium Silicate
(crystalline, alpha 33.35 66.7 triclinic) Hubersorb 600 NF
(amorphous 10 20 calcium silicate) Crospovidone 3 6 Amorphous
silica 2 4 Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid
2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.75
185.5
[0114] The ingredients except for the magnesium stearate were
blended in a commercial V-blender in geometric proportions for 5
minutes each until all were added. The magnesium stearate was added
and the mixture blended for an additional three minutes. The
blended formulation was compacted, and screened to form stable
granules in accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00005 [0115] Ingredient Percent w/w Mg. per tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
[0116] The intragranulation was placed in the blender and the
Avicel.RTM. PH 200 and crospovidone added thereto and blended for
five minutes. The magnesium stearate was then added and the mixture
blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.0 kP (3.1
SCU) and disintegrated in 10 seconds in 5 ml of water.
Example 3
[0117] Flash-melt tablets containing aripiprazole, an
antischizophrenic drug, were prepared as follows:
Intragranulation
TABLE-US-00006 [0118] Ingredient Percent w/w Mg. per tablet
Aripiprazole 15 30 Xylitol (300) Xylisorb 25 50 Avicel .RTM. PH 102
6 12 Calcium Silicate 37 74 Crospovidone 3 6 Amorphous silica 2 4
Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4
Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 94.4
188.8
[0119] The ingredients except for the magnesium stearate were
blended in a commercial V-blender in geometric proportions for 5
minutes each until all were added. The magnesium stearate was added
and the mixture blended for an additional three minutes. The
blended formulation was compacted, and screened to form stable
granules in accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00007 [0120] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.4 188.8 Avicel .RTM. PH 200 1.1 2.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
[0121] The intragranulation was placed in the blender and the
Avicel.RTM. PH 200 and crospovidone added thereto and blended for
five minutes. The magnesium stearate was then added and the mixture
blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.0 kP (3.1
SCU) and disintegrated in 10 seconds in 5 ml of water.
Example 4
[0122] Flash-melt tablets containing aripiprazole were prepared as
follows:
Intragranulation:
TABLE-US-00008 [0123] Ingredient Percent w/w Mg. per tablet
Aripiprazole 0.5 1 Xylitol (300) Xylisorb 27 54 Avicel .RTM. PH 102
12 24 Calcium Silicate 42 84 Crospovidone 3 6 Amorphous silica 2 4
Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4
Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.9
185.8
[0124] The ingredients except for the magnesium stearate were
blended in a commercial V-blender in geometric proportions for 5
minutes each until all were added. The magnesium stearate was added
and the mixture blended for an additional three minutes. The
blended formulation was compacted, and screened to form stable
granules in accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00009 [0125] Ingredient Percent w/w Mg. per tablet
Intragranulation 92.9 185.8 Avicel .RTM. PH 200 2.6 5.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
[0126] The intragranulation was placed in the blender and the
Avicel.RTM. PH 200 and crospovidone added thereto and blended for
five minutes. The magnesium stearate was then added and the mixture
blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.3 kP (3.5
SCU) and disintegrated in 10 seconds in 5 ml of water.
Example 5
[0127] Flash-melt tablets can be prepared containing the antiviral
medicament entecavir as follows:
Intragranulation:
TABLE-US-00010 [0128] Ingredient Percent w/w Mg. per tablet
Entecavir 1 2 Xylitol (300) Xylisorb 26 52 Avicel .RTM. PH 102 10
20 Calcium Silicate 45 90 Crospovidone 4 8 Amorphous silica 2. 4
Aspartame 2 4 Wild cherry flavor 0.25 0.5 Tartaric acid 2 4
Acesulfame K 2. 4 Magnesium stearate 0.25 0.5 Total weight 94.5
189
[0129] The ingredients except for the magnesium stearate were
blended in a commercial V-blender in geometric proportions for 5
minutes each until all were added. The magnesium stearate was added
and the mixture blended for an additional three minutes. The
blended formulation was compacted, and screened to form stable
granules in accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00011 [0130] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.5 189 Avicel .RTM. PH 200 2 4 Crospovidone 3 6
Magnesium stearate 0.5 1 Total weight 100 200
[0131] The intragranulation was placed in the blender and the
Avicel.RTM. PH 200 and crospovidone added thereto and blended for
five minutes. The magnesium stearate was then added and the mixture
blended for an additional three minutes to form the final blend.
