SOLID DOSAGE FORMULATIONS OF AN OREXIN RECEPTOR ANTAGONIST

FORMES PHARMACEUTIQUES POSOLOGIQUES SOLIDES D'UN ANTAGONISTE DES RECEPTEURS DES OREXINES

English Abstract

The present invention is directed to a pharmaceutical composition comprising the compound suvorexant, or a pharmaceutically acceptable salt thereof, a concentration-enhancing polymer, and optionally a pharmaceutically acceptable surfactant.

French Abstract

La présente invention concerne une composition pharmaceutique comprenant le composé suvorexant, ou un sel pharmaceutiquement acceptable de celui-ci, un polymère augmentant la concentration, et facultativement un tensioactif pharmaceutiquement acceptable.

Claims

CLAIMS:

1. A pharmaceutical composition comprising:
(1) suvorexant in an amorphous form; and
(2) a concentration-enhancing polymer, which is selected from the group
consisting of polyvinylpyrrolidinone and polyvinylpyrrolidinone-
polyvinylacetate
copolymers.
2. The pharmaceutical composition of Claim 1, wherein the
concentration-enhancing polymer is a polyvinylpyrrolidinone-polyvinylacetate
copolymer.
3. The pharmaceutical composition of Claim 1, wherein the
concentration-enhancing polymer is a polyvinylpyrrolidinone copolymer.
4. The pharmaceutical composition of Claim 1, wherein the composition
comprises
one or more surfactants selected from the group consisting of anionic
surfactants and nonionic
surfactants.
5. The pharmaceutical composition of Claim 4, wherein the composition
comprises
sodium dodecyl sulfate, one or more nonionic surfactants selected from (a)
sorbitan fatty acid
esters, (b) polyoxyethylene sorbitan fatty acid esters, (c) polyoxyethylene
castor oils, (d)
polyoxyethylene hydrogenated castor oils, and (e) vitamin E TPGS: or a mixture
thereof.
6. The pharmaceutical composition of Claim 1, wherein the
concentration-enhancing polymer is copovidone.
7. The pharmaceutical composition of Claim 1, wherein the composition is
made by
hot melt extrusion of a mixture comprising suvorexant, the concentration-
enhancing polymer,
and optionally one or more surfactants.
8. The pharmaceutical composition of Claim 6, wherein the composition is
made by
hot melt extrusion of a mixture comprising suvorexant, copovidone, and
optionally one or
more surfactants.

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9. The pharmaceutical composition of any one of Claims 6-8, wherein the
pharmaceutical composition additionally comprises lactose.
10. The pharmaceutical composition of any one of Claims 6-8, wherein the
pharmaceutical composition additionally comprises microcrystalline cellulose.
11. The pharmaceutical composition of any one of Claims 6-8, wherein the
pharmaceutical composition additionally comprises croscarmellose sodium.
12. The pharmaceutical composition of any one of Claims 6-8, wherein the
pharmaceutical composition additionally comprises magnesium stearate.
13. The pharmaceutical composition of any one of Claims 1-12, wherein the
suvorexant is present in a form that contains at least 90 weight % of the
amorphous form of
suvorexant relative to other morphological forms of suvorexant.
14. The pharmaceutical composition of any one of Claims 1-12, wherein the
suvorexant is present in a form that contains at least 95 weight % of the
amorphous form of
suvorexant relative to other morphological forms of suvorexant.
15. The pharmaceutical composition of any one of Claims 1-12, wherein the
suvorexant is present in a form that contains at least 98 weight % of the
amorphous form of
suvorexant relative to other morphological forms of suvorexant.
16. The pharmaceutical composition of any one of Claims 1-12, wherein the
suvorexant is present in a form that contains at least 99 weight % of the
amorphous form of
suvorexant relative to other morphological forms of suvorexant.
17. The pharmaceutical composition of any one of Claims 1-16, which
comprises 5
mg, 10 mg, 15 mg or 20 mg of suvorexant.
18. A pharmaceutical composition comprising:
suvorexant in an amorphous form;
copovidone;
lactose monohydrate;

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microcrystalline cellulose;
croscarmellose sodium; and
magnesium stearate.
19. The pharmaceutical composition of Claim 18, wherein the composition is
made
by hot melt extrusion of a mixture comprising suvorexant and copovidone.
20. The pharmaceutical composition of Claim 18, wherein the suvorexant is
present
in a form that contains at least 90 weight % of the amorphous form of
suvorexant relative to
other morphological forms of suvorexant.
21. The pharmaceutical composition of Claim 18, wherein the suvorexant is
present
in a form that contains at least 95 weight % of the amorphous form of
suvorexant relative to
other morphological forms of suvorexant.
22. The pharmaceutical composition of Claim 18, wherein the suvorexant is
present
in a form that contains at least 98 weight % of the amorphous form of
suvorexant relative to
other morphological forms of suvorexant.
23. The pharmaceutical composition of Claim 18, wherein the suvorexant is
present
in a form that contains at least 99 weight % of the amorphous form of
suvorexant relative to
other morphological forms of suvorexant.
24. The pharmaceutical composition of any one of Claim 18-23, which
comprises 5
mg, 10 mg, 15 mg or 20 mg of suvorexant.

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Description

CA 02795550 2012-11-13
TITLE OF THE INVENTION
SOLID DOSAGE FORMULATIONS OF AN OREXIN RECEPTOR ANTAGONIST
BACKGROUND OF THE INVENTION
The orexins (hypocretins) comprise two neuropeptides produced in the
hypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and the orexin B
(OX-B) (a 28
amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are
found to stimulate
food consumption in rats suggesting a physiological role for these peptides as
mediators in the
central feedback mechanism that regulates feeding behavior (Sakurai T. et al.,
Cell, 1998, 92,
573-585). Orexins regulate states of sleep and wakefulness opening potentially
novel therapeutic
approaches for narcoleptic or insomniac patients (Chemelli R.M. et al., Cell,
1999, 98, 437-451).
Orexins have also been indicated as playing a role in arousal, reward,
learning and memory
(Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin
receptors have been
cloned and characterized in mammals. They belong to the super family of G-
protein coupled
receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor
(OX or OX1R) is
selective for OX-A and the orexin-2 receptor (0X2 or OX2R) is capable to bind
OX-A as well as
OX-B. The physiological actions in which orexins are presumed to participate
are thought to be
expressed via one or both of OX 1 receptor and OX 2 receptor as the two
subtypes of orexin
receptors.
Orexin receptors are found in the mammalian brain and the scientific
literature
suggests that they may be involved in various pathologies such as depression;
anxiety;
addictions; obsessive compulsive disorder; affective neurosis; depressive
neurosis; anxiety
neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual
dysfunction;
psychosexual dysfunction; sex disorder; schizophrenia; manic depression;
delirium; dementia;
severe mental retardation and dyskinesias such as Huntington's disease and
Tourette syndrome;
eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive
feeding behaviors;
binge/purge feeding behaviors; cardiovascular diseases; diabetes;
appetite/taste disorders;
emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's
syndrome/disease;
basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis
tumour/adenoma;
hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric
ulcers; Froehlich's
syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis
hypofunction;
adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome
(anosmia,
hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic

