U.S. patent application number 16/312258 was filed with the patent office on 2019-08-01 for modified release formulations of 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]- piperidine-1-carbony.
This patent application is currently assigned to Principia Biopharma Inc.. The applicant listed for this patent is Principia Biopharma Inc.. Invention is credited to Abu J. FERDOUS, Wu LIN, Mohammad R. MASJEDIZADEH.
Application Number | 20190231784 16/312258 |
Document ID | / |
Family ID | 59315766 |
Filed Date | 2019-08-01 |
United States Patent
Application |
20190231784 |
Kind Code |
A1 |
FERDOUS; Abu J. ; et
al. |
August 1, 2019 |
MODIFIED RELEASE FORMULATIONS OF
2-[3-[4-AMINO-3-(2-FLUORO-4-PHENOXY-PHENYL)PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]-
PIPERIDINE-1-CARBONYL]-4-METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-1-YL]PENT-2-EN-
ENITRILE
Abstract
Modified release formulations, such as solid oral dosage forms
comprising a core composition comprising Compound (I) and/or a
pharmaceutically acceptable salt thereof; a sub-coating layer
coating the core composition, said sub-coating layer comprising a
polyvinyl alcohol and/or a hydroxypropyl methyl cellulose; and an
enteric coating layer encapsulating the sub-coating layer and the
core composition, said enteric coating layer comprising at least
one polymer selected from an acrylic/methacrylic/ethacrylic acid
homopolymer and copolymers thereof, a cellulose derivative, and a
polyvinylpyrrolidone, and methods of administration of a Bruton's
tyrosine kinase (BTK) inhibitor using said formulations.
Inventors: |
FERDOUS; Abu J.; (Belmont,
CA) ; MASJEDIZADEH; Mohammad R.; (San Jose, CA)
; LIN; Wu; (San Jose, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Principia Biopharma Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Principia Biopharma Inc.
South San Francisco
CA
|
Family ID: |
59315766 |
Appl. No.: |
16/312258 |
Filed: |
June 29, 2017 |
PCT Filed: |
June 29, 2017 |
PCT NO: |
PCT/US2017/040075 |
371 Date: |
December 20, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62356345 |
Jun 29, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 11/06 20180101; A61P 27/02 20180101; A61P 27/16 20180101; A61P
25/00 20180101; A61P 37/06 20180101; A61K 9/2846 20130101; A61K
9/2886 20130101; A61P 21/04 20180101; A61P 29/00 20180101; A61P
43/00 20180101; A61K 31/519 20130101; A61K 9/2866 20130101; A61P
9/00 20180101; A61K 9/5073 20130101; A61P 17/06 20180101; A61P
37/02 20180101; A61P 25/04 20180101; A61P 37/08 20180101; A61K
9/5026 20130101; A61K 9/2018 20130101; A61K 9/5047 20130101; A61P
35/02 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 9/28 20060101 A61K009/28; A61K 9/20 20060101
A61K009/20 |
Claims
1. A modified release solid oral dosage form comprising: (a) a core
composition comprising Compound (I) and/or a pharmaceutically
acceptable salt thereof; (b) a sub-coating layer coating the core
composition, said sub-coating layer comprising a polyvinyl alcohol
and/or a hydroxypropyl methyl cellulose; and (c) an enteric coating
layer encapsulating the sub-coating layer and the core composition,
said enteric coating layer comprising at least one polymer selected
from an acrylic/methacrylic/ethacrylic acid homopolymer and
copolymers thereof, a cellulose derivative, and a
polyvinylpyrrolidone.
2. The modified release solid oral dosage form of claim 1, wherein
the cellulose derivative is selected from cellulose acetate
phthalate, cellulose acetate tritnellitate, methylcellulose,
hydroxypropylmethyl cellulose phthalate (HPMCP),
hydroxypropylmethyl cellulose succinate (HPMCS), and
hydroxypropylmethylcellulose acetate succinate. (HPMCAS).
3. The modified release solid oral dosage form of claim 1 or 2,
wherein the sub-coating layer (b) comprises a polyvinyl alcohol,
and the enteric coating layer (c) comprises a poly (methacrylic
acid-co-ethyl acrylate) copolymer.
4. The modified release solid oral dosage form of claim 3, wherein
the polyvinyl alcohol is a pigmented polyvinyl alcohol.
5. The modified release solid oral dosage form of any of claims
1-4, wherein the solid oral dosage form releases less than about
10% by weight of Compound (I) and/or a pharmaceutically acceptable
salt thereof, in less than two hours at a pH less than or equal to
about 2.0; at least about 80% by weight of Compound (I) and/or the
pharmaceutically acceptable salt thereof in about 15 minutes to
about two hours at a pH equal to or more than about 6.0; and any
unreleased amount of Compound (I) is released by the end of about
7.5 hours at a pH equal to or more than about 6.0.
6. The modified release solid oral dosage form of any of claims
1-5, wherein the core composition comprises Compound (I).
7. The modified release solid oral dosage form of any of claims
1-6, wherein Compound (I) and/or a pharmaceutically acceptable salt
thereof is an (E) and (Z) mixture of a mixture of (R) and (S)
isomers of
2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl-
]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-e-
nenitrile.
8. The modified release solid oral dosage form of any of claims
1-7, wherein Compound (I) and/or a pharmaceutically acceptable salt
thereof is an (E) and (Z) mixture of
(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin--
1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-
-2-enenitrile.
9. The modified release solid oral dosage form of any of claims
1-8, wherein at least about 85% by weight of Compound (I) and/or
said pharmaceutically acceptable salt thereof is the (E)
isomer.
10. The modified release solid oral dosage form of any of claims
1-9, wherein at least about 90% by weight of Compound (I) and/or
said pharmaceutically acceptable salt thereof is the (E)
isomer.
11. The modified release solid oral dosage form of any of claims
1-10, wherein Compound (I) and/or a pharmaceutically acceptable
salt thereof is a substantially pure amorphous form.
12. The modified release solid oral dosage form of any of claims
1-11, wherein the core composition comprises about 30 mg to about
100 mg of Compound (I) and/or a pharmaceutically acceptable salt
thereof.
13. The modified release solid oral dosage form of any of claims
1-12, wherein the core composition further comprises at least one
excipient selected from fillers, drug release modifiers,
disintegrants, and lubricants.
14. The modified release solid oral dosage form of claim 13,
wherein the filler comprises at least one of a cellulose derivative
and a sugar molecule.
15. The modified release solid oral dosage form of claim 14,
wherein the cellulose derivative is microcrystalline cellulose.
16. The modified release solid oral dosage form of claim 15,
wherein the microcrystalline cellulose is Avicel.RTM. PH-101.
17. The modified release solid oral dosage form of any of claims
14-16, wherein the sugar molecule is spray-dried mannitol.
18. The modified release solid oral dosage form of claim 17,
wherein the spray dried mannitol is Pearlitol.RTM. 100SD.
19. The modified release solid oral dosage form of any of claims
13-18, wherein the drug release modifier is hydroxypropyl methyl
cellulose.
20. The modified release solid oral dosage form of claim 19,
wherein the hydroxypropyl methyl cellulose is METHOCEL.TM. K 100
Premium CR.
21. The modified release solid oral dosage form of any of claims
13-20, wherein the disintegrant is crosslinked homopolymer of
N-vinyl-2-pyrrolidone (crospovidone).
22. The modified release solid oral dosage form of claim 21,
wherein the crospovidone is Kollidon.TM. CL.
23. The modified release solid oral dosage form of any of claims
13-22, wherein the lubricant is sodium stearyl fumarate.
24. The modified release solid oral dosage form of any of claims
13-23, comprising by weight of the core composition: about 6% to
about 20% of Compound (I) and/or a pharmaceutically acceptable salt
thereof; about 34% to about 72% of microcrystalline cellulose;
about 5% to about 25% mannitol; about 0% to about 20% of
hydroxypropyl methyl cellulose; about 0.5% to about 1.5% of
crosslinked homopolymer of N-vinyl-2-pyrrolidone; and about 0.5% to
about 1.5% of sodium stearyl fumarate.
25. The modified release solid oral dosage form of any of claims
1-24, wherein the core composition weighs about 83% to about 91% of
the total weight of the solid oral dosage form.
26. The modified release solid oral dosage form of any of claims
1-25, wherein the pigmented polyvinyl alcohol is OPADRY.RTM.
II.
27. The modified release solid oral dosage form of any of claims
1-26, wherein the sub-coating layer weighs about 2% to about 4% by
weight of the solid oral dosage form.
28. The modified release solid oral dosage form of any of claims
1-27, wherein the poly(methacrylic acid-co-ethyl acrylate)
copolymer of the enteric coating layer is EUDRAGIT.RTM. L 30 D-55
or EUDRAGIT.RTM. L 100-55.
29. The modified release solid oral dosage form of any of claims
1-28, wherein the enteric coating layer further comprises a
solubilizer and a plasticizer/anti-tacking agent.
30. The modified release solid oral dosage form of claim 29,
wherein the solubilizer is a polyethoxylated sorbitan ester of
oleic acid.
31. The modified release solid oral dosage form of claim 29 or 30,
wherein the solubilizer is Polysorbate 80 (Tween.TM. 80).
32. The modified release solid oral dosage form of claim 29,
wherein the plasticizer/anti-tacking agent is PlasACRYL.TM.
T20.
33. The modified release solid oral dosage form of any of claims
1-32, wherein the enteric coating layer weighs about 6% to about
20% of the total weight of the solid oral dosage form.
34. The modified release solid oral dosage form of any of claims
1-33, wherein the enteric coating layer comprises by total weight
of the solid oral dosage form: about 5% to about 16% of
EUDRAGIT.RTM. L 30 D-55 or EUDRAGIT.RTM. L 100-55; about 1% to
about 3% of PlasACRYL.TM. T20; and about 0.3% to about 0.8% of
Polysorbate 80.
35. The modified release solid oral dosage form of any of claims
1-34, wherein the core composition weighs about 80% to about 91% of
the total weight of the solid oral dosage form.
36. A method of inhibiting Bruton's tyrosine kinase (BTK) in a
mammal in need thereof comprising administering to the mammal in
need of such BTK inhibition a therapeutically effective amount of
Compound (I) and/or a pharmaceutically acceptable salt thereof in a
modified release solid oral dosage form of any of claims 1-35.
37. A method of treating a disease mediated by Bruton's tyrosine
kinase (BTK) in a mammal in need thereof comprising administering
to the mammal in need of such disease treatment a therapeutically
effective amount of Compound (I) and/or a pharmaceutically
acceptable salt thereof in a modified release solid oral dosage
form of any of claims 1-35.
38. The method of claim 37, wherein the disease is an autoimmune
disease, an inflammatory disease, or cancer.
39. The method of claim 37 or 38, wherein the disease is acute
necrotizing hemorrhagic leukoencephalitis, acute disseminated
encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune
retinopathy, axonal & neuronal neuropathies, chronic
inflammatory demyelinating polyneuropathy (CIDP), demyelinating
neuropathies, Devic's disease (neuromyelitis optica), experimental
allergic encephalomyelitis, giant cell arteritis (temporal
arteritis), Guillain-Barre syndrome, Lambert-Eaton syndrome,
chronic Meniere's disease, myasthenia gravis, neuromyotonia,
opsoclonus-myoclonus syndrome, optic neuritis, paraneoplastic
cerebellar degeneration, peripheral neuropathy, perivenous
encephalomyelitis, restless legs syndrome, stiff person syndrome,
sympathetic ophthalmia, Takayasu's arteritis, temporal
arteritis/Giant cell arteritis, transverse myelitis, multiple
sclerosis, dysautonomia, age-related macular degeneration (wet and
dry), corneal transplantation, encephalitis, meningitis,
vasculitis, or systemic lupus erythematosus (SLE).
40. The method of claim 37 or 38, wherein the disease is rheumatoid
arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis,
warm autoimmune hemolytic anemia, Wegener's granulomatosis,
Sjogren's disease, Sjogren's dry eye, non-Sjogren's dry eye
disease, psoriasis, pemphigus, urticaria, or asthma.
41. The method of claim 37 or 38, wherein the disease is diffuse
large B cell lymphoma, follicular lymphoma, chronic lymphocytic
lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic
leukemia, small lymphocytic lymphoma (SLL), multiple myeloma,
B-cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, Burkitt
lymphoma/leukemia, or lymphomatoid granulomatosis.
42. The method of any of claims 37-41, wherein the Compound (I)
and/or the pharmaceutically acceptable salt thereof is administered
in combination with one or more anti-cancer or anti-inflammatory
agents.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application. No. 62/356,345, filed Jun. 29, 2016, which
is incorporated herein by reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to modified release
formulations of and methods of administration of a Bruton's
tyrosine kinase (BTK) inhibitor.
[0003] The Bruton's tyrosine kinase (BTK) inhibitor is Compound (I)
as disclosed herein and/or a pharmaceutically acceptable salt
thereof. Compound (I) and/or a pharmaceutically acceptable salt
thereof is a potent BTK inhibitor and hence can be useful for the
treatment of diseases such as cancer, autoimmune diseases, and
inflammatory diseases.