Tablets compressed therefrom had a breaking force of 2.3 kP (3.5
SCU) and disintegrated in 10 seconds in 5 ml of water. The percent
w/w/ratios taught in this example can also be used to formulate a
suitable formulation of the present invention comprising 0.1 mg of
entecavir per unit dose.
Example 6
[0132] Flash-melt tablets can be prepared containing the antibiotic
medicament cefprozil as follows:
Intragranulation:
TABLE-US-00012 [0133] Ingredient Percent w/w Mg. per tablet Cefzil
25 125 Xylitol (300) Xylisorb 17 85 Avicel .RTM. PH 102 6 30
Calcium Silicate 35 175 Crospovidone 3 15 Amorphous silica 2. 10
Aspartame 2 10 Wild cherry flavor 0.25 1.25 Tartaric acid 2 10
Acesulfame K 2 10 Magnesium stearate 0.25 1.25 Total weight 94.5
472.5
[0134] Blend the ingredients except for the magnesium stearate in a
commercial V-blender in geometric proportions for 5 minutes each
until all are added. Then add the magnesium stearate to the mixture
prepared and mix for an additional three minutes. Then compact the
blended formulation, and screen to form stable granules in
accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00013 [0135] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.5 472.5 Avicel .RTM. PH 200 2 10 Crospovidone 3
15 Magnesium stearate 0.5 2.5 Total weight 100 500
[0136] Place the intragranulation in the blender and add the
Avicel.RTM. PH 200 and crospovidone thereto and blend for five
minutes. Then add magnesium stearate to the mixture and blend for
an additional three minutes to form the final blend. Compress
tablets therefrom to have a breaking force of 2.5 kP (3.8 SCU) and
a disintegration time of 10 seconds or less in 5 ml of water.
Example 7
[0137] Flash-melt tablets can be prepared containing the
antihypertensive medicament irbesartan as follows:
Intragranulation:
TABLE-US-00014 [0138] Ingredient Percent w/w Mg. per tablet
Irbesartan 25 125 Xylitol (300) Xylisorb 17 85 Avicel .RTM. PH 102
6. 30 Calcium Silicate 35 175 Crospovidone 3 15 Amorphous silica 2
10 Aspartame 2 10 Wild cherry flavor 0.25 1.25 Tartaric acid 2 10
Acesulfame K 2 10 Magnesium stearate 0.25 1.25 Total weight 94.5
472.5
[0139] Blend the ingredients except for the magnesium stearate in a
commercial V-blender in geometric proportions for 5 minutes each
until all are added. Then add the magnesium stearate to the mixture
prepared and mix for an additional three minutes. Then compact the
blended formulation, and screen to form stable granules in
accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00015 [0140] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.5 472.5 Avicel .RTM. PH 20 2 10 Crospovidone 3
15 Magnesium stearate 0.5 2.5 Total weight 100 500
[0141] Place the intragranulation in the blender and add the
Avicel.RTM. PH 200 and crospovidone thereto and blend for five
minutes. Then add magnesium stearate to the mixture and blend for
an additional three minutes to form the final blend. Compress
tablets therefrom to have a breaking force of 2.5 kP (3.8 SCU) and
a disintegration time of 10 seconds or less in 5 ml of water.
Example 8
[0142] Flash-melt tablets can be prepared containing the quinolone
antibiotic, des-Quinolone as follows:
Intragranulation:
TABLE-US-00016 [0143] Ingredient Percent w/w Mg. per tablet
des-Quinolone 20.0 100 Xylitol (300) Xylisorb 22.0 110 Avicel .RTM.
PH 102 6.0 30 Calcium Silicate 35.0 175 Crospovidone 3.0 15
Amorphous silica 2.0 10 Aspartame 2.0 10 Wild cherry flavor 0.25
1.25 Tartaric acid Acesulfame K Magnesium starate 0.25 Total
weight
[0144] Blend the ingredients except for the magnesium stearate in a
commercial V-blender in geometric proportions for 5 minutes each
until all are added. Then add the magnesium stearate to the mixture
prepared and mix for an additional three minutes. Then compact the
blended formulation, and screen to form stable granules in
accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00017 [0145] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.5 472.5 Avicel .RTM. PH 200 2.0 10.0
Crospovidone 3.0 15.0 Magnesium stearate 0.5 2.5 Total weight 100
500
[0146] Place the intragranulation in the blender and add the
Avicel.RTM. PH 200 and crospovidone thereto and blend for five
minutes. Then add magnesium stearate to the mixture and blend for
an additional three minutes to form the final blend. Compress
tablets therefrom to have a breaking force of 2.5 kP (3.8 SCU) and
a disintegration time of 10 seconds or less in 5 ml of water.