hypothyroidism; hypothalamic- adrenal dysfunction; idiopathic
hyperprolactinemia;
hypothalamic disorders of growth hormone deficiency; idiopathic growth
deficiency; dwarfism;
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CA 02795550 2012-11-13
gigantism; acromegaly; disturbed biological and circadian rhythms; sleep
disturbances associated
with diseases such as neurological disorders, neuropathic pain and restless
leg syndrome; heart
and lung diseases, acute and congestive heart failure; hypotension;
hypertension; urinary
retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or
haemorrhagic
stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic
hypertrophy; chronic renal
failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia;
pain; enhanced or
exaggerated sensitivity to pain such as hyperalgesia, causalgia, and
allodynia; acute pain; burn
pain; atypical facial pain; neuropathic pain; back pain; complex regional pain
syndrome I and II;
arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-
chemotherapy pain;
post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting;
conditions associated
with visceral pain such as irritable bowel syndrome, and angina; migraine;
urinary bladder
incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from
narcotics; sleep
disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome;
and
neurodegenerative disorders including nosological entities such as
disinhibition-dementia-
parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy;
seizure
disorders and other diseases related to general orexin system dysfunction.
The compound of the formula I:
-..---
CI 0 N 1
0 N `N¨N
--N N
õ
rCH3 fa
CH3
I
5-chloro-2- {(5R)-5-methyl-415-methy1-2-(2H-1,2,3-triazol-2-y1)benzoyl]-1,4-
diazepan-1-y1 1 -
1,3-benzoxazole (aka. "suvorexant") is disclosed as an antagonist of orexin
receptors in US
Patent 7,951,797, US Patent Application Publication US 2008/0132490, PCT
Patent Publication
WO 2008/069997, Cox et al., J. Med. Chem. 2010, 53, 5320-5332, Strotman et
al., JACS, 2011,
133(21), 8362-8371, Baxter et al., Org. Process Res. & Dev., 2011, 15(2) 367-
375. This
compound may be named as, e.g., "5-chloro-2-1(5R)-5-methy1-445-methy1-2-(2H-
1,2,3-triazol-
2-yObenzoyl] -1,4-diazepan-1 -y11-1,3 -benzoxazole, " "[(R)-4-(5-chloro-
benzooxazol-2-y1)-7-
methy141,4]diazepan-l-y1]-(5-methy1-241,2,31triazol-2-yl-pheny1)-methanone" or
"[(7R)-4-(5-
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CA 02795550 2012-11-13
chloro-1,3-benzoxazol-2-y1)-7-methy1-1,4-diazepan-l-yl] [5-methy1-2-(2H-1,2,3-
triazol-2-
y1)phenyl]methanone."
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition comprising
the
compound suvorexant, or a pharmaceutically acceptable salt thereof, a
concentration-enhancing
polymer, and optionally a pharmaceutically acceptable surfactant.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of a hot melt
extrusion
formulation of suvorexant.
FIG. 2 shows the modulated differential scanning calorimetry (mDSC)
thermogram of a hot melt extrusion formulation of suvorexant.
FIG. 3 shows the Raman spectrogram of a hot melt extrudate of suvorexant.
FIG. 4 shows the Raman spectrogram of a tablet formulation that comprises a
hot
melt extrudate of suvorexant.
FIG. 5 shows the Raman spectrogram of a hot melt extrudate of suvorexant
overlayed with the Raman spectrogram of a tablet formulation that comprises a
hot melt
extrudate of suvorexant, and further overlayed with the Raman spectrogram of
individual
excpients in such tablet formulation that comprises a hot melt extrudate of
suvorexant.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a pharmaceutical composition comprising:
(1) suvorexant, or a pharmaceutically acceptable salt thereof;
(2) a concentration-enhancing polymer, where the polymer increases the
bioavailability of suvorexant, and is water soluble or readily disperses in
water; and
(3) optionally one or more surfactants.
The concentration-enhancing polymer is a polymer that forms an amorphous
dispersion with an active pharmaceutical ingredient (API), such as suvorexant,
that is insoluble
or almost completely insoluble in water by (a) dissolving the API or (b)
interacting with the API
in such a way that the API does not form crystals or crystalline domains in
the polymer. A
concentration-enhancing polymer is water soluble or readily disperse in water,
so that when the
polymer is placed in water or an aqueous environment (e.g. fluids in the
gastrointestinal (GI)
tract or simulated GI fluids), the solubility and/or bioavailability of the
API is increased over the
solubility or bioavailability in the absence of the polymer.
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CA 02795550 2012-11-13
One class of polymers suitable for use with the present invention comprises
neutral non-cellulosic polymers. Exemplary polymers include: vinyl polymers
and copolymers
having substituents that are hydroxy, alkyl, acyloxy, and cyclic amides. These
include polyvinyl
alcohols that have at least a portion of their repeat units in the
unhydrolyzed (vinyl acetate) form
(e.g. polyvinyl alcohol-polyvinyl acetate copolymers); polyvinyl
pyrrolidinone; polyethylene
polyvinyl alcohol copolymers; and polyvinylpyrrolidinone-polyvinyl acetate
copolymers. A class
of non-cellulosic nonionic polymers comprises polyvinylpyrrolidinone and
polyvinylpyrrolidinone copolymers, such as polyvinylpyrrolidinone-polyvinyl
acetate
copolymers, available as Kollidon polymers and copolymers or Plasdone polymers
and
copolymers. A representative copolymer is copovidone. A representative
copolymer is Kollidon
VA64 or Plasdone S630.
Another class of polymers suitable for use with the present invention
comprises
ionizable non-cellulosic polymers. Exemplary polymers include: carboxylic acid
functionalized
vinyl polymers, such as the carboxylic acid functionalized polymethacrylates
and carboxylic acid
functionalized polyacrylates, such as the EUDRAGITS copolymers, manufactured
by Rohm
Tech Inc., of Malden, Massachusetts; amine-functionalized polyacrylates and
polymethacrylates;
proteins; and carboxylic acid functionalized starches such as starch
glycolate.
Concentration enhancing polymers may also be non-cellulosic polymers that are
amphiphilic, which are copolymers of a relatively hydrophilic and a relatively
hydrophobic
monomer. Examples include the acrylate and methacrylate copolymers (EUDRAGITS)
mentioned previously. Another example of amphiphilic polymers are block
copolymers of
ethylene oxide (or glycol) and propylene oxide (or glycol), where the
poly(propylene glycol)
oligomer units are relatively hydrophobic and the poly(ethylene glycol) units
are relatively
hydrophilic. These polymers are often sold under the Poloxamer trademark.
A class of polymers comprises ionizable and neutral cellulosic polymers with
at
least one ester- and/or ether- linked substituent in which the polymer has a
degree of substitution
of at least 0.1 for each substituent. In the nomenclature used herein, ether-
linked substituents are
recited prior to "cellulose" as the moiety attached to the cellulose backbone
by an ether linkage;
for example, "ethylbenzoic acid cellulose" has ethoxybenzoic acid substituents
on the cellulose
backbone. Analogously, ester-linked substituents are recited after "cellulose"
as the carboxylate;
for example, "cellulose phthalate" has one carboxylic acid of each phthalate
moiety ester-linked
to the polymer, with the other carboxylic acid group of the phthalate group
remaining as a free
carboxylic acid group.
It should also be noted that a polymer name such as "cellulose acetate
phthalate"
(CAP) refers to any of the family of cellulosic polymers that have acetate and
phthalate groups
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CA 02795550 2012-11-13
attached via ester linkages to a significant fraction of the cellulosic
polymer's hydroxyl groups.
Generally, the degree of substitution of each substituent group can range from
0.1 to 2.9 as long
as the other criteria of the polymer are met. "Degree of substitution" refers
to the average
number of the three hydroxyls per saccharide repeat unit on the cellulose
chain that have been
substituted. For example, if all of the hydroxyls on the cellulose chain have