BACKGROUND OF THE DISCLOSURE
[0004] Therapeutic agents can be administered to patients via
several different routes such as oral, topical, intravenous,
subcutaneous, inhalation, etc. Oral dosing of therapeutics is by
far the most preferred route of administration and offers multiple
advantages over other routes of administration. Orally delivered
drugs are easily self-administered, thereby resulting in increased
patient compliance and obviating the requirement for specialized
delivery devices for injectable or inhaled therapies or delivery in
a therapeutic setting. Oral administration is typically the safest
route of getting a drug into the body since it does not require
complicated devices or puncturing of body surfaces or membranes.
Additionally, dosage is readily controlled, which can be
challenging for other modes of administration such as inhaled
therapies.
[0005] Despite numerous advantages, obtaining consistent and
adequate circulating levels of drug with oral dosing can be
challenging due to, among other things: poor aqueous solubility;
slow dissolution rate in biological fluids; poor stability of drug
at physiological pH; poor permeation through biomembranes;
extensive presystemic metabolism; and inadequate or inconsistent
systemic absorption between individuals or within specific regions
of the gastro-intestinal system. Additionally, drug absorption can
vary from therapy to therapy and depends upon numerous factors such
as whether the patient is in a fed or fasted state at the time of
administration, or whether the drug is taken concurrently with
other medications. From a safety standpoint, minimizing the total
dosage requirement for efficacy as well as reducing variability in
absorption should allow for fewer unwanted side effects. Therefore,
specific methods for delivery of an oral medication which allow
efficient and consistent exposure of the medication are highly
desirable.
[0006] Targeted therapy has received increased attention,
particularly in the oncology area, due to the clinical success of
kinase inhibitors as anti-cancer agents. The ongoing challenges to
the development of targeted therapies include achieving high
selectivity for the primary target and prolonged inhibition to
maximize their therapeutic efficacy. Covalent drugs have become a
highly attractive approach to designing next generation targeted
therapies due to their enhanced ability to achieve high selectivity
as well as prolonged inhibition even with significantly reduced
systemic exposure of the drugs. Covalent drugs achieve their high
selectivity and exceptional potency due to the covalent interaction
with a specific cysteine residue in the active site of proteins to
which the drug molecule binds. This covalent binding additionally
provides prolonged efficacy with increased duration of action that
outlasts the systemic exposure of the drug. Drugs containing an
acrylamide moiety as Michael acceptors generally react irreversibly
with thiols like glutathione and may also react irreversibly with
proteins other than the desired target, especially proteins with
hyper-reactive cysteines.
[0007] Reversible covalent drug molecules (i.e., drugs which
contain a Michael acceptor with a second electron withdrawing
group) can exhibit poor bioavailability or delayed systemic
absorption when the drug is administered orally, which can be
manifested by low plasma area under the curve (AUC) and/or
C.sub.max values, resulting in suboptimal efficacy in vivo. The
poor bioavailability of this new class of drugs can be attributed,
in part, to the reactivity of reversible covalent Michael acceptor
moieties in these drugs. Accordingly, by limiting the exposure of
the reversible covalent drugs to the stomach where the combination
of low pH and digestive or metabolic enzymes and other sources of
thiols occur, a significant increase in systemic exposure of the
drug can be obtained.
[0008] In addition, limiting the exposure of irreversible covalent
drug molecules to the stomach may also lead to a significant
increase in systemic exposure of the drug and a reduction in
potential adverse side effects such as diarrhea, nausea, emesis,
and dizziness. For example, when ibrutinib, an irreversible
covalently bound drug molecule, is administered intraduodenally,
the bioavailability unexpectedly increased from 21% to 100%
compared to direct oral administration as determined by AUC (D. M.
Goldstein, Formulations Comprising Ibrutinib, WO 2014/004707,
published Jan. 3, 2014). Gastric bypass of ibrutinib should
increase bioavailability and/or reduce or altogether eliminate
potential adverse side effects of this drug, such as diarrhea,
nausea, emesis, and dizziness.
[0009] Furthermore, the expression of metabolizing enzymes, such as
cysteine proteases, mucins, transporters, and reactive thiol
containing molecules in the stomach, such as glutathione, can also
contribute to the low oral bioavailability of reversible covalent
Michael acceptor-containing drugs (see, e.g., Johnson D. S., et.
al., Future Med Chem. 2010 Jun. 1; 2(6):949-964 and Potashman M. H.
et al. J. Med. Chem., Vol 52, No. 5. Pgs. 1231-1246). For example,
the combination of digestive enzymes, such as the cysteine
protease, pepsin, transporters, and metabolizing enzymes such as
CYP enzymes in the gastric mucosa, can result in high chemical
and/or metabolic transformation of the reversible and irreversible
covalent Michael acceptors at low pH. Accordingly, by avoiding
exposure of the reversible covalent drugs to the stomach where the
combination of low pH and digestive or metabolic enzymes and other
sources of thiols occur, a significant increase in systemic
exposure of these drugs can be obtained. Additionally, avoidance of
exposure to the stomach may reduce or altogether eliminate
potential adverse side effects of these drugs such as diarrhea and
emesis, commonly called vomiting.
[0010] Accordingly, it would be desirable to have modified release
formulations of covalent drug molecules which avoid extensive
exposure to the stomach. The present disclosure provides such
advantageous formulations.
[0011] Compound (I) is a reversible covalent inhibitor of Bruton's
tyrosine kinase (BTK), which is a member of the Tec tyrosine kinase
family. BTK is expressed in most hematopoietic cells, such as B
cells, mast cells, and macrophages, but not in T cells, natural
killer cells, and plasma cells. BTK plays a role in the development
and activation of B cells. Mutations in the human BTK gene cause
the inherited disease X-linked agammaglobulinemia (XLA), with lack
of peripheral B cells and low levels of serum Ig. In XLA, the
primary immune deficit is B cell specific. The development of drugs
which inhibit BTK can have therapeutic significance in the
treatment of both B cell-related hematological cancers (e.g.,
non-Hodgkin lymphoma (NHL) and B cell chronic lymphocytic leukemia
(B-CLL)), and autoimmune diseases (e.g., rheumatoid arthritis,
Sjogren's syndrome, pemphigus, IBD, lupus, and asthma).
[0012] Compound (I), currently in development for treatment of
autoimmune diseases, is disclosed in Example 31 of the PCT
International Application No. PCT/US2013/058614, filed on Sep. 6,
2013.
[0013] PCT International Application No. PCT/US2015/000303, filed
on Dec. 23, 2015, refers to site specific administration of
Compound (I) and/or a pharmaceutically acceptable salt thereof.
[0014] PCT International Application No. PCT/US2015/000515, filed
on Dec. 23, 2015, refers to formulations which deliver reversible
and irreversible covalent kinase inhibitors into the small
intestine and specifically into the ileum and jejunum of the small
intestine.
SUMMARY OF THE DISCLOSURE
[0015] The present disclosure provides a modified release solid
oral dosage form comprising: [0016] (a) a core composition
comprising Compound (I) and/or a pharmaceutically acceptable salt
thereof; [0017] (b) a sub-coating layer coating the core
composition, said sub-coating layer comprising a polyvinyl alcohol
and/or hydroxypropyl methyl cellulose; and [0018] (c) an enteric
coating layer encapsulating the sub-coating layer and the core
composition, said enteric coating layer comprising at least one
polymer selected from an acrylic/methacrylic/ethacrylic acid
homopolymer and copolymer thereof, a cellulose derivative, and a
polyvinylpyrrolidone.
[0019] The present disclosure also provides a method of treating a
disease mediated by BTK to a subject in need thereof, comprising
administering to the subject in need of such treatment the modified
release solid oral dosage form of this disclosure.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 is a schematic of a modified release solid oral
dosage form of this disclosure, comprising the core composition,
the sub-coating layer, and the enteric coating layer.
[0021] FIG. 2 depicts the "design space" concept to optimize the
performance of modified release compositions/formulations of
Compound (I). The "design space" is three dimensional, with varying
dose, the percentage of drug release modifier, and the polymer coat
percentage to control the region of drug release and therefore the
drug release delay time.
[0022] Eight corners of "design space" are shown: [0023] Corner
1--30 mg, fast release core, fast coat; [0024] Corner 2--30 mg,
slow release core, fast coat; [0025] Corner 3--30 mg, slow release
core, slow coat; [0026] Corner 4--30 mg, fast release core, slow
coat; [0027] Corner 5--100 mg, fast release core, slow coat; [0028]
Corner 6--100 mg, fast release core, fast coat; [0029] Corner
7--100 mg, slow release core, fast coat; [0030] Corner 8--100 mg,
slow release core, slow coat;
[0031] FIG. 3 depicts the dissolution profile of all eight corners
of the "design space" in pH 6 dissolution media.
DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions
[0032] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
application and have the following meanings. All undefined
technical and scientific terms used in this application have the
meaning as commonly understood by one of ordinary skill in the art
to which this disclosure belongs.
[0033] As used herein, "a" or "an" entity refers to one or more of
that entity; for example, a compound refers to one or more
compounds or at least one compound unless stated otherwise. As
such, the terms "a" (or "an"), "one or more", and "at least one"
can be used interchangeably herein.
[0034] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
5%.
[0035] Compound (I) as used herein means (E) isomer, (Z) isomer, or
a mixture of (E) and (Z) isomers of
(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-
-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent--
2-enenitrile,
(S)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-
-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent--
2-enenitrile, or a mixture of (R) and (S) isomers of
2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-
piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-en-
enitrile having the structure:
##STR00001##
where *C is a stereochemical center;
[0036] or a pharmaceutically acceptable salt thereof.
[0037] It will be understood by a person of ordinary skill in the
art that when Compound (I) is denoted as
(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-
-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent--
2-enenitrile, it may contain the corresponding (S) enantiomer as an
impurity in less than about 1% by weight. Accordingly, when
Compound (I) is denoted as a mixture of (R) and (S) isomers of
2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-
piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-en-
enitrile, it means that the amount of (R) or (S) enantiomer in the
mixture is greater than about 1% by weight. Similar analysis
applies when Compound (I) is denoted as the (E) isomer, (Z) isomer,
or a mixture of (E) and (Z) isomers. Compound (I) or a
pharmaceutically acceptable salt thereof may also referred to in
the specification as "drug", "active agent", or "a therapeutically
active agent" or a "API".
[0038] "Mammal" as used herein means domesticated animals (such as
dogs, cats, and horses), and humans. In one embodiment, a mammal is
a human.
[0039] A "pharmaceutically acceptable salt" as used herein means an
acid addition salt that is pharmaceutically acceptable and that
possesses the desired pharmacological activity of the compound from
which the salt is made (hereafter, sometimes referred to as "parent
compound"). Such salts include salts, formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, and the like; or formed with organic acids such as
formic acid, acetic acid, propionic acid, hexanoic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, benzenesulfonic acid, 4-toluenesulfonic acid, and the
like.
[0040] A "pharmaceutically acceptable carrier or excipient" means a
carrier or an excipient that is useful in preparing a
pharmaceutical composition; is generally safe and neither
biologically nor otherwise undesirable, and includes a carrier or
an excipient that is acceptable for mammalian pharmaceutical
use.
[0041] As used herein, "modified-release" as applied to a drug
product refers to drug products that alter the timing and/or the
rate of release of the drug substance. A modified-release dosage
form is a formulation in which the drug-release characteristics of
time course and/or location are chosen to accomplish therapeutic or
convenience objectives not offered by conventional dosage forms
such as solutions, ointments, or promptly dissolving dosage forms.
Several types of modified-release oral drug products are
recognized. Non-limiting examples include: [0042] 1.
Extended-release drug products. A dosage form that allows at least
about a two-fold reduction in dosage frequency as compared to that
drug presented as an immediate-release (conventional) dosage form.
Examples of extended-release dosage forms include
controlled-release, sustained-release, and long-acting drug
products. [0043] 2. Delayed-release drug products. A dosage form
that releases a discrete portion or portions of drug at a time
other than promptly after administration. An initial portion may be
released promptly after administration. Enteric-coated dosage forms
are common delayed-release products (e.g., enteric-coated aspirin
and other NSAID products). [0044] 3. Targeted-release drug
products. A dosage form that releases drug at or near the intended
physiologic site of action. Targeted-release dosage forms may have
either immediate- or extended-release characteristics. [0045] 4.
Orally disintegrating tablets (ODT). ODT have been developed to
disintegrate rapidly in the saliva after oral administration. ODT
may be used without the addition of water. The drug is dispersed in
saliva and swallowed with little or no water.
[0046] "Treating" or "treatment" of a disease includes: [0047] (1)
inhibiting the disease, i.e., arresting or reducing the development
of the disease or its clinical symptoms; or [0048] (2) relieving
the disease, i.e., causing regression of the disease or its
clinical symptoms.
[0049] A "therapeutically effective amount" means the amount of
Compound (I) and/or a pharmaceutically acceptable salt thereof
that, when administered to a mammal in need or recognized need of
treatment for treating a disease, is sufficient to effect such
treatment for the disease. The "therapeutically effective amount"
will vary depending on the compound, the disease and its severity,
and the age, weight, etc., of the mammal to be treated.
