NZ770365B2 - Compositions comprising 2-((1-(2(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one for treating schizophrenia - Google Patents
Compositions comprising 2-((1-(2(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one for treating schizophrenia Download PDFInfo
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- NZ770365B2 NZ770365B2 NZ770365A NZ77036515A NZ770365B2 NZ 770365 B2 NZ770365 B2 NZ 770365B2 NZ 770365 A NZ770365 A NZ 770365A NZ 77036515 A NZ77036515 A NZ 77036515A NZ 770365 B2 NZ770365 B2 NZ 770365B2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The disclosure provides a novel polymorph of Compound (I): 2-((1-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one monohydrochloride dihydrate, i.e., Form (A) of Compound (I)·HCl·2H2O. Pharmaceutical compositions comprising Compound (I) and a release modifier are also disclosed.
Description
COMPOSITIONS COMPRISING 2-((1-(2(4-FLUOROPHENYL)
OXOETHYL)PIPERIDINYL)METHYL)ISOINDOLINONE FOR TREATING
SCHIZOPHRENIA
CROSS REFERENCES
This application is a divisional of New Zealand Patent Application No. 732033,
filed on November 30, 2015 which is the National Phase Entry of International Application
No. filed on November 30, 2015 and claims the benefit of U.S.
Provisional Application Serial No. 62/086,691, filed December 2, 2014, and U.S. Provisional
Application Serial No. 62/248,071, filed October 29, 2015, each of which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention in some embodiments relates to compositions and methods
for treating schizophrenia in a patient.
BACKGROUND OF THE INVENTION
Schizophrenia is a complex, challenging, and heterogeneous psychiatric condition,
affecting up to 0.7% of the world population according to the World Health Organization
(WHO, 2006). Patients suffering with schizophrenia present with a range of symptoms,
including: positive symptoms, such as delusions, hallucinations, thought disorders, and
agitation; negative symptoms, such as mood flatness and lack of pleasure in daily life;
cognitive symptoms, such as the decreased ability to understand information and make
decisions, difficulty focusing, and decreased working memory function; and sleep disorders.
The etiology of schizophrenia is not fully understood. A major explanatory
hypothesis for the pathophysiology of schizophrenia is the Dopamine (DA) hypothesis, which
proposes that hyperactivity of DA transmission is responsible for expressed symptoms of the
disorder. This hypothesis is based on the observation that drugs effective in treating
schizophrenia share the common feature of blocking DA D2 receptors. However, these so-
called typical antipsychotics are associated with a very high incidence of extrapyramidal
symptoms (EPS). Furthermore, negative symptoms and cognitive impairment are considered
relatively unresponsive to typical antipsychotics.
Most currently approved therapies for schizophrenia show efficacy primarily in the
management of positive symptoms. An estimated 4.2 million people suffered from
schizophrenia in 2012 in the United States and the five major European Union markets. Of
those, an estimated 48% experienced predominantly negative symptoms and 80% suffered
from cognitive impairment. In addition, about 50% of patients with schizophrenia experience
sleep disorders, which can further exacerbate both positive and negative symptoms.
The introduction of the so-called atypical antipsychotics in the last decade
represented a significant advance in the treatment of schizophrenia. Although these atypical
antipsychotics differ widely in chemical structure and receptor-binding profiles, they share a
characteristic of potent antagonism of the Serotonin (5-hydroxytryptamine) type 2 receptor (5-
HT2A). A high 5-HT2A:D2 affinity ratio is thought to substantially reduce the liability for
inducing EPS, compared with typical antipsychotics.
However, many patients are still treatment-noncompliant despite the advantage of
atypical antipsychotics of tolerability. Although the risk of EPS is clearly lower with the
atypical antipsychotics, the high doses required with some atypical antipsychotics are likely to
result in an increased incidence of EPS and require concomitant medications such as
antiparkinson drugs.
In addition to EPS, antipsychotic medications cause a broad spectrum of side effects
including sedation, anticholinergic effects, prolactin elevation, orthostatic hypotension,
weight gain, altered glucose metabolism, and QTc prolongation. These side effects can affect
patients’ compliance with their treatment regimen. It should be noted that noncompliance with
treatment regimen is a primary reason for relapse of the disease.
Although atypical antipsychotics offer advantages over typical antipsychotics in
terms of symptom alleviation and side effect profile, these differences are generally modest. A
certain population of patients still remains refractory to all currently available antipsychotics.
Newer agents to address these issues continue to be sought.
The disclosure provides compositions, methods, and kits to address this long-felt
and unmet need for a treatment for schizophrenia that is effective for all subjects, particularly
those who are not effectively treated by currently available therapies. The compositions,
methods, and kits of the disclosure lead to greater patient compliance.
SUMMARY
The disclosure provides a novel polymorph of Compound (I),
(also known as MIN-101, CYR-101 and MT-210),
which has shown effectiveness in animal models of psychosis (see also U.S. Patent No.
7,166,617, the contents of which are incorporated herein in their entirety). Compound (I) is an
antipsychotic drug belonging to a new chemical class, the cyclic amido derivatives. The
chemical designation is 2-((1-(2-(4-Fluorophenyl)oxoethyl)piperidin
yl)methyl)isoindolinone monohydrochloride dihydrate.
As used herein, the novel polymorph of Compound (I):
, 2-((1-(2-(4-Fluorophenyl)oxoethyl)piperidin
yl)methyl)isoindolinone monohydrochloride dihydrate, is also referred to as Form (A) of
Compound (I) ·HCl ·2H O.
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O is characterized by
XRPD.
[0014] In one embodiment, Form (A) of Compound (I) ·HCl ·2H O is characterized by IR.
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O is characterized by H
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O is characterized by C
[0017] The disclosure provides a process for preparing Form (A) of Compound
(I) ·HCl ·2H O.
The disclosure provides pharmaceutical compositions comprising Form (A) of
Compound (I) ·HCl ·2H O and a pharmaceutically acceptable diluent, excipient, or carrier.
The disclosure provides a method of treating a neuropsychiatric disease or disorder,
comprising administering a therapeutically effective amount of Form (A) of Compound
(I) ·HCl ·2H O or a pharmaceutical composition thereof to a subject in need thereof.
The disclosure provides a method for treating schizophrenia, comprising
administering a therapeutically effective amount of Form (A) of Compound (I) ·HCl ·2H O or a
pharmaceutical composition thereof to a subject in need thereof.
[0021] The disclosure relates to use of a pharmaceutical formulation of the invention, in the
manufacture of a medicament for treating schizophrenia.
The disclosure provides a kit comprising a pharmaceutical composition comprising
Form (A) of Compound (I) ·HCl ·2H O and instructions for use.
Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art to which this
invention belongs. In the specification, the singular forms also include the plural unless the
context clearly dictates otherwise. Although methods and materials similar or equivalent to
those described herein can be used in the practice or testing of the disclosure, suitable
methods and materials are described below. All publications, patent applications, patents, and
other references mentioned herein are incorporated by reference. The references cited herein
are not admitted to be prior art to the claimed invention. In the case of conflict, the present
specification, including definitions, will control. In addition, the materials, methods, and
examples are illustrative only and are not intended to be limiting.
Other features and advantages of the disclosure will be apparent from the following
detailed description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing summary, as well as the following detailed description of the
invention, will be better understood when read in conjunction with the appended drawings.
Figure 1 is a graph illustrating plasma concentration – time profiles of MIN-101.
Figure 2 is a graph illustrating plasma concentration – time profiles of BFB-520.
[0028] Figure 3 is a graph illustrating plasma concentration – time profiles of BFB-999.
Figure 4 is a graph illustrating plasma concentrations of MIN-101, BFB-520, and
BFB-999 by period.
Figure 5 is a series of graphs illustrating the changes in QTcF by BFB-520, BFB-
999, and CYR-101 concentrations.
[0031] Figure 6 is a diagram illustrating a scheme of monitoring sleep using PSG and V-
Watch.
Figure 7 is a diagram illustrating Part 1 Study Design.
Figure 8 is a diagram illustrating Part 2 Study Design.
Figure 9 is a diagram illustrating Study Period Scheme.
[0035] Figure 10 is a diagram illustrating Global Study Design for Phase IIB in patients
with schizophrenia.
Figure 11 is an X-ray powder diffraction of Form (A) of Compound (I) ·HCl ·2H O.
Figure 12 is an IR spectrum of Form (A) of Compound (I) ·HCl ·2H O.
Figure 13 is a H-NMR spectrum of Form (A) of Compound (I) ·HCl ·2H O.
[0039] Figure 14 is a C-NMR spectrum of Form (A) of Compound (I) ·HCl ·2H O.
Figure 15 is an IR spectrum comparison between batch C001 and V039SS
(secondary reference standard from MTPC).
Figure 16 is a H-NMR spectrum of batch C001 (from PCAS).
Figure 17 is a C-NMR spectrum for batch C001 (from PCAS).
Figure 18 is a mass spectrum of Form (A) of Compound (I) ·HCl ·2H O by MALDI-
TOF (from MTPC).
Figure 19 is a mass spectrum of Form (A) of Compound (I) ·HCl ·2H O by ESI
ionization for bath C001 (from PCAS).
DETAILED DESCRIPTION OF THE INVENTION
The disclosure provides compositions, methods, and kits for the treatment of a
neuropsychiatric disease or condition. Preferably the neuropsychiatric disease or condition is
schizophrenia. Compositions and kits of the disclosure include pharmaceutical compositions.
Compositions of the disclosure comprise a stable polymorph of Compound (I) ·HCl ·2H O,
which is preferably Form (A) of Compound (I) ·HCl ·2H O.
Form A of Compound (I)
The disclosure pertains, at least in part, to a stable polymorph of Compound
(I) ·HCl ·2H O.
In one embodiment, the polymorph of Compound (I) ·HCl ·2H O is Form (A).
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O has an X-ray powder
diffraction pattern substantially similar to that shown in Figure 11.
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O has X-ray powder
diffraction peaks at approximately 7.6 and 14.3 °2? using Cu Ka radiation.
In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 14.3, and 14.7 °2? using Cu Ka radiation.
In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 14.3, and 27.5 °2? using Cu Ka radiation.
[0052] In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 14.3, 14.7, and 27.5 °2? using Cu Ka radiation.
In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 14.3, 14.7, 18.6, and 27.5 °2? using Cu Ka radiation.
In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 14.3, 14.7, 14.9, 18.6, 27.5 and 30.1 °2? using Cu Ka radiation.
In one embodiment, Form (A) has X-ray powder diffraction peaks at approximately
7.6, 11.2, 14.3, 14.7, 14.9, 18.6, 22.0, 25.9, 27.5 and 30.1 °2? using Cu Ka radiation.
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O has an IR absorption
spectrum substantially similar to that shown in Figure 12.
In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 2916 cm .
In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 1684 cm .
[0059] In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 1665 cm .
In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 1594 cm .
In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 1235 cm .
In one embodiment, Form (A) has an IR absorption spectrum with a main wave
number of absorption at 1684 and 1665
In one embodiment, Form (A) has an IR absorption spectrum with main wave
numbers of absorption at 2916, 1684, and 1665 cm .
In one embodiment, Form (A) has an IR absorption spectrum with main wave
numbers of absorption at 2916, 1684, and 1665 cm .
In one embodiment, Form (A) has an IR absorption spectrum with main wave
numbers of absorption at 2916, 1594, and 1235 cm .
[0066] In one embodiment, Form (A) has an IR absorption spectrum with main wave
numbers of absorption at 2916, 1684, 1665, and 1235 cm .
In one embodiment, Form (A) has an IR absorption spectrum with main wave
numbers of absorption at 2916, 1684, 1665, 1594, and 1235 cm .
In one embodiment, Form (A) of Compound (I) ·HCl ·2H2O has a H NMR spectrum
substantially similar to that shown in Figure 13.
In one embodiment, Form (A) of Compound (I) ·HCl ·2H O has a C NMR spectrum
substantially similar to that shown in Figure 14.
In one embodiment, Form (A) has C NMR spectrum peaks at 164.7, 166.7, 167.6,
and 190.1 d in d -dimethyl sulfoxide.
[0071] In one embodiment, Form (A) has C NMR spectrum peaks at 60.6, 164.7, 166.7,
167.6, and 190.1 d in d -dimethyl sulfoxide.
In one embodiment, Form (A) has C NMR spectrum peaks at 50.2, 60.6, 164.7,
166.7, 167.6, and 190.1 d in d -dimethyl sulfoxide.
In one embodiment, Form (A) has C NMR spectrum peaks at 46.5, 50.2, 60.6,
164.7, 166.7, 167.6, and 190.1 d in d -dimethyl sulfoxide.
The application also pertains, at least in part, to a process for preparing a polymorph
of Compound (I) ·HCl ·2H O.