Example 9
[0147] Flash-melt tablets can be prepared containing the antibiotic
gatifloxacin (Tequin.RTM.), as a taste masked co-precipitate (30%
w/w active) to deliver 50 mg dose:
Intragranulation:
TABLE-US-00018 [0148] Ingredient Percent w/w Mg. per tablet
Gatifloxacin:stearic acid 33.3 166.7 co-precipitate Xylitol (300)
Xylisorb 11.7 58.5 Avicel .RTM. PH 102 6.0 30 Calcium Silicate 32.0
160 Crospovidone 3.0 15 Amorphous silica 2.0 10 Aspartame 2.0 10
Wild cherry flavor 0.25 1.23 Tartaric acid 2.0 10 Acesulfame K 2.0
10 Magnesium stearate 0.25 1.25 Total weight 94.5 472.5
[0149] Blend the ingredients except for the magnesium stearate in a
commercial V-blender in geometric proportions for 5 minutes each
until all are added. Then add the magnesium stearate to the mixture
prepared and mix for an additional three minutes. Then compact the
blended formulation, and screen to form stable granules in
accordance with the procedure of Example 1.
Extragranulation Ingredients:
TABLE-US-00019 [0150] Ingredient Percent w/w Mg. per tablet
Intragranulation 94.5 472.5 Avicel .RTM. PH 200 2.0 10.0
Crospovidone 3.0 15.0 Magnesium stearate 0.5 2.5 Total weight 100
500
[0151] Place the intragranulation in the blender and add the
Avicel.RTM. PH 200 and crospovidone thereto and blend for five
minutes. Then add magnesium stearate to the mixture and blend for
an additional three minutes to form the final blend. Compress
tablets therefrom to have a breaking force of 2.5 kP (3.8 SCU) and
a disintegration time of 10 seconds or less in 5 ml of water.
Example 10
Preparation of 2.5% w/w Aripiprazole Granulation for and 2 mg and 5
mg Tablets--Prototype II
Intragranular Formulation:
TABLE-US-00020 [0152] Ingredient % w/w Aripiprazole 2.50 Xylitol,
NF (Xylisorb 300) 21.15 Microcrystalline Cellulose, NF (Avicel PH
102) 12.0 Calcium Silicate, NF 42.0 Crospovidone, NF (XL-10) 3.0
Silicon Dioxide, NF (previously referred to as 2.0 Amorphous
Silica) Croscarmellose Sodium, NF 3.0 Aspartame, NF 2.0 Flavor
Creme de Vanilla 0.5 Tartaric Acid, NF 2 Acesulfame K (E.P) 2.0
Magnesium stearate NF 0.25 Total 92.40
Intragranular Blend Preparation:
[0153] 1. V-blender is chosen (that operates at 50 rpm speed) for
the mixing operation. In the first mixing step, aripiprazole is
placed in between Xylitol and Avicel PH 102 mixed in the V-blender
for 10 minutes. [0154] 2. In step 2, all other excipients are
weighed out and placed in the V-blender from step 1. Deaggregation
was performed where necessary. Mixing was done for 5 minutes.
[0155] 3. Finally, 0.25% magnesium stearate was added and blended
for 3 minutes. [0156] 4. For roller compaction Alexanderwerk WP
120X40 (roller compactor) or other similar equipment can be used
with the following parameters: [0157] Screw speed: 25 rpm Rolls
speed: 5 rpm; Vacuum pressure: -105 mbar [0158] Granulator: 75 rpm
(fixed with top 4 mm screen and bottom 0.8 mm or 20# screen) [0159]
Hydraulic pressure: 50 bar
[0160] Post Dry Granulation Blend Preparation:
TABLE-US-00021 Ingredient % w/w Granulation from step 4 92.40
Crospovidone, NF (XL-10) 4.00 Microcrystalline Cellulose, NF 3.10
(Avicel .RTM. PH 200) Magnesium stearate, NF 0.5 Total 100.00
[0161] 1. Based on the yield from step 4 calculate the new batch
size and place the intragranulation in the blender with the
calculated amounts of Avicel.RTM. PH 200 and crospovidone and blend
for 5 minutes. [0162] 2. Finally add the remaining amount of
magnesium stearate and mix for 3 minutes. 2 mg tablets may have a
green pigment blend incorporated in the extragranular portion above
in a concentration of 0.3% w/w adjusted by replacing the same
amount of Avicel PH 200, i.e. the amount of Avicel PH 200 will be
2.8% w/w. 5 mg tablets may have a blue aluminum lake incorporated
in the extragranular portion above in a concentration of 0.3% w/w
adjusted by replacing the same amount of Avicel PH 200, i.e. the
amount of Avicel PH 200 will be 2.8% w/w.