[0050] "Substantially pure" as used herein refers to a compound (or
salt thereof) such as Compound (1) (or salt thereof), wherein at
least about 70% by weight of the compound (or salt thereof) is
present as the given solid state form. For example, the phrase
"amorphous form of a salt of Compound (I) (or a salt thereof) in
substantially pure amorphous form" refers to a solid state form of
Compound (I) (or a salt thereof), wherein more than about 70% by
weight of Compound (I) (or a salt thereof) is an amorphous form
with the remaining present in a crystalline form. In one
embodiment, such compositions contain at least about 80% by weight
of Compound (I) (or a salt thereof) in amorphous form. In another
embodiment, at least about 85% by weight of Compound (I) (or a salt
thereof) is in amorphous form. In yet another embodiment, at least
about 90% by weight of Compound (I) (or a salt thereof) is in
amorphous form. In yet another embodiment, at least about 95% by
weight of Compound (I) (or a salt thereof) is in amorphous form. In
yet another embodiment, at least about 97% by weight or at least
about 98% by weight of Compound (I) (or a salt thereof) is in
amorphous form. In yet another embodiment, at least about 99% by
weight of Compound (I) is in amorphous form. The relative amounts
of crystalline and/or amorphous forms in a solid mixture can be
determined by methods well-known in the art. For example, X-Ray
diffraction provides a convenient and practical means for
quantitative determination of the relative amounts of crystalline
and/or amorphous forms in a solid mixture. X-Ray diffraction is
adaptable to quantitative applications because the intensities of
the diffraction peaks of a given compound in a mixture are
proportional to the fraction of the corresponding powder in the
mixture. Although all salts of Compound (I) are amorphous, if any
crystalline form of Compound (I) (or a salt thereof) is present in
a mixture, percent composition of crystalline Compound (I) (or a
salt thereof) in an unknown composition can be determined.
Preferably, the measurements are made on solid powder of Compound
(I) (or a salt thereof). The X-Ray powder diffraction patterns of
an unknown composition may be compared to known quantitative
standards containing pure crystalline forms, if any, of Compound
(I) (or a salt thereof) to identify the percent ratio of a
particular crystalline form. If an amorphous form is the major
fraction of the composition, the amount may be further compared to
the total weight of the solid subject to analysis. This is done by
comparing the relative intensities of the peaks from the
diffraction pattern of the unknown solid powder composition with a
calibration curve derived from the X-Ray diffraction patterns of
pure known samples. The curve can be calibrated based on the X-Ray
powder diffraction pattern for the strongest peak from a pure
sample of crystalline forms of Compound (I) (or a salt thereof).
The calibration curve may be created in a manner known to those of
skill in the art. For example, five or more artificial mixtures of
crystalline forms of Compound (I) (or a salt thereof), at different
amounts, may be prepared. In a non-limiting example, such mixtures
may contain, about 2%, about 5%, about 7%, about 8%, and about 10%
of Compound (I) (or a salt thereof) for each crystalline form.
Then, X-Ray diffraction patterns are obtained for each artificial
mixture using standard X-Ray diffraction techniques. Slight
variations in peak positions, if any, may be accounted for by
adjusting the location of the peak to be measured. The intensities
of the selected characteristic peak(s) for each of the artificial
mixtures are then plotted against the known weight percentages of
the crystalline form. The resulting plot is a calibration curve
that allows determination of the amount of the crystalline forms of
Compound (I) (or a salt thereof) in an unknown sample. For the
unknown mixture of crystalline and amorphous forms of Compound (I)
(or a salt thereof), the intensities of the selected characteristic
peak(s) in the mixture, relative to an intensity of this peak in a
calibration mixture, may be used to determine the percentage of the
given crystalline form in the composition, with the remainder
determined to be the amorphous material. The overall crystallinity
may be determined as follows:
% Crystallinity=(C/A+C-B).times.100
[0051] where C is area under crystalline peaks, A is area under
amorphous halo, and B is background noise due to air scattering,
fluorescence, etc.
[0052] "Amorphous form" means a solid which does not possess a
distinguishable crystal lattice and the molecular arrangement of
molecules lack a long range order characteristic of a crystal. In
particular, amorphous denotes a material that does not show a sharp
Bragg diffraction peak.
[0053] The term "cellulose derivative" or "polysaccharide
derivative" refers to a cellulose polymer or polysaccharide wherein
at least a portion of the hydroxyls on the saccharide repeat units
have been reacted to form an ether or ester linkage. Examples
include and are not limited to hydroxyalkyl celluloses,
hydroxyalkyl alkylcelluloses, and carboxyalkyl cellulose esters,
such as hydroxypropyl methylcelluloses (e.g., hypromelloses or
HPMC), hydroxypropylcelluloses (e.g., HPC), and the like.
[0054] The term "hydrophilic" for purposes of the present
disclosure relates to materials that have affinity toward
water.
[0055] The term "water soluble" for purposes of the present
disclosure relates to materials that dissolve to the extent
required, in an aqueous media at a pH of from about 1 to about 8,
and is not particularly limited.
[0056] The term "water swellable" for purposes of the present
disclosure relates to materials that are relatively insoluble in
water, but which can absorb water.
EMBODIMENTS
[0057] Without limitation, some specific embodiments of the
disclosure include:
Embodiment 1
[0058] A modified release solid oral dosage form comprising: [0059]
(a) a core composition comprising Compound (I) and/or a
pharmaceutically acceptable salt thereof as defined hereinbefore;
[0060] (b) a sub-coating layer coating the core composition, said
sub-coating layer comprising a polyvinyl alcohol or a hydroxypropyl
methyl cellulose; and [0061] (c) an enteric coating layer
encapsulating the sub-coating layer and the core composition said
enteric coating layer comprising at least one polymer selected from
an acrylic/methacrylic/ethacrylic acid homopolymer and copolymers
thereof, a cellulose derivative, and a polyvinylpyrrolidone.
Embodiment 2
[0062] The modified release solid oral dosage form of Embodiment 1,
wherein the cellulose derivative is selected from cellulose acetate
phthalate, cellulose acetate tritnellitate, methylcellulose,
hydroxypropylmethyl cellulose phthalate (HPMCP),
hydroxypropylmethyl cellulose succinate (HPMCS), and
hydroxypropylmethylcellulose acetate succinate (HPMCAS).
Embodiment 3
[0063] The modified release solid oral dosage form of Embodiment 1
or 2, wherein the sub-coating layer (b) comprises a polyvinyl
alcohol, and the enteric coating layer (c) comprises a poly
(methacrylic acid-co-ethyl acrylate) copolymer.
Embodiment 4
[0064] The modified release solid oral dosage form of Embodiment 3,
wherein the polyvinyl alcohol is a pigmented polyvinyl alcohol.
[0065] In one embodiment, the pigmented polyvinyl alcohol (PVA) is
Opadry.RTM. II, available from Colorcon. Opadry.RTM. II is a high
productivity, water soluble, pH independent complete dry powder
film coating system containing polymer, plasticizer, and pigment,
which allows for immediate disintegration for fast, active
release.
[0066] In one embodiment, the poly(methacrylic acid-co-ethyl
acrylate) that is comprised in the enteric coating layer of this
disclosure is EUDRAGIT.RTM. L30 D-55 available from Evonik
Industries. This polymer is a poly(methacrylic acid-co-ethyl
acrylate 1:1 copolymer that is available in the form of a 30%
aqueous dispersion. It has a molar mass of approximately 320,000
g/mol and an acid value of about 315 mg KOH/g polymer.
[0067] In another embodiment, the poly(methacrylic acid-co-ethyl
acrylate) that is comprised in the enteric coating layer of this
disclosure is EUDRAGIT.RTM. L 100-55, also available from Evonik.
It is also a poly(methacrylic acid-co-ethyl acrylate 1:1 copolymer,
which is in the form of solid (white powder), and has a molar mass
of approximately 320,000 g/mol and an acid value of about 315 mg
KOH/g polymer.
Embodiment 5
[0068] The modified release solid oral dosage form of any of
Embodiments 1-4, wherein the solid oral dosage form releases less
than about 10% by weight of Compound (I) and/or a pharmaceutically
acceptable salt thereof, in less than about two hours at a pH less
than or equal to about 2.0; at least about 80% by weight of
Compound (I) and/or a pharmaceutically acceptable salt thereof in
about 15 minutes to about two hours at a pH equal to or more than
about 6.0; and any unreleased amount of Compound (I) and/or the
pharmaceutically acceptable salt thereof is released by the end of
about 7.5 hours at a pH equal to or more than about 6.0.
Embodiment 6
[0069] The modified release solid oral dosage form of any of
Embodiments 1-5, wherein the core composition comprises Compound
(I).
Embodiment 7
[0070] The modified release solid oral dosage form of any of
Embodiments 1-6, wherein Compound (I) is an (E) and (Z) mixture of
a mixture of (R) and (S) isomers of
2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl-
]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-e-
nenitrile.
Embodiment 8
[0071] The modified release solid oral dosage form of any of
Embodiments 1-7, wherein Compound (I) is an (E) and (Z) mixture of
(R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin--
1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-
-2-enenitrile.
Embodiment 9
[0072] The modified release solid oral dosage form of any of
Embodiments 1-8, wherein at least about 85% by weight of Compound
(I) and/or a pharmaceutically acceptable salt thereof is the (E)
isomer.
Embodiment 10
[0073] The modified release solid oral dosage form of any of
Embodiments 1-9, wherein at least about 90% by weight of Compound
(I) and/or a pharmaceutically acceptable salt thereof is the (E)
isomer.
Embodiment 11
[0074] The modified release solid oral dosage form of any of
Embodiments 1-10, wherein Compound (I) and/or a pharmaceutically
acceptable salt thereof is a substantially pure amorphous form.
Embodiment 12
[0075] The modified release solid oral dosage form of any of
Embodiments 1-11, wherein the core composition comprises about 30
mg to about 100 mg of Compound (1) and/or a pharmaceutically
acceptable salt thereof.
Embodiment 13
[0076] The modified release solid oral dosage form of any of
Embodiments 1-12, wherein the core composition further comprises at
least one excipient selected from fillers, drug release modifiers
(also referred to as "dissolution modifiers" or "dissolution
aids"), disintegrants, and lubricants.
Embodiment 14
[0077] The modified release solid oral dosage form of Embodiment
13, wherein the filler comprises at least one of a cellulose
derivative and a sugar molecule.
Embodiment 15
[0078] The modified release solid oral dosage form of Embodiment
14, wherein the cellulose derivative is microcrystalline
cellulose.
Embodiment 16
[0079] The modified release solid oral dosage form of Embodiment
15, wherein the microcrystalline cellulose is Avicel.RTM. PH-101.
This material is available from a number of vendors, such as
Sigma-Aldrich and FMC Corporation. The particle size of this
material is approximately 50 micrometers.
Embodiment 17
[0080] The modified release solid oral dosage form of any of
Embodiments 14-16, wherein the sugar molecule is mannitol.
Embodiment 18
[0081] The modified release solid oral dosage form of Embodiment
17, wherein the mannitol is spray dried mannitol, available as
"Pearlitol.RTM. 100SD" from a number of vendors, such as
Roquette-Pharma, and having a mean particle diameter of about 100
micrometer.
Embodiment 19
[0082] The modified release solid oral dosage form of any of
Embodiments 13-18, wherein the drug release modifier is
hydroxypropyl methyl cellulose (also known as "Hypromellose").
Embodiment 20
[0083] The modified release solid oral dosage form of Embodiment
19, wherein the hydroxypropyl methyl cellulose is METHOCEL.TM. K
100 Premium LV CR. This material is available from The Dow Chemical
Company. The letter "K" denotes that it is a hypromellose product;
the number "100" that follows the chemistry designation identifies
the viscosity of the product, which is about 100
millipascal-seconds (mPas), measured at 2% concentration in water
at 20.degree. C. "LV" refers to special low-viscosity products, and
"CR" denotes a controlled-release grade.
Embodiment 21
[0084] The modified release solid oral dosage form of any of
Embodiments 13-20, wherein the disintegrant is crosslinked
homopolymer of N-vinyl-2-pyrrolidone (crospovidone).
Embodiment 22
[0085] The modified release solid oral dosage form of Embodiment
21, wherein the crospovidone is Kollidon.TM. CL, available from
such vendors as BASF.
Embodiment 23
[0086] The modified release solid oral dosage form of any of
Embodiments 13-22, wherein the lubricant is sodium stearyl
fumarate.
Embodiment 24
[0087] The modified release solid oral dosage form of any of
Embodiments 13-23, comprising by weight of the core
composition:
[0088] about 6 to about 20% of Compound (I) and/or a
pharmaceutically acceptable salt thereof;
[0089] about 34 to about 72% of microcrystalline cellulose;
[0090] about 5 to about 25% mannitol;
[0091] about 0 to about 20% of hydroxypropyl methyl cellulose;
[0092] about 0.5 to about 1.5% of crosslinked homopolymer of
N-vinyl-2-pyrrolidone; and
[0093] about 0.5 to about 1.5% of sodium stearyl fumarate.
Embodiment 25
[0094] The modified release solid oral dosage form of any of
Embodiments 1-24, wherein the core composition weighs about 83% to
about 91% of the total weight of the solid oral dosage form (i.e.,
weight of core composition+sub-coating layer+enteric coating).