been phthalate
substituted, the phthalate degree of substitution is 3.
Also included within each polymer family type are cellulosic polymers that
have
additional substituents added in relatively small amounts that do not
substantially alter the
performance of the polymer.
Amphiphilic cellulosics may be prepared by substituting the cellulose at any
or all
of the 3 hydroxyl substituents present on each saccharide repeat unit with at
least one relatively
hydrophobic substituent. Hydrophobic substituents may be essentially any
substituent that, if
substituted at a high enough level or degree of substitution, can render the
cellulosic polymer
essentially aqueous insoluble. Hydrophilic regions of the polymer can be
either those portions
that are relatively unsubstituted, since the unsubstituted hydroxyls are
themselves relatively
hydrophilic, or those regions that are substituted with hydrophilic
substituents. Examples of
hydrophobic substituents include ether-linked alkyl groups such as methyl,
ethyl, propyl, butyl,
etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate,
etc.; and ether- and/or
ester-linked aryl-groups such as phenyl, benzoate, or phenylate. Hydrophilic
groups include
ether- or ester-linked nonionizable groups such as the hydroxyalkyl
substituents hydroxyethyl,
hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy or
methoxyethoxy. Hydrophilic
substituents include those that are ether- or ester-linked ionizable groups
such as carboxylic
acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or
sulfonates.
One class of cellulosic polymers comprises neutral polymers, meaning that the
polymers are substantially non-ionizable in aqueous solution. Such polymers
contain non-
ionizable substituents, which may be either ether- linked or ester-linked.
Exemplary etherlinked
non-ionizable substituents include: alkyl groups, such as methyl, ethyl,
propyl, butyl, etc.;
hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.;
and aryl groups
such as phenyl. Exemplary ester-linked non- ionizable groups include: alkyl
groups, such as
acetate, propionate, butyrate, etc.; and aryl groups such as phenylate.
However, when aryl groups
are included, the polymer may need to include a sufficient amount of a
hydrophilic substituent so
that the polymer has at least some water solubility at any physiologically
relevant pH of from 1 to
8.
Exemplary non-ionizable polymers that may be used as the polymer include:
hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose,
hydroxypropyl
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CA 02795550 2012-11-13
cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl
cellulose acetate, and
hydroxyethyl ethyl cellulose.
An embodiment of neutral cellulosic polymers are those that are amphiphilic.
Exemplary polymers include hydroxypropyl methyl cellulose and hydroxypropyl
cellulose
An embodiment of cellulosic polymers comprises polymers that are at least
partially ionizable at physiologically relevant pH and include at least one
ionizable substituent,
polymer water soluble at least at pH values where any ionizable groups are
ionized. In some
cases, the aromatic group may itself be ionizable, such as phthalate or
trimellitate substituents.
Exemplary cellulosic polymers that are at least partially ionized at
physiologically
relevant pH's include: hydroxypropyl methyl cellulose acetate succinate,
hydroxypropyl methyl
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CA 02795550 2012-11-13
succinate, hydroxypropyl methyl cellulose acetate succinate phthalate,
hydroxypropyl methyl
cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl
cellulose butyrate
phthalate, cellulose acetate trimellitate, methyl cellulose acetate
trimellitate, ethyl cellulose
acetate trimellitate, hydroxypropyl cellulose acetate trimellitate,
hydroxypropyl methyl cellulose
acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate,
cellulose propionate
trimellitate, cellulose butyrate trimellitate, cellulose acetate
terephthalate, cellulose acetate
isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid
cellulose acetate,
hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose
acetate, hydroxypropyl
ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate,
ethyl nicotinic acid
cellulose acetate, and ethyl picolinic acid cellulose acetate.
Exemplary cellulosic polymers that meet the definition of amphiphilic, having
hydrophilic and hydrophobic regions include polymers such as cellulose acetate
phthalate and
cellulose acetate trimellitate where the cellulosic repeat units that have one
or more acetate
substituents are hydrophobic relative to those that have no acetate
substituents or have one or
more ionized phthalate or trimellitate substituents.
A subset of cellulosic ionizable polymers are those that possess both a
carboxylic
acid functional aromatic substituent and an alkylate substituent and thus are
amphiphilic.
Exemplary polymers include cellulose acetate phthalate, methyl cellulose
acetate phthalate, ethyl
cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,
hydroxylpropyl methyl
cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate,
hydroxypropyl cellulose
acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl
cellulose butyrate
phthalate, cellulose acetate trimellitate, methyl cellulose acetate
trimellitate, ethyl cellulose
acetate trimellitate, hydroxypropyl cellulose acetate trimellitate,
hydroxypropyl methyl cellulose
acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate,
cellulose propionate
trimellitate, cellulose butyrate trimellitate, cellulose acetate
terephthalate, cellulose acetate
isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid
cellulose acetate,
hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose
acetate, hydroxypropyl
ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate,
ethyl nicotinic acid
cellulose acetate, and ethyl picolinic acid cellulose acetate.
Another subset of cellulosic ionizable polymers are those that possess a non-
aromatic carboxylate substituent. Exemplary polymers include hydroxypropyl
methyl cellulose
acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl
cellulose acetate
succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl
methyl cellulose
succinate, and hydroxyethyl cellulose acetate succinate.
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CA 02795550 2012-11-13
As listed above, a wide range of polymers may be used to form amorphous
dispersions of suvorexant. In an embodiment of the present invention, the
concentration-
enhancing polymer comprises a cellulosic polymer that is water soluble in
their nonionized state
and are also water soluble in their ionized state. A particular subclass of
such polymers are the
so-called "enteric" polymers, which include, for example, certain grades of
hydroxypropyl
methyl cellulose acetate phthalate and cellulose acetate trimellitate.
Dispersions formed from
such polymers generally show large enhancements of the maximum drug
concentration in
dissolution tests relative to that for a crystalline drug control. In
addition, non-enteric grades of
such polymers and closely related cellulosic polymers are also useful.
In an embodiment of the present invention, the concentration-enhancing polymer
comprises hydroxypropyl methyl cellulose acetate succinate (HPMCAS),
hydroxypropyl methyl
cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose
acetate trimellitate
(CAT), methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate
phthalate, cellulose
acetate terephthalate and cellulose acetate isophthalate.
In an embodiment of the present invention, the concentration-enhancing polymer
is selected from the group consisting of hydroxypropyl methyl cellulose
acetate succinate
(HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate
phthalate
(CAP), cellulose acetate trimellitate (CAT), methyl cellulose acetate
phthalate, hydroxypropyl
cellulose acetate phthalate, cellulose acetate terephthalate, cellulose
acetate isophthalate,
polyvinylpyrrolidinone, vinyl pyrrolidinone/vinyl acetate copolymers, and
acrylate and
methacrylate copolymers.
In an embodiment of the present invention, the concentration-enhancing polymer