In one embodiment, the disclosure pertains to a process for making Form (A) of
Compound (I) ·HCl ·2H2O.
[0076] In one embodiment, Form (A) of Compound (I) ·HCl ·2H O is prepared by a process
comprising: (1) reaction of the free base of Compound (I) with hydrochloric acid in acetone;
(2) heating of the crude Compound (I) in acetone and water, followed by cooling, filtration,
and drying under reduced pressure.
[0077] The disclosure also pertains, at least in part, to a process for preparing a highly pure
form of a polymorph of Compound (I) ·HCl ·2H O. In one embodiment, the highly pure form
of a polymorph of Compound (I) ·HCl ·2H O is Form (A). In one embodiment, Form (A) has a
purity of at least 90%. In one embodiment, Form (A) has a purity of at least 92%. In one
embodiment, Form (A) has a purity of at least 94%. In one embodiment, Form (A) has a
purity of at least 95%. In one embodiment, Form (A) has a purity of at least 96%. In one
embodiment, Form (A) has a purity of at least 97%. In one embodiment, Form (A) has a
purity of at least 98%. In one embodiment, Form (A) has a purity of at least 99%. In one
embodiment, Form (A) has a purity of at least 99.5%. In one embodiment, Form (A) has a
purity of at least 99.6%. In one embodiment, Form (A) has a purity of at least 99.7%. In one
embodiment, Form (A) has a purity of at least 99.8%.
The disclosure also pertains, at least in part, to a process for preparing a polymorph
form of Compound (I) ·HCl ·2H O with minimal amounts of impurities. In one embodiment,
the polymorph form of Compound (I) ·HCl ·2H O with minimal amounts of impurities is Form
(A). In one embodiment, the form of a polymorph of Compound (I) ·HCl ·2H2O with minimal
amounts of impurities is Form (A), wherein the impurities are (V), ,
O O F
(VI), , or (VII), . In
one embodiment, Form (A), contains less than 3% combined of impurities (V), (VI), and
(VII). In one embodiment, Form (A), contains less than 2.5% combined of impurities (V),
(VI), and (VII). In one embodiment, Form (A), contains less than 2% combined of impurities
(V), (VI), and (VII). In one embodiment, Form (A), contains less than 1.5% combined of
impurities (V), (VI), and (VII). In one embodiment, Form (A), contains less than 1%
combined of impurities (V), (VI), and (VII). In one embodiment, Form (A), contains less
than 0.5% combined of impurities (V), (VI), and (VII).
In another embodiment, Form (A) contains less than 0.5% of impurity (V). In
another embodiment, Form (A) contains less than 0.2% of impurity (V). In another
embodiment, Form (A) contains less than 0.1% of impurity (V).
In another embodiment, Form (A) contains less than 1% of impurity (VI). In
another embodiment, Form (A) contains less than 0.5% of impurity (VI). In another
embodiment, Form (A) contains less than 0.2% of impurity (VI). In another embodiment,
Form (A) contains less than 0.1% of impurity (VI).
In another embodiment, Form (A) contains less than 1% of impurity (VII). In
another embodiment, Form (A) contains less than 0.5% of impurity (VII). In another
embodiment, Form (A) contains less than 0.2% of impurity (VII). In another embodiment,
Form (A) contains less than 0.1% of impurity (VII).
The disclosure also pertains to pharmaceutical compositions comprising a
polymorph of Compound (I) ·HCl ·2H O and one or more pharmaceutically acceptable
diluents, excipients, or carriers. In one embodiment, the pharmaceutical compositions
comprise Form (A) of Compound (I) ·HCl ·2H O and one or more pharmaceutically acceptable
diluents, excipients, or carriers.
The disclosure also pertains to a method of treating a neuropsychiatric disease or
disorder, comprising administering a therapeutically effective amount of a polymorph of
Compound (I) ·HCl ·2H2O or a pharmaceutical composition thereof to a subject in need
thereof.
In one embodiment, the disclosure also pertains to a method of treating a
neuropsychiatric disease or disorder, comprising administering a therapeutically effective
amount of Form (A) of Compound (I) ·HCl ·2H O, or a pharmaceutical composition thereof, to
a subject in need thereof.
[0085] In one embodiment, the neuropsychiatric disease is schizophrenia.
The term “polymorph” is synonymous with “crystalline polymorph”, “crystal
polymorph”, “crystal form” and “polymorphic form.” Each term refers to a crystal structure
in which Compound (I) ·HCl ·2H O crystallizes in a specific crystal packing arrangements, i.e.,
Form (A), which has the same elemental composition as Compound (I) ·HCl ·2H2O.
The differences in physical properties exhibited by polymorphs affect
pharmaceutical parameters such as storage stability, compressibility and density (important in
formulation and product manufacturing), and dissolution rates (an important factor in
bioavailability). Differences in stability can also result from changes in chemical reactivity
(e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised
of one polymorph than when comprised of another polymorph or amorphous form) or
mechanical property (e.g., tablets crumble on storage as a kinetically favored polymorph or
amorphous form converts to thermodynamically more stable polymorph or amorphous form)
or both (e.g., tablets of one polymorph or amorphous form are more susceptible to breakdown
at high humidity). In addition, the physical properties of the crystal may be important in
processing, for example, a polymorph or amorphous form might be more likely to form
solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size
distribution might be different between a polymorph and an amorphous form).
A polymorph of a molecule can be obtained by a number of methods, as known in
the art. Such methods include, but are not limited to, melt recrystallization, melt cooling,
solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor
diffusion, and sublimation.
Techniques for characterizing polymorphs include, but are not limited to,
differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal
X-ray diffractometry, vibrational spectroscopy (e.g., IR and Raman spectroscopy), TGA,
DTA, DVS, solid state NMR, hot stage optical microscopy, scanning electron microscopy
(SEM), electron crystallography and quantitative analysis, particle size analysis (PSA),
surface area analysis, solubility studies, and dissolution studies.
As used herein, the term “amorphous form” refers to a noncrystalline solid state
form of a substance.
As used herein, a compound is “stable” where significant amounts of degradation
products are not observed under constant conditions of humidity (e.g., 10%, 20%, 30%, 40%,
50%, 60%, 70%, 75%, 80%, 85%, 90%, and 95% relative humidity , light exposure and
o o o o o o o o
temperatures (e.g., higher than 0 C, e.g., 20 C, 25 C, 30 C, 35 C, 40 C, 45 C, 50 C, 55
o o o o
C, 60 C, 65 C, and 70 C) over a certain period (e.g., one week, two weeks, three weeks,
and four weeks). A compound is not considered to be stable at a certain condition when
degradation impurities appear or an area percentage (e.g., AUC as characterized by HPLC) of
existing impurities begins to grow. The amount of degradation growth as a function of time is
important in determining compound stability.
As used herein, the term “mixing” means combining, blending, stirring, shaking,
swirling, or agitating. The term “stirring” means mixing, shaking, agitating, or swirling. The
term “agitating” means mixing, shaking, stirring, or swirling.
Unless explicitly indicated otherwise, the terms “approximately” and “about” are
synonymous. In one embodiment, “approximately” and “about” refer to recited amount,
value, or duration ± 20%, ± 15%, ± 10%, ± 8%,± 6%, ± 5%, ± 4%,± 2%, ± 1%, or ± 0.5%. In
another embodiment, “approximately” and “about” refer to listed amount, value, or duration ±
%, ± 8%,± 6%, ± 5%, ± 4%, or ± 2%. In yet another embodiment, “approximately” and
“about” refer to listed amount, value, or duration ±5%.
[0094] When the terms “approximately” and “about” are used when reciting XRPD peaks,
these terms refer to the recited X-ray powder diffraction peak ± 0.5 °2?, ± 0.4 °2? ± 0.3 °2? ,
± 0.2 °2?, or ± 0.1 °2?. In another embodiment, the terms “approximately” and “about” refer
to the listed X-ray powder diffraction peak ± 0.2 °2?. In another embodiment, the terms
“approximately” and “about” refer to the listed X-ray powder diffraction peak ± 0.1 °2?.
[0095] When the terms “approximately” and “about” are used when reciting temperature or
temperature range, these terms refer to the recited temperature or temperature range ± 5 °C, ±
2 °C, or ± 1 °C. In another embodiment, the terms “approximately” and “about” refer to the
recited temperature or temperature range ± 2 °C.
Compound (I)
The disclosure provides pharmaceutical formulations of Compound (I):
or a pharmaceutically acceptable salt thereof.
In one embodiment, the formulations of the disclosure provide maximum plasma
concentration (C ) and area under the curve (AUC) of Compound (I) and its two active
metabolites (BFB-520 and BFB-999) at levels associated with improved therapeutic response
and fewer adverse reactions (e.g., prolongation of QT intervals).
In one embodiment, the formulations of the disclosure increase the maximum
plasma concentration (C ) and area under the curve (AUC) of BFB-999 and at the same
time reduce the maximum plasma concentration (C ) and area under the curve (AUC) of
BFB-520.
In one embodiment, the formulations of the disclosure provide a maximum plasma
concentration (C ) of Compound (I) below 50 ng/mL, below 45 ng/mL, below 40 ng/mL,
below 35 ng/mL, below 30 ng/mL, below 25 ng/mL, below 20 ng/mL, below 15 ng/mL, or
below 10 ng/mL. In one embodiment, the formulations of the disclosure provide an AUC of
Compound (I) below 400 hr*ng/mL, below 350 hr*ng/mL, below 300 hr*ng/mL, below 250
hr*ng/mL, below 200 hr*ng/mL, below 150 hr*ng/mL, or below 100 hr*ng/mL.
[00100] In one embodiment, the formulations of the disclosure provide a maximum
plasma concentration (C ) of BFB-520 below 5.0 ng/mL, below 4.5 ng/mL, below 4.0
ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5 ng/mL, below 2.0 ng/mL, below 1.5
ng/mL, or below 1.0 ng/mL. In one embodiment, the formulations of the disclosure provide
an AUC of BFB-520 below 40 hr*ng/mL, below 35 hr*ng/mL, below 30 hr*ng/mL, below 25
hr*ng/mL, below 20 hr*ng/mL, below 15 hr*ng/mL, or below 10 hr*ng/mL. In one
embodiment, BFB-520 is associated with prolongation of QT intervals at supra-therapeutic
levels.
In one embodiment, to avoid QT prolongation, maximum plasma
concentration (Cmax) of Compound (I) and BFB-520 should not exceed 80 ng/mL and 12
ng/mL respectively. In one embodiment, the formulations of the disclosure provide a C of
BFB-520 below 10 ng/mL, below 9.0 ng/mL, below 8.0 ng/mL, below 7.0 ng/mL, below 6.0
ng/mL, 5.0 ng/mL, below 4.5 ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL,
below 2.5 ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL. In one
embodiment, the formulations of the disclosure provide a C of BFB-999 below 5.0 ng/mL,
below 4.5 ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5 ng/mL,
below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL. In one embodiment, the
formulations of the disclosure provide an AUC of BFB-999 below 40 hr*ng/mL, below 35
hr*ng/mL, below 30 hr*ng/mL, below 25 hr*ng/mL, below 20 hr*ng/mL, below 15
hr*ng/mL, or below 10 hr*ng/mL.
[00102] In one embodiment, the formulations of the disclosure comprise about 1-100
mg of Compound (I), about 1-75 mg of Compound (I), about 2-75 mg of Compound (I), about
-75 mg of Compound (I), about 10-75 mg of Compound (I), about 15-75 mg of Compound
(I), about 15-70 mg of Compound (I), about 15-65 mg of Compound (I). In one embodiment,
the formulations of the disclosure comprise about 16 mg of Compound (I), about 32 mg of
Compound (I), about 40 mg of Compound (I), or about 64 mg of Compound (I).
In one embodiment, the formulations of the disclosure are suitable for chronic
administration (e.g., one week, two weeks, three weeks, four weeks, two months, four
months, six months, eight months, ten months, one year, two years, three years, four years,
and five years).
In one embodiment, the formulations of the disclosure are administered once
daily.
In one embodiment, the formulations of the disclosure are administered to a
subject under a fast condition. In one embodiment, the formulations of the disclosure are
administered to a subject at least 4 hours after the subject has taken a meal, at least 6 hours
after the subject has taken a meal, at least 8 hours after the subject has taken a meal, at least
hours after the subject has taken a meal, at least 12 hours after the subject has taken a meal.
In one embodiment, the formulations of the disclosure are administered to a subject under a
fed condition. In one embodiment, the formulations of the disclosure are administered to a
subject within 4 hour after the subject has taken a meal, within 3 hours after the subject has
taken a meal, within 2 hours after the subject has taken a meal, within 1 hour after the subject
has taken a meal, or within 0.5 hour after the subject has taken a meal.
By “a meal” it means any amount of food, which includes any sources of
carbohydrate, protein, amino acid, etc.