Tablet Compression:
[0162] [0163] 1. Using the granulation prepared above, 2 mg potency
aripiprazole tablets can be prepared by compressing 80 mg weight
tablets on any conventional tablet press that can produce tablets
having a breaking force of 3.0 kP or 4.5 SCU. [0164] 2. Using the
granulation prepared above, 5 mg potency aripiprazole tablets can
be prepared by compressing 200 mg weight tablets on any
conventional tablet press that can produce tablets having a
breaking force of 3.0 kP or 4.5 SCU.
Example 11
Preparation of 10% w/w Aripiprazole Granulation for and 10 mg, 15
mg, 20 mg and 30 mg Tablets--Prototype II
Intragranular Formulation:
TABLE-US-00022 [0165] % Ingredient w/w Aripiprazole 10.00 Xylitol,
NF (Xylisorb 300) 21.15 Microcrystalline Cellulose, NF (Avicel PH
102) 10.0 Calcium Silicate, NF 36.5 Crospovidone, NF (XL-10) 3.0
Silicon Dioxide, NF (previously referred to as Amorphous Silica)
3.0 Croscarmellose Sodium, NF 2.0 Aspartame, NF 2.0 Flavor Creme de
Vanilla 0.5 Tartaric Acid, NF 2 Acesulfame K (E.P) 2.0 Magnesium
stearate NF 0.25 Total 92.40
Intragranular Blend Preparation:
[0166] 1. V-blender is chosen (that operates at 50 rpm speed) for
the mixing operation. In the first mixing step, aripiprazole is
placed in between Xylitol and Avicel PH 102 mixed in the V-blender
for 10 minutes. [0167] 2. In step 2, all other excipients are
weighed out and placed in the V-blender from step 1. Deaggregation
was performed where necessary. Mixing was done for 5 minutes.
[0168] 3. Finally, 0.25% magnesium stearate was added and blended
for 3 minutes. [0169] 4. For roller compaction Alexanderwerk WP
120X40 (roller compactor) or other similar equipment can be used
with the following parameters: [0170] Screw speed: 25 rpm Rolls
speed: 5 rpm; Vacuum pressure: -105 mbar [0171] Granulator: 75 rpm
(fixed with top 4 mm screen and bottom 0.8 mm or 20# screen) [0172]
Hydraulic pressure: 50 bar
[0173] Post Dry Granulation Blend Preparation:
TABLE-US-00023 Ingredient % w/w Granulation from step 4 92.40
Crospovidone, NF (XL-10) 4.00 Microcrystalline Cellulose, 3.10 NF
(Avicel .RTM. PH 200) Magnesium stearate, NF 0.5 Total 100.00
[0174] 5. Based on the yield from step 4 calculate the new batch
size and place the intragranulation in the blender with the
calculated amounts of Avicel.RTM. PH 200 and crospovidone and blend
for 5 minutes. [0175] 6. Finally add the remaining amount of
magnesium stearate and mix for 3 minutes. [0176] 10 mg tablets may
have red iron oxide incorporated in the extragranular portion above
in a concentration of 0.04% w/w adjusted by replacing the same
amount of Avicel PH 200, i.e. the amount of Avicel PH 200 will be
3.06% w/w. [0177] 15 mg tablets may have yellow iron oxide
incorporated in the extragranular portion above in a concentration
of 0.3% w/w adjusted by replacing the same amount of Avicel PH 200,
i.e. the amount of Avicel PH 200 will be 2.8% w/w. [0178] 20 mg
tablets may be white in color and directly made from the
formulation shown above. [0179] 30 mg tablets may have red iron
oxide incorporated in the extragranular portion above in a
concentration of 0.04% w/w adjusted by replacing the same amount of
Avicel PH 200, i.e. the amount of Avicel PH 200 will be 3.06%
w/w.
Tablet Compression:
[0179] [0180] 1. Using the granulation prepared above, 10 mg
potency aripiprazole tablets can be prepared by compressing 100 mg
weight tablets on any conventional tablet press that can produce
tablets having a breaking force of 3.0 kP or 4.5 SCU. [0181] 2.