is hydroxypropyl methyl cellulose acetate succinate (HPMCAS) or a vinyl
pyrrolidinone/vinyl
acetate copolymer.
In an embodiment of the present invention, the concentration-enhancing polymer
is a pH-insensitive polymer. The term "pH-insensitive polymer" means a polymer
that has no
appreciable differences in solubility between gastric pH (pH 1-4) and
intestinal pH (pH 5-8).
Representative pH-insensitive polymers include: vinyl pyrrolidinone/vinyl
acetate copolymer,
polyvinyl pyrrolidinone/vinyl acetate copolymer, hydroxypropyl
methylcellulose, hydroxypropyl
cellulose, ethyl cellulose, polyvinyl pyrrolidinone, methacrylate copolymer,
polyethylene oxide,
polyoxypropylene/polyoxyethylene copolymers (poloxamers), and polyethylene
glycol. In an
embodiment of the present invention, the concentration-enhancing polymer is
vinyl
pyrrolidinone/vinyl acetate copolymer or polyvinyl pyrrolidinone/vinyl acetate
copolymer.
In an embodiment of the present invention, the concentration-enhancing polymer
is a vinyl pyrrolidinone/vinyl acetate copolymer.
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CA 02795550 2012-11-13
In an embodiment of the present invention, the concentration-enhancing polymer

