DIRECTLY COMPRESSIBLE PHARMACEUTICAL
COMPOSITION FOR THE ORAL ADMINISTRATION OF CCI-779
BACKGROUND OF THE INVENTION
Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid
(CCI-779) is an anticancer agent and is characterized by the following structure.

CCI-779 exhibits cytostatic, as opposed to cytotoxic properties, and may delay the
progression of tumors or tumor recurrence. The mechanism of action of CCI-779 that
results in the Gl to S phase block is novel for an anticancer drug. In vitro, CCI-779 has
been shown to inhibit the growth of a number of histologically diverse tumor cells.
Central nervous system (CNS) cancer, leukemia (T-cell), breast cancer, prostate cancer,
and melanoma lines were among the most sensitive to CCI-779. The compound arrested
cells in the Gl phase of the cell cycle.
CCI-779 has poor water solubility (less than 1 µg/ml) and high permeability (Log
PC > 4.1 in 1 -octanol/water system and Peff = 4-5 X 10 cm/sec obtained from in situ
rat intestinal perfusion study using metoprolol tartrate as a marker) and is classified as
class II compound according to BCS classification system. One obstacle towards the
formulation of CCI-779 is its poor aqueous dissolution and low oral bioavailability.

Additionally. CC1-779 exhibits aqueous instability and has shown its potential to undergo
oxidation.
A CCI-779 formulation was developed that employed a wet granulation
manufacturing process. US Published Patent Application, Publication No. US- 2004-
0077677-A1. This process involved preparation of a hydroalcoholic granulation solution
of CCI-779. Further, although the resulting tablets were stable and bioavailable, the
preparation of the hydroalcoholic solution was very tedious. Further, CCI-779 was
thermodynamically unstable, precipitating within one day after its preparation, requiring
it to be used immediately after its preparation.
In view of this, a simple manufacturing process is required that can produce stable
and bioavailable tablets and can be used for commercial manufacturing.
SUMMARY OF THE INVENTION
The present invention provides a convenient and effective method to deliver
therapeutic levels of CCI-779 to the patient. The invention provides pharmaceutical
compositions containing a stable and bioavailable form of micronized CCI-779, and
optionally, an antioxidant or a chelating agent, or mixtures thereof, in an immediate
release dosage form for oral administration. The composition is in the form of a tablet or
in filled capsules.
Other aspects and advantages of the invention will be readily apparent from the
following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides micronized CCI-779, that can be readable formulated into
an oral dosage unit, and is particularly well suited for a directly compressible unit. The
inventors have found that tablets prepared by direct compression of micronized CCI-779
formulations of the invention exhibited rapid and complete drug release, as compared to
nonmicronized CCI-779, even when the nonmicronized CCI-779 was formulated with
surfactants. See, e.g., Example 4. Thus, the compositions of the invention provide fast
drug release.