Embodiment 26
[0095] The modified release solid oral dosage form of any of
Embodiments 1-25, wherein the pigmented polyvinyl alcohol is OPADRY
II.
Embodiment 27
[0096] The modified release solid oral dosage form of any of
Embodiments 1-26, wherein the sub-coating layer weighs about 2% to
about 4% by weight of the solid oral dosage form (i.e., weight of
core composition+sub-coating layer+enteric coating).
Embodiment 28
[0097] The modified release solid oral dosage form of any of
Embodiments 1-27, wherein the poly(methacrylic acid-co-ethyl
acrylate) copolymer of the enteric coating layer is EUDRAGIT.RTM. L
30 D-55 or EUDRAGIT.RTM. L 100-55.
Embodiment 29
[0098] The modified release solid oral dosage form of any of
Embodiments 1-28, wherein the enteric coating layer further
comprises a solubilizer and a plasticizer/anti-tacking agent.
Embodiment 30
[0099] The modified release solid oral dosage form of Embodiment
29, wherein the solubilizer is a polyethoxylated sorbitan ester of
oleic acid.
Embodiment 31
[0100] The modified release solid oral dosage form of Embodiment 29
or 30, wherein the solubilizer is Polysorbate 80 (Tween.TM. 80),
available from such vendors as Sigma-Aldrich. Polysorbate 80 is
derived from polyethoxylated sorbitan and oleic acid. The
hydrophilic groups in this compound are polyethers, also known as
polyoxyethylene groups, which are polymers of ethylene oxide. In
the nomenclature of polysorbates, the numeric designation following
polysorbate refers to the lipophilic group, in this case the oleic
acid. The full chemical names for polysorbate 80 are:
Polyoxyethylene (20) sorbitan monooleate and (x)-sorbitan
mono-9-octadecenoate poly(oxy-1,2-ethanediyl).
Embodiment 32
[0101] The modified release solid oral dosage form of Embodiment
29, wherein the plasticizer/anti-tacking agent is PlasACRYL.TM.
T20, available from such vendors as Emerson Resources and Evonik
Industries. PlasACRYL.TM. T20 is a 20% emulsion of anti-tacking
agent and plasticizer that eases the preparation of a robust spray
suspension.
Embodiment 33
[0102] The modified release solid oral dosage form of any of
Embodiments 1-32, wherein the enteric coating layer weighs about 6%
to about 20% of the total weight of the solid oral dosage form
(i.e., weight of core composition+sub-coating layer+enteric
coating).
Embodiment 34
[0103] The modified release solid oral dosage form of any of
Embodiments 1-33, wherein the enteric coating layer comprises by
total weight of the solid oral dosage form (i.e., weight of core
composition+sub-coating layer+enteric coating layer):
[0104] about 5 to about 16% of EUDRAGIT.RTM. L 30 D-55 or
EUDRAGIT.RTM. L 100-55;
[0105] about 1 to about 3% of PlasACRYL.TM. T20; and
[0106] about 0.3 to about 0.8% of Polysorbate 80.
Embodiment 35
[0107] The modified release solid oral dosage form of any of
Embodiments 1-34, wherein the core composition weighs about 80% to
about 91% of the total weight of the solid oral dosage form (i.e.,
weight of core composition+sub-coating layer+enteric coating).
Embodiment 36
[0108] The modified release solid oral dosage form of any of
Embodiments 1-35, wherein the sub-coating layer weighs about 2% to
about 4% of the total weight of the solid oral dosage form (i.e.,
weight of core composition+sub-coating layer+enteric coating).
Embodiment 37
[0109] A method of inhibiting Bruton's tyrosine kinase (BTK) in a
mammal in need thereof comprising administering to the mammal in
need of such BTK inhibition a therapeutically effective amount of
Compound (I) and/or a pharmaceutically acceptable salt thereof in a
modified release solid oral dosage form of any of Embodiments
1-36.
Embodiment 38
[0110] A method of treating a disease mediated by BTK in a mammal
in need thereof comprising administering to the mammal in need of
such disease treatment a therapeutically effective amount of
Compound (I) and/or a pharmaceutically acceptable salt thereof in a
modified release solid oral dosage form of any of Embodiments
1-36.
Embodiment 39
[0111] The method of Embodiment 38, wherein the disease is an
autoimmune disease, cancer, or an inflammatory disease.
Embodiment 40
[0112] The method of Embodiment 38 or 39, wherein the disease is
acute necrotizing hemorrhagic leukoencephalitis, acute disseminated
encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune
retinopathy, axonal & neuronal neuropathies, chronic
inflammatory demyelinating polyneuropathy (CIDP), demyelinating
neuropathies, Devic's disease (neuromyelitis optica), experimental
allergic encephalomyelitis, giant cell arteritis (temporal
arteritis), Guillain-Barre syndrome, Lambert-Eaton syndrome,
chronic Meniere's disease, myasthenia gravis, neuromyotonia,
opsoclonus-myoclonus syndrome, optic neuritis, paraneoplastic
cerebellar degeneration, peripheral neuropathy, perivenous
encephalomyelitis, restless legs syndrome, stiff person syndrome,
sympathetic ophthalmia, Takayasu's arteritis, temporal
arteritis/Giant cell arteritis, transverse myelitis, multiple
sclerosis, dysautonomia, age-related macular degeneration (wet and
dry), corneal transplantation, encephalitis, meningitis,
vasculitis, or systemic lupus erythematosus (SLE).
Embodiment 41
[0113] The method of Embodiment 38 or 39, wherein the disease is
rheumatoid arthritis, psoriatic arthritis, lupus, uveitis,
myasthenia gravis, warm autoimmune hemolytic anemia, Wegener's
granulomatosis, Sjogren's disease, Sjogren's dry eye, non-Sjogren's
dry eye disease, psoriasis, pemphigus, urticaria, or asthma.
Embodiment 42
[0114] The method of Embodiment 38 or 39, wherein disease is
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell
prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple
myeloma, B-cell non-Hodgkin lymphoma, lymphoplamascytic
lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone
lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal
zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle
cell lymphoma, mediastinal (thymic) large B cell lymphoma,
intravascular large B cell lymphoma, primary effusion lymphoma,
Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis.
Embodiment 43
[0115] Diseases that may be treated by the modified release solid
oral dosage form of this disclosure include: acute necrotizing
hemorrhagic leukoencephalitis, acute disseminated
encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia
areata, alopecia universalis, amyloidosis, ankylosing spondylitis,
anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS),
antiphospholipid antibody syndrome, aplastic anemia, arthritis,
autoimmune angioedema, autoimmune dysautonomia, autoimmune
hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency,
autoimmune inner ear disease (AIED), autoimmune myocarditis,
autoimmune oophoritis, autoimmune pancreatitis, autoimmune
retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune
thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia,
axonal & neuronal neuropathies, Balo disease, Behcet's disease,
bullous pemphigoid, cardiomyopathy, Castleman disease, celiac
disease, Chagas disease, chronic fatigue syndrome, chronic
inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent
multifocal osteomyelitis (CRMO), Churg-Strauss syndrome,
cicatricial pemphigoid/benign mucosal pemphigoid, coeliac disease,
Cogan's syndrome, cold agglutinin disease, congenital heart block,
coxsackie myocarditis, CREST disease, Crohn's disease,
demyelinating neuropathies, dermatitis herpetiformis,
dermatomyositis, Devic's disease (neuromyelitis optica), diabetes,
discoid lupus, Dressler's syndrome, dry eye, dysautonomia,
endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,
erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome,
experimental allergic encephalomyelitis, fibromyalgia, fibrosing
alveolitis, giant cell arteritis (temporal arteritis), giant cell
myocarditis, glomerulonephritis, Goodpasture's syndrome,
granulomatosis with polyangiitis (GPA) (formerly called Wegener's
Granulomatosis), Graves' disease, Guillain-Barre syndrome,
Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein
purpura, herpes gestationis, hypogammaglobulinemia, idiopathic
pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA
nephropathy, IgG4-related sclerosing disease, immunoregulatory
lipoproteins, inclusion body myositis, inflammatory bowel disease,
interstitial cystitis, juvenile arthritis, juvenile diabetes (Type
1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton
syndrome, leukocytoclastic vasculitis, lichen planus, lichen
sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus
(SLE), lupus including lupus nephritis, lyme disease, chronic,
Meniere's disease, microscopic polyangiitis, mixed connective
tissue disease (MCTD), mooren's ulcer, Mucha-Habermann disease,
mucous membrane pemphigoid, multiple sclerosis, myasthenia gravis,
myositis, narcolepsy, neuromyotonia, neutropenia, ocular
cicatricial pemphigoid, opsoclonus-myoclonus syndrome, optic
neuritis, Ord's thyroiditis, osteoarthritis, palindromic
rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcus), paraneoplastic cerebellar
degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry
Romberg syndrome, pars planitis (peripheral uveitis),
Parsonnage-Turner syndrome, peripheral neuropathy, perivenous
encephalomyelitis, pernicious anemia, pemphigus such as pemphigus
vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis
nodosa, polymyalgia rheumatica, polymyositis, postmyocardial
infarction syndrome, postpericardiotomy syndrome, primary biliary
cirrhosis, primary sclerosing cholangitis, primary biliary
cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis,
psoriaticarthritis, pure red cell aplasia, pyoderma gangrenosum,
raynauds phenomenon, reactive arthritis, reflex sympathetic
dystrophy, Reiter's syndrome, relapsing polychondritis, restless
legs syndrome, retroperitoneal fibrosis, rheumatic fever,
rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis,
scleroderma, Sjogren's syndrome, sperm & testicular
autoimmunity, stiff person syndrome, Still's disease, subacute
bacterial endocarditis (SBE), Susac's syndrome, sympathetic
ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell
arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,
transverse myelitis, Type I, I, & III autoimmune polyglandular
syndromes, ulcerative colitis, undifferentiated connective tissue
disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis,
vitiligo, vulvodynia, and lupus.
[0116] Additional diseases include autoimmune disease, e.g.,
inflammatory bowel disease, arthritis, lupus including Lupus
Nephritis, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, Still's disease, juvenile arthritis, diabetes,
myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's
thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's
syndrome, dry eye (including Sjogren's dry eye and non-Sjogren's
dry eye), multiple sclerosis, Guillain-Barre syndrome, acute
disseminated encephalomyelitis, Addison's disease,
opsoclonus-myoclonus syndrome, ankylosing spondylitisis,
antiphospholipid antibody syndrome, aplastic anemia, autoimmune
hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic
thrombocytopenic purpura, optic neuritis, scleroderma, primary
biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,
temporal arteritis, autoimmune hemolytic anemia, Wegener's
granulomatosis, psoriasis, alopecia universalis, Behcet's disease,
chronic fatigue, dysautonomia, endometriosis, interstitial
cystitis, neuromyotonia, scleroderma, pemphigus such as pemphigus
vulgaris and/or foliaceus, bullous pemphigoid, age-related macular
degeneration (wet and dry), diabetic macular edema, corneal
transplantation, abdominal aortic aneurysm, mucous membrane
pemphigoid, and vulvodynia.
[0117] In another embodiment, the autoimmune disease is lupus,
pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye,
multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic
anemia, idiopathic thrombocytopenic purpura, Granulomatosis with
Polyangiitis, or rheumatoid arthritis.
[0118] In another embodiment, the disease is a heteroimmune
condition or disease, e.g., graft versus host disease,
transplantation, transfusion, anaphylaxis, allergy, type I
hypersensitivity, allergic conjunctivitis, allergic rhinitis, or
atopic dermatitis. In another embodiment, the disease is atopic
dermatitis.
[0119] In yet another embodiment, the disease is an inflammatory
disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis,
bronchitis, bursitis, cervicitis, cholangitis, cholecystitis,
colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis,
dermatomyositis, encephalitis, endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis
suppurativa, laryngitis, mastitis, meningitis, myelitis
myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,
otitis, pancreatitis, parotitis, pericarditis, peritonitis,
pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,
proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,
sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis,
vaginitis, vasculitis, or vulvitis. In another embodiment of this
aspect, the mammal is suffering from inflammatory skin disease
which includes, by way of example, dermatitis, contact dermatitis,
eczema, urticaria, pemphigus such as pemphigus vulgaris and/or
foliaceus, bullous pemphigoid, rosacea, and scarring psoriatic
lesions in the skin, joints, or other tissues or organs. In another
embodiment, the inflammatory disease is asthma or dermatitis.
[0120] In yet another embodiment, the disease is an inflammatory
and/or autoimmune disease, including acute inflammatory and/or
autoimmune disease, where corticosteroid therapy is used as the
first or second line therapy or first or second line maintenance
therapy. In one embodiment, the solid oral dosage form of this
disclosure is used for the treatment of:
[0121] Endocrine Disorders: Primary or secondary adrenocortical
insufficiency (hydrocortisone or cortisone is the first choice:
synthetic analogs may be used in conjunction with
mineralocorticoids where applicable; in infancy mineralocorticoid
supplementation is of particular importance); congenital adrenal
hyperplasia; nonsuppurative thyroiditis; hypercalcemia associated
with cancer.