is polyvinyl pyrrolidinone/vinyl acetate copolymer.
When specific polymers that are suitable for use in the compositions of the
present invention are blended, the blends of such polymers may also be
suitable. Thus the term
',polymer" is intended to include blends of polymers in addition to a single
species of polymer.
The pharmaceutical composition of the present invention may optionally
comprise
one or more surfactants, which may be ionic or nonionic surfactants. The
surfactants can
increase the rate of dissolution by facilitating wetting, thereby increasing
the maximum
concentration of dissolved drug. The surfactants may also make the dispersion
easier to process.
Surfactants may also stabilize the amorphous dispersions by inhibiting
crystallization or
precipitation of the drug by interacting with the dissolved drug by such
mechanisms as
complexation, formation of inclusion complexes, formation of micelles, and
adsorption to the
surface of the solid drug. Suitable surfactants include cationic, anionic, and
nonionic surfactants.
These include for example fatty acids and alkyl sulfonates; cationic
surfactants such as
benzalkonium chloride (Hyamine 1622, available from Lonza, Inc., Fairlawn, New
Jersey);
anionic surfactants, such as dioctyl sodium sulfosuccinate (Docusate Sodium,
available from
Mallinckrodt Spec. Chem., St. Louis, Missouri) and sodium lauryl sulfate
(sodium dodecyl
sulfate); sorbitan fatty acid esters (SPAN series of surfactants); Vitamin E
TPGS;
polyoxyethylene sorbitan fatty acid esters (Tween series of surfactants,
available from ICI
Americas Inc., Wilmington, Delaware); polyoxyethylene castor oils and
hydrogenated castor oils
such as Cremophor RH-40 and Cremopher EL; Liposorb P-20, available from
Lipochem Inc.,
Patterson New Jersey; Capmul POE-0, available from Abitec Corp., Janesville,
Wisconsin), and
natural surfactants such as sodium taurocholic acid, 1-palmitoy1-2-oleoyl-sn-
glycero-3-
phosphocholine, lecithin, and other phospholipids and mono- and diglycerides.
The pharmaceutical composition of the present invention may optionally
comprise
other excipients, such as one or more disintegrants, diluents or lubricants.
Representative
disintegrants may include croscarmellose sodium, sodium starch glycolate,
crospovidone, and
starch. Representative glidants may include silicon dioxide and talc.
Representative lubricants
may include magnesium stearate, stearic acid, and sodium stearyl fumarate.
Representative
diluents may include microcrystalline cellulose, lactose, and mannitol.
The pharmaceutical compositions of the present invention are prepared by
processes that are suitable for causing a compound (the drug) to form a
dispersion (also referred
to as an amorphous dispersion) in the polymer such that the drug is generally
amorphous or
dissolved in the polymer or a component of the composition, such as a
surfactant. The
dispersions are stable, and the drug does not form crystals or other insoluble
particles. Such
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CA 02795550 2012-11-13
methods include solution methods, such as spray drying, spray coating, freeze-
drying, and
evaporation of a co-solvent under vacuum or by heating a solution of polymer
and drug. Such
methods also include methods that blend the solid drug with the polymer in the
molten state,
such as hot melt extrusion, and methods of compounding the solid non-molten
polymer and drug
under heat and pressure to form a dispersion.
The compositions comprising the concentration-enhancing polymer increase the
concentration of suvorexant in an aqueous environment, such as water, the
gastrointestinal (GI)
tract, or a simulated GI fluid prepared for in vitro laboratory tests relative
to a control
composition comprising an equivalent amount of suvorexant without polymer.
Once the
composition is introduced into an aqueous environment, the composition
comprising the
concentration-enhancing polymer and suvorexant provides a higher maximum
aqueous
concentration of suvorexant relative to a control composition having the same
concentration of
suvorexant but without the concentration-enhancing polymer. An inert filler
may be used in
place of the polymer in the control to keep the suvorexant at the same
concentration as in the
composition comprising the polymer. In an embodiment of the present invention,
the polymer
increases the maximum concentration of suvorexant in an aqueous solution by at
least 25%. In
an embodiment of the present invention, the polymer increases the maximum
concentration of
suvorexant in an aqueous solution by at least 50%. In an embodiment of the
present invention,
the polymer increases the maximum concentration of suvorexant in an aqueous
solution to at
least double relative to a control composition. In an embodiment of the
present invention, the
polymer increases the maximum concentration of suvorexant in an aqueous
solution to at least 5-
times greater that than that of a control composition. In an embodiment of the
present invention,
the polymer increases the maximum concentration of suvorexant in an aqueous
solution by at
least 10-fold. Such large enhancements in concentration may be necessary in
order for
suvorexant to achieve effective blood levels through oral dosing. Such aqueous
solutions are
generally supersaturated solutions with respect to suvorexant.
In in vivo pharmacokinetics measurements in which the concentration of
suvorexant is measured as a function of time in blood or serum after
administration of the
formulation to a test animal, the compositions of the present invention
exhibit an area under the
concentration versus time curve (AUC) and a maximum concentration Cmax that is
greater than
that of a control composition comprising an equivalent quantity of the
compound without the
concentration-enhancing polymer. In an embodiment of the present invention,
the area under the
concentration versus time curve (AUC) is at least 25% greater than that of a
control composition.
In an embodiment of the present invention, the AUC is at least 50% greater
than that of a control
composition containing the same amount of drug but without the polymer. In an
embodiment of
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CA 02795550 2012-11-13
the present invention, the area under the AUC is at least double than that of
a control
composition containing the same amount of drug but without the polymer. In an
embodiment of
the present invention, the area under the AUC is at least 5-times greater than
that of a control
composition containing the same amount of drug but without the polymer. In an
embodiment of
the present invention, the area under the AUC is at least 10-fold greater than
that of a control
composition containing the same amount of drug but without the polymer. In an
embodiment of
the present invention, the area under the AUC is at least 15-fold greater than
that of a control
composition containing the same amount of drug but without the polymer. In an
embodiment of
the present invention, the area under the AUC is at least 20-fold greater than
that of a control
composition containing the same amount of drug but without the polymer.
In an embodiment of the present invention, the Cmax is increased by at least
25%
relative to a control composition without the polymer after it is administered
to a test animal or
patient. In an embodiment of the present invention, the Cmax is increased by
at least 50%
relative to a control composition without the polymer after it is administered
to a test animal or
patient. In an embodiment of the present invention, the Cmax is increased by
at least double
relative to a control composition without the polymer after it is administered
to a test animal or
patient. In an embodiment of the present invention, the Cmax is also increased
by at least 5-
times greater that than that of a control composition without the polymer
after it is administered
to a test animal or patient. In an embodiment of the present invention, the
Cmax is also
increased by at least 10 times greater than the drug concentration of a
control composition
without the polymer after it is administered to a test animal or patient. In
an embodiment of the
present invention, the Cmax is also increased by at least 20 times greater
than the drug
concentration of a control composition without the polymer after it is
administered to a test
animal or patient. In an embodiment of the present invention, the Cmax is also
increased by at
least 30 times greater than the drug concentration of a control composition
without the polymer
after it is administered to a test animal or patient. In an embodiment of the
present invention, the
Cmax is also increased by at least 40 times greater than the drug
concentration of a control
composition without the polymer after it is administered to a test animal or
patient.
The compositions disclosed herein exhibit improved in vivo bioavailability
compared with formulations that do not have the concentration-enhancing
polymer. The
compound suvorexant is absorbed more rapidly after oral administration of
these formulations.
The AUC of the drug and the maximal concentration of the drug in the blood or
serum are
increased when the formulations are administered to a patient.
In in vivo pharmacokinetics measurements in which the concentration of
suvorexant is measured as a function of time in blood or serum after
administration of the
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CA 02795550 2012-11-13
formulation to a test animal or human patient upon co-administration with food
(such as a high
fat meal), the compositions of the present invention that employ a
concentration-enhancing
polymer that is a pH-insensitive polymer may exhibit a time to peak
concentration (Tmax) that is
shorter than that of a composition comprising an equivalent quantity of the
compound that
employ a concentration-enhancing polymer that is not a pH-insensitive polymer.
Accordingly,
the use of a concentration-enhancing polymer that is a pH-insensitive polymer
may help to
reduce the food effect that otherwise delays the Tmax when a formulation of
suvorexant is
administered with food (such as a high fat meal).
In an embodiment of the present invention, the pharmaceutical composition of
suvorexant and concentration-enhancing polymer is prepared according to any
known process
which results in at least a major portion of suvorexant is present in the
amorphous state relative
to other morphological forms of suvorexant. In an embodiment of the present
invention, at least
60% of suvorexant is present in the amorphous state relative to other
morphological forms
relative to other morphological forms of suvorexant. In an embodiment of the