Briefly, CCI-779 is micronized under nitrogen and conventional micronizing
techniques, for example with a Trost or jet mill, applied to non-micronized CCI-779. The
preparation of non-micronized CCI-779 is described in U.S. Patent 5,362,718, which is
hereby incorporated by reference. A regioselective preparation of non-micronized CCI-
779 is described in US Patent 6,277,983, which is hereby incorporated by reference.
However, the invention is not limited to the method by which the non-micronized CCI-
779 is produced. Micronized CCI-779 typically has a particle size of about 0.2 to about
30 microns, about 0.5 to 25 microns, or about 0.5 to 20 microns, as described above.
The compositions of the invention contain micronized CCI-779 with a particle
size range in which 10% are less than or equal to about 3 microns (µ), 50% are about 10
µ, and 90% are less than or equal to about 20 µ as determined by Malvern method. In
one embodiment, the micronized CCI-779 has a particle size range of 10% are less than
or equal to about 2 µ, 50% are about 5 µ, and 90% are less than or equal to about 16 µ as
determined by Malvern method.
Suitably, the micronized CCI-779 is present in the composition of the invention in
an amount from 0.1 % w/w to 50% w/w, based on the weight of an uncoated composition
of the invention. This amount may be varied, depending upon the amount of micronized
CCI-779 to be delivered to a patient. For example, an effective amount of micronized
CCI-779 is generally in the range, e.g., about 0.1 to about 50 mg, about 10 mg to about 30
mg, or about 0.5 to about 2 mg micronized CCI-779. The desired therapeutic regimen
can be taken into consideration when formulating a composition of the invention. For
example, micronized CCI-779 can be in the range of 0.1% w/w to 10% w/w for an
uncoated composition of the invention. In another example, micronized CCI-779 can be
in the range of 5% w/w to 25% w/w based upon the weight of an uncoated unit dose. In
yet another example, micronized CCI-779 can be in the range of 6% w/w to 8% w/w,
15% w/w to 40% w/w, or 20% w/w to 30% w/w based on the weight of an uncoated unit
dose.
In addition to containing micronized CCI-779, the composition of the present
invention can contain pharmaceutically acceptable additives and/or excipients.
Typically, these additives are biologically inert and useful for manufacture of a dosing

unit. The compositions of the invention may contain one or more filler/binder,
disintegrant, a dissolution enhancer (including, e.g., a surfactant), glidant, and lubricant.
In certain embodiments, the compositions further contain one or more antioxidants,
chelating agents, or pH modifiers. Optionally, the antioxidant, chelating agent, and/or pH
modifier may be micronized. Micronized additives and excipients are prepared using
conventional techniques, as described.
Examples of pharmaceutically acceptable binders, fillers, and disintegrants
include sucrose, lactose, magnesium stearate, gum acacia, cholesterol, tragacanth, stearic
acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline
cellulose, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, lactose,
dextrose, glyceryl rnonooleate, glyceryl monostearate, glyceryl palmitostearate,
polyoxyethylene allcyl ethers, polyethylene glycols, polyoxyethylene castor oil
derivatives, polyoxyethylene stearates, and polyvinyl alcohol, and the like.
In one embodiment, the disintegrant is croscarmellose sodium. Suitably, a
composition of the invention contains a total of about 3% w/w to 8% w/w disintegrant,
e.g., about 4% to about 6% w/w.
In one embodiment, the binders and fillers are selected from the group consisting
of polyvinylpyn-olidone (povidone), lactose (including anhydrous lactose), and
microcrystalline cellulose, and mixtures thereof. Suitably, a composition of the invention
contains a total of about 75 % w/w to 88% w/w binder/filler, or about 80% w/w to 82%
w/w binder/filler, based on tire weight of an uncoated composition. For example, a
composition of the invention may contain, in addition to the micronized CCI-779 and
other components, about a low amount of povidone, e.g. about 5 to 7% w/w, and more
desirably, about 6% w/w, with the remainder of the filler in the uncoated composition
being supplied by other components. In another example, a composition of the invention
may contain a high amount of povidone, e.g., about 25 to 35% w/w, and more desirably,
about 30 to 32 % w/w povidone, with the remainder of the filler in the uncoated
composition being supplied by other components. In yet another example, a composition