[0122] Rheumatic Disorders: As adjunctive therapy for short-term
administration (to tide the patient over an acute episode or
exacerbation) in: psoriatic arthritis, rheumatoid arthritis,
including juvenile rheumatoid arthritis (selected cases may require
low-dose maintenance therapy), ankylosing spondylitis, acute and
subacute bursitis, acute nonspecific tenosynovitis, gout, acute
gouty arthritis, post-traumatic osteoarthritis, synovitis of
osteoarthritis, epicondylitis.
[0123] Collagen Diseases: During an exacerbation or as maintenance
therapy in selected cases of: systemic lupus erythematosus,
systemic dermatomyositis (polymyositis), and acute rheumatic
carditis.
[0124] Dermatologic Diseases: Pemphigus; bullous dermatitis
herpetiformis; severe erythema multiforme (Stevens-Johnson
syndrome); exfoliative dermatitis; mycosis fungoides; severe
psoriasis; severe seborrheic dermatitis.
[0125] Allergic States: Control of severe or incapacitating
allergic conditions intractable to adequate trials of conventional
treatment: seasonal or perennial allergic rhinitis; bronchial
asthma; contact dermatitis; atopic dermatitis; serum sickness; drug
hypersensitivity reactions.
[0126] Ophthalmic Diseases: Severe acute and chronic allergic and
inflammatory processes involving the eye and its adnexa such as:
allergic corneal marginal ulcers, herpes zoster ophthalmicus,
anterior segment inflammation, diffuse posterior uveitis and
choroiditis, sympathetic ophthalmia, allergic conjunctivitis,
keratitis, chorioretinitis, optic neuritis, iritis and
iridocyclitis.
[0127] Respiratory Diseases: Symptomatic sarcoidosis; Loeffler's
syndrome not manageable by other means; berylliosis; aspiration
pneumonitis, fulminating or disseminated pulmonary tuberculosis
when used concurrently with appropriate antituberculous
chemotherapy
[0128] Hematologic Disorders: Idiopathic thrombocytopenic purpura
in adults; secondary thrombocytopenia in adults; acquired
(autoimmune) hemolytic anemia; erythroblastopenia (RBC anemia);
congenital (erythroid) hypoplastic anemia.
[0129] Neoplastic Diseases: For palliative management of: leukemias
and lymphomas in adults, acute leukemia of childhood.
[0130] Edematous States: To induce a diuresis or remission of
proteinuria in the nephrotic syndrome, without uremia, of the
idiopathic type or that due to lupus erythematosus.
[0131] Gastrointestinal Diseases: To tide the patient over a
critical period of the disease in: ulcerative colitis, regional
enteritis.
[0132] Miscellaneous: Tuberculous meningitis with subarachnoid
block or impending block when used concurrently with appropriate
antituberculous chemotherapy; trichinosis with neurologic or
myocardial involvement.
[0133] The solid oral dosage forms of this disclosure can be used
for the treatment of above listed diseases optionally in
combination with a corticosteroid, noncorticosteroidal,
immunosupressive, and/or anti-inflammatory agents. In one
embodiment, the immunosuppressive agent is selected from interferon
alpha, interferon gamma, cyclophosphamide, tacrolimus,
mycophenolate mofetil, methotrexate, dapsone, sulfasalazine,
azathioprine, an anti-CD20 agent (such as rituximab, ofatumumab,
obinutuzumab, or veltuzumab, or a biosimilar version thereof),
anti-TNFalpha agent (such as entanercept, infliximab, golilumab,
adalimumab, or certolizumab pegol or a biosimilar version thereof),
anti-IL6 agent toward ligand or its receptors (such as tocilizumab,
sarilumab, olokizumab, elsililumab, or siltuximab), anti-IL17 agent
to ligand or its receptors (such as secukinumab, ustekinumab,
brodalumab, or ixekizumab), anti-IL1 agent to ligand or its
receptors (such as with rilonacept, canakinumab, or anakinra),
anti-IL2 agent to ligand or its receptors (such as basiliximab or
daclizumab), anti-CD2 agent such as alefacept, anti-CD3 agent such
as muromonab-cd3, anti-CD80/86 agent such as abatacept or
belatacept, anti-sphingosine-1-phosphate receptor agent such as
fingolimod, anti-C5 agent such as eculizumab, anti-integrin alpha4
agent such as natalizumab, anti-.alpha.,.beta., agent such as
vedolizumab, anti-mTOR agent such as sirolimus or everolimus,
anti-calcineurin agent such as tacrolimus, and anti-BAFF/BlyS agent
(such as belimumab, VAY736, or blisibimod), leflunomide, and
teriflunomide. Preferably, the immunosuppressive agent is
rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar
version thereof.
[0134] In yet another embodiment the disease to be treated by the
solid oral dosage form of this disclosure is a cancer. In one
embodiment, the cancer is a B-cell proliferative disorder, e.g.,
diffuse large B cell lymphoma, follicular lymphoma, chronic
lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chronic
myleogenous leukemia, B-cell acute lymphoblastic leukemia (B-ALL),
Philadelphia chromosome positive B-ALL, B-cell prolymphocytic
leukemia, small lymphocytic lymphoma (SLL), multiple myeloma,
B-cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom
macroglobulinemia, splenic marginal zone lymphoma, plasma cell
myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma,
nodal marginal zone B cell lymphoma, mantle cell lymphoma,
mediastinal (thymic) large B cell lymphoma, intravascular large B
cell lymphoma, primary effusion lymphoma, Burkitt
lymphoma/leukemia, or lymphomatoid granulomatosis.
[0135] In yet another embodiment, the disease to be treated by a
solid oral dosage form of this disclosure is a thromboembolic
disorder, e.g., myocardial infarct, angina pectoris, reocclusion
after angioplasty, restenosis after angioplasty, reocclusion after
aortocoronary bypass, restenosis after aortocoronary bypass,
stroke, transitory ischemia, a peripheral arterial occlusive
disorder, pulmonary embolism, or deep venous thrombosis.
[0136] Where the subject is suffering from or at risk of suffering
from an autoimmune disease, an inflammatory disease, or an allergy
disease, Compound (I) and/or a pharmaceutically acceptable salt
thereof in the present oral dosage form can be used with one or
more of the following therapeutic agents in any combination:
immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,
methotrexate, cyclophosphamide, azathioprine, mercaptopurine,
mycophenolate, or FTY720), glucocorticoids (e.g., prednisone,
cortisone acetate, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, beclometasone, fludrocortisone
acetate, deoxycorticosterone acetate, aldosterone), non-steroidal
anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,
2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or
sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,
celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold
thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,
minocycline, TNF-.alpha. binding proteins (e.g., infliximab,
etanercept, or adalimumab), abatacept, anakinra, interferon-.beta.,
interferon-.gamma., interleukin-2, allergy vaccines,
antihistamines, antileukotrienes, beta-agonists, theophylline, or
anticholinergics.
[0137] Where the subject is suffering from or at risk of suffering
from a B-cell proliferative disorder (e.g., plasma cell myeloma),
the subject can be treated with the solid oral dosage form of the
present disclosure in any combination with one or more other
anti-cancer agents. In some embodiments, one or more of the
anti-cancer agents are proapoptotic agents. Examples of anti-cancer
agents include, but are not limited to, any of the following:
gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic
acid (ATRA), bryostatin, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all
trans retinoic acid, doxorubicin, vincristine, etoposide,
gemcitabine, imatinib (Gleevec.TM.), geldanamycin,
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,
LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or
PD184352, Taxol.TM., also referred to as "paclitaxel," which is a
well-known anti-cancer drug which acts by enhancing and stabilizing
microtubule formation, and analogs of Taxol.TM., such as
Taxotere.TM.. Compounds that have the basic taxane skeleton as a
common structure feature have also been shown to have the ability
to arrest cells in the G2-M phases due to stabilized microtubules
and may be useful for treating cancer in combination with the
compounds described herein.
[0138] Further examples of anti-cancer agents for use in
combination with a solid oral dosage form of this disclosure
include inhibitors of mitogen-activated protein kinase signaling,
e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063,
SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors;
mTOR inhibitors; and antibodies (e.g., rituxan).
[0139] Other anti-cancer agents that can be employed in combination
with a solid oral dosage form of this disclosure include
Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar
sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer, carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;
cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;
dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;
dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflomithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin
hydrochloride; ifosfamide; ilmofosine; interleukin II (including
recombinant interleukin II, or rIL2), interferon alfa-2a;
interferon alfa-2b; interferon alfa-n1; interferon alfa-n3;
interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan
hydrochloride; lanreotide acetate; letrozole; leuprolide acetate;
liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine;
peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone hydrochloride; plicamycin; plomestane; porfimer
sodium; porfiromycin; prednimustine; procarbazine hydrochloride;
puromycin; puromycin hydrochloride; pyrazofurin; riboprine;
rogletimide; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin;
streptozocin; sulofenur, talisomycin; tecogalan sodium; tegafur;
teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trestolone acetate; triciribine
phosphate; trimetrexate; trimetrexate glucuronate; triptorelin;
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and
zorubicin hydrochloride.
[0140] Other anti-cancer agents that can be employed in combination
with a solid oral dosage form of this disclosure include: 20-epi-1,
25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK
antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN
700; cartilage derived inhibitor, carzelesin; casein kinase
inhibitors (ICOS); castanospermine; cecropin B; cetrorelix;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor,
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine;
docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
eflomithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists;
etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; fludarabine; fluorodaunomnicin
hydrochloride; forfenimex; formestane; fostriecin; fotemustine;
gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors;
hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor, interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin;
ipomeanol, 4-; iroplact; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim;
lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting
factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin;
lysofylline; lytic peptides; maitansine; mannostatin A; marimastat;
masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor, mifepristone; miltefosine;
mirimostim; mismatched double stranded RNA; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
monoclonal antibody, human chorionic gonadotrophin; monophosphoryl
lipid A+myobacterium cell wall sk; mopidamol; multiple drug
resistance gene inhibitor, multiple tumor suppressor 1-based
therapy; mustard anticancer agent; mycaperoxide B; mycobacterial
cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic
acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol;
phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor, platinum complex;
platinum compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator, protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylerie conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor,
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;
sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence
derived 1; sense oligonucleotides; signal transduction inhibitors;
signal transduction modulators; single chain antigen-binding
protein; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stem cell inhibitor, stem-cell division
inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista;
suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan;
thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor, translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor, urokinase
receptor antagonists; vapreotide; variolin B; vector system,
erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0141] Yet other anticancer agents that can be employed in
combination with a solid oral dosage form of this disclosure
include alkylating agents, antimetabolites, natural products, or
hormones, e.g., nitrogen mustards (e.g., mechloroethamine,
cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,
busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), and
triazenes (e.g., decarbazine, etc.). Examples of antimetabolites
include but are not limited to folic acid analogs (e.g.,
methotrexate), pyrimidine analogs (e.g., Cytarabine), and purine
analogs (e.g., mercaptopurine, thioguanine, pentostatin).
[0142] Examples of natural products useful in combination with a
solid oral dosage form of this disclosure include but are not
limited to vinca alkaloids (e.g., vinblastin, vincristine),
epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,
daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,
L-asparaginase), and biological response modifiers (e.g.,
interferon alpha).
[0143] Examples of alkylating agents that can be employed in
combination with a solid oral dosage form of this disclosure
include, but are not limited to, nitrogen mustards (e.g.,
mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.),
ethylenimine and methylmelamines (e.g., hexamethlymelamine,
thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,
carmustine, lomusitne, semustine, streptozocin, etc.), and
triazenes (decarbazine, etc.). Examples of antimetabolites include,
but are not limited to folic acid analog (e.g., methotrexate), and
pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine),
and purine analogs (e.g., mercaptopurine, thioguanine,
pentostatin).
[0144] Examples of hormones and antagonists useful in combination
with a solid oral dosage form of this disclosure include, but are
not limited to, adrenocorticosteroids (e.g., prednisone),
progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,
medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,
ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens
(e.g., testosterone propionate, fluoxymesterone), antiandrogen
(e.g., flutamide), and gonadotropin releasing hormone analog (e.g.,
leuprolide). Other agents that can be used in the methods and
compositions described herein for the treatment or prevention of
cancer include platinum coordination complexes (e.g., cisplatin,
carboblatin), anthracenedione (e.g., mitoxantrone), substituted
urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g.,
procarbazine), and adrenocortical suppressant (e.g., mitotane,
aminoglutethimide).