present invention,
at least 80% of suvorexant is present in the amorphous state relative to other
morphological
forms of suvorexant. In an embodiment of the present invention, at least 90%
of suvorexant is
present in the amorphous state relative to other morphological forms of
suvorexant. These
processes include mechanical processes, such as milling and extrusion; melt
processes, such as
high temperature fusion, hot melt extrusion, solvent modified fusion, and melt
congealing
processes; and solvent processes, including non-solvent precipitation
processes, spray coating,
and spray-drying. Although the dispersions of the present invention may be
made by any of these
processes, in an embodiment of the invention suvorexant in the pharmaceutical
composition is
substantially amorphous and is substantially homogeneously distributed
throughout the polymer.
The relative amounts of crystalline and amorphous suvorexant can be determined
by several
analytical methods, including differential scanning calorimetry (DSC), x-ray
powder diffraction
(XRPD) and Raman spectroscopy.
Processes for making pharmaceutical compositions of suvorexant with a
concentration-enhancing polymer include (a) hot melt extrusion and (b) spray
drying. In an
embodiment of the present invention, polymers for use in these processes are
polyvinylpyrrolidinone, polyvinylpyrrolidinone-polyvinylacetate copolymers
(for example
copovidone), HPC, HPMCAS, HPMC, HPMCP, CAP, and CAT. In an embodiment of the
present invention, polymers for use in hot melt extrusion are
polyvinylpyrrolidinone and
polyvinylpyrrolidinone-polyvinylacetate copolymers (copovidone such as
Kollidon VA64 or
Plasdone S630). In an embodiment of the present invention, the polymer for use
in hot melt
extrusion is copovidone. In an embodiment of the present invention, the
polymer for use in hot
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CA 02795550 2012-11-13
melt extrusion is Kollidon VA64. In an embodiment of the present invention,
the polymer for
use in hot melt extrusion is Plasdone S630. In an embodiment of the present
invention, polymers
for spray drying include HPC, HPMCAS, HPMC, HPMCP, CAP, and CAT. In an
embodiment
of the present invention, the polymer for spray drying is HPMCAS.
Both of these processes are well known in the art. In spray drying, the
polymer,
active compound, and other optional ingredients, such as surfactants, are
dissolved in a solvent
and are then sprayed through a nozzle as a fine spray into a chamber where the
solvent is
evaporated quickly to make fine particles comprising polymer, drug, and
optional other
ingredients. The solvent is any solvent in which all of the components of the
composition are
soluble and which is readily evaporated in a spray drier. The solvent should
also be suitable for
use in preparing pharmaceutical compositions. Exemplary solvents are acetone,
methanol and
ethanol. Methanol and acetone are preferred. In hot melt extrusion, the
polymer, drug, and
optional surfactants are mixed together in a wet granulation process or other
mixing process, and
then the mixture of polymer, drug and surfactant are fed into the chamber of
an extruder,
preferably a twin screw extruder to obtain better mixing, and are then
thoroughly melted and
mixed to make an amorphous dispersion.
In an alternate embodiment, the present invention is directed to an amorphous
form of the compound suvorexant. In an alternate embodiment, the present
invention is directed
to an isolated amorphous form of the compound suvorexant. In an alternate
embodiment, the
present invention is directed to suvorexant in a form which contains at least
about 40 wt. % of
the amorphous form relative to other morphological forms of suvorexant. In an
alternate
embodiment, the present invention is directed to suvorexant in a form which
contains at least
about 50 wt. % of the amorphous form relative to other morphological forms of
suvorexant. In
an alternate embodiment, the present invention is directed to suvorexant in a
form which
contains at least about 60 wt. % of the amorphous form relative to other
morphological forms of
suvorexant. In an alternate embodiment, the present invention is directed to
suvorexant in a form
which contains at least about 70 wt. % of the amorphous form relative to other
morphological
forms of suvorexant. In an alternate embodiment, the present invention is
directed to suvorexant
in a form which contains at least about 80 wt. % of the amorphous form
relative to other
morphological forms of suvorexant. In an alternate embodiment, the present
invention is
directed to suvorexant in a form which contains at least about 90 wt. % of the
amorphous form
relative to other morphological forms of suvorexant. In an alternate
embodiment, the present
invention is directed to suvorexant in a form which contains at least about 95
wt. % of the
amorphous form relative to other morphological forms of suvorexant. In an
alternate
embodiment, the present invention is directed to suvorexant in a form which
contains at least
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CA 02795550 2012-11-13
about 98 wt. % of the amorphous form relative to other morphological forms of
suvorexant. In
an alternate embodiment, the present invention is directed to suvorexant in a
form which
contains at least about 99 wt. % of the amorphous form relative to other
morphological forms of
suvorexant.
The amorphous form of the compound suvorexant was prepared by dissolving a
sample of suvorexant in acetone then removing the acetone. In particular, the
amorphous form
of the compound suvorexant was prepared by dissolving a sample of suvorexant
in acetone,
heating the solution to 60 C then removing the acetone on a rotary evaporator.
The resultant
solid was dried overnight in a vacuum oven at 40 C to remove any remaining
solvent. The
thermogram and the diffractogram of the resulting material indicated that it
was amorphous.
An embodiment of the present invention is directed to a process for the
preparation of an amorphous form of the compound suvorexant which comprises
dissolving a
sample of suvorexant in acetone then removing the acetone.
The amorphous form of the compound suvorexant may have benefits relative to
other morphological forms of suvorexant such as greater solubility and/or a
faster dissolution
rate than crystalline forms of the compound, which may improve bioavailability
of the
compound, may facilitate a faster onset of therapeutic action, may reduce
variability of
therapeutic response among subjects, and may reduce any food effect.
X-ray powder diffraction studies are widely used to characterize molecular
structures, crystallinity, and polymorphism. The X-ray powder diffraction
patterns were
generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with
PW3040/60
console. A PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation was used as
the source.
DSC data were acquired using TA Instruments DSC 2910 or equivalent
instrumentation. A sample with a weight between 2 and 6 mg was weighed into a
pan and the
pan was crimped. This pan was placed in the sample position in the calorimeter
cell. An empty
pan was placed in the reference position. The calorimeter cell was closed and
a flow of nitrogen
is passed through the cell. The heating program was set to heat the sample at
a heating rate of 10
C/min to a temperature of approximately 200 C. When the run was completed,
the data were
analyzed using the DSC analysis program in the system software. The observed
endotherms
were integrated between baseline temperature points that are above and below
the temperature
range over which the endotherm is observed. The data reported are the onset
temperature, peak
temperature and enthalpy.
Raman spectroscopy is widely used to determine the composition and
morphological character of samples of interest. FT-Raman (Fourier transform
Raman) spectra
were collected over the range of 50-4000 cm-1 with a Bruker IFS 66v/S system
coupled with the
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CA 02795550 2012-11-13
FRA106/S Raman attachment. The signal was averaged for 5-10 minutes at a
resolution of 4
cm-1 and a laser power of 300-500 mW. The samples were presented to the laser
using a
spinning stage which that was rotated during the measurement to provide a
large sampling
volume.
FIGURE 1 shows an X-ray powder diffraction pattern of a hot melt extrusion
formulation of suvorexant. The X-ray powder diffraction pattern indicates that
the amorphous
form of suvorexant is present. The absence of sharp reflections indicate the
lack of crystallinity.
FIGURE 2 shows the modulated differential scanning calorimetry (mDSC)
thermogram of a hot melt extrusion formulation of suvorexant. As noted by the
thermogram, in
hot melt extrusion formulations the compound suvorexant is present as an
amorphous form that
is characterized by a single glass transition temperature. This sample
exhibited a single glass
transition temperature of approximately 99 C.
FIGURE 3 shows the Raman spectrogram of a hot melt extrudate of suvorexant.
As noted by the spectrogram, a hot melt extrudate of suvorexant in the
amorphous form is
characterized by a Raman spectrogram peak at 1614cm-1. A hot melt extrudate of
suvorexant in
the amorphous form is alternatively characterized by a Raman spectrogram peak
at 1590cm-1. A
hot melt extrudate of suvorexant in the amorphous form is alternatively
characterized by a
Raman spectrogram peak at 1571cm-1.
FIGURE 4 shows the Raman spectrogram of a tablet formulation that comprises a
hot melt extrudate of suvorexant. As noted by the spectrogram, a tablet
formulation that
comprises a hot melt extrudate of suvorexant in the amorphous form is
characterized by a Raman
spectrogram peak at 1614 cm-1. A tablet formulation that comprises a hot melt
extrudate of
suvorexant in the amorphous form is alternatively characterized by a Raman
spectrogram peak at
1590 cm-1. A tablet formulation that comprises a hot melt extrudate of
suvorexant in the
amorphous form is alternatively characterized by a Raman spectrogram peak at
1571 cm-1. A
tablet formulation that comprises a hot melt extrudate of suvorexant in the
amorphous form is
alternatively characterized by Raman spectrogram peaks at 1614 cm-1, 1590 cm-I
and 1571
cm-1.
FIGURE 5 shows the Raman spectrogram of a hot melt extrudate of suvorexant
overlayed with the Raman spectrogram of a tablet formulation that comprises a
hot melt
extrudate of suvorexant, and further overlayed with the Raman spectrogram of
individual
excpients in such tablet formulation that comprises a hot melt extrudate of
suvorexant.
Suvorexant is disclosed as having activity in antagonizing the human orexin-1