of the invention contains a combination of lactose, preferably anhydrous lactose, and
microcrystalline cellulose, optionally with povidone or another filler/binder. In such a
composition (based on uncoated weight), anhydrous lactose is generally present in an
amount of about 30% vv/w to about 60% w/w, and more desirably, about 30 % w/w,
about 32% w/w, about 50% w/w, or about 55% w/w anhydrous lactose. Suitably, in such
an uncoated composition, microcrystalline cellulose is present in an amount of about 15%
w/w to about 30% w/w of the uncoated composition, and more desirably, about 16%
w/w, about 23% w/w, about 25% w/w, about 28% w/w of the uncoated composition.
Dissolution enhancers may be included in the micronized CCI-779 composition
(based on uncoated weight) of the invention. Preferably, one or more dissolution
enhancers may optionally be present in the composition in an amount of from about 0.5
% w/w to about 10 % w/w, and preferably, from about 5% w/w to about 8% w/w, about
5.5%, about 6% w/w, or 6.5% w/w, based on the weight of an uncoated composition.
Examples of dissolution enhancers include surfactants, chelating agents (e.g.. EDTA),
disintegrants, or combinations thereof.
In one embodiment, the surfactant is about 0.25 % w/w to about 10 % w/w of an
uncoated composition, and preferably, about 5% w/w to about 6.5% w/w. In one
embodiment, the surfactant is selected from sodium lauryl sulfate (also blown as sodium
dodecy] sulfate). Other suitable surfactants are well known to those of skill in the art and
can be selected including, without limitation, polysorbates including, e.g., polysorbate 80,
Polaxamer 188™ surfactant, sodium lauryl sulfate (sodium dodecy] sulfate), salts of bile
acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) which may be combined
with lecithin. Alternatively, ethoxylated vegetable oils, such as Cremophor EL, vitamin
E tocopherol propylene glycol succinate (Vitamin E TGPS), polyoxyethylene-
polyoxypropylene block copolymers, and poloxamers.
Acceptable antioxidants include, but are not limited to, citric acid, d,I-α-
tocopherol. butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT),
monothioglycerol, ascorbic acid, propyl gallate, and mixtures thereof. It is expected that
the total amount of antioxidants in the formulations of this invention will be in
concentrations ranging from 0.001 % to 3% w/w, and preferably, about 0.01 w/w to about

1% w/w, and more preferably, about 0.02 % w/w to 0.1% w/w, based on the weight of an
uncoated composition. In one embodiment, the antioxidant is a combination of BHA and
BHT, which may be in nonmicronized form or preferably, in micronized form.
Chelating agents and other materials capable of binding metal ions, such as
ethylene diamine tetra acetic acid (EDTA) and its salts and hydrates (e.g., EDTA calcium
disodium hydrous) are useful in the compositions of the invention. Typically, where
present, a chelating agent is present in an amount less than 1 % w/w, e.g., about 0.001 %
w/w to about 0.01 % w/w, based on the weight of an uncoated composition. In one
embodiment, the chelating agent is present in micronized form.
Acceptable pH modifying agents include, but are not limited to citric acid and
salts thereof (e.g., sodium citrate), dilute HC1, and other mild acids or bases capable of
buffering a solution containing CCI-779 to a pH of 4 to 6. Where present in a
composition of the invention, such pH modifiers are present in an amount up to about 1%
w/w, e.g.. about 0.001% w/wto about 0.1% w/w, based on the weight of an uncoated
composition. Optionally, the pH modifier, can be present in micronized form.
Other suitable components include lubricants and/or glidants. In one embodiment,
the lubricant and the glidants can each be present in the composition of the invention in
an amount of 0.01 wt% to about 1 wt%, about 0.1 wt% to about 2 wt%, or about 0.2 to
about 0.5%. of an uncoated composition. In some embodiments, the lubricant and
glidants are present in the composition in amounts of less than 1 wt% of an uncoated
composition. An example of a suitable lubricant is magnesium stearate and an example
of a suitable glidants is silicone dioxide.
Other suitable inert components of the formulation will be readily apparent to one
of skill in the art.
The compositions of the invention are formed into a suitable dosing unit for
delivery to a patient. Suitable dosing units include oral dosing units, such as a directly
compressible tablet, a capsule, a powder and a suspension. The compositions of the
invention can also be formulated for delivery by other suitable routes. These dosing units
are readily prepared using the methods described herein and those known to those of skill
in the art.

In one embodiment, a composition of the invention is prepared by dry mixing
micronized CCI-779 with the other additives in a suitable mixer. The powder mix is then
directly compressed into unit dose tablets.
Without limitation as to the method of preparation of a composition of the
invention, an example of a suitable micronized CCI-779 formulation includes a low
amount of povidone. The following weight percentages are based upon an uncoated
composition of the invention.