[00107] In one embodiment, the formulations of the disclosure are suitable for oral
administration, intravenous administration, intramuscular administration, or subcutaneous
administration. In one embodiment, the formulations of the disclosure are suitable for oral
administration. In one embodiment, the formulations of the disclosure are in the form of a
tablet or capsule.
[00108] In one embodiment, the tablet formulation comprises Compound (I), a release
modifier, a filler, a glidant, and a lubricant. In one embodiment, the release modifier is
hypromellose (e.g., hypromellose K100LV CR, hypromellose K4M CR, hypromellose E50,
or a combination thereof). In one embodiment, the filler is microcrystalline cellulose, lactose,
or a combination thereof. In one embodiment, the glidant is silica colloidal anhydrous. In one
embodiment, the lubricant is magnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or
a combination thereof.
In a further embodiment, the tablet formulation may further comprise a binder,
such as hydroxypropylcellulose. In a further embodiment, the tablet formulation may further
comprise a disintegrant, such as crospovidone. In a further embodiment, the tablet formulation
may further comprise an anti-adherent, such as talc. In a further embodiment, the tablet
formulation may further comprise a pH adjuster, such as an organic or inorganic acid or an
organic or inorganic base. In a further embodiment, the tablet formulation may further
comprise sweeting agent, such a sugar (e.g., mannitol).
In one embodiment, the release profile of the tablet formulation is controlled
by varying the amount of the release modifier in the formulation. In one embodiment, the
release rate of Compound (I) from the tablet formulation is decreased by increasing the
amount of the release modifier.
In one embodiment, the formulations of the disclosure are in an immediate
release form. In one embodiment, the formulations of the disclosure are in a modified release
form. In one embodiment, the modified release formulations are in a slow- (release rate of 16-
24 hours), medium- (release rate of 10-12 hours) or fast- (release rate of 5-7 hours) release
form.
In one embodiment, the formulations of the disclosure are in a controlled
release form.
[00113] In one embodiment, the formulations of the disclosure are in a sustained
release form (e.g., the release takes place for at least 4 hours, 6 hours, 8 hours, 10 hours, 12
hours, 18 hours, or 24 hours). In one embodiment, the formulations of the disclosure are in the
form of a slow sustained release form.
The disclosure also relates to methods for treating neuropsychiatric diseases
and disorders, in particular, schizophrenia, comprising administering a therapeutically
effective amount of a formulation of the invention to a subject in need thereof.
In one embodiment, a method for treating or diminishing at least one symptom
of neuropsychiatric diseases and disorders, in particular, schizophrenia, is provided,
comprising administering a therapeutically effective amount of a formulation of the invention
to a subject in need thereof.
In one embodiment, a method for treating or diminishing at least one symptom
of schizophrenia is provided, comprising administering a therapeutically effective amount of a
formulation of the invention to a subject in need thereof.
In one embodiment, a method for treating or diminishing at least one symptom
of schizophrenia is provided, comprising administering a formulation of the invention to a
subject in need thereof, wherein the amount of Compound (I) is in the range of about 1-100
mg, about 1-75 mg, about 2-75 mg, about 5-75 mg, about 10-75 mg, about 15-75, about 15-70
mg, or about 15-65 mg.
In one embodiment, a method for treating or diminishing at least one symptom
of schizophrenia is provided, comprising administering a formulation of the invention to a
subject in need thereof, wherein the amount of Compound (I) is about 16 mg, about 32 mg,
about 40 mg, or about 64 mg.
In one embodiment, the formulations of the disclosure are administered for
treating or diminishing at least one symptom of schizophrenia associated with the negative
and/or positive symptoms of schizophrenia, cognitive function, sleep architecture and
continuity, and social functioning.
In another embodiment, the formulations of the disclosure are administered for
improving depressive symptoms.
[00121] In one embodiment, a method for treating or diminishing at least one condition
or disorder associated with depression is provided, comprising administering a formulation of
the invention to a subject in need thereof.
In another embodiment, a method for improving sleep, such as sleep
architecture and continuity, is provided, comprising administering a formulation of the
invention to a subject in need thereof.
In one embodiment, a method for treating or diminishing at least one aspect of
a sleep disorder in a subject afflicted with neuropsychiatric diseases and disorders, in
particular, schizophrenia, is provided, comprising administering a formulation of the
invention to the subject. In one embodiment, at least one aspect of a sleep disorder is treated.
In another embodiment, at least one aspect of a sleep disorder is improved. In an aspect, the
disruption of at least one aspect of sleep is associated with schizophrenia.
Various aspects of sleep may be treated, including, but not limited to, sleep
onset latency, latency to persistent sleep, distribution of slow wave sleep across the sleep
period time, or one or more segments of sleep period time, overall sleep continuity and sleep
architecture.
Cognitive impairment is the diminished ability to think, concentrate, formulate
ideas, reason and remember. In one embodiment, a method for treating or diminishing
cognitive impairment or improving cognition is provided, comprising administering a
formulation of the invention to a subject in need thereof. In one embodiment, a method is
provided for treating schizophrenia without provoking cognitive impairment.
In one embodiment, a method is provided for treating schizophrenia and
restoring, enhancing, and improving cognition, in a subject following discontinuation of
treatment with another active pharmaceutical ingredient, for example, an anti-depressant
compound.
[00127] In one embodiment, a method is provided for treating schizophrenia in
combination with a cognition impairing active pharmaceutical ingredient (for example, a
cognition impairing anti-depressant compound), without causing or increasing cognitive
impairment, or for improving, enhancing or restoring cognition in a subject.
In another embodiment, cognitive impairment present in a subject suffering
from schizophrenia is treated or diminished by the administration of a formulation of the
invention to the subject. As will be understood based on the disclosure herein, modification of
sleep parameters can improve cognition. By way of a non-limiting example, improvement
and/or an increase in slow wave sleep (SWS) improves cognition. In an aspect, cognition in
general is improved. In another aspect, one or more aspects of cognition are improved,
including, among others, memory consolidation, executive functions, verbal memory, and
verbal fluency. In one embodiment, cognition is improved in a subject to the point where
normal cognition is restored in the subject. In another embodiment, cognition is improved in a
subject beyond the point of normal cognition in the subject, such that levels of cognition in
the subject are enhanced.
[00129] In one embodiment, cognition is improved in a subject afflicted with
schizophrenia.
The active ingredient is Compound (I) (also known as CYR-101 and MT-210).
U.S. Pat. No. 7,166,617, incorporated herein by reference in its entirety, discloses cyclic
amide derivatives including Compound (I), 2-{1-[2-(4-Fuorophenyl)oxoethyl] piperidin
ylmethyl}-2,3-dihydroisoindolone monohydrochloride dihydrate. The derivatives
disclosed in U.S. Pat. No. 7,166,617 were found to have high affinity for the sigma ligand
binding site and low inhibition constant Ki for sigma 1 and/or sigma 2. It was also found that
these compounds had a selective binding profile completely different from those of
conventional known compounds, and were useful for treatment of diseases that can be
therapeutically and/or preventively treated by the nerve control function of the sigma ligands.
The formulations of Compound (I) as described herein represent an important
milestone in an effort to develop customized formulations of neuropsychiatric therapies based
on optimal efficacy, safety, tolerability and pharmacokinetic profiles. The formulations as
described herein are able to target significant areas of unmet need in the treatment of negative
symptoms, cognitive impairments and sleep disorders while offering a highly favorable safety
profile.
The formulations of the disclosure are able to maintain plasma levels of
Compound (I) over the course of one day while reducing BFB-520 levels and increasing
levels of BFB-999 associated with sleep improvements due to its affinity to 5-HT2A and
histaminergic H1 receptors. It is shown that the formulations of the disclosure lower levels of
BFB-520, which is associated with prolongation of QT intervals at supra-therapeutic levels.
The QT interval represents the duration of ventricular depolarization and
subsequent repolarization, and is measured from the beginning of the QRS complex to the end
of the T wave. A delay in cardiac repolarization creates an electrophysiological environment
that favors the development of cardiac arrhythmias, most clearly torsade de pointes (TdP), but
possibly other ventricular tachyarrhythmias as well. TdP is a polymorphic ventricular
tachyarrhythmia that appears on the ECG as continuous twisting of the vector of the QRS
complex around the isoelectric baseline. A feature of TdP is pronounced prolongation of the
QT interval in the supraventricular beat preceding the arrhythmia. TdP can degenerate into
ventricular fibrillation, leading to sudden death. According to ICH-E14 on Clinical Evaluation
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs,
discontinuation of a subject from a clinical trial should be considered if there is a marked
prolongation of the QT/QTc interval during treatment with the study drug, especially if the
measurement is obtained from more than one ECG.
[00134] The disclosure provides an optimal formulation which reduces the risk of
QT/QTc prolongation and achieves a once a day dosing strategy to facilitate patient
compliance.
Definitions
[00135] In other embodiments, as set forth in greater detail elsewhere herein, the
dosage and dosing regimen for Compound (I) and/or Form A of Compound (I) may be
optimized based on the health and condition of the subject to be treated, as well as the desired
outcome of the treatment.
The term "receptor", as used herein, means a molecule, with which one or
more kinds of signaling molecules can specifically interact. For example, the 5-HT1A
receptor is a subtype of the 5-HT receptor, which binds the neurotransmitter serotonin ("5-
hydroxytryptamine").
The term "subject" refers to any animal, including mammals, such as, but not
limited to, humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or
primates.
The term "treating" (and corresponding terms "treat" and "treatment") includes
palliative, restorative, and preventative ("prophylactic") treating of a subject. The term
"palliative treating" refers to treatment that eases or reduces the effect or intensity of a
condition in a subject without curing the condition. The term "preventative treating" (and the
corresponding term "prophylactic treating") refers to treatment that prevents the occurrence of
a condition in a subject. The term "restorative treating" ("curative") refers to treatment that
halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a
condition in a subject. Treating can be done with a therapeutically effective amount of
compound, salt or composition that elicits the biological or medicinal response of a tissue,
system or subject that is being sought by an individual such as a researcher, doctor,
veterinarian, or clinician. The term "treatment" will also be understood to include not only a
complete remission of all symptoms experienced by the treated individual, but also the
alleviation of one or more existing symptoms, as well as the prevention of occurrence of
symptoms by preemptive administration of a compound of formula I to an individual prone to
or likely to develop any of the symptoms, such as those with chronic or recurrent
neuropsychiatric disease or disorder.
The term “modified release” as used herein can be understood as the escape of
the drug from the tablet has been modified in some way. Usually this is to slow the release of
the drug so that the medicine does not have to be taken too often and therefore improves
compliance. The other benefit from modifying release is that the drug release is controlled and
there are smaller peaks and troughs in blood levels therefore reducing the chance of peak
effects and increasing the likelihood of therapeutic effectiveness for longer periods of time.
The pattern of drug release from modified-release (MR) dosage forms is
deliberately changed from that of a conventional (immediate-release) dosage formulation to
achieve a desired therapeutic objective or better patient compliance. Types of MR drug
products may include delayed release (e.g., enteric coated), extended release (ER), and orally
disintegrating tablets (ODT).
The term modified-release formulation can be used to describe formulation
that alters 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 including:
An extended-release formulation refers to a formulation that allows at least a
two-fold reduction in dosage frequency as compared to an immediate-release (conventional)
dosage form. Examples of extended-release dosage forms include controlled-release,
sustained-release, and long-acting drug products.
A delayed-release formulation refers to a formulation 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).
The term “compounds of the disclosure” of “compound of the disclosure”
refers to Compound (I), Form A of Compound (I) or a pharmaceutically acceptable salt
thereof as described herein.
The term "pharmaceutically acceptable", as used herein with respect to a
compound or composition, refers to a form of the compound or composition that can increase
or enhance the solubility or availability of the compound in a subject, in order to promote or
enhance the bioavailability of the compound or composition.
[00146] The term "pharmaceutically acceptable salt" is to describe a salt form of one or
more of the compositions herein which are presented to increase the solubility of the
compound, for example, in the gastric juices of the patient's gastrointestinal tract in order to
promote dissolution and the bioavailability of the compounds and/or compositions. In an
embodiment, pharmaceutically acceptable salts include those derived from pharmaceutically
acceptable inorganic or organic bases and acids. Suitable salts include those derived from
alkali metals such as potassium and sodium, alkaline earth metals such as calcium,
magnesium and ammonium salts, among numerous other acids well known in the
pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization
salts of carboxylic acids and free acid phosphate containing compositions encompassed by the
present disclosure. The term "salt" shall mean any salt consistent with the use of the
compounds encompassed by the present disclosure. In the case where the compounds are used
in pharmaceutical indications, including the treatment of depression, the term "salt" shall
mean a pharmaceutically acceptable salt, consistent with the use of the compounds as
pharmaceutical agents.