[0145] Examples of anti-cancer agents which act by arresting cells
in the G2-M phases due to stabilized microtubules and which can be
used in combination with an BTK inhibitor compound of the
disclosure include, but are not limited to, the following marketed
drugs and drugs in development: Erbulozole (also known as R-55104),
Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin
isethionate (also known as CI-980), Vincristine, NSC-639829,
Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also
known as E-7010), Altorhyrtins (such as Altorhyrtin A and
Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin
2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6,
Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin
hydrochloride (also known as LU-103793 and NSC-D-669356),
Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also
known as desoxyepothilone A or dEpoA), Epothilone D (also referred
to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E,
Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,
16-aza-epothilone B, 21-aminoepothilone B (also known as
BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone
F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as
NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P
(Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known
as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877
(Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198
(Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,
also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis),
SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132
(Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),
Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also
known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known
as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),
Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as
NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and
TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261
and WHI-261), H10 (Kansas State University), H116 (Kansas State
University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313
(Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2
(Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also
known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of
Medicine, also known as MF-569), Narcosine (also known as
NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott),
Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine,
also known as MF-191), TMPN (Arizona State University), Vanadocene
acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also
known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of
Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as
T-900607), RPR-115781 (Aventis), Eleutherobins (such as
Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and
Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131
(Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620
(Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis),
A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as
NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),
Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099
(Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110,
trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318
(Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium,
BPR-OY-007 (National Health Research Institutes), and SSR-250411
(Sanofi).
[0146] Where the subject is suffering from or is at risk of
suffering from a thromboembolic disorder (e.g., stroke), the
subject can be treated with a solid oral dosage form of the present
disclosure in any combination with one or more other
anti-thromboembolic agents. Examples of anti-thromboembolic agents
include, but are not limited any of the following: thrombolytic
agents (e.g., alteplase anistreplase, streptokinase, urokinase, or
tissue plasminogen activator), heparin, tinzaparin, warfarin,
dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors
(e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban,
LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel,
LY640315), ximelagatran, and BIBR 1048.
Additional Optional Ingredients of Solid Oral Dosage Forms of the
Present Disclosure
Hydrophilic Materials:
[0147] Suitable hydrophilic materials comprise water soluble or
water swellable materials. Examples of such materials include
salts, sugars, and polymers such as hydroxyalkyl celluloses,
hydroxyalkyl alkylcelluloses, and carboxyalkyl cellulose esters,
for example, hydroxypropyl methylcelluloses (hypromelloses or
HPMC), hydroxypropylcelluloses (HPC), and combinations comprising
one or more of the foregoing materials. Hydroxypropyl
methylcelluloses that are hydrophilic in nature and may be used in
the present disclosure are sold in different viscosity grades such
as those sold under the brand name Methocel.TM. available from Dow
Chemical Co. Examples of hydroxypropyl methylcelluloses of a low
viscosity grade include those available under the brand names
Methocel E5, Methocel E-15 LV, Methocel E50 LV, Methocel K100 LV
and Methocel F50 LV whose 2% by weight aqueous solutions have
viscosities of 5 cP, 15 cP, 50 cP, 100 cP, and 50 cP, respectively.
Examples of hydroxypropyl methylcelluloses having medium viscosity
include those available under the brand names Methocel E4M and
Methocel K4M, both of whose 2% by weight aqueous solutions have a
viscosity of 4000 cP. Examples of hydroxypropyl methylcellulose
polymers having high viscosity include those available under the
brand names Methocel K15M and Methocel K100M whose 2% by weight
aqueous solutions have viscosities of 15,000 cP and 100,000 cP,
respectively. The hydroxypropyl methylcellulose polymers may be
present in the pharmaceutical compositions of the present
disclosure in amounts from about 0.1% to about 50% by weight.
[0148] The hydroxypropylcellulose polymers that may be used in the
present disclosure also include, for example, polymers available
under the brand name Klucel.TM., available from Nippon Soda Co.
Hydroxypropylcellulose polymers available under the brand names
Klucel EF, Klucel LF, Klucel JF and Klucel GF, whose 2% by weight
aqueous solutions have viscosities less than 1000 cP, are examples
of low viscosity hydrophilic polymers. A hydroxypropylcellulose
polymer available under the brand name Klucel ME, whose 2% by
weight aqueous solution has a viscosity in the range from
4,000-6,500 cP, is a medium viscosity hydrophilic polymer.
Hydroxypropyl cellulose polymers available sold as HPC-SL, HPC-L,
and HPC-M, whose 2% by weight aqueous solutions have viscosities of
3-6 cP, 6-10 cP, and 150-400 cP, respectively, are examples of low
viscosity hydrophilic polymers, while HPC-H has a viscosity of
1,000-4000 cP and is an example of a medium viscosity hydrophilic
polymer. The hydroxypropylcellulose polymers may be present in an
amount from about 0.1% to about 50% by weight.
[0149] Water swellable materials suitable for making modified
release dosage forms are compounds that are able to expand when
they are exposed to aqueous fluids, such as gastro-intestinal
fluids. One or more water swellable compounds may be present in a
coating and optionally one or more pharmaceutically acceptable
excipients.
[0150] Suitable compounds which can be used as water swellable
substances include, for example, low-substituted hydroxypropyl
celluloses, e.g., L-HPC, cross-linked polyvinylpyrrolidones, e.g.,
PVP-XL, Kollidone.TM. CL and Polyplasdone.TM. XL, sodium
carboxymethylcellulose, cross-linked sodium carboxymethylcellulose,
e.g., Ac-di-sol.TM. and Primellose.TM., sodium starch glycolate,
e.g., Primojel.TM., sodium carboxymethylcelluloses, e.g.,
Nymcel.TM. ZSB10, sodium carboxymethyl starches, e.g.,
Explotab.TM., ion-exchange resins, e.g., Dowex.TM. or Amberlite.TM.
products, microcrystalline cellulose, e.g., Avicel.TM. products,
starches and pregelatinized starches, e.g., Starch 1500.TM. and
Sepistab ST200.TM., formalin-casein, e.g., Plas-Vita.TM., and
combinations comprising one or more of the foregoing water
swellable substances.
[0151] In some embodiments, hydrophilic materials include
polyalkylene oxides, polysaccharide gums, and crosslinked
polyacrylic acids. Suitable polyalkylene oxides, such as linear
polymers of unsubstituted ethylene oxide, include Polyox.TM.
products from The Dow Chemical Company, U.S., having molecular
weights about 100,000 to about 7,000,000 Da. Other useful
polyalkylene oxide polymers are made from propylene oxide or
mixtures of ethylene oxide and propylene oxide.
[0152] Polysaccharide gums, both natural and modified
(semi-synthetic), can be used. Non-limiting examples are dextran,
xanthan gum, gellan gum, welan gum, and rhamsan gum.
[0153] Crosslinked polyacrylic acids that can be used include those
having properties similar to those described above for
alkyl-substituted cellulose and polyalkylene oxide polymers. Useful
crosslinked polyacrylic acids include those with viscosities about
4,000 to about 40,000 cP (for a 1% aqueous solution at 25.degree.
C.). Three specific examples are CARBOPOL.TM. grades 971 P, 974P,
and 934P (sold by The Lubrizol Corporation, Cleveland, Ohio, USA).
Further examples are polymers known as WATER LOCK.TM., which are
starch/acrylate/acrylamide copolymers available from Grain
Processing Corporation, Muscatine, Iowa, USA.
[0154] The hydrophilicity and water swellability of these polymers
cause the subcoat to swell in size after oral administration, due
to ingress of water. The release rate of an active agent from the
subcoat is primarily dependent upon the rate of water inhibition
and the rate at which the active agent dissolves and diffuses from
the swollen polymer, which in turn is related to the solubility and
dissolution rate of the active agent, the active agent particle
size, and/or the active agent concentration in the dosage form.
[0155] Suitable "hydrophobic" materials are water-insoluble neutral
or synthetic waxes, fatty alcohols such as lauryl, myristyl,
stearyl, cetyl, or cetostearyl alcohol, fatty acids and derivatives
thereof, including fatty acid esters such as such as glyceryl
monostearate, glycerol monooleate, acetylated monoglycerides,
stearin, palmitin, laurin, myristin, cetyl esters wax, glyceryl
palmitostearate, glyceryl behenate, hydrogenated castor oils,
cottonseed oils, fatty acid glycerides (mono-, di-, and
tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes,
stearic acid, stearyl alcohol, materials having hydrocarbon
backbones, and combinations comprising one or more of the foregoing
materials. Suitable waxes include, but are not limited to, beeswax,
Glycowax.RTM. (a N,N'-distearoylethyelenediamine, from Lonza),
castor wax, carnauba wax, and wax-like substances.
[0156] The solid dosage forms described herein comprise an enteric
coating, i.e., as an oral dosage form of a pharmaceutical
composition as described herein which utilizes an enteric coating
to affect the release of the compound in the intestine of the
gastrointestinal tract. An "enterically coated" drug or tablet
refers to a drug or tablet that is coated with a substance--i.e.,
with an "enteric coating"--that remains intact in the stomach but
dissolves and releases the drug once the intestine (in one
embodiment small intestine) is reached. As used herein, "enteric
coating" is a material, such as a polymer material or materials
which encase the therapeutically active agent either as a dosage
form or as particles. Typically, a substantial amount or all of the
enteric coating material is dissolved before the therapeutically
active agent is released from the dosage form, so as to achieve
delayed dissolution of the therapeutically active agent in the
intestine. Enteric coatings are discussed, for example, Loyd, V.
Allen; Remington: The Science and Practice of Pharmacy,
Twenty-first Ed., (Pharmaceutical Press, 2005; and P. J. Tarcha,
Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991.
Methods for applying enteric coatings to pharmaceutical
compositions are well known in the art, and include, for example,
methods disclosed in U.S. Patent Publication No. 2006/0045822.
[0157] The dosage form may be a compressed or molded or extruded
tablet (coated with an enteric coating or uncoated) containing
granules, powder, pellets, beads or particles of Compound (I)
and/or a pharmaceutically acceptable salt thereof (or any
embodiments thereof) optionally admixed with other excipient(s),
which are themselves coated with an enteric coating or uncoated
provided at least the tablet and/or the granules, powder, pellets,
beads or particles of Compound (I) and/or a pharmaceutically
acceptable salt thereof is coated. The oral dosage form may also be
a capsule containing pellets, beads, or granules of Compound (1)
and/or a pharmaceutically acceptable salt thereof (or any
embodiments thereof) optionally admixed with other excipient(s).
Some examples of coatings that were originally used as enteric
coatings are beeswax and glyceryl monostearate; beeswax, shellac
and cellulose, cetyl alcohol, and mastic and shellac, as well as
shellac and stearic acid (U.S. Pat. No. 2,809,918) and
polyvinylacetate and ethyl cellulose (U.S. Pat. No. 3,835,221).
More recently, the enteric coatings used are neutral copolymers of
polymethacrylic acid esters (Eudragit L30D). (F. W. Goodhart et al,
Pharm. Tech., p. 64-71, April, 1984), copolymers of methacrylic
acid and methacrylic acid methyl ester (Eudragit S), a neutral
copolymer of polymethacrylic acid esters containing metallic
stearates (see Mehta et al U.S. Pat. Nos. 4,728,512 and 4,794,001),
cellulose acetate succinate, and hypromellose phthalate.
[0158] In some embodiments, the polymers described herein are ionic
carboxylic polymers. In other embodiments, the polymers and
compatible mixtures thereof, and some of their properties, include,
but are not limited to:
[0159] Shellac: Also called purified lac, it is a refined product
obtained from the resinous secretion of an insect. This coating
dissolves in media of pH>7;
[0160] Acrylic polymers: The performance of acrylic polymers
(primarily their solubility in biological fluids) can vary based on
the degree and type of substitution. Examples of suitable acrylic
polymers include methacrylic acid copolymers and ammonium
methacrylate copolymers. The Eudragit series L, S, and RS
(manufactured by Rohm Pharma and known as Evonik.RTM.) are
available as solubilized in organic solvent, aqueous dispersion, or
dry powders. The Eudragit series RL, NE, and RS are insoluble in
the gastrointestinal tract but are permeable and are used primarily
for colonic targeting. The Eudragit series L, L-30D and S are
insoluble in stomach and dissolve in the intestine;
[0161] Cellulose Derivatives: Examples of suitable cellulose
derivatives are: ethyl cellulose; reaction mixtures of partial
acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type of substitution.
Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric
(FMC) is an aqueous based system and is a spray dried CAP
pseudolatex with particles <1 .mu.m. Other components in
Aquateric can include pluronics, Tweens, and acetylated
monoglycerides. Other suitable cellulose derivatives include:
cellulose acetate tritnellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (HPMCAS, e.g., AQOAT
(Shin Etsu)). The performance can vary based on the degree and type
of substitution. For example, HPMCP such as HP-50, HP-55, HP-55S,
and HP-55F grades are suitable. The performance can vary based on
the degree and type of substitution. For example, suitable grades
of hydroxypropylmethylcellulose acetate succinate include, but are
not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),
which dissolves at pH 5.5, and AS-HG (HF), which dissolves at
higher pH. These polymers are offered as granules, or as fine
powders for aqueous dispersions.
[0162] Poly Vinyl Acetate Phthalate (PVAP): PVAP dissolves in
pH>5, and it is much less permeable to water vapor and gastric
fluids. Detailed description of above polymers and their
pH-dependent solubility can be found at in the article entitled
"Enteric coated hard gelatin capsules" by Professor Karl Thoma and
Karoline Bechtold at
http://pop.www.capsugel.com/media/library/enteric-coated-hard-gelatin-cap-
sules.pdf.