(0X1) receptor with a Ki of 0.55 nM and in antagonizing the human orexin-2
(0X2) receptor
with a Ki of 0.35 nM. Relative to standard pharmaceutical formulations of
suvorexant, the
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CA 02795550 2012-11-13
present invention may have benefits such as providing greater solubility of
suvorexant and/or a
faster dissolution rate than standard formulations of the compound, which may
improve
bioavailability of the compound, may facilitate a faster onset of therapeutic
action, may reduce
variability of therapeutic response among subjects, and may reduce any food
effect.
The term "pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including inorganic or
organic bases and
inorganic or organic acids. Salts derived from inorganic bases include
aluminum, ammonium,
calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts,
manganous, potassium,
sodium, zinc, and the like. Particular embodiments include the ammonium,
calcium,
magnesium, potassium, and sodium salts. Salts in the solid form may exist in
more than one
crystal structure, and may also be in the form of hydrates. Salts derived from
pharmaceutically
acceptable organic non-toxic bases include salts of primary, secondary, and
tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines, and basic ion
exchange resins, such as arginine, betaine, caffeine, choline, N,N1-
dibenzylethylene-diamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine,
polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine,
and the like.
When the compound employed in the present invention is basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids, including inorganic
and organic
acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic,
citric,
ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular
embodiments include
the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric,
and tartaric acids. It
will be understood that, as used herein, references to the compound of Formula
I are meant to
also include the pharmaceutically acceptable salts.
The term "salts" refers to salts prepared from acceptable bases or acids
including
inorganic or organic bases and inorganic or organic acids. Salts derived from
inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic
salts, manganous, potassium, sodium, zinc, and the like. Particular
embodiments include the
ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid
form may exist
in more than one crystal structure, and may also be in the form of hydrates.
Salts derived from
organic bases include salts of primary, secondary, and tertiary amines,
substituted amines
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CA 02795550 2012-11-13
including naturally occurring substituted amines, cyclic amines, and basic ion
exchange resins,
such as arginine, betaine, caffeine, choline, N,NI-dibenzylethylene-diamine,
diethylamine, 2-
diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-
ethyl-
morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine,
lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine,
purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine, and the like.
When the compound employed in the present invention is basic, salts may be
prepared from acids, including inorganic and organic acids. Such acids include
acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric,
gluconic, glutamic,
hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic,
nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-
toluenesulfonic acid, and
the like. Particular embodiments include the citric, hydrobromic,
hydrochloric, maleic,
phosphoric, sulfuric, fumaric, and tartaric acids.
Exemplifying the invention is the use of the formulations disclosed in the
Examples and herein. The compound of Formula I is useful in a method of
antagonizing orexin
receptor activity in a patient such as a mammal in need of such inhibition
comprising the
administration of an effective amount of the compound. The present invention
is directed to the
use of the formulations of the compound of Formula I as antagonists of orexin
receptor activity.
In addition to primates, especially humans, it is possible that a variety of
other mammals may be
treated according to the method of the present invention.
The subject treated in the present methods is generally a mammal, such as a
human being, male or female. The term "therapeutically effective amount" means
the amount of
the subject compound that will elicit the biological or medical response of a
tissue, system,
animal or human that is being sought by the researcher, veterinarian, medical
doctor or other
clinician. It is recognized that one skilled in the art may affect the
neurological and psychiatric
disorders by treating a patient presently afflicted with the disorders or by
prophylactically
treating a patient afflicted with the disorders with an effective amount of
the compound of the
present invention. As used herein, the terms "treatment" and "treating" refer
to all processes
wherein there may be a slowing, interrupting, arresting, controlling, or
stopping of the
progression of the neurological and psychiatric disorders described herein,
but does not
necessarily indicate a total elimination of all disorder symptoms, as well as
the prophylactic
therapy of the mentioned conditions, particularly in a patient who is
predisposed to such disease
or disorder. The terms "administration of' and or "administering a" compound
should be
understood to mean providing a compound of the invention or a prodrug of a
compound of the
invention to the individual in need thereof.
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CA 02795550 2012-11-13
The term "composition" as used herein is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any
product which
results, directly or indirectly, from combination of the specified ingredients
in the specified
amounts. Such term in relation to pharmaceutical composition, is intended to
encompass a
product comprising the active ingredient(s), and the inert ingredient(s) that
make up the carrier,
as well as any product which results, directly or indirectly, from
combination, complexation or
aggregation of any two or more of the ingredients, or from dissociation of one
or more of the
ingredients, or from other types of reactions or interactions of one or more
of the ingredients.
Accordingly, the pharmaceutical compositions of the present invention
encompass any
composition made by admixing a compound of the present invention and a
pharmaceutically
acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier,
diluent or excipient
must be compatible with the other ingredients of the formulation and not
deleterious to the
recipient thereof
The scientific literature has implicated the orexin receptors in a wide range
of
biological functions. This has suggested a potential role for these receptors
in a variety of
disease processes in humans or other species. In accordance with the present
invention, the
formulations of the compound of Formula I may have utility in treating,
preventing,
ameliorating, controlling or reducing the risk of neurological and psychiatric
disorders associated
with orexin receptors. In accordance with the present invention, the
formulations of the
compound of Formula I may provide methods for: preventing and treating sleep
disorders and
sleep disturbances; treating insomnia; enhancing the quality of sleep;
augmenting sleep
maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing
fragmentation of sleep
patterns; treating insomnia; enhancing cognition; increasing memory retention;
treating or
controlling obesity; treating or controlling depression; in a mammalian
patient in need thereof
which comprises administering to the patient a therapeutically effective
amount of the compound
of Formula I in a formulation of the present invention.
In accordance with the present invention, the formulations of the compound of
Formula I may also be useful in a method for the prevention, treatment,
control, amelioration, or
reduction of risk of the diseases, disorders and conditions noted herein. The
dosage of active
ingredient in the compositions of this invention may be varied, however, it is
necessary that the
amount of the active ingredient be such that a suitable dosage form is
obtained. The active
ingredient may be administered to patients (animals and human) in need of such
treatment in
dosages that will provide optimal pharmaceutical efficacy. The selected dosage
depends upon
the desired therapeutic effect, on the route of administration, and on the
duration of the
treatment. The dose will vary from patient to patient depending upon the
nature and severity of
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CA 02795550 2012-11-13
disease, the patient's weight, special diets then being followed by a patient,
concurrent
medication, and other factors which those skilled in the art will recognize.
Generally, dosage
levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to
the patient, e.g.,
humans and elderly humans, to obtain effective antagonism of orexin receptors.
The dosage
range will generally be about 0.5 mg to 1.0 g. per patient per day which may
be administered in
single or multiple doses. In one embodiment, the dosage range will be about
0.5 mg to 500 mg
per patient per day; in another embodiment about 0.5 mg to 200 mg per patient
per day; and in
yet another embodiment about 5 mg to 50 mg per patient per day. Pharmaceutical
compositions
of the present invention may be provided in a solid dosage formulation such as
comprising about
0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active
ingredient. The
pharmaceutical composition may be provided in a solid dosage formulation
comprising about 1
mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, or 100 mg active
ingredient. In
specific embodiments, the pharmaceutical composition may be provided in a
solid dosage
formulation comprising about 10 mg, 15 mg, 20 mg, 30 mg, or 40 mg active
ingredient. For oral
administration, the compositions may be provided in the form of tablets
containing 1.0 to 1000
milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75,
100, 150, 200, 250, 300,
400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for
the symptomatic
adjustment of the dosage to the patient to be treated. The compound may be
administered on a
regimen of 1 to 4 times per day, such as once or twice per day. In an
embodiment of the present
invention, the compound may be administered in a regimen of once per day in
the evening, such
as prior to initiating sleep.
The compound of the Formula I that is employed in the present invention may be