Still a further example of a suitable micronized CCI-779 composition contains a
high amount of povidone, with weight percentages based upon an uncoated composition
of the invention:


Yet a further example of a suitable micronized CCI-779 dosing unit, with weight
percentages based on total uncoated composition, is:

Yet another example of a suitable dosing unit, with weight percentages based on
total uncoated composition, is:


Optionally, the tablets are film-coated. Suitable film-coatings are known to those
of skill in the art. For example, the film-coating can be selected from among suitable
polymers such as hydroxypropylmethylcellulose, ethyl cellulose, polyvinyl alcohol, and
combinations thereof. Such coatings may also contain placticizers and other desirable
components. In one embodiment, the coatings are inert. Other suitable film-coatings can
be readily selected by one of skill in the art. Where applied, the weight percent of the
film coat is generally in the range of 1 % w/w to 6 % w/w, about 2 % w/w, about 3%
vv/w, about 4% w/w or about 5% w/w, and more desirably, about 2% w/w, based on the
total weight of the coated composition.
The invention further provides a method of delivering CCI-779 to a patient, said
method comprising the step of administering a micronized CCI-779 dosing unit
according to the invention.
It is contemplated that when the formulations of this invention are used as an
immunosuppressive or anti-inflammatory agent, they can be administered in conjunction
with one or more other immunoregulatory agents. Such other antirejection
chemotherapeutic agents include, but are not limited to azathioprine, corticosteroids, such
as prednisone and methylprednisolone, cyclophosphamide, cyclosporin A, FK-506. OKT-
3, and ATG. By combining one or more of the formulations of the present invention with
such other drugs or agents for inducing immunosuppression or treating inflammatory
conditions, lesser amounts of each of the agents may be required to achieve the desired
effect. See, e.g., Transplantation Proc. 23: 507 (1991).
The dosage requirements may vary the severity of the symptoms presented and
the particular subject being treated. Daily oral dosages of micronized CCI-779 can be
0.05 to 30 mg, about 1 mg to 25 mg, about 5 mg to about 10 mg. In one example, when
micronized CCI-779 is used in combination therapy at daily doses in the range of 0.5 to
10 mg. In another example, micronized CCI-779 is used in monotherapy at daily doses
in the range of 1 mg to 30 mg. In other embodiments, daily doses are 2 to 5 mg when
micronized CCI-779 is used in combination therapy, and 5 to 15 mg when micronized
CCI-779 is used as monotherapy.

Treatment can be initiated with small dosages less than the optimum dose of the
compound. Thereafter the dosage is increased until the optimum effect under the
circumstances is reached. Precise dosages will be determined by the administering
physician based on experience with the individual subject treated. In general, the
formulations of this invention are most desirably administered at a concentration that will
generally afford effective results without causing any unacceptable harmful or deleterious
side effects.
The following examples of illustrative of specific embodiments of the invention
and are not a limitation on the present invention. The following provide representative
examples of the formulations of this invention. These examples are illustrative only, and
do not limit the invention.
EXAMPLE 1: Directly Compressible Tablet Formulations Prepared By Employing Non-
Micronized CCI-779
The compositions included in this example employed non-micronized CCI-779
and were prepared with or without a surfactant. The tabletting was carried out by dry
blending and direct compression method.



CCI-779 tablets prepared by direct compression of nonmicronized CC1-779 with
standard excipients and fillers, in the presence or absence of surfactants yielded tablets
that did not exhibit rapid and complete drug release, and thereby resulted in an unsuitable
formulation for CCI-779.