[0163] In one embodiment, the enteric coating is made from acrylic
acid, methacrylic acid or ethacrylic acid polymers or copolymers,
cellulose acetate (and its succinate and phthalate derivatives),
hydroxypropyl methyl cellulose phthalate, polyvinyl acetate
phthalate, hydroxyethyl ethyl cellulose phthalate, cellulose
acetate tetrahydrophtalate, acrylic resin or shellac. In another
embodiment the polymer is chosen from cellulose acetate phthalate
(CAP; dissolves above pH 6), polyvinyl acetate phthalate (PVAP,
disintegrates at pH 5), hydroxypropyl methyl cellulose phthalate
(HPMCP, grade HP50 disintegrates at pH 5 and HP50 disintegrates at
5.5), methylacrylic acid copolymers (Eudragit L 100 and L12.5
disintegrate between about 6 and about 7, Eudragit L-30 and L100-55
disintegrate at pH greater than 5.5 and Eudragit S100, S12.5 and FS
30D disintegrate at pH greater than 7).
[0164] In some embodiments, the enteric coating can, and usually
does, contain a plasticizer and possibly other coating excipients
such as colorants, talc, and/or magnesium stearate, which are well
known in the art. Suitable plasticizers include triethyl citrate
(Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl
citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400),
diethyl phthalate, tributyl citrate, acetylated monoglycerides,
glycerol, fatty acid esters, propylene glycol, and dibutyl
phthalate. In particular, ionic carboxylic acrylic polymers usually
will contain about 10% to about 25% by weight of a plasticizer,
especially dibutyl phthalate, polyethylene glycol, triethyl
citrate, and triacetin.
[0165] Conventional coating techniques such as fluid bed or Wurster
coaters, or spray or pan coating are employed to apply coatings.
The coating thickness must be sufficient to ensure that the oral
dosage form remains intact until the desired site of delivery in
the intestinal tract is reached. The amount of plasticizer is
optimized for each enteric coating layer and the applied amount of
said polymer(s), in such a way that the mechanical properties,
i.e., flexibility and hardness of the enteric coating layer(s), for
instance exemplified as Vickers hardness, are adjusted so that if a
tablet is desired the acid resistance of the pellets covered with
enteric coating layer(s) does not decrease significantly during
compression of pellets into tablets. The amount of plasticizer is
usually above about 5% by weight of the enteric coating layer
polymer(s). In one embodiment the amount of plasticizer is about
15% to 50% by weight of the enteric coating layer polymer(s). In
another embodiment, the amount of plasticizer is about 20% to about
50% by weight of the enteric coating layer polymer(s). The maximum
thickness of the applied enteric coating is normally only limited
by processing conditions and the desired dissolution profile.
[0166] Colorants, surfactants, anti-adhesion agents, antifoaming
agents, lubricants (e.g., carnuba wax or PEG) and other additives
may be added to the coatings besides plasticizers to solubilize or
disperse the coating material, and to improve coating performance
and the coated product. To accelerate the dissolution of the
enteric coat, a half-thickness, double coat of enteric polymer (for
instance, Eudragit L30 D-55) may be applied, and the inner enteric
coat may have a buffer up to about pH 6.0 in the presence of about
10% citric acid, followed by a final layer of standard Eudragit L
30 D-55. Applying two layers of enteric coat, each half the
thickness of a typical enteric coat, Liu and Basit were able to
accelerate enteric coating dissolution compared to a similar
coating system applied, unbuffered, as a single layer (Liu, F. and
Basit, A. Journal of Controlled Release. 147 (2010) 242-245). The
intactness of the enteric coating may be measured, for example, by
the degradation of the drug within the micropellets. The enteric
coated dosage forms or pellets may be tested in dissolution testing
first in gastric fluid and separately in intestinal fluid as
described in USP to determine its function. Additives such as
dispersants, colorants, pigmented polymers (e.g.,
poly(ethylacrylate, methylmethacrylate), anti-tacking and
anti-foaming agents may also be included into the enteric coating
layer(s). Other compounds may be added to increase film thickness
and to decrease diffusion of acidic gastric juices into the acid
susceptible material.
[0167] Formulations disclosed herein contain, unless stated
otherwise, one or more pharmaceutically acceptable excipient(s)
such as binders, surfactants, diluents, buffering agents,
antiadherents, glidants, hydrophilic or hydrophobic polymers,
retardants, stabilizing agents or stabilizers, disintegrants or
superdisintegrants, dispersants, antioxidants, antifoaming agents,
fillers, flavors, colorants, lubricants, sorbents, preservatives,
plasticizers, or sweeteners, or mixtures thereof, which facilitate
processing of the drug molecule (or embodiments thereof disclosed
herein) or a pharmaceutically acceptable salt thereof into
preparations which can be used pharmaceutically. The
pharmaceutically acceptable excipients can be in the coating and/or
the core. Any of the well-known techniques and excipients may be
used as suitable and as understood in the art, see for example,
Remington: The Science and Practice of Pharmacy, Twenty-first Ed.,
(Pharmaceutical Press, 2005); Liberman, H. A., Lachman, L., and
Schwartz, J. B. Eds., Pharmaceutical Dosage Forms, Vol. 1-2 Taylor
& Francis 1990; and R. I. Mahato, Ansel's Pharmaceutical Dosage
Forms and Drug Delivery Systems, Second Ed. (Taylor & Francis,
2012).
[0168] In some embodiments, the formulations may include one or
more pH adjusting agents or buffering agents, for example, acids
such as acetic, boric, citric, lactic, phosphoric, and hydrochloric
acids; bases such as sodium hydroxide, sodium phosphate, sodium
borate, sodium citrate, sodium acetate, sodium lactate, and
tris-hydroxymethylaminomethane; and buffers such as
citrate/dextrose, sodium bicarbonate, ammonium chloride, and the
like. Such acids, bases and buffers are included in an amount
required to maintain pH of the composition in an acceptable
range.
[0169] In some embodiments, the formulations may also include one
or more salts in an amount required to bring osmolality of the
composition into an acceptable range. Such salts include those
having sodium, potassium or ammonium cations and chloride, citrate,
ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or
bisulfite anions; suitable salts include sodium chloride, potassium
chloride, sodium thiosulfate, sodium bisulfite, and ammonium
sulfate.
[0170] In some embodiments, the formulations may also include one
or more antifoaming agents to reduce foaming during processing,
which can result in coagulation of aqueous dispersions, bubbles in
the finished film, or generally impair processing. Exemplary
anti-foaming agents include silicon emulsions and sorbitan
sesquoleate.
[0171] In some embodiments, the formulations may also include one
or more antioxidants, such as non-thiol antioxidants, for example,
butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid,
and tocopherol. In certain embodiments, antioxidants enhance
chemical stability where required.
[0172] In some embodiments, the formulations may also include one
or more preservatives to inhibit microbial activity. Suitable
preservatives include mercury-containing substances such as merfen
and thiomersal; stabilized chlorine dioxide; and quaternary
ammonium compounds such as benzalkonium chloride,
cetyltrimethylammonium bromide and cetylpyridinium chloride.
[0173] In some embodiments, the formulations may also include one
or more binders. Binders impart cohesive qualities and include,
e.g., alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinyl-pyrrolidone/vinyl acetate copolymer, crosspovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin,
maltodextrin, a sugar, such as sucrose (e.g., Dipac.RTM.), glucose,
dextrose, molasses, mannitol, sorbitol, xylitol (e.g.,
Xylitab.RTM.), and lactose; a natural or synthetic gum such as
acacia, tragacanth, ghatti gum mucilage of isapol husks,
polyvinylpyrrolidone (e.g., Polyvidone.RTM. CL, Kollidon.RTM. CL,
Polyplasdone XL-10), larch arabogalactan, Veegum.RTM., polyethylene
glycol, polyethylene oxide, waxes, sodium alginate, and the
like.
[0174] In general, binder levels of about 10% to about 70% are used
in powder-filled gelatin capsule formulations. Binder usage level
in tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of other excipients such
as fillers which themselves can act as moderate binder. Formulators
skilled in art can determine the binder level for the formulations,
but binder usage level of up to about 70% in tablet formulations is
common.
[0175] In some embodiments, the formulations may also include
dispersing agents and/or viscosity modulating agents. Dispersing
agents and/or viscosity modulating agents include materials that
control the diffusion and homogeneity of a drug through liquid
media or a granulation method or blend method. In some embodiments,
these agents also facilitate the effectiveness of a coating or
eroding matrix. Exemplary diffusion facilitators/dispersing agents
include, e.g., hydrophilic polymers, electrolytes, Tween.RTM. 20,
60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as
Plasdone.RTM.), and the carbohydrate-based dispersing agents such
as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and
HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC K4M,
HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, triethylcellulose, hydroxyethyl-cellulose,
hydroxypropyl-cellulose, hydroxypropylmethylcellulose phthalate,
hydroxypropyl-methylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl
acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics.RTM. F68, F88, and F108,
which are block copolymers of ethylene oxide and propylene oxide);
and poloxamines (e.g., Tetronic.RTM. 908, also known as
Poloxamine.RTM. 908, which is a tetrafunctional block copolymer
derived from sequential addition of propylene oxide and ethylene
oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)),
polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,
polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene
glycol, e.g., the polyethylene glycol can have a molecular weight
of about 300 to about 6000, or about 3350 to about 4000, or about
7000 to 5400, sodium carboxymethylcellulose, methylcellulose,
polysorbate-80, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, carbomers, polyvinyl alcohol (PVA),
alginates, chitosans and combinations thereof.
[0176] In some embodiments, the formulations may also include one
or more "diluents," which refer to chemical compounds that are used
to dilute a compound of interest prior to delivery. Diluents can
also be used to stabilize compounds because they can provide a more
stable environment Salts dissolved in buffered solutions (which
also can provide pH control or maintenance) are utilized as
diluents in the art, including, but not limited to a phosphate
buffered saline solution. In certain embodiments, diluents increase
bulk of the composition to facilitate compression or create
sufficient bulk for homogenous blend for capsule filling. Such
compounds include, e.g., lactose, starch, mannitol, sorbitol,
dextrose, microcrystalline cellulose such as Avicel.RTM.; dibasic
calcium phosphate, dicalcium phosphate dihydrate; tricalcium
phosphate; calcium phosphate; anhydrous lactose; spray-dried
lactose; pregelatinized starch; compressible sugar, such as
Di-Pac.RTM. (Amstar); hydroxypropyl-methylcellulose,
hydroxypropylmethylcellulose acetate stearate; sucrose-based
diluents; confectioner's sugar; monobasic calcium sulfate
monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate;
dextrates; hydrolyzed cereal solids; amylose; powdered cellulose;
calcium carbonate; glycine; kaolin; mannitol, sodium chloride;
inositol; bentonite; and the like.
[0177] In some embodiments, the formulation may contain surface
active agents or surfactants are long chain molecules that can
accumulate at hydrophilic/hydrophobic (water/oil) interfaces and
lower the surface tension at the interface. As a result they can
stabilize an emulsion. In some embodiments, the surfactant may
comprise: Tween.RTM. (polyoxyethylene sorbate) family of
surfactants, Span.RTM. (sorbitan long chain carboxylic acid esters)
family of surfactants, Pluronic.RTM. (ethylene or propylene oxide
block copolymers) family of surfactants, Labrasol.RTM.,
Labrafil.RTM. and Labrafac.RTM. (each polyglycolyzed glycerides)
families of surfactants, sorbitan esters of oleate, stearate,
laurate or other long chain carboxylic acids, poloxamers
(polyethylene-polypropylene glycol block copolymers or
Pluronic.RTM.), other sorbitan or sucrose long chain carboxylic
acid esters, mono and diglycerides, PEG derivatives of
caprylic/capric triglycerides and mixtures thereof or mixture of
two or more of the above. In some embodiments the surfactant phase
may comprise a mixture of Polyoxyethylene (20) sorbitan monooleate
(Tween 80.RTM.) and sorbitan monooleate (Span 80.RTM.).
[0178] In some embodiments, the formulations may also include one
or more "disintegrants," which includes both the dissolution and
dispersion of the dosage form when contacted with gastrointestinal
fluid. "Disintegration agents" or "disintegrants" facilitate the
breakup or disintegration of a substance. Examples of
disintegration agents include a starch, e.g., a natural starch such
as corn starch or potato starch, a pregelatinized starch such as
National 1551 or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM., a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH 01,
Avicel.RTM. PH 102, Avicel.RTM. PHi05, Elceme.RTM. P100,
Emcocel.RTM., Vivacel.RTM., and Solka-Floc.RTM., methylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked
sodium carboxymethyl-cellulose (Ac-Di-Sol.RTM.), cross-linked
carboxymethylcellulose, or cross-linked croscarmellose, a
cross-linked starch such as sodium starch glycolate, a cross-linked
polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone,
alginate such as alginic acid or a salt of alginic acid such as
sodium alginate, a clay such as Veegum.RTM. HV (magnesium aluminum
silicate), a gum such as agar, guar, locust bean, Karaya, pectin,
or tragacanth, sodium starch glycolate, bentonite, a natural
sponge, a surfactant, a resin such as a cation-exchange resin,
citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in
combination starch, and the like.