[00147] As used herein, the term pharmaceutically acceptable salts refer to salts that
retain the desired biological activity of the parent compound and exhibit minimal, if any,
undesired toxicological effects. Nonlimiting examples of such salts are (a) acid addition salts
formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic
acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic
acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acids,
naphthalenedisulfonic acids, and polygalacturonic acid; (b) base addition salts formed with
polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum,
copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with an organic cation
formed from N,N-dibenzylethylene-diamine, ammonium, or ethylenediamine; or (c)
combinations of (a) and (b); e.g., a zinc tannate salt or the like.
In an embodiment, compositions comprise base addition salts of the present
compound. The chemical bases that may be used as reagents to prepare pharmaceutically
acceptable base salts of the present compounds that are acidic in nature are those that form
non-toxic base salts with such compounds. Such non-toxic base salts include, but are not
limited to those derived from such pharmacologically acceptable cations such as alkali metal
cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and
magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine
(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically
acceptable organic amines, among others.
A “composition” or “pharmaceutically acceptable composition” is a
formulation containing a compound of the invention or salt, solvate, ester, or amino acid
conjugate thereof. In one embodiment, the pharmaceutical composition is in bulk or in unit
dosage form. The unit dosage form is any of a variety of forms, including, for example, a
capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of
active ingredient (e.g., a formulation of a compound of the invention or salts thereof) in a unit
dose of composition is an effective amount and is varied according to the particular treatment
involved. One skilled in the art will appreciate that it is sometimes necessary to make routine
variations to the dosage depending on the age and condition of the patient. The dosage will
also depend on the route of administration. A variety of routes are contemplated, including
oral, ocular, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous,
intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for the
topical or transdermal administration of a compound of this invention include powders,
sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In another
embodiment, the active compound is mixed under sterile conditions with a pharmaceutically
acceptable carrier, and with any preservatives, buffers, or propellants that are required.
In certain embodiments, the pharmaceutical formulations or compositions of
the present invention may additionally contain other adjunct components conventionally
found in pharmaceutical compositions, at their art-established usage levels. Thus, for
example, the compositions may contain additional materials useful in physically formulating
various dosage forms of the compositions of the present invention, such as dyes, flavoring
agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However,
such materials, when added, should not unduly interfere with the biological activities of the
components of the compositions of the present invention. The formulations can be sterilized
and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting
agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings
and/or aromatic substances and the like which do not deleteriously interact with the
oligonucleotide(s) of the formulation.
In certain embodiments, pharmaceutical compositions of the present invention
comprise one or more excipients. In certain such embodiments, excipients are selected from
water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium
stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
In certain embodiments, a pharmaceutical composition of the present invention
is prepared using known techniques, including, but not limited to mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting
processes.
Modifications of a compound can affect the solubility, bioavailability and rate
of metabolism of the active species, thus providing control over the delivery of the active
species. Further, the modifications can affect the desired activity of the compound, in some
cases increasing the activity over the parent compound. This can easily be assessed by
preparing the derivative and testing its antidepressant activity according to the methods
encompassed herein, or other methods known to those skilled in the art.
Compositions encompassed herein may be administered orally. In other
embodiments, compositions may be administered parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, percutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or
infusion techniques. As will be understood by the skilled artisan, in view of the embodiments
encompassed herein, the means of administration and the dosage of active ingredient or
ingredients (e.g., a compound of formula I) may be adjusted upward or downward based on
the selected route of administration. Furthermore, it will be understood that optimizing the
dosage of active ingredient for any selected dosage form may be desired and can be achieved
by using the methods described herein or known in the art to evaluate the effectiveness of
antipsychotic compounds.
[00155] The pharmaceutical compositions embodied herein may be orally administered
in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous
suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used
include lactose and corn starch. In an embodiment, lubricating agents, such as magnesium
stearate, are also added. For oral administration in a capsule form, useful diluents include
lactose and/or dried corn starch, as two non-limiting examples. When aqueous suspensions
are required for oral use, the active ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
In one embodiment, formulations of the present invention may be administered
in conjunction with one or more other medications. Such other medications may be
administered or co-administered in forms and dosages as known in the art.
The term "co-administration" or "combination therapy" is used to describe a
therapy in which at least two compounds are used to treat schizophrenia or another
neuropsychiatric disease or condition as described herein at the same time. In an embodiment,
at least two compounds in effective amounts are used to treat schizophrenia or another
neuropsychiatric disease or condition at the same time. In another embodiment, at least two
compounds, the combination of which comprises an effective amount, are used to treat
schizophrenia or another neuropsychiatric disease or condition as described herein at the same
time. In an embodiment, the result of treatment with the at least two compounds may be
additive of the treatment results obtained using each compound separately, either directly
additive, or additive to a degree lesser than the results obtained with the two compounds
separately. In an embodiment, the result of treatment with the at least two compounds may be
synergistic, to varying degrees. In an embodiment, the result of treatment with the at least two
compounds may be less than the treatment results obtained using each compound separately.
In an aspect, the result of treatment with a composition encompassed herein is such that, for
one compound, the result of treatment is less than that obtained with the compound
separately, while the results of treatment with respect to the other compounds in the
composition are about the same as the results of treatment obtained separately.
Although the term co-administration encompasses the administration of two
active compounds to the patient at the same time, it is not necessary that the compounds be
administered to the patient at the same time, although effective amounts of the individual
compounds will be present in the patient at the same time.
In an embodiment, a compound set forth herein can be co-administered with
one or more atypical antipsychotics. Examples of atypical antipsychotics include, but are not
limited to fluphenazine, risperidone, olanzapine, clozapine, quetiapine, ziprasidone,
aripiprazole, seritindole, zotepine, and perospirone. Examples of antidepressants useful in
combination therapy as encompassed herein include, but are not limited to, fluoxetine,
citalopram, escitalopram, venlafaxine, duloxetine, bupropion.
Synthesis of Compound (I)
[00160] Standard synthetic methods and procedures for the preparation of organic
molecules and functional group transformations and manipulations, including the use of
protective groups, can be obtained from the relevant scientific literature or from standard
reference textbooks in the field. Although not limited to any one or several sources,
recognized reference textbooks of organic synthesis include: Smith, M. B.; March, J. March’s
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 ed.; John Wiley &
Sons: New York, 2001; and Greene, T.W.; Wuts, P.G. M. Protective Groups in Organic
Synthesis, 3 ; John Wiley & Sons: New York, 1999.
A method for preparing Compound (I) is described in U.S. Patent No.
7,166,617, the entire contents of which is incorporated herein by reference.
Pharmaceutical Compositions of Form (A) of Compound (I) ·HCl ·2H O
The disclosure also provides pharmaceutical compositions comprising form
(A) of Compound (I) ·HCl ·2H O and one or more pharmaceutically acceptable diluents,
excipients, or carriers.
[00163] A “pharmaceutical composition” is a formulation containing form (A) of
Compound (I) ·HCl ·2H O in a form suitable for administration to a subject. In one
embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit
dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a
tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a
formulation of form (A) of Compound (I) ·HCl ·2H O) in a unit dose of composition is an
effective amount and is varied according to the particular treatment involved. One skilled in
the art will appreciate that it is sometimes necessary to make routine variations to the dosage
depending on the age and condition of the patient. The dosage will also depend on the route
of administration. A variety of routes are contemplated, including oral, pulmonary, rectal,
parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal,
inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage
forms for the topical or transdermal administration of form (A) of Compound (I) ·HCl ·2H O
include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and
inhalants. In one embodiment, form (A) of Compound (I) ·HCl ·2H2O is mixed under sterile
conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or
propellants that are required.
As used herein, the phrase “pharmaceutically acceptable” refers to those
compounds, materials, compositions, carriers, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for use in contact with the tissues of human beings
and animals without excessive toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
“Pharmaceutically acceptable excipient” means an excipient that is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary
use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used
in the specification and claims includes both one and more than one such excipient.
A pharmaceutical composition of the disclosure is formulated to be compatible
with its intended route of administration. Examples of routes of administration include
parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal
(topical), and transmucosal administration. Solutions or suspensions used for parenteral,
intradermal, or subcutaneous application can include the following components: a sterile
diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine,
propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such
as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents
for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted
with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral
preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of
glass or plastic.
The term “therapeutically effective amount”, as used herein, refers to an
amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or
condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected
by any assay method known in the art. The precise effective amount for a subject will depend
upon the subject’s body weight, size, and health; the nature and extent of the condition; and
the therapeutic or combination of therapeutics selected for administration. Therapeutically
effective amounts for a given situation can be determined by routine experimentation that is
within the skill and judgment of the clinician. In an aspect, the disease or disorder to be
treated is a neuropsychiatric disease or disorder. In another aspect, the disease or condition to
be treated is schizophrenia.
For any compound, the therapeutically effective amount can be estimated
initially either in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or
pigs. The animal model may also be used to determine the appropriate concentration range
and route of administration. Such information can then be used to determine useful doses and
routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be
determined by standard pharmaceutical procedures in cell cultures or experimental animals,
e.g., ED (the dose therapeutically effective in 50% of the population) and LD (the dose
50 50
lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the
therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical
compositions that exhibit large therapeutic indices are preferred. The dosage may vary within
this range depending upon the dosage form employed, sensitivity of the patient, and the route
of administration.
Dosage and administration are adjusted to provide sufficient levels of the
active ingredient or to maintain the desired effect. Factors which may be taken into account
include the severity of the disease state, general health of the subject, age, weight, and gender
of the subject, diet, time and frequency of administration, drug combination(s), reaction
sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions
may be administered every 3 to 4 days, every week, or once every two weeks depending on
half-life and clearance rate of the particular formulation.
[00170] The pharmaceutical compositions containing form (A) of Compound
(I) ·HCl ·2H O may be manufactured in a manner that is generally known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be
formulated in a conventional manner using one or more pharmaceutically acceptable carriers
comprising excipients and/or auxiliaries that facilitate processing of the active ingredient into
preparations that can be used pharmaceutically. Of course, the appropriate formulation is
dependent upon the route of administration chosen.
Pharmaceutical compositions suitable for injectable use include sterile aqueous
solutions (where water soluble) or dispersions and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersion. For intravenous administration,
suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ? (BASF,
Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be
sterile and should be fluid to the extent that easy syringeability exists. It must be stable under
the conditions of manufacture and storage and must be preserved against the contaminating
action of microorganisms such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol,
propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
The proper fluidity can be maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of dispersion and by the use of
surfactants. Prevention of the action of microorganisms can be achieved by various
antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic
acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents,
for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the
composition. Prolonged absorption of the injectable compositions can be brought about by
including in the composition an agent which delays absorption, for example, aluminum
monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating form (A) of
Compound (I) ·HCl ·2H2O in the required amount in an appropriate solvent with one or a
combination of ingredients enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating form (A) of Compound (I) ·HCl ·2H O
into a sterile vehicle that contains a basic dispersion medium and the required other
ingredients from those enumerated above. In the case of sterile powders for the preparation of
sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that
yields a powder of form (A) of Compound (I) ·HCl ·2H O plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
Oral compositions generally include an inert diluent or an edible
pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed
into tablets. For the purpose of oral therapeutic administration, form (A) of Compound
(I) ·HCl ·2H O can be incorporated with excipients and used in the form of tablets, troches, or
capsules. Oral compositions can also be prepared using a fluid carrier for use as a
mouthwash, wherein form (A) of Compound (I) ·HCl ·2H O in the fluid carrier is applied
orally and swished and expectorated or swallowed. Pharmaceutically compatible binding
agents, and/or adjuvant materials can be included as part of the composition. The tablets,
pills, capsules, troches and the like can contain any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid,
Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as
colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent
such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, form (A) of Compound (I) ·HCl ·2H O is
delivered in the form of an aerosol spray from pressured container or dispenser, which
contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means.
For transmucosal or transdermal administration, penetrants appropriate to the barrier to be
permeated are used in the formulation. Such penetrants are generally known in the art, and
include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid
derivatives. Transmucosal administration can be accomplished through the use of nasal
sprays or suppositories. For transdermal administration, form (A) of Compound
(I) ·HCl ·2H O is formulated into ointments, salves, gels, or creams as generally known in the
Form (A) of Compound (I) ·HCl ·2H O can be prepared with pharmaceutically
acceptable carriers that will protect the compound against rapid elimination from the body,
such as a controlled release formulation, including implants and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods
for preparation of such formulations will be apparent to those skilled in the art. The materials
can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
Liposomal suspensions (including liposomes targeted to infected cells with monoclonal
antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These
can be prepared according to methods known to those skilled in the art, for example, as
described in U.S. Pat. No. 4,522,811 (the contents of which are incorporated herein in their
entirety).