Using the granulation prepared above, 15 mg potency aripiprazole
tablets can be prepared by compressing 150 mg weight tablets on any
conventional tablet press that can produce tablets having a
breaking force of 3.0 kP or 4.5 SCU. [0182] 3. Using the
granulation prepared above, 20 mg potency aripiprazole tablets can
be prepared by compressing 200 mg weight tablets on any
conventional tablet press that can produce tablets having a
breaking force of 3.0 kP or 4.5 SCU. [0183] 4. Using the
granulation prepared above, 30 mg potency aripiprazole tablets can
be prepared by compressing 300 mg weight tablets on any
conventional tablet press that can produce tablets having a
breaking force of 3.0 kP or 4.5 SCU.
Pharmacokinetic Evaluation of 5 mg Flash-Melt Tablets--Prototypes I
and II in Healthy Human Subjects
[0184] Open label, randomized, 2-period, 3 treatment control
balanced crossover study involving 33 healthy volunteers was
conducted. Each subject received one single 5 mg aripiprazole
commercial tablet and a 5 mg dose of aripiprazole as either
flash-melt Prototype I or flash-melt Prototype II (both from a 2.5%
w/w granulation).
TABLE-US-00024 COMPOSITION (mg/tablet) Prototype I Prototype II
INGREDIENT 5 mg.sup.a % 5 mg.sup.b % Aripiprazole 5.0 2.50 5.0 2.50
Calcium Silicate, NF 84.0 42.00 84.0 42.00 Crospovidone NF (XL-10)
14.0 7.00 14.0 7.00 Croscarmellose Sodium, NF -- -- 6.0 3.00
Silicon Dioxide, NF (Syloid) 4.0 2.00 4.0 2.00 Xylitol NF (Xylisorb
.RTM. 300) 48.3 24.15 42.3 21.15 Microcrystalline Cellulose NF 24
12.00 24 12.00 (Avicel .RTM. PH 102) Microcrystalline Cellulose NF
6.2 3.10 6.2 3.10 (Avicel .RTM. PH 200) Aspartame NF 4.0 2.00 4.0
2.00 Acesulfame Potassium 4.0 2.00 4.0 2.00 Creme de Vanilla
(Natural & 1.0 0.50 1.0 0.50 Artifical Flavors) Tartaric Acid
NF 4.0 2.00 4.0 2.00 Magnesium Stearate NF 1.5 0.75 1.5 0.75 Total
200 mg 100.00 200 mg 100.0 .sup.aProduct Identification Number:
337039-A005-050; .sup.bProduct Identification Number:
337039-A005-051
[0185] The disintegration time for both prototypes in the mouth was
less than 30 seconds. However, the two prototypes show different
dissolution rates in in-vitro dissolution tests using USP
dissolution testing methods. Hence, the goal of this study was to
evaluate if these differences would affect in-vivo performance of
the two prototypes.
The pharmacokinetic parameters from the clinical study are shown
below:
TABLE-US-00025 AUC (INF) Dose Cmax Tmax* [ng h/ F** Formulation
(mg) N (ng/mL) (h) mL] (%) Commercial 5 33 21.4 3 1393 -- Tablet
(5.85) (1, 8) (504) Flashmelt 5 16 17.8 4 1260 99.7 Prototype I
(3.85) (2, 12) (474) (21.8) Flashmelt 5 17 21.0 4 1567 105
Prototype II (4.40) (1.5, 8) (677) (18.4)
Based on statistical analysis for C.sub.max and AUC for the two
prototypes (shown below) it was concluded that Prototype II is
bioequivalent to the regular commercial aripiprazole tablets.
TABLE-US-00026 Point Parameter Ratio N Estimate 90% CI C.sub.max
B/A 16 0.8809 (0.7534, 1.0300) C/A 17 0.9741 (0.8767, 1.0823) AUC
(INF) B/A 16 0.9744 (0.9107, 1.0491) C/A 17 1.0141 (0.9688, 1.0616)
AUC (0-T) B/A 16 0.9647 (0.8941, 1.0408) C/A 17 0.9979 (0.9438,
1.0551) A = Aripiprazole 5 mg commercial tablet B = Aripiprazole 5
mg flash-melt prototype I C = Aripiprazole 5 mg flash-melt
prototype II
One Year Chemical Stability of 2 mg and 30 mg Potency Aripiprazole
Flash-Melt Tablets:
[0186] Shown below are the stability results for the 2 mg and 30 mg
potency tablets placed on official IND stability testing. As seen
from the results, only one degradant is seen that shows growth
under accelerated conditions as well as at room temperature. This
degradant has been identified as the N-oxide of aripiprazole
(SFO-14094). The levels seen in the 2 mg tablets are significantly
higher than those in the 30 mg tablets. Also, the N-oxide levels in
the Prototype II formulation are significantly lower than those in
the Prototype I formulation.