EXAMPLE 2: Directly Compressible Tablet Formulations Prepared By Employing
Micronized CCI-779, Sodium Lauryl Sulphate And Povidone
The tablet formulations for this example are manufactured using the following
protocol.
Microcrystalline cellulose (Avicel PH-112) and povidone K-25 are passed
through a screen and transferred to a V-blender of suitable size. Micronized CCI-779 is
preblended with a portion of lactose anhydrous separately, then passed through a screen
and added to the V-blender. Sodium lauryl sulfate, croscarmellose sodium, silicone
dioxide and a portion of lactose anhydrous are passed through a screen and transferred to
the V blender. The remaining lactose anhydrous is passed through a screen and
transferred it to V-blender and the lids are closed. The material is blended without
activation of intensifier bar. Magnesium stearate is passed through a screen, premixed
with a weight equivalent portion of powder, blended from V-blender, transferred to the
lubricant premix to V-blender and blended without activation of intensifier bar. The final
blend is compressed using a tablet press with suitable tooling.



EXAMPLE 3: Directly Compressible Tablet Formulations Prepared By Employing
Micronized CCI-779 And Poloxamer As Surfactant
The table formulations for this example are manufactured according to the
following protocol.
Pass the poloxamer 188, microcrystalline cellulose (Avicel PH-112) and a portion
of anhydrous lactose through a screen and blend. Mill the blend containing poloxamer
with the help of a Fitz mill and transfer it to a V-blender of suitable size.
Preblend a portion of anhydrous lactose with micronized butylated
hydroxyanisole, butylated hydroxytoluene, EDTA calcium disodium, hydrous, and citric
acid anhydrous. Then add CCI-779 to this preblend, mix and add to the V-blender.

Take a portion of anhydrous lactose, croscarmellose sodium, and colloidal silicon
dioxide (Aerosil 200) and pass through a screen, blend and transfer it to V-blender. Pass
the remaining anhydrous lactose through a screen and transfer it to V-blender. Close the
lids and blend the material without activation of the intensifier bar. Pass magnesium
stearate through a screen, premix with a weight equivalent portion of powder blend and
transfer the lubricant premix to V-blender and blend without the activation of the
intensifier bar. Compress the final blend using a tablet press equipped with suitable
tooling.


EXAMPLE 4 - Dissolution of CCI-779 Tablets
All the CCI-779 tablet formulations were evaluated by dissolution test.
Dissolution test was performed using USP method II in 500 ml of 0.4% sodium lauryl
sulfate at 75 RPM paddle speed. Table 6 summarizes the dissolution characteristics of the
neat CCI-779 API and various tablet formulations of CCI-779.

Dissolution results in Table 6 show that the tablets prepared by direct
compression method (Table 1) did not exhibit rapid and complete drug release. Even the
addition of a surfactant (Table 2) did not enhance dissolution of CCI-779 from these
tablets. However, the directly compressible compositions of the invention containing
micronized CCI-779 (Tables 3, 4, 5) exhibited fast and complete drug release.
EXAMPLE 5: Bioavailability of CCI-779 in Human - Evaluation of Oral Dosage Forms
The three prototype tablet formulations containing micronized CCI-779
(Tables 3, 4 and 5) were further evaluated for absorption in human volunteers. A

previously used clinical formulation prepared by wet granulation process was used as a
control. The results of this biostudy are shown in Table 7 below.
The following chart relates the treatments of the bio-study to the compositions in
this document and respective batch numbers of clinical batches:


EXAMPLE 6: CCI-779 10 mg Film Coated Tablet Formulation Prepared By Employing
Micronized CCI-779


EXAN4PLE 7: CCI-779 30 mg Film Coated Tablet Formulation Prepared By Employing
Micronized CCI-779

The documents cited throughout this specification are hereby incorporated by
reference. Minor variations and modifications to the methods and materials set forth in
the foregoing detailed description and illustrative examples will be readily apparent to
those of skill in the art and are encompassed within the scope of the invention.

CLAIMS:
1. A pharmaceutical composition comprising rnicronized CCI-779.
2. A pharmaceutical composition according to claim 1. wherein the
rnicronized CCI-779 has a particle size range of 10% are less than or equal to about 3 a,
50% are about 10 µ, and 90% are less than or equal to about 20 µ as determined by
Malvern, method.
3. A pharmaceutical composition according to claim 1, wherein the
rnicronized CCI has a particle size range of 10% are less than or equal to about 2 µ, 50%
are about 5 µ, and 90% are less than or equal to about 16 µ as determined by Malvern
method.