[00177] It is especially advantageous to formulate oral or parenteral compositions in
dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as
used herein refers to physically discrete units suited as unitary dosages for the subject to be
treated; each unit containing a predetermined quantity of active ingredient calculated to
produce the desired therapeutic effect in association with the required pharmaceutical carrier.
The specification for the dosage unit forms of the disclosure are dictated by and directly
dependent on the unique characteristics of form (A) of Compound (I) ·HCl ·2H O and the
particular therapeutic effect to be achieved.
In therapeutic applications, the dosages of the pharmaceutical compositions
used in accordance with the application vary depending on the agent, the age, weight, and
clinical condition of the recipient patient, and the experience and judgment of the clinician or
practitioner administering the therapy, among other factors affecting the selected dosage.
Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In an aspect,
dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In an aspect, the
dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25
g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to
about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the
patient’s weight in kg, body surface area in m , and age in years). In other aspects, dosages
can range from about 16 mg of Compound (I) per day to about 64 mg of Compound (I) per
day administered in a single dose. In another aspect, dosages can range from about 30 mg of
Compound (I) per day to about 50 mg of Compound (I) per day administered in a single dose.
In an aspect, the dosage of Compound (I) in the pharmaceutical composition is 30 mg per day,
31 mg per day, 32 mg per day, 33 mg per day, 34 mg per day, 35 mg per day, 36 mg per day,
37 mg per day, 38 mg per day, 39 mg per day, 40 mg per day, 41 mg per day, 42 mg per day,
43 mg per day, 44 mg per day, 45 mg per day, 46 mg per day, 47 mg per day, 48 mg per day,
49 mg per day, and 50 mg per day administered in a single dose. In one embodiment, the
dosage of Compound (I) in the pharmaceutical composition is 40 mg per day administered as
a single dose.
An effective amount of a pharmaceutical agent is that which provides an
objectively identifiable improvement as noted by the clinician or other qualified observer. As
used herein, the term “dosage effective manner” refers to amount of form (A) of Compound
(I) ·HCl ·2H O to produce the desired effect in a subject.
The pharmaceutical compositions can be included in a container, pack, or
dispenser together with instructions for administration.
The pharmaceutical composition of the disclosure, are administered orally,
nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally,
subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and
parenterally. In one embodiment, form (A) of Compound (I) ·HCl ·2H O is administered
orally. One skilled in the art will recognize the advantages of certain routes of administration.
The dosage regimen utilizing form (A) of Compound (I) ·HCl ·2H O is selected
in accordance with a variety of factors including type, species, age, weight, sex and medical
condition of the patient; the severity of the condition to be treated; the route of administration;
the renal and hepatic function of the patient; and the particular compound or salt thereof
employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe
the effective amount of the drug required to prevent, counter or arrest the progress of the
condition.
Techniques for formulation and administration of the disclosed compounds of
the application can be found in Remington: the Science and Practice of Pharmacy, 19
edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, form (A) of Compound
(I) ·HCl ·2H O is used in pharmaceutical preparations in combination with a pharmaceutically
acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid
fillers or diluents and sterile aqueous or organic solutions. Form (A) of Compound
(I) ·HCl ·2H O will be present in such pharmaceutical compositions in amounts sufficient to
provide the desired dosage amount in the range described herein.
All percentages and ratios used herein, unless otherwise indicated, are by
weight.
Methods of Treatment
The disclosure also provides methods of treating a neuropsychiatric disease or
disorder in a subject in need thereof by administering to a subject in need of such treatment, a
therapeutically effective amount of form (A) of Compound (I) ·HCl ·2H O, or a pharmaceutical
composition thereof. The neuropsychiatric disease or disorder can be schizophrenia.
The term "subject" refers to any animal, including mammals, such as, but not
limited to, humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or
primates. Subjects may or may not have been diagnosed with Schizophrenia. Subjects may
present one or more signs or symptoms of schizophrenia.
In certain embodiments, subjects of the disclosure may have been treated for
schizophrenia with one or more typical or atypical anti-psychotic therapies prior to, in
combination with, or following treatment with a pharmaceutical composition comprising form
(A) of Compound (I). In certain embodiments, subjects of the disclosure may have been
treated for schizophrenia with one or more typical or atypical anti-psychotic therapies prior to
treatment with a pharmaceutical composition comprising form (A) of Compound (I) and the
one or more typical or atypical anti-psychotic therapies may have been ineffective to treat a
sign or symptom of schizophrenia in the subject.
Other features and advantages of the disclosure are apparent from the different
examples. The provided examples illustrate different components and methodology useful in
practicing the disclosure.
The examples do not limit the claimed compositions, methods, and kits of the
disclosure. Based on the present disclosure the skilled artisan can identify and employ other
components and methodology useful for practicing the disclosure.
EXAMPLES
Example 1
Increases in QTc interval were observed and seemed to be related to the
exposure to Compound (I) and its metabolite BFB-520. QT prolongation was particularly
obvious in a patient who was CYP2D6 poor metabolizer and who showed high plasmatic
levels of BFB-520. A further analysis of the relationship between QT/QTc and Compound (I)
and BFB-520 concentrations was performed. It was determined that to avoid QT
prolongation, Cmax of Compound (I) and BFB-520 should not exceed 80 ng/mL and 12
ng/mL respectively.
In order to further evaluate the incidence of QT/QTc changes from baseline
greater than 30 and 60 ms and the incidence of QTc values greater than 450, 480 and 500 ms,
the following study was conducted.
Part 1 of this study was designed to characterize and compare the
pharmacokinetic (PK) profile of Compound (I) when administered as MR formulations, and
food effects, following a single dose administration in a 6-way, within subject, crossover
design.
Part 2 of the study was designed to evaluate the effect of multiple doses of the
MR formulation chosen on safety, tolerability and cardiovascular parameters. Effects of
Compound (I) on sleep parameters will be also evaluated. In the CYR-101C01 study,
Compound (I) had an effect on slow wave sleep (SWS) distribution: Compound (I)
significantly increased SWS in the first third of the night and decreased it in the last third of
the night. Results also suggested that Compound (I) could have sleep promoting effects since
it improved sleep initiation parameters (sleep onset latency, latency to persistent sleep). In the
current study, sleep will be used as a biomarker that could help in defining the minimal active
dose to be assessed in the next patient study. Sleep parameters will be analyzed by mean of
VWatch methodology.
The formulations used in Part 1 of the study were selected from a design space
with active treatment, Compound (I) and HPMC a release controlling agent as the 2 main
compositional variables. On the release rate axis of the design space, MR formulations will be
described as slow (release rate of 16-19 hours), medium (release rate of 10-12 hours) or fast
(release rate of 5-7 hours). The 2-dimensional compositional formulation design space is
shown in Scheme 1, where F1 to F4 represent the boundary formulations.
Part 2 of the study was designed to assess the multiple dose administration of
the selected formulation from Part 1 at a low and high dose level compared with placebo in a
larger naïve cohort of subjects.
Pharmacologic Profile (Nonclinical Studies):
In in vitro receptor binding studies, Compound (I) demonstrated a unique
binding profile. Compound (I) bound with high affinity only to 5-HT2A, a1-adrenergic and
sigma2 receptors (K =7.53, 14.43, 8.19 nmol/ L, respectively). The affinity for DA receptors
was fairly weak (IC > 1000 nmol/L). Both main metabolites BFB-520 and BFB-999 showed
a similar profile as Compound (I), with lower affinity for s2 receptors, and lower and equal
affinity to that of Compound (I) for 5-HT2A receptors, respectively.
In in vivo functional tests, Compound (I) acted as an antagonist at sigma2 and
-HT2A receptors. Following oral administration, Compound (I) slightly increased dopamine
turnover in the accumbens and striatum and increased the output of DA metabolites such as
DOPAC and HVA in prefrontal cortex at high dose levels. At effective dose levels in animal
models of antipsychotic activity, Compound (I) did not affect monoamine levels, whereas,
other antipsychotics markedly increased DA turnover and the output of DOPAC and HVA,
reflecting their potent D2 antagonistic effects.
Compound (I) was tested in male Wistar rats in several behavioral paradigms
designed to evaluate the potential for producing antipsychotic activity of drugs in humans.
Compound (I) inhibited methamphetamine-, apomorphine-, and phencyclidine-induced
hyperlocomotion in a similar manner to other antipsychotics. Likewise, BFB-520 and BFB-
999 also inhibited methamphetamine-induced hyperlocomotion with an ED50 higher than that
of Compound (I). Furthermore, Compound (I) significantly ameliorated PCP-induced social
interaction impairment after repeated administration, whereas, other atypical antipsychotics
did not ameliorate this impairment, and improved impairment of spontaneous alternation
behavior induced by MK-801.
Safety Pharmacology:
In a series of safety pharmacology studies, the effects of Compound (I) on
general activity and behavior, the CNS, respiratory function, gastrointestinal system, and
water and electrolyte excretion were examined in rats at an oral dose range of 1 to 30 mg/kg
Compound (I) induced various changes in general activity and behavior. These clinical signs
were observed between 0.25 to 4 hours post-dosing and disappeared by 6 hours post-dosing.
Compound (I) inhibited CNS function and decreased thresholds for electroshock-induced
convulsion. High doses (> 10 mg/kg) of Compound (I) affected respiratory function, inhibited
gastric emptying, damaged the gastrointestinal membrane, decreased urine volume, and
increased urine potassium excretion.
The effects of Compound (I) on the cardiovascular system were examined in in
vitro and in vivo studies. In in vitro electrophysiological studies using guinea pig papillary
muscle, Compound (I) at 1 µM or more prolonged the action potential duration (APD) and at
the same degree as risperidone and haloperidol. Likewise, BFB-520 at 0.1 µM or more and
BFB-999 at 1 µM or more prolonged the APD in isolated guinea pig papillary muscles with
the same or stronger degree than Compound (I). In in vitro electrophysiological studies using
cultured cells expressing cloned cardiac ion channels, Compound (I) inhibited IKr current
with an IC50 of 0.325 µM, comparable to that of risperidone (0.319 µM). As for BFB-520, it
blocked IKr current with an IC50 of 0.181 µM lower than that of the parent compound but
higher than those of haloperidol (0.026 µM), thioridazine (0.145 µM) or ziprasidone (0.134
Pharmacokinetic profile:
Pharmacokinetic (PK) studies of Compound (I) have been performed
particularly in rats and monkeys. Following a single oral administration, Compound (I) was
rapidly absorbed. Plasma radioactivity peaked between 0.63 and 2.75 hours in male rats, and
between 3 and 3.5 hours in male monkeys. The oral absorption rates were 90.3 to 94.7% in
rats and 70.0 to 99.9% in monkeys. The elimination half-lives of radioactivity from plasma
were 45.13 to 51.52 hours in rats and 174.74 to 184.78 hours in monkeys. The elimination
half-lives of unchanged Compound (I) were 1.68 to 2.06 hours in rats, and 1.68 to 2.57 hours
in monkeys. The absolute oral bioavailability of Compound (I) was 52.4 to 64.5% in rats and
90% or higher in monkeys.
[00202] During repeated administration of 1 mg/kg/day for 14 days to male rats,
plasma radioactivity increased with increasing number of doses, reaching steady-state after
the 7 administration. Food and gender effects were also assessed in rats. When Compound
(I) was administered orally to non-fasted rats at 1 mg/kg, plasma radioactivity has a delayed
T by about 1 h and a decreased C to about 72% of the value in fasted male rats, though
max max
AUCs were similar in the two groups. Moreover pharmacokinetic parameters for total
radioactivity in female rats were comparable to those in male rats. When C-Compound (I)
was orally administered to lactating rats, it was considered that Compound (I) and/or its
metabolites rapidly transferred into milk and were slowly eliminated.
Compound (I) absorption was also studied in single and repeated dose toxicity
studies in rats and monkeys for toxicokinetics and, in genotoxicity and embryofetal
development studies for plasma exposure evidence. After single and repeated administration,
exposure levels of Compound (I) and its main metabolites BFB-520 and BFB-999 increased
in a dose-dependent manner in both rats and monkeys, with gender difference in rats only.
After single administration of BFB-520 in monkeys, exposure levels of BFB-
520, Compound (I) and BFB-999 increased with a dose increment larger than the
proportionate one. BFB-520 reached its maximum concentration within 4 hours post-dosing,
and T for Compound (I) and BFB-999 were comparable to that of BFB-520. Finally, the
brain transfer of Compound (I) was studied with male rats after oral administration (10
mg/kg). The Cmax of plasma and brain concentrations were 3164.62 ng/mL and 4946.62 ng/g,
respectively. The K value (brain/plasma concentration ratio) was 1.38 mL/g.