TABLE-US-00027 TABLE 1 Aripiprazole Flash-Melt Tablets; IND
Stability Study -- 2-mg Prototype I (%) calculated from the area
under the chromatagram peak normalized for the area under the
entire chromatogram Metabolite of aripiprazole/ oxidation N-oxide
of Unknown product aripiprazole aripiprazole Impurities Potency % %
% % Total Potency Potency (Reported Time Point and Storage RRT RRT
RRT RRT Impurities (Result #1) (Result #2) Result) Condition 0.91
1.00 1.08 in ( ) % mg/tab mg/tab mg/tab Initial 0.06 99.94 -- --
0.06 2.01 1.97 1.99 1 day @ 25 C./75% RH (open) 0.07 99.86 0.07 --
0.14 1.98 NP 1.98 4 days @ 25 C./HIL/UVA (exposed 0.06 99.81 0.13
-- 0.19 1.97 NP 1.97 4 days @ 25 C./HIL/UVA (wrapped -- 99.95 0.05
-- 0.05 2.02 NP 2.02 1 week @ 25 C./75% RH (open) 0.09 99.73 0.18
-- 0.27 1.96 NP 1.96 2 wks @ 25 C./HIL/UVA (exposed) 0.08 99.71
0.15 .06 0.29 2.02 NP 2.02 (0.87) 2 wks @ 25 C./HIL/UVA (wrapped)
0.05 99.90 0.05 -- 0.10 1.98 NP 1.98 2 wks @ 25 C./60% RH (closed)
0.05 99.95 -- -- 0.05 2.03 NP 2.03 2 wks @ 25 C./75% RH (open) 0.11
99.63 0.26 -- 0.37 1.98 NP 1.98 4 wks @ 25 C./60% RH (closed) 0.05
99.95 -- -- 0.05 2.01 NP 2.01 4 wks @ 40 C./75% RH (closed) 0.05
99.82 0.13 -- 0.18 2.01 NP 2.01 4 wks @ 50 C. (closed) 0.06 99.62
0.32 -- 0.38 1.97 NP 1.97 13 wks @ 25 C./60% RH (closed) 0.06 99.85
0.09 -- 0.15 1.97 NP 1.97 13 wks @ 40 C./75% RH (closed) 0.09 99.46
0.45 -- 0.54 1.95 NP 1.95 13 wks @ 50 C. (closed) 0.13 98.70 0.92
0.19 1.30 1.95 NP 1.95 (0.38) 26 wks @ 25 C./60% RH (closed) 0.05
99.81 0.14 -- 0.19 2.05 NP 2.05 26 wks @ 40 C./75% RH (closed) 0.11
99.18 0.71 -- 0.82 2.03 NP 2.03 52 wks @ -15 C. (closed) -- 100.00
-- -- 0.00 2.05 NP 2.05 52 wks @ 25 C./60% RH (closed) -- 99.77
0.23 -- 0.23 1.97 NP 1.97 RRT = relative retention time (relative
to the active compound, aripiprazole) during the chromatography
analysis Comments: "--" indicates that no peak was detected or that
the peak measured less than the reporting limit (<0.05 I.I.)