used in combination with one or more other drugs in the treatment, prevention,
control,
amelioration, or reduction of risk of diseases or conditions for which
compounds of the present
invention or the other drugs may have utility, where the combination of the
drugs together are
safer or more effective than either drug alone. Such other drug(s) may be
administered, by a
route and in an amount commonly used therefor, contemporaneously or
sequentially with a
compound of the present invention. When a compound of the present invention is
used
contemporaneously with one or more other drugs, a pharmaceutical composition
in unit dosage
form containing such other drugs and the compound of the present invention is
contemplated.
However, the combination therapy may also includes therapies in which the
compound of the
present invention and one or more other drugs are administered on different
overlapping
schedules. It is also contemplated that when used in combination with one or
more other active
ingredients, the compounds of the present invention and the other active
ingredients may be used
in lower doses than when each is used singly. Accordingly, the pharmaceutical
compositions of
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CA 02795550 2012-11-13
the present invention include those that contain one or more other active
ingredients, in addition
to a compound of the present invention. The above combinations include
combinations of a
compound of the present invention not only with one other active compound, but
also with two
or more other active compounds.
Likewise, the compound of the Formula I that is employed in the present
invention may be used in combination with other drugs that are used in the
prevention, treatment,
control, amelioration, or reduction of risk of the diseases or conditions for
which compounds of
the present invention are useful. Such other drugs may be administered, by a
route and in an
amount commonly used therefor, contemporaneously or sequentially with a
compound of the
present invention. When the compound of the Formula I is used
contemporaneously with one or
more other drugs, a pharmaceutical composition containing such other drugs in
addition to the
compound of the present invention is contemplated. Such pharmaceutical
compositions are
prepared without undue experimentation in accordance with the methods
described herein and
known in the art. Accordingly, the pharmaceutical compositions of the present
invention include
those that also contain one or more other active ingredients, in addition to a
compound of the
present invention.
The weight ratio of the compound of the Formula I to the second active
ingredient
may be varied and will depend upon the effective dose of each ingredient.
Generally, an
effective dose of each will be used. Thus, for example, when a compound of the
present
invention is combined with another agent, the weight ratio of the compound of
the present
invention to the other agent will generally range from about 1000:1 to about
1:1000, such as
about 200:1 to about 1:200. Combinations of a compound of the present
invention and other
active ingredients will generally also be within the aforementioned range, but
in each case, an
effective dose of each active ingredient should be used. In such combinations
the compound of
the present invention and other active agents may be administered separately
or in conjunction.
In addition, the administration of one element may be prior to, concurrent to,
or subsequent to the
administration of other agent(s).
The pharmaceutical compositions of this invention may conveniently be
presented
in dosage unit form and may be prepared by any of the methods well known in
the art of
pharmacy. All methods include the step of bringing the active ingredient into
association with
the carrier which constitutes one or more accessory ingredients. In general,
the pharmaceutical
compositions are prepared by uniformly and intimately bringing the active
ingredient into
association with a liquid carrier or a finely divided solid carrier or both,
and then, if necessary,
shaping the product into the desired formulation. In the pharmaceutical
composition the active
object compound is included in an amount sufficient to produce the desired
effect upon the
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CA 02795550 2012-11-13
process or condition of diseases. As used herein, the term "composition" is
intended to
encompass a product comprising the specified ingredients in the specified
amounts, as well as
any product which results, directly or indirectly, from combination of the
specified ingredients in
the specified amounts.
Pharmaceutical compositions intended for oral use may be prepared in
accordance
with the methods described herein and other method known to the art for the
manufacture of
pharmaceutical compositions. Such compositions may further contain one or more
agents
selected from the group consisting of sweetening agents, flavoring agents,
coloring agents and
preserving agents in order to provide pharmaceutically elegant and palatable
preparations.
Tablets may contain the active ingredient in admixture with non-toxic
pharmaceutically
acceptable excipients which are suitable for the manufacture of tablets. These
excipients may be
for example, inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating agents, for
example, corn starch,
or alginic acid; binding agents, for example starch, gelatin or acacia, and
lubricating agents, for
example magnesium stearate, stearic acid or talc. The tablets may be uncoated
or they may be
coated by known techniques to delay disintegration and absorption in the
gastrointestinal tract
and thereby provide a sustained action over a longer period. Compositions for
oral use may also
be presented as hard gelatin capsules wherein the active ingredient is mixed
with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium, for
example peanut oil,
liquid paraffin, or olive oil. Aqueous suspensions contain the active
materials in admixture with
excipients suitable for the manufacture of aqueous suspensions. Dispersible
powders and
granules suitable for preparation of an aqueous suspension by the addition of
water provide the
active ingredient in admixture with a dispersing or wetting agent, suspending
agent and one or
more preservatives.
Several methods for preparing the pharmaceutical formulations of this
invention
are illustrated in the following Examples. In some cases the order of carrying
out the foregoing
examples may be varied to facilitate the efficiency of the process or desired
properties of the
formulation. The following examples are provided so that the invention might
be more fully
understood. These examples are illustrative only and should not be construed
as limiting the
invention in any way.
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CA 02795550 2012-11-13
EXAMPLES
Examples of preparations of pharmaceutical formulations are provided below.
Bioavailability is determined in vivo by dosing trial formulations and/or
other formulations of the
active pharmaceutical ingredient (API) to Beagle dogs at a dose of 5 mg/kg of
the API and then
measuring the amount of API in the serum or blood as a function of time.
Comparisons are made
with other formulations containing the same amount and same concentration of
the API, such as
a solid formulation with conventional excipients. The API is suvorexant, or a
pharmaceutically
acceptable salt thereof
Dissolution of the formulations in water or simulated gastric fluid can be
observed
and measured to determine the concentration and rate of dissolution of
suvorexant in the fluid
using the formulations of this invention or other formulations, including
formulations with
conventional excipients as controls to determine the improvements in
dissolution using the
formulations of this invention.
EXAMPLE 1: PREPARATION OF SPRAY DRY FORMULATIONS
Formulation 1:
Spray dried formulations comprised: suvorexant (10-20% w/w); an optional
surfactant, such as (1) 2-4% SDS (sodium dodecyl sulfate), (2) 2.5% Vitamin E
TPGS, (3) 2%
Tween 80, (4) 2% Span 80, or (5) 2% Cremophor EL, or a mixture of two or more
of these
surfactants; and the balance is either HPMCAS-L, HPMCAS-M, or HPMCAS-H
(purchased as
AQOAT from Shin Etsu). The components were dissolved or suspended in a solvent
system,
such as acetone, methanol, and mixtures of organic solvents with water (0.5-
18% w/v solids),
and then spray dried as described below.
Solution Preparation:
Suvorexant, optional surfactant or surfactants, and polymer were mixed with
acetone, methanol, or mixtures of organic solvents with water as follows,
yielding a solution
(which may be a structured suspension). The drug, surfactant, and polymer were
dissolved in the
solvent. The polymer was slow to dissolve and was added to the solvent over an
extended period
of time with vigorous stirring, such as by using an impeller or magnetic stir
bar and stir plate.
The resulting solution/suspension was stirred for at least an additional 60
min prior to spray
drying.
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CA 02795550 2012-11-13
Spray Drying Process 1:
Spray drying was carried out in a Niro SD Micro spray drier. Heated dry
nitrogen
and formulation solution were fed concurrently into a two-fluid nozzle and are
then discharged
as a spray into the drying chamber, along with additional heated gas,
resulting in rapid
evaporation to form particles. The dried particles were carried by the
processing gas into a
cyclone and then into a bag filter chamber for collection. Three processing
rates were controlled
and monitored: 1) solution feed rate, 2) processing nitrogen flow rate, and 3)
atomizing nitrogen
flow rate. The solution feed rate was controlled by an external peristaltic
pump, and is ¨5-20
ml/min on a laboratory scale. The atomizing nitrogen rate and processing
nitrogen rates were 2-3
kg/hr for atomizing nitrogen and 20-30 kg/hr for processing nitrogen. The
targeted processing
gas temperature at the drying chamber outlet was slightly below the boiling
point of the solvent
system, although temperatures in the range of 30 to 70 C were demonstrated to
be adequate, and
the inlet chamber temperature (at the outlet of the nozzle) was adjusted to
obtain the desired
outlet temperature. An inlet temperature set point of 80-90 C was typical.
Residual solvent
levels