Several metabolites (i.e. BFB-999, BFB-520 and BFB-885) were detected in
plasma and urine of male and female rats and male monkeys after oral administration of
14CCompound (I). The metabolic rate in female rats was slower than that in male rats, but the
metabolic profiles were similar between male and female rats. Even if Compound (I) was
shown to be metabolized in BFB-520 and BFB-999 by cytochromes P450 CYP1A2,
CYP2C19, CYP2D6 and CYP3A4, further studies using human liver microsomes suggest that
Compound (I) is mainly metabolized by enzymatic reaction other than CYP isoforms. As for
BFB-520, it was metabolized by CYP2D6 and CYP3A4. No remarkable inhibitory effects on
human P450 isoforms (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2E1 and 3A4) were observed,
while a weak inhibitory effect was shown on CYP2D6. Investigation of the drug-drug
interaction of Compound (I) on in vitro metabolism determined IC value more than 50 µM
for the following concomitant drugs: ketoconazole, fluvoxamine, paroxetine, and lorazepam.
The major route of elimination of radioactivity in rats and monkeys following
a single oral or intravenous administration was via the feces. The excretion to bile was 44.2%
within 48 hours after a single oral administration to bile duct cannulated rats. Urinary
excretion rates of radioactivity were about 35% in rats and monkeys. Total recovery of given
radioactivity was 101.1% (including the carcass) for rats and 92.6% for monkeys within 168
hours after a single oral administration. After repeated administration to rats for 14 days, the
total recovery of given radioactivity was 96.6% in urine and feces, and 0.7% in carcass within
168 hours after the last administration. The enterohepatic circulation rate was determined to
be about 27% after intraduodenal administration of bile samples from C-Compound (I)-
treated rats.
In an embodiment, the compositions may be formulated in a conventional
manner using one or more pharmaceutically acceptable carriers and may also be administered
in controlled-release formulations.
Example 2
Part 1 of the study is an open-label, non-randomized, single dose, 6-period
crossover design in 12 healthy CYP 2D6 EM male subjects. For Part 1, subjects will receive
the following regimens in a non-randomised manner:
Regimen A: MR Formulation prototype 1: 32 mg Compound (I) slow release
administered in the fasted state
Regimen B: MR Formulation prototype 2 administered in the fasted state
Regimen C: MR Formulation prototype 3 administered in the fasted state or
formulation prototype 1 or 2 administered in the fed state
Regimen D: MR Formulation prototype 4 administered in the fasted state or
formulation prototype 1, 2 or 3 administered in the fed state
Regimen E: MR Formulation prototype 5 administered in the fasted state or
formulation prototype 1, 2, 3 or 4 administered in the fed state
[00214] Regimen F: MR Formulation prototype 1, 2, 3, 4 or 5 administered in fed state.
Formulation selection within Part 1 are made after a complete review of all
data collected from the previous regimen and the formulation, doses and requirement for the
optional return visit for Part 2 are made after a complete review of all data from Part 1.
Part 2 of the study is a double-blind, randomized, placebo-controlled, 6-
sequence, 3-period crossover design in 24 healthy CYP 2D6 EM male and female subjects.
For Part 2, on each of the 3 study periods, subjects receive the following regimes in a
randomized manner:
Regimen G: Placebo QD for 7 days
Regimen H: High dose MR formulation prototype QD for 7 days
[00219] Regimen I: Low dose MR formulation prototype QD for 7 days
Based on the above concept of design space, the IMP formulations used in Part
1 of the study are selected from a design space with active treatment Compound (I) and
Hypromellose (HPMC) as the release controlling agent (the release controlled by the HPMC
viscosity based on the ratio of 2 HPMC polymers) as the two main compositional variables.
The 2-dimensional compositional formulation design space is shown in Table 1, where F1 to
F4 represent the boundary formulations. Part 2 of the study is designed to assess the multiple
dose administration of the selected formulation from Part 1 at a low and high dose level
compared with placebo in a larger naïve cohort of subjects.
Table 1: Excipient Quantitative Composition Range for Design Space
Component 16mg Slow 64mg Slow 16mg Fast 64mg Fast
Formulation 1 Formulation 2 Formulation 3 Formulation 4
% w/w % w/w % w/w % w/w
Compound (I)* 6.40 25.60 6.40 25.60
Hypromellose 12.00 6.00 36.00 30.00
K100LV CR
Hypromellose 24.00 24.00 - -
K4M CR
Microcrystalline 36.10 22.90 36.10 22.90
Cellulose
PH102**
Lactose Fastflo 20.00 20.00 20.00 20.00
Silica Colloidal 0.50 0.50 0.50 0.50
Anhydrous,
Aerosil 200
Pharma
Magnesium 1.00 1.00 1.00 1.00
stearate
Total 100.00 100.00 100.00 100.00
* Salt correction factor of 1.2 applied.
**The amount of Microcrystalline Cellulose PH102 will be adjusted accordingly to maintain
the same tablet weight.
[00222] Under the composition details we therefore present the extremes of dose range
of 16 - 64 mg Compound (I) and ranges for levels of Hypromellose K100LV CR and
Hypromellose K4M CR in the MR tablet, with the understanding that any interim formulation
within these ranges could be manufactured and dosed as an IMP during the clinical study. All
other components of the formulations remain constant with the exception of Microcrystalline
Cellulose PH102 which may be adjusted to maintain tablet weight based on the potency and
purity of the drug substance and weights for Hypromellose K100LV CR and Hypromellose
K4M CR. The final composition of the selected formulations is recorded in batch records
produced for clinical trial manufactures.
Composition of Compound (I) Prototype MR Tablet (Formulations 1, 2, 3, and 4)
The complete statement of the components and quantitative composition of
Compound (I) Prototype MR Tablet Formulations 1, 2, 3, and 4 is given in Table 2. In line
with the formulation design space approach described in Section 2.1.P.1, this formulation
represents the extremes of dose range of 16 - 64 mg Compound (I) and ranges in
concentrations of Hypromellose K100LV CR and Hypromellose K4M CR that could be used
in the study.
Table 2: Composition of Compound (I) Prototype MR Tablet (Formulations 1,
2, 3 and 4)
Component 16mg Slow 64mg Slow 16mg Fast 64mg Fast Function Ref. to
Formulation Formulation Formulation Formulation Standard
1 2 3 4
mg/tablet mg/tablet mg/tablet mg/tablet
Compound (I) 19.20 76.80 19.20 76.80 Active DS Section
or other as
appropriate
Hypromellose 36.00 18.00 108.00 90.00 Release USP, Ph.
K100LV CR Modifier Eur., JP
Hypromellose 72.00 72.00 - - Release USP, Ph.
K4M CR Modifier Eur., JP
Microcrystalline 108.30 68.70 108.30 68.70 Filler Ph. Eur.,
Cellulose NF, JP
PH102
Lactose Fastflo 60.00 60.00 60.00 60.00 Filler NF/ USP,
316 Ph. Eur.,
Silica Colloidal 1.50 1.50 1.50 1.50 Glidant USP, Ph.
Anhydrous, Eur., JP
Aerosil 200
Pharma
Magnesium 3.00 3.00 3.00 3.00 Lubricant Ph. Eur.,
stearate NF, JP
Total weight 300.00 300.00 300.00 300.00
Salt correction factor of 1.2 applied
The amount of Microcrystalline Cellulose PH102 will be adjusted accordingly to maintain
the same tablet weight.
[00225] Table 3 shows the batch formulae for Compound (I) Prototype MR Tablet
Formulations 1, 2, 3 and 4. These formulations represent the extremes of the dose range of
Compound (I) and concentrations of Hypromellose K100LV CR and Hypromellose K4M CR
that could be used in the study. The compositional ratio of Silica Colloidal Anhydrous,
Lactose Fastflo 316 and Magnesium Stearate will remain constant. The compositional ratio of
Microcrystalline Cellulose PH102 may be adjusted based on the potency and purity of the
drug substance and the weights for Hypromellose K100LV CR and Hypromellose K4M CR
to maintain tablet weight of 300mg.
Table 3: “Design Space” Batch Formulae for Compound (I) Prototype MR
Tablet
Component 16mg Slow 64mg Slow 16mg Fast 64mg Fast
Formulation 1 Formulation 2 Formulation 3 Formulation 4
% w/w % w/w % w/w % w/w
Compound (I) 6.40 25.60 6.40 25.60
Hypromellose 12.00 6.00 36.00 30.00
K100LV CR
Hypromellose 24.00 24.00 - -
K4M CR
Microcrystalline 36.10 22.90 36.10 22.90
Cellulose
PH102
Lactose Fastflo 20.00 20.00 20.00 20.00
Silica Colloidal 0.50 0.50 0.50 0.50
Anhydrous,
Aerosil 200
Pharma
Magnesium 1.00 1.00 1.00 1.00
stearate
Total 100.00 100.00 100.00 100.00
Salt correction factor of 1.2 applied.
The amount of Microcrystalline Cellulose PH102 will be adjusted accordingly to maintain
the same tablet weight.
Scheme 2: Manufacture of Compound (I) Prototype MR Tablet
Component Process Control
Compound (I) Weigh the required Quantity of Compound (I)
Hypromellose K100LV quantity of Compound (I), Quantity of Hypromellose
CR Hypromellose K100LV K100LV CR
Hypromellose K4M CR CR, Hypromellose K4M Quantity of Hypromellose
(if required) CR (if required), K4M CR (if required)
Microcrystalline Cellulose Microcrystalline Cellulose Quantity of
PH102 PH102, Lactose Fastflo Microcrystalline Cellulose
Lactose Fastflo 316 316 and Silica Colloidal PH102
Silica Colloidal Anhydrous and screen Quantity of Lactose
Anhydrous, Aerosil 200 through a suitably sized Fastflo 316
Pharma sieve. Transfer into a Quantity of Silica
suitably sized container Colloidal Anhydrous,
and mix. Aerosil 200 Pharma
Mesh size of sieve screen
Screen the entire blend Mixing Time and Speed
through a suitably sized
sieve. Transfer into the
original suitably sized
container and mix.
Magnesium stearate Weigh the required Quantity of Magnesium
quantity of Magnesium Stearate
Stearate and screen Mesh size of sieve screen
through a suitably sized Mixing Time and Speed
sieve. Transfer to the
container above and mix
This is the Compound (I)
Prototype MR Tablet
Blend
Compound (I) Prototype Compress the Compound Quantity of Compound (I)
MR Tablet Blend (I) Prototype MR Tablet Prototype MR Tablet
Blend into tablets Blend
This is the Compound (I) Tablet appearance
Prototype MR Tablet. Compression force
Tablet Hardness
? Tablet weight
Package the Compound (I)
Prototype MR Tablet in
container closure.
Tablet appearance will be assessed as an in process control during batch
manufacture, the details of which will be recorded in the batch manufacturing record
Compression force will be used throughout the manufacturing process and this may
be adjusted to ensure that the correct tablet hardness is achieved.
Tablet hardness will be measured periodically throughout batch manufacture as
defined in the batch manufacturing record.
Tablet weight will be measured as an in process control during batch manufacture,
the details of which will be recorded in the batch manufacturing record.
The amount of Compound (I) and each excipient is controlled by weight using
a suitably calibrated balance to confirm that the correct formulation composition is achieved.
A second operator verifies the weight. Blend uniformity is controlled by the pre-defined
mixing conditions detailed in Scheme 2. These parameters have been developed to ensure
homogeneity of all potential formulation blends within the proposed design space. Execution
of these processing instructions will be controlled and documented within the batch
manufacturing record. To ensure that content uniformity is uniform throughout the design
space, development batches at the points in the design space described in Scheme 1 have been
manufactured and tested. Uniformity of content of the final tablet is assessed by assay.
Tablet hardness is controlled by application of a consistent pressure with
regular testing (destructive) throughout the batch using the Tablet Compression Hardness
Test.
The tablets are pressed manually; each tablet is weighed separately using a
suitably calibrated balance and a second operator verifies the weight.
All excipients used in the formulations comply with the current monographs of
the Ph. Eur., the USP/NF or JP requirements as indicated below. All excipients are purchased
from approved suppliers. Manufacturer’s Certificate of Analysis will be accepted and all
excipients received at Quotient Clinical Ltd will undergo identification tests as appropriate
according to Quotient Clinical Ltd receipt requirements.
Table 4. Specification for Compound (I) Prototype MR Tablet
Test Method Acceptance Criteria
Appearance Visual Off-white tablets with
mottled beige speckles,
free from visual defects
Assay HPLC 90.0% – 110.0% of
nominal
Identity HPLC Retention time of test
sample conforms with the
retention time of
reference standard ±3%
Related Substances HPLC Report = 0.1%
Impurity A = 1.0%
2-isomer = 1.0%
Unspecified Impurities
NMT 0.5%
Total Impurities NMT
Content Uniformity HPLC AV =15.0
Dissolution HPLC Report results
Dissolution Test
The dissolution test is a pharmacopoeial method conducted according to USP
monograph <711> apparatus 2. The dissolution medium is 450mL 0.01M hydrochloric acid
with a pH switch with double strength Fasted State Simulated Intestinal Fluid (version 2)
giving a total volume of 900mL and agitation at 75 rpm.