"NP" indicates, "Not Performed"
TABLE-US-00028 TABLE 2 Aripiprazole Flash-Melt Tablets; IND
Stability Study -- 2-mg Prototype II (%) calculated from the area
under the chromatogram peak normalized for the area under the
entire chromatogram Metabolite of aripiprazole/ oxidation N-oxide
of Unknown product aripiprazole aripiprazole Impurities Potency % %
% % Total Potency Potency (Reported Time Point and Storage RRT RRT
RRT RRT Impurities (Result #1) (Result #2) Result) Condition 0.91
1.00 1.08 in ( ) % mg/tab mg/tab mg/tab Initial 0.05 99.95 -- --
0.05 2.05 2.04 2.05 1 day @ 25 C./75% RH (open) 0.07 99.86 0.07 --
0.14 2.01 NP 2.01 4 days @ 25 C./HIL/UVA (exposed 0.06 99.86 0.08
-- 0.14 2.00 NP 2.00 4 days @ 25 C./HIL/UVA (wrapped 0.06 99.89
0.06 -- 0.11 2.00 NP 2.00 1 week @ 25 C./75% RH (open) 0.08 99.80
0.12 -- 0.20 2.00 NP 2.00 2 wks @ 25 C./HIL/UVA (exposed) 0.09
99.74 0.12 0.06 0.26 2.00 NP 2.00 (0.87) 2 wks @ 25 C./HIL/UVA
(wrapped) 0.05 99.95 -- -- 0.05 2.02 NP 2.02 2 wks @ 25 C./60% RH
(closed) 0.06 99.89 0.05 -- 0.11 2.00 NP 2.00 2 wks @ 25 C./75% RH
(open) 0.10 99.72 0.18 -- 0.28 1.99 NP 1.99 4 wks @ 25 C./60% RH
(closed) 0.05 99.95 -- -- 0.05 2.01 NP 2.01 4 wks @ 40 C./75% RH
(closed) 0.05 99.90 0.05 -- 0.10 2.04 NP 2.04 4 wks @ 50 C.
(closed) 0.07 99.68 0.25 -- 0.32 2.02 NP 2.02 13 wks @ 25 C./60% RH
(closed) 0.06 99.88 0.06 -- 0.12 2.00 NP 2.00 13 wks @ 40 C./75% RH
(closed) 0.08 99.63 0.29 -- 0.37 1.98 NP 1.98 13 wks @ 50 C.
(closed) 0.12 98.89 0.74 0.20 1.11 1.98 NP 1.98 (0.38) 26 wks @ 25
C./60% RH (closed) 0.06 99.86 0.08 -- 0.14 2.06 NP 2.06 26 wks @ 40
C./75% RH (closed) 0.16 99.29 0.55 -- 0.71 2.02 NP 2.02 52 wks @
-15 C. (closed) -- 100.00 -- -- 0.00 2.01 NP 2.01 52 wks @ 25
C./60% RH (closed) -- 99.89 0.11 -- 0.11 2.02 NP 2.02 RRT =
relative retention time (relative to the active compound,
aripiprazole) during the chromatography analysis Comments: "--"
indicates that no peak was detected or that the peak measured less
than the reporting limit (<0.05 I.I.) "NP" indicates, "Not
Performed"
TABLE-US-00029 TABLE 3 Aripiprazole Flash-Melt Tablets; IND
Stability Study -- 30-mg Prototype I (%) calculated from the area
under the chromatogram peak normalized for the area under the
entire chromatogram Metabolite of aripiprazole/ oxidation N-oxide
of Unknown product aripiprazole aripiprazole Impurities Potency % %
% % Total Potency Potency (Reported Time Point and Storage RRT RRT
RRT RRT Impurities (Result #1) (Result #2) Result) Condition 0.91
1.00 1.08 in ( ) % mg/tab mg/tab mg/tab Initial 0.06 99.94 -- --
0.06 29.54 29.90 29.7 1 day @ 25 C./75% RH (open) 0.07 99.88 0.05
-- 0.12 28.98 NP 29.0 4 days @ 25 C./HIL/UVA (exposed 0.05 99.89
0.06 -- 0.11 29.39 NP 29.4 4 days @ 25 C./HIL/UVA (wrapped 0.06
99.89 0.05 -- 0.11 29.41 NP 29.4 1 week @ 25 C./75% RH (open) 0.10
99.82 0.08 -- 0.18 28.24 29.30 29.3* 2 wks @ 25 C./HIL/UVA
(exposed) 0.05 99.85 0.10 -- 0.15 29.52 NP 29.5 2 wks @ 25
C./HIL/UVA (wrapped) 0.05 99.89 0.06 -- 0.11 29.98 NP 30.0 2 wks @
25 C./60% RH (closed) 0.06 99.87 0.07 -- 0.13 29.77 NP 29.8 2 wks @
25 C./75% RH (open) 0.08 99.81 0.11 -- 0.19 29.74 NP 29.7 4 wks @
25 C./60% RH (closed) 0.05 99.95 -- -- 0.05 29.08 NP 29.1 4 wks @
40 C./75% RH (closed) -- 99.95 0.05 -- 0.05 29.37 NP 29.4 4 wks @
50 C. (closed) 0.06 99.87 0.07 -- 0.13 29.70 NP 29.7 13 wks @ 25
C./60% RH (closed) 0.06 99.90 0.05 -- 0.10 29.73 NP 29.7 13 wks @
40 C./75% RH (closed) 0.06 99.85 0.09 -- 0.15 29.89 NP 29.9 13 wks
@ 50 C. (closed) 0.06 99.77 0.17 -- 0.23 29.74 NP 29.7 26 wks @ 25
C./60% RH (closed) 0.05 99.91 0.04 -- 0.09 29.26 NP 29.3 26 wks @
40 C./75% RH (closed) 0.06 99.81 0.13 -- 0.19 29.41 NP 29.4 52 wks
@ -15 C. (closed) 0.05 99.95 -- -- 0.05 29.70 NP 29.7 52 wks @ 25
C./60% RH (closed) 0.06 99.88 0.06 -- 0.12 29.90 NP 29.9 RRT =
relative retention time (relative to the active compound,
aripiprazole) during the chromatography analysis Comments: "--"
indicates that no peak was detected or that the peak measured less
than the reporting limit (<0.05 I.I.) "NP" indicates, "Not
Performed" *Only Result 2 is reported (29.3); Result 1 (28.2) is
believed to be low because of incomplete extraction.