4. A pharmaceutical composition according to any one of claims 1 to 3 which
is an immediate release solid dosage form.
5. A composition according to any one of claims 1 to 3 selected from the
group consisting of a directly compressible tablet, a capsule, a powder and a suspension.
6. A pharmaceutical composition according to any one of claims 1 to 5,
wherein the rnicronized CCI-779 is present in an amount from 5 % w/w to 10% w/w of
the composition.
7. A pharmaceutical composition according to any one of claims 1 to 6,
further comprising:
about 5% w/w to about 6.5% w/w surfactant;
about 75 % w/w to about 85% w/w filler/binder;
about 4% w/w to about 6% w/w disintegrant.
8. A pharmaceutical composition according to claim 7, wherein the surfactant
is sodium lauryl sulfate.

9. A pharmaceutical composition according to claim 7 or claim 8, wherein
the filler/binder is selected from the group consisting of povidone, lactose, and
microcrystalline cellulose, and mixtures thereof.
10. A pharmaceutical composition according to any one of claims 7 to 9,
wherein the disintegrant is croscarmellose sodium.

11. A pharmaceutical composition according to any one of claims 1 to 11,
further comprising one or more antioxidants, a chelating agent, and/or a pH modifier.
12. A pharmaceutical composition according to claim 11, wherein any one of
the one or more antioxidants, a chelating agent and/or pH modifier is micronized.
13. An oral CCI-779 dosing unit comprising micronized CCI-779, a surfactant,
a filler/binder, a distintegrant, a glidant, and a lubricant.
14. An oral CCI-779 dosing unit according to claim 13, wherein the
micronized CCI-779 has a particle size range of 10% are less than or equal to about 2 µ,
50% are about 5 µ, and 90% are less than or equal to about16 µ as determined by Malvern
method.

15. An oral CCI-779 dosing unit according to claim 13 or claim 14, wherein
the micronized CCI-779 is present in an amount from 0.1 % w/w to 10% w/w of the
dosing unit, based on total uncoated weight.
16. An oral CCI-779 dosing unit according to any one of claims 13 to 15,
wherein the surfactant is selected from the group consisting of sodium lauryl sulfate and
Polaxamer 188 surfactant.

17. An oral CCI-779 dosing unit according to any one of claims 13 to 16,
wherein the filler is selected from the group consisting of microcrystalline cellulose,
anhydrous lactose, povidone, and mixtures thereof.
18. An oral CCI-779 dosing unit according to any one of claims 13 to 17,
wherein the disintegrant is croscarmellose sodium.
19. An oral CCI-779 dosing unit according to any one of claims 13 to 18,
wherein the lubricant is magnesium stearate.

25. An oral CCI-779 dosing unit according to any of claims 13 to 24, wherein
said dosing unit further comprises a seal coat.
26. An oral CCI-779 dosing unit according to claim 25, wherein said seal
comprises about 2% w/w hydroxypropylmethylcellulose of the coated composition.
27. An oral CCI-779 dosing unit according to any of claims 13 to 26, wherein
said dosing unit is selected from the group consisting of a tablet and a capsule.

28. A method of delivering CCI-779 to a patient, said method comprising the
step of administering an oral CCI-779 dosing unit according to any of claims 13 to 27.
29. Use of micronized CCI-779 in preparing a medicament.
30. Use according to claim 29, wherein said micronized CCI-779 is directly
compressed to form the medicament.
31. Use of micronized CCI-779 in preparing an oral dosing unit according to
any of claims 13 to 27.

Micronized CCI-779 is described. This directly compressible rapamycin 42ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid provides a convenient and effective method to deliver therapeutic levels of CCI-779 to a patient.