Samples are analyzed for Compound (I) content by a reverse phase isocratic
HPLC method using an Intersil ODS-3V (4.6 mm x 150 mm) 5 µm column or suitably
validated alternative with UV detection at 248 nm. Mobile phase is comprised of Acetonitrile:
Water: Trifluroacetic acid.
Description of HPLC Assay, Identity and Content Uniformity method for Compound (I)
Prototype MR Tablets
[00234] The method for assay of the active ingredient content of the Compound (I)
Prototype MR Tablet is a reverse phase isocratic HPLC method using an Intersil ODS-3V
(4.6 mm x 150 mm) 5 µm column or suitably validated alternative with UV detection at 248
nm. Mobile phase is comprised of Acetonitrile: Water: Trifluroacetic acid.
Description of Related Substances Test
The method for related substances of the Compound (I) Prototype MR Tablet
is a reverse phase gradient HPLC method using an Intersil ODS-3V (4.6 mm x 150 mm) 5 µm
column or suitably validated alternative with UV detection at 248 nm. Mobile phase A is
comprised of 0.1% TFA in Water, mobile phase B is 0.1% TFA in Acetonitrile.
Compound (I) C02: Once a day formulation
A Two-Part Study Designed to Evaluate the Pharmacokinetic Profile of
Compound (I) and its Main Metabolites Following Single and Multiple Dose Modified
Release Prototype Formulation Administration in Healthy CYP2D6 Extensive Metabolizer
Male and Female Subjects, and to Evaluate the Relationship Between the Pharmacokinetic
Profile of Compound (I) and its Main Metabolites and Cardiovascular Parameters. The study
designs for part 1 and part 2 are shown in figures 7 and 8, respectively, and figure 9 shows the
period scheme for dosing.
Table 5. Summary of Select PK Parameters – Period 1 (32 mg Slow Release,
Fasted)
In addition, the plasma concentration-time profiles for Compound (I), BFB-
520, and BFB-999 are shown in figures 1-3. The C for Compound (I), BFB-520, and BFB-
999 is shown in figure 4. Effects on QTcF by Compound (I), BFB-520, and BFB-999 is
shown in figure 5.
MR Formulation under Fasted Conditions:
? Short lag time suggestive of fast bioavailability
? Exposure variability is generally low
? Low to non-quantifiable values for most by Hour 24
? PK is generally dose proportional for Compound (I) & BFB-999, and less so for BFB-
? Inversion of BFB-520 & BFB-999 occurred with generally suppressed levels of BFB-
520, and a higher BFB-999 to BFB-520 ratio
? MR formulation findings suggest shorter time in small intestine is helpful in
suppressing BFB-520 levels
? Half-life for Compound (I) and 2 metabolite in 3-8 hour range, longer for 40 mg slow
release most likely due to flip-flop (absorption & elimination balanced during terminal
phase)
? Simulation results indicate steady state within 10-14 days, and no accumulation for all
3 analytes.
Food Effect:
? Positive food effect evident – Higher exposure
? MR formulation behaved similar to IR formulation with rapid release and absorption,
mostly prior to reaching colon
• This explains further increase in BFB-520 levels
? Due to rapid absorption Compound (I) Cmax increase was ~ 2x, BFB-520 Cmax
increase was ~ 3x, and BFB-999 Cmax increase was ~ 0.5x
? Half-life was shortened substantially: Fed to Fasted ratios were
• 0.5 for Compound (I)
• 0.8 for BFB-520
• 0.6 for BFB-999
? Consequently, accumulation is not expected
? AUC increase was minimal (compared to C ): 1.3 to 1.8 multiples with highest
increase to BFB-520
Compound (I) C03 Phase IIB in patients with schizophrenia
A Phase IIb, Multi-centre, Randomized, Double-blind, Parallel-group,
Placebo-controlled Study to Evaluate the Efficacy, Tolerability and Safety of Compound (I) in
Patients with Negative Symptoms of Schizophrenia Followed by a 24-week, Open-label
extension. The study design is shown in figure 10.
Study Objectives:
Primary: To evaluate the efficacy of Compound (I) compared to placebo in
improving the negative symptoms of schizophrenia as measured by the change from Baseline
in the Positive and Negative Syndrome Scale (PANSS) negative subscale score of the
pentagonal model over 12 weeks of treatment.
[00243] Main Secondary:
? To evaluate the efficacy of Compound (I) compared to placebo in improving other
symptoms of schizophrenia as measured by the change from baseline in the PANSS total
score, and sub-scores of the pentagonal model AND 3 factors analysis over 12 weeks of
double blind treatment.
? To evaluate the efficacy of Compound (I) compared to placebo in improving negative
symptoms of schizophrenia as measured by the change from Baseline in the Brief
Negative Symptoms Scale (BNSS) total score over 12 weeks of double blind treatment.
? To assess the effects versus placebo of Compound (I) on cognitive function as measured
by the Brief Assessment of Cognition in Schizophrenia (BACS) battery over 12 weeks of
double blind treatment.
? To assess the persistence of efficacy, and the safety and tolerability of Compound (I)
during the 24-week, of open-label extension phase.
Other objectives:
? To evaluate the effects versus placebo of Compound (I) on depressive symptoms as
measured by the Calgary Depression Scale for Schizophrenia (CDSS) over 12 weeks of
double blind treatment.
? To evaluate the effects versus placebo of Compound (I) on social functioning by means of
the Personal and Social Performance (PSP) over 12 weeks of double blind treatment.
? To assess the effects versus placebo of Compound (I) on sleep architecture and continuity
as measured with the help of the V-Watch methodology over 12 weeks of double blind
treatment.
Main Inclusion Criteria:
? Male or female patient, 18 to 60 years of age, inclusive.
? Patient meets the diagnostic criteria for schizophrenia as defined in the Diagnostic and
Statistical Manual of Mental Disorders-Fifth Edition (DSM-V)
? Patient being stable in terms of positive symptoms over the last three months according
to his treating psychiatrist
? Patient presenting with negative symptoms over the last three months according to his
treating psychiatrist
? Patient with PANSS negative sub-score of at least 20.
? Patient with PANSS item score of <4 on: P4 Excitement, hyperactivity P7 Hostility P6
Suspiciousness G8 Uncooperativeness G14 Poor impulse control
? No change in psychotropic medication during the last month
? Patient must be extensive metabolizers for P450 CYP2D6, as determined by
genotyping test before the first drug dose is administered.
Main Exclusion Criteria:
? Current bipolar disorder, panic disorder, obsessive compulsive disorder, or evidence of
mental retardation.
? Patient’s condition is due to direct physiological effects of a substance (e.g., a drug of
abuse, or medication) or a general medical condition.
? Significant risk of suicide or attempted suicide, or of danger to self or others.
? Patient who cannot be discontinued from psychotropics other than those allowed.
? Patient who received clozapine within 6 months of the Screening visit.
? Patient receiving treatment with depot antipsychotic medication can be enrolled in the
study 4 weeks after the last injection.
? Patient with a history of significant other major or unstable neurological, neurosurgical
(e.g., head trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular,
metabolic, gastrointestinal, or urological disorder.
? Patient with a clinically significant electrocardiogram (ECG) abnormality that could be
a safety issue in the study, including QT interval value corrected for heart rate using the
Fridericia’s formula (QTcF) > 430 msec for males and > 450 msec for females.
Main Efficacy Assessments:
- Positive and Negative Symptoms Scale (PANSS)
- Brief Negative Symptoms Scale (BNSS): semi structured interview, designed to
measure the current level of severity of negative symptoms in schizophrenia and
schizoaffective disorder (Kirkpatrick et al.)
o Anhedonia
o Distress
o Asociality
o Avolition
o Blunted affect
o Alogia
- Brief Assessment of Cognition in Schizophrenia (BACS)
- Personal and Social Performance (PSP): assess social functioning; clinician rated
- socially useful activities,
- personal and social relationships,
- self-care
- disturbing and aggressive behavior
- Sleep architecture and continuity
Sleep Assessment:
- Sleep and circadian rhythm disruptions are reported in 30% to 80% of patients with
schizophrenia.
- Patients with insomnia report
• lower quality of life
• greater symptom severity
• worse adherence/compliance to treatment
- Sleep disturbances have also been associated with enhanced psychosis
- Sleep is important for memory consolidation, thus disturbances in sleep architecture, or
circadian de-synchronization could also contribute to the cognitive impairment observed
in schizophrenia.
- Compound (I) showed effects on sleep architecture in the previous Phase 2a study that
could possibly be linked to the improvements observed on negative symptoms and
cognition, thus they will be further investigated in the present study.
• In a subgroup of patients (20) who underwent sleep recordings (PSG), sleep was
evaluated at Baseline and Day 14. Compound (I) had an effect on
- Slow Wave Sleep (SWS) distribution: it shifted SWS from the end to the
beginning of the night: Compound (I) significantly increased SWS in the first
third of the night and decreased it in the last third of the night.
- Sleep initiation parameters (sleep onset latency, latency to persistent sleep).
• Subjective sleep quality as measured by PSQI improved and this improvement was
greater with Compound (I) than with placebo although not statistically significant.
V-Watch: A sleep biomarker & companion diagnostic tool
VWatch methodology overview-1 (figure 6): Compared to the standard
polysomnography (PSG) which rely on the measure of brain waves, V-Watch methodology
uses physiological measures to assess sleep.
Physiological systems and their regulations are dependent of the physiological
state (waking or sleeping)
The sleeping process affects the whole body and not only the brain
• Changes seen in cortical waves during sleep are only reflections of transitions between
sleep stages and they are not the only method to assess these transitions
• These transitions can also be detected from other physiological systems
[00252] Heart rate characteristics (level, regularity, variability and sudden changes) and
body motor activity can be used to discriminate waking from sleeping and to distinguish the
main sleep stages.
Example 3. Various tablet formulations of Compound (I)
[00253] Table 6-1. Compositions for 16mg and 64 mg MIN-101 MR tablet
formulations
Table 6-2. Compositions for 16mg and 64 mg MIN-101 MR tablet
formulations
Table 7. Compositions for 16mg and 64 mg MIN-101 MR tablet formulations
Table 8. Compositions for 16mg and 64 mg MIN-101 MR tablet formulations
Table 9. Compositions for 64 mg MIN-101 MR tablet formulations
Table 10. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
[00259] Table 11. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
Table 12. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
Table 13. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
[00262] Table 14. Analytical investigation for 64 mg MIN-101 MR tablet formulations
(64 mg slow of Experiment 9)
Table 15. Compositions for 64 mg MIN-101 MR tablet formulations
Table 16. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
[00265] Table 17. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
Table 18. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
Table 19. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations
Table 20. Batch Formula for reference MIN-101 SR tablets
Table 21. Compositions for 16 mg and 64 mg MIN-101 MR tablet
formulations (manufacturing process development)
Example 4: Preparation of Form (A) of Compound (I)·HCl·2H O
2-((1-(2-(4-Fluorophenyl)oxoethyl)piperidinyl)methyl)isoindolinone,
i.e., the free base of Compound (I), is dissolved in acetone and filtered through amorphous
volcanic glass, i.e., Perlite®, to remove any foreign matter. To this solution is added 2 mol/L-
hydrochloric acid water solution, i.e., 2 N HCl). The mixture is cooled while stirring for
several hours and crude crystals of the hydrochloric acid salt of Compound (I) are filtered and
dried under reduced pressure. The crude crystals are then purified by heating the crude
material in acetone and deionized water and stirring for several hours. Foreign matter is then
removed by filtration and then additional acetone is added to the filtrate. The mixture is
cooled and the crystals are filtered and dried under reduced pressure to provide Form (A) of
Compound (I)·HCl·2H O.
Example 5: X-ray powder diffraction of Form (A) of Compound (I) ·HCl ·2H O
X-ray diffractometry was performed using RIGAKU, RINT 2500. The X-ray
powder diffraction of Form (A) of Compound (I) ·HCl ·2H O is shown in Figure 11.
Example 6: IR Absorption Spectrum of Form (A) of Compound (I) ·HCl ·2H O
Infrared (IR) absorption spectrometry was performed using Perkin-Elmer,
Paragon1000. The IR spectrum of Form (A) of Compound (I) ·HCl ·2H O was measured by a
potassium chloride disk method as shown in Figure 12. The main wave numbers of
absorption and their assignment are as follows:
Table 22. Assignments of Form (A) of Compound (I) ·HCl ·2H O IR Spectrum
Wave number (cm ) Assignment
2916 C-H stretching vibration
1684, 1665 C=O stretching vibration
1594 Benzene ring
1235 C-F stretching vibration
Example 7: Nuclear Magnetic Resonance Spectrometry of Form (A) of Compound
(I) ·HCl ·2H O
H-NMR spectrum and C-NMR spectrum of Form (A) of Compound
(I) ·HCl ·2H O measured in d -dimethyl sulfoxide is shown in Figure 13 and Figure 14,
respectively.