[0179] In some embodiments, the formulations may also include
erosion facilitators. "Erosion facilitators" include materials that
control the erosion of a particular material in gastrointestinal
fluid. Erosion facilitators are generally known to those of
ordinary skill in the art. Exemplary erosion facilitators include,
e.g., hydrophilic polymers, electrolytes, proteins, peptides, and
amino acids.
[0180] In some embodiments, the formulations may also include one
or more filling agents, also referred to herein as fillers, which
include compounds such as lactose, calcium carbonate, calcium
phosphate, dibasic calcium phosphate, calcium sulfate,
microcrystalline cellulose, cellulose powder, dextrose, dextrates,
dextran, starches, pregelatinized starch, sucrose, xylitol,
lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol,
and the like.
[0181] In some embodiments, the formulations may also include one
or more flavoring agents and/or "sweeteners," e.g., acacia syrup,
acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian
cream berry, black currant, butterscotch, calcium citrate, camphor,
caramel, cherry, cherry cream chocolate, cinnamon, bubble gum,
citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool
cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus,
eugenol, fructose, fruit punch, ginger, glycyrrhetinate,
glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt,
lemon, lime, lemon cream, monoammonium glyrrhizinate, maltol,
mannitol, maple, marshmallow, menthol, mint cream, mixed berry,
neohesperidine DC, neotame, orange, pear, peach, peppermint,
peppermint cream, powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof.
[0182] In some embodiments, the formulations may also include one
or more lubricants and/or glidants, which are compounds that
prevent, reduce, or inhibit adhesion or friction of materials.
Exemplary lubricants include, e.g., stearic acid, calcium
hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as
mineral oil, or hydrogenated vegetable oil such as hydrogenated
soybean oil, higher fatty acids and their alkali-metal and alkaline
earth metal salts, such as aluminum, calcium, magnesium, zinc,
stearic acid, sodium stearates, glycerol, talc, waxes, boric acid,
sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol (e.g., PEG4000) or a methoxypolyethylene glycol
such as Carbowax.RTM., sodium oleate, sodium benzoate, glyceryl
behenate, polyethylene glycol, magnesium or sodium lauryl sulfate,
colloidal silica such as Syloid.RTM., Cab-O-Sil.RTM., a starch such
as corn starch, silicone oil, a surfactant, and the like.
[0183] In some embodiments, the formulations may also include one
or more solubilizers, which include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl
sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins for example Captisol.RTM., ethanol, n-butanol,
isopropyl alcohol, cholesterol, bile salts, polyethylene glycol
200-600, glycofurol, transcutol, propylene glycol, dimethyl
isosorbide, and the like. In one embodiment, the solubilizer is
vitamin E TPGS and/or Captisol.RTM..
[0184] In some embodiments, the formulations may also include one
or more suspending agents, which include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K112,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer
(S630), polyethylene glycol, e.g., the polyethylene glycol can have
a molecular weight of about 300 to about 6000, or about 3350 to
about 4000, or about 7000 to about 5400, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, hydroxymethylcellulose acetate
stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate,
gums, such as, e.g., gum tragacanth and gum acacia, guar gum,
xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, and the like.
[0185] In certain embodiments, the formulations may also include
one or more surfactants which include compounds such as sodium
lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin
E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like. Some other surfactants include
polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,
polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene
alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol
40. In some embodiments, surfactants may be included to enhance
physical stability or for other purposes.
[0186] In certain embodiments, the formulations may also include
one or more viscosity enhancing agents which include, e.g., methyl
cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose acetate stearate, hydroxypropylmethyl cellulose
phthalate, carbomer, polyvinyl alcohol alginates, acacia, chitosans
and combinations thereof.
[0187] In some embodiments, the formulations may also include one
or more wetting agents which include compounds such as oleic acid,
glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, sodium docusate, sodium
oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween
80, vitamin E TPGS, ammonium salts, and the like.
[0188] It should be appreciated that there is considerable overlap
between excipients used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of excipients that can be
included in solid dosage forms described herein. The types and
amounts of such excipient can be readily determined by one skilled
in the art, according to the particular properties desired.
EXAMPLES
Example 1
Examples of Composition of the Modified Release Drug Product
[0189] Compound (I) tablet is a modified release oral dosage form.
The present disclosure employs a "design space" concept to optimize
the modified release (MR) performance of the tablet drug product.
The "design space" is three dimensional, with varying dose, the
percentage of drug release modifier and the polymer coat percentage
to control the region of drug release and therefore delay the drug
release time.
[0190] The design space limits are: [0191] 1. Varying dose range
from 30 mg (low dose; D.sub.L (D=Dose; L=Low)) to 100 mg (high
dose; D.sub.H (H=High)); [0192] 2. Drug release modifier
(Dissolution Aid) to control drug release in the range of 0.5 to
1.5 hours post-gastric emptying. The drug release modifier is
Hypromellose K100 Premium LV and will be varied between 0%
(Dissomod is A.sub.F; F=Fast; No drug release modifier) and 35%
(Dissomod is A.sub.S; S=Slow; 35% drug release modifier); and
[0193] 3. Enteric polymer coat (e.g., Eudragit L30 D-55) percentage
between 7% (P.sub.F; F=Fast) and 16% (P.sub.S; S=Slow) to control
drug release, post gastric emptying.
[0194] Compound (I) tablet can be manufactured as a unit dose
selected from within the `design space`. If higher doses than 100
mg are required, multiple dose units can be administered.
[0195] The design space is shown in FIG. 2.
[0196] Under the composition details for the extremes of the
"design space" the Compound (1) drug substance mass, Hypromellose
K100 Premium LV and Eudragit L30 D55, as shown in Table 1 and 2,
can be varied. Any interim formulation within the "design space"
can be manufactured. All other components of the formulation will
remain constant or adjusted to maintain the weight of the
tablet.
TABLE-US-00001 TABLE 1 Composition of Compound (I) MR Tablet,
Corner 1, 2, 3 and 4 Quantity Quantity Quantity Quantity per
Tablet, per Tablet, per Tablet, per Tablet, (mg) (mg) (mg) (mg)
Component Corner 1 Corner 2 Corner 3 Corner 4 Compound (I) Drug
30.00 30.00 30.00 30.00 Substance Microcrystalline 347.15 172.15
172.15 347.15 cellulose PH101 Hypromellose K100 -- 175.00 175.00 --
Premium LV Mannitol (Pearlitol) 112.85 112.85 112.85 112.85 100SD
Crospovidone CL 5.00 5.00 5.00 5.00 Sodium Stearyl Fumarate 5.00
5.00 5.00 5.00 Total Weight of 500.0 500.0 500.0 500.0 Core Tablet
Opadry II yellow 17.50 17.5 17.50 17.50 Total weight of Sub- 517.5
517.5 517.5 517.5 Coated Tablet Eudragit L30 D55 28.53 28.53 65.25
65.25 PlasACRYL 5.64 5.64 12.89 12.89 Polysorbate 80 2.04 2.04 4.66
4.66 Total weight of 553.7 553.7 600.3 600.3 Coated Tablet Corner 1
- Formulation 1 low dose, fast release core, fast coat Corner 2 -
Formulation 2 low dose, slow release core, fast coat Corner 3 -
Formulation 3 low dose, slow release core, slow coat Corner 4 -
Formulation 4 low dose, fast release core, slow coat
TABLE-US-00002 TABLE 2 Composition of Compound (I) MR Tablet,
Corner 5, 6, 7 and 8 Quantity Quantity Quantity Quantity per
Tablet, per Tablet, per Tablet, per Tablet, (mg) (mg) (mg) (mg)
Component Corner 5 Corner 6 Corner 7 Corner 8 Compound (I) 100.00
100.00 100.00 100.00 Microcrystalline 347.15 347.15 172.15 172.15
cellulose PH101 Hypromellose K100 -- -- 175.00 175.00 Premium LV
Mannitol (Pearlitol) 42.85 42.85 42.85 42.85 100SD Crospovidone CL
5.00 5.00 5.00 5.00 Sodium Stearyl Fumarate 5.00 5.00 5.00 5.00
Total Weight of 500.0 500.0 500.0 500.0 Core Tablet Opadry II
yellow 17.50 17.50 17.50 17.50 Total weight of Sub- 517.5 517.5
517.5 517.5 Coated Tablet Eudragit L30 D55 65.25 28.53 28.53 65.25
PlasAcryl 12.89 5.64 5.64 12.89 Polysorbate 80 4.66 2.04 2.04 4.66
Total weight of 600.3 553.7 553.7 600.3 Coated Tablet Corner 5 -
Formulation 5 high dose, fast release core, slow coat Corner 6 -
Formulation 6 high dose, fast release core, fast coat Corner 7 -
Formulation 7 high dose, slow release core, fast coat Corner 8 -
Formulation 8 high dose, slow release core, slow coat
Example 2
[0197] General Procedure for Drug Dissolution and pH Change: The
tablet is placed in acid medium (pH 2) and kept therein for two (2)
hours. Thereafter phosphate buffer is added, which changes the pH
to 6.0. The tablet coating is dissolved at this pH; the tablet
breaks down and the drug is released. Prior to the pH change, i.e.,
in acid media, less than about 10% of the drug is released.
Dissolution profiles are obtained using HPLC.
Example 3
[0198] Dissolution profile of corner 1 formulation (30 mg, low dose
tablet, fast release core, fast coat, D.sub.LA.sub.FP.sub.F). It
takes approximately 30 minutes to approximately 45 minutes to
release about 80% of the drug after pH switch (from pH 2 to pH
6).
Example 4
[0199] Dissolution profile of corner 2 formulation (30 mg, low dose
tablet, slow release core, fast coat, D.sub.LA.sub.SP.sub.F). It
takes approximately 1 hour to release about 80% of drug after the
pH switch.
Example 5
[0200] Dissolution profile of corner 3 formulation (30 mg, low dose
tablet, slow release core, slow coat, D.sub.LA.sub.SP.sub.S). It
takes approximately 1.5 hours to release about 80% of drug after
the pH switch.
Example 6
[0201] Dissolution profile of corner 4 formulation (30 mg, low dose
tablet, fast release core, slow coat, D.sub.LA.sub.FP.sub.S). It
takes approximately 1.5 hours to release about 80% of drug after
the pH switch.
Example 7
[0202] Dissolution profile of corner 5 formulation (100 mg, high
dose tablet, fast release core, slow coat, D.sub.HA.sub.FP.sub.S).
It takes approximately 45 minutes to release about 80% of the drug
after pH switch.
Example 8
[0203] Dissolution profile of corner 6 formulation (100 mg, high
dose tablet, fast release core, fast coat, D.sub.HA.sub.FP.sub.F).
It takes approximately less than 30 minutes to release about 80% of
the drug after pH switch.
Example 9
[0204] Dissolution profile of corner 7 formulation (100 mg, high
dose tablet, slow release core, fast coat, D.sub.HA.sub.SP.sub.F).
It takes less than 2 hours to release about 80% of drug after the
pH switch.
Example 10
[0205] Dissolution profile of corner 8 formulation (100 mg, high
dose tablet, slow release core, slow coat, D.sub.HA.sub.SP.sub.S).
It takes approximately 2 hours to release about 80% of drug after
the pH switch.
Example 11
[0206] FIG. 3 shows the dissolution profile of all eight corners of
the "Design Space" Modified Release Tablet Formulation of Compound
(I), which is described in detail in Examples 3-10.
Example 12
[0207] Protocol for Preparing the Compound (I) Core Tablet: The
Compound (1) drug substance, Microcrystalline Cellulose PH 101,
Mannitol 100SD, and Hypromellose K100 Premium LV (if required) are
weighted and screened through a suitably sized sieve. The required
quantity of each is transferred into a suitably sized blender and
mechanically mixed.
[0208] The Crospovidone CL is weighed and screened through a
suitably sized sieve. The required quantity of Crospovidone is
transferred into the above-mentioned suitably sized container.
[0209] The sodium stearyl fumarate is weighed and screened through
a suitably sized sieve. The required quantity is transferred into
the above-mentioned suitably sized container and mechanically
mixed. This provides the Compound (I) Modified Release Tablet Blend
for compression.
[0210] The above-mentioned Compound (I) Modified Release Tablet
Blend for compression is individually weighed and transferred into
a tablet die for compression using a suitable tablet press. This
provides the Compound (I) Modified Release Core Tablet.
[0211] This core tablet is placed into a container closure
system.
Example 13
[0212] Protocol for Preparing the Compound (I) Modified Release
Prototype Tablet: The required amount of Opadry II yellow in
sterile water is dispersed for irrigation. It is stirred until
homogeneous. This provides the Sub-coating Suspension. The sub-coat
is applied on the Compound (I) core tablets with the Sub-coating
suspension in a perforated coating pan.
[0213] The Polysorbate 80 is dissolved in sterile water for
irrigation. The Eudragit L30 D-55 and PlasACRYL are dispersed into
the Polysorbate solution. The mixture is stirred until homogeneous.
This provides the Enteric coating Suspension.
[0214] The enteric coat is applied on the sub-coated Compound (I)
Modified Release Tablets in the perforated coating pan. The coated
tablets are cured. This provides the Enteric coated Compound (I)
Modified Release Tablet. All acceptable tablets are placed into the
final container closure and labeled.
[0215] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the disclosure should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *
References