TABLE-US-00030 TABLE 4 Aripiprazole Flash-Melt Tablets; IND
Stability Study - 30-mg Prototype II (%) calculated from the area
under the chromatogram peak normalized for the area under the
entire chromatogram Metabolite of aripiprazole/ oxidation N-oxide
of Unknown product aripiprazole aripiprazole Impurities Potency % %
% % Total Potency Potency (Reported Time Point and Storage RRT RRT
RRT RRT Impurities (Result #1) (Result #2) Result) Condition 0.91
1.00 1.08 in ( ) % mg/tab mg/tab mg/tab Initial 0.05 99.95 -- 0.05
28.86 29.78 29.3 1 day @ 25 C./75% RH (open) 0.07 99.88 0.05 --
0.12 29.01 NP 29.0 4 days @ 25 C./HIL/UVA (exposed) 0.05 99.91 0.05
-- 0.09 29.20 NP 29.2 4 days @ 25 C./HIL/UVA (wrapped) 0.06 99.94
-- -- 0.06 29.54 NP 29.5 1 week @ 25 C./75% RH (open) 0.08 99.86
0.06 -- 0.14 28.94 NP 28.9 2 wks @ 25 C./HIL/UVA (exposed) 0.05
99.87 0.07 -- 0.13 29.23 NP 29.2 2 wks @ 25 C./HIL/UVA (wrapped)
0.05 99.95 -- -- 0.05 29.45 NP 29.5 2 wks @ 25 C./60% RH (closed)
0.05 99.95 -- -- 0.05 29.02 NP 29.0 2 wks @ 25 C./75% RH (open)
0.07 99.86 0.07 -- 0.14 29.79 NP 29.8 4 wks @ 25 C./60% RH (closed)
0.05 99.95 -- -- 0.05 29.53 NP 29.5 4 wks @ 40 C./75% RH (closed)
0.05 99.95 -- -- 0.05 29.14 NP 29.1 4 wks @ 50 C. (closed) 0.05
99.90 0.05 -- 0.10 29.68 NP 29.7 13 wks @ 25 C./60% RH (closed)
0.05 99.95 -- -- 0.05 30.145 NP 30.1 13 wks @ 40 C./75% RH (closed)
0.06 99.88 0.06 -- 0.12 29.80 NP 29.8 13 wks @ 50 C. (closed) 0.07
99.83 0.10 -- 0.17 30.14 NP 30.1 26 wks @ 25 C./60% RH (closed)
0.05 99.95 -- -- 0.05 29.76 NP 29.8 26 wks @ 40 C./75% RH (closed)
0.05 99.87 0.07 -- 0.13 28.98 NP 29.0 52 wks @ -15 C. (closed) 0.05
99.95 -- -- 0.05 29.14 NP 29.1 52 wks @ 25 C./60% RH (closed) 0.07
99.93 -- -- 0.07 30.17 NP 30.2 RRT = relative retention time
(relative to the active compound, aripiprazole) during the
chromatography analysis Comments: "--" indicates that no peak was
detected or that the peak measured less than the reporting limit
(<0.05 I.I.) "NP" indicates, "Not Performed"
* * * * *