INCORPORATION BY REFERENCE
The entire disclosure of each of the patent documents and scientific articles
referred to herein is incorporated by reference for all purposes.
EQUIVALENTS
The disclosure of the application can be embodied in other specific forms
without departing from the spirit or essential characteristics thereof. The foregoing
embodiments are therefore to be considered in all respects illustrative rather than limiting on
the disclosure of the application described herein. Scope of the disclosure of the application is
thus indicated by the appended claims rather than by the foregoing description, and all
changes that come within the meaning and range of equivalency of the claims are intended to
be embraced therein.
The term “comprise” and variants of the term such as “comprises” or
“comprising” are used herein to denote the inclusion of a state integer or stated integers but
not to exclude any other integer or any other integers, unless in the context or usage an
exclusive interpretation of the term is required.
Any reference to publications cited in this specification is not an admission
that the disclosures constitute common general knowledge in New Zealand.
Other embodiments of the invention as described herein are defined in the
following paragraphs:
1. A crystalline form of Compound (I);
comprising a polymorph form (A) of Compound (I) ·HCl ·2H O, and wherein the form (A) has
a X-ray powder diffraction pattern with at least one major peak substantially similar to at least
one major peak shown in Figure 11.
2. The crystalline form of paragraph 1, wherein the form (A) has X-ray powder diffraction
pattern peaks at approximately 7.6 and 14.3 °2? using Cu Ka radiation.
3. The crystalline form of paragraph 1 or 2, wherein the form (A) has X-ray
powder diffraction peaks at approximately 7.6, 14.3, and 14.7 °2? using Cu Ka radiation.
4. The crystalline form of any one of paragraphs 1-3, wherein the form (A) has
X-ray powder diffraction peaks at approximately 7.6, 14.3, and 27.5 °2? using Cu Ka
radiation.
. The crystalline form of any one of paragraphs 1-4, wherein the form (A) has
X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, and 27.5 °2? using Cu Ka
radiation.
6. The crystalline form of any one of paragraphs 1-5, wherein the form (A) has
X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, 18.6, and 27.5 °2? using Cu
Ka radiation.
7. The crystalline form of any one of paragraphs 1-6, wherein the form (A) has
X-ray powder diffraction peaks at approximately 7.6, 14.3, 14.7, 14.9, 18.6, 27.5 and 30.1 °2?
using Cu Ka radiation.
8. The crystalline form of any one of paragraphs 1-7, wherein the form (A) has
X-ray powder diffraction peaks at approximately 7.6, 11.2, 14.3, 14.7, 14.9, 18.6, 22.0, 25.9,
27.5 and 30.1 °2? using Cu Ka radiation.
9. A pharmaceutical formulation comprising Compound (I);
wherein the formulation comprises a release modifier that provides a maximum plasma
concentration (C ) of Compound (I) or the polymorph form (A) of Compound (I) ·HCl ·2H O
max 2
below 50 ng/mL when a dose of between about 1-100 mg of the formulation is administered
to a human.
. The pharmaceutical formulation of paragraph 9, when Compound (I) is present
as the polymorph form (A) of Compound (I) ·HCl ·2H O.
11. The pharmaceutical formulation of paragraph 10, comprising about 10-75 mg
of Compound (I) or the polymorph form (A) of Compound (I) ·HCl ·2H O.
12. The pharmaceutical formulation of paragraph 10, comprising about 15-65 mg
of Compound (I) or the polymorph form (A) of Compound (I) ·HCl ·2H O.
13. The pharmaceutical formulation of paragraph 10, comprising about 16 mg,
about 32 mg, about 40 mg, or about 64 mg of Compound (I) or the polymorph form (A) of
Compound (I) ·HCl ·2H O.
14. The pharmaceutical formulation of paragraph 10, wherein the release modifier
is a hypromellose.
. The pharmaceutical formulation of paragraphs 9-14, further comprising a filler,
a glidant, and a lubricant.
16. The pharmaceutical formulation of paragraphs 15, wherein the filler is
microcrystalline cellulose, lactose, or a combination thereof.
17. The pharmaceutical formulation of paragraph 15, wherein the glidant is silica
colloidal anhydrous.
18. The pharmaceutical formulation of paragraph 15, wherein the lubricant is
magnesium stearate, Kolliwax HCO, sodium stearyl fumarate, or a combination thereof.
19. The pharmaceutical formulation of paragraphs 9-18, wherein the formulation
provides a maximum plasma concentration (C ) of BFB-520 below 10.0 ng/mL, preferably
below 5.0 ng/mL.
. The pharmaceutical formulation of paragraphs 9-19, wherein the formulation
provides a maximum plasma concentration (Cmax) of BFB-999 below 5.0 ng/mL.
21. The pharmaceutical formulation of paragraphs 9-20, wherein the formulation
provides an AUC of Compound (I) or the polymorph form (A) of Compound (I) ·HCl ·2H O
below 400 hr*ng/mL.
22. The pharmaceutical formulation of paragraphs 9-21, wherein the formulation
provides an AUC of BFB-520 below 40 hr*ng/mL.
23. The pharmaceutical formulation of paragraphs 9-22, wherein the formulation
provides an AUC of BFB-999 below 40 hr*ng/mL.
24. The pharmaceutical formulation of paragraphs 9-23, wherein the formulation is
suitable for chronic administration.
. The pharmaceutical formulation of any one of paragraphs 9-24, wherein the
formulation is in an immediate release form.
26. The pharmaceutical formulation of paragraphs 9-25, wherein the formulation is
in a controlled release form.
27. The pharmaceutical formulation of paragraphs 9-26, wherein substantially all
of the administered dose of Compound (I) or the polymorph form (A) of Compound
(I) ·HCl ·2H O is released from the pharmaceutical formulation over 16-24 hours.
28. A method of treating a neuropsychiatric disease or disorder, comprising
administering a therapeutically effective amount of the pharmaceutical formulation of
paragraphs 9-27 to a subject in need thereof.
29. The method of paragraph 28, wherein the neuropsychiatric disease or disorder
is schizophrenia.
. The method of paragraph 28 or 21, wherein the pharmaceutical formulation is
administered once daily.
31. The method of any one of paragraphs 28-30, wherein the amount of
Compound (I) or the polymorph form (A) of Compound (I) ·HCl ·2H O administered is in the
range of about 1-100 mg.
32. The method of paragraph 31, wherein the amount of Compound (I) or the
polymorph form (A) of Compound (I) ·HCl ·2H O administered is in the range of about 10-75
33. The method of paragraph 32, wherein the amount of Compound (I) or the
polymorph form (A) of Compound (I) ·HCl ·2H O administered is in the range of about 15-65
34. The method of paragraph 31, wherein the amount of Compound (I) or the
polymorph form (A) of Compound (I) ·HCl ·2H2O administered is about 16 mg, about 32 mg,
about 40 mg, or about 64 mg.
. The method of paragraph 28, wherein at least one symptom of schizophrenia is
treated or diminished.
36. The method of paragraph 35, wherein the symptom is associated with the
negative and/or positive symptoms of schizophrenia, cognitive function, sleep architecture
and continuity, and social functioning.
37. The method of paragraph 28, wherein at least one condition or disorder
associated with depression is treated.
38. A method of treating a sleep disorder, comprising administering a
therapeutically effective amount of the pharmaceutical formulation of paragraphs 9-37 to a
subject in need thereof.
39. The method of paragraph 38, wherein at least one aspect of a sleep disorder is
treated or diminished.
40. The method of paragraph 39 wherein the at least one aspect of a sleep disorder
is selected from sleep period time, one or more segments of sleep period time, overall sleep
continuity, and sleep architecture.
41. The method of paragraph 38, wherein the sleep disorder is associated with
schizophrenia.
42. A kit comprising the pharmaceutical formulation of paragraphs 9-41, and
instructions for use.
According to a first embodiment of the invention, there is provided a
pharmaceutical formulation comprising a release modifier and between about 1 mg and about
100 mg of Compound (I),
, or a pharmaceutically acceptable salt or solvate
thereof, provided that when the formulation is administered to a human, the maximum plasma
concentration (C ) of BFB-520 detected in the human is below 10.0 ng/mL, wherein BFB-
520 is an active metabolite of Compound (I).
According to a second embodiment of the invention, there is provided a
pharmaceutical formulation comprising a release modifier and between about 1 mg and about
100 mg of Compound (I),
, or a pharmaceutically acceptable salt or solvate
thereof, provided that when the formulation is administered to a human, the maximum plasma
concentration (C ) of BFB-999 detected in the human is below 5.0 ng/mL, wherein BFB-
999 is an active metabolite of Compound (I).
According to a third embodiment of the invention, there is provided a tablet
comprising a release modifier and between about 1 mg and about 100 mg of Compound (I),
, or a pharmaceutically acceptable salt or solvate
thereof, provided that when the tablet is administered to a human, the maximum plasma
concentration (C ) of BFB-520 detected in the human is below 10.0 ng/mL, wherein BFB-
520 is an active metabolite of Compound (I).
According to a fourth embodiment of the invention, there is provided a tablet
comprising a release modifier and between about 1 mg and about 100 mg of Compound (I),
, or a pharmaceutically acceptable salt or solvate
thereof, provided that when the tablet is administered to a human, the maximum plasma
concentration (C ) of BFB-999 detected in the human is below 5.0 ng/mL, wherein BFB-
999 is an active metabolite of Compound (I).
Claims (19)
1. A pharmaceutical formulation comprising a hypromellose and between about 1 mg and about 100 mg of Compound (I), , or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the maximum plasma concentration (C ) of BFB-520 detected in a human recipient of the formulation is below 10.0 ng/mL, wherein BFB-520 is an active metabolite of Compound (I).
2. The pharmaceutical formulation according to claim 1, wherein the maximum plasma concentration (C ) of BFB-520 detected in a human recipient of the formulation is below 5.0 ng/mL.
3. The pharmaceutical formulation according to claim 1 or 2, wherein the area under the curve (AUC) of BFB-520 detected in a human recipient of the formulation is below 40 hr*ng/mL.
4. The pharmaceutical formulation according to claim 1 or 2, wherein the AUC of BFB-520 detected in a human recipient of the formulation is below 20 hr*ng/mL.
5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the formulation further comprises a filler, a glidant, and a lubricant.
6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the formulation comprises 32 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
7. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the formulation comprises 64 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
8. The pharmaceutical formulation according to any one of claims 1 to 7, which is in the form of a tablet.
9. A pharmaceutical formulation comprising a hypromellose and between about 1 mg and about 100 mg of Compound (I), , or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, wherein the maximum plasma concentration (C ) of BFB-999 detected in a human recipient of the formulation is below 5.0 ng/mL, wherein BFB-999 is an active metabolite of Compound (I).
10. The pharmaceutical formulation according to claim 9, wherein the maximum plasma concentration (C ) of BFB-999 detected in a human recipient of the formulation is below 2.5 ng/mL.
11. The pharmaceutical formulation according to claim 9 or 10, wherein the area under the curve (AUC) of BFB-999 detected in a human recipient of the formulation is below 40 hr*ng/mL.
12. The pharmaceutical formulation according to claim 9 or 10, wherein the AUC of BFB- 999 detected in a human recipient of the formulation is below 20 hr*ng/mL.
13. The pharmaceutical formulation according to any one of claims 9 to 12, wherein the formulation further comprises a filler, a glidant, and a lubricant.
14. The pharmaceutical formulation according to any one of claims 9 to 13, wherein the formulation comprises 32 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
15. The pharmaceutical formulation according to any one of claims 9 to 13, wherein the formulation comprises 64 mg of Compound (I) or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
16. The pharmaceutical formulation according to any one of claims 9 to 15, which is in the form of a tablet.
17. A kit comprising the pharmaceutical formulation of any one of claims 1-16 and instructions for use.
18. Use of a therapeutically effective amount of the pharmaceutical formulation of any one of claims 1-16 in the preparation of a medicament for treating a negative symptom of schizophrenia.
19. The use of claim 18, wherein the pharmaceutical formulation is formulated to be administered once daily.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462086691P | 2014-12-02 | 2014-12-02 | |
US201562248071P | 2015-10-29 | 2015-10-29 | |
NZ732033A NZ732033B2 (en) | 2015-11-30 | Compositions comprising 2-((1-(2(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-1-one for treating schizophrenia |
Publications (2)
Publication Number | Publication Date |
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NZ770365A NZ770365A (en) | 2023-10-27 |
NZ770365B2 true NZ770365B2 (en) | 2024-01-30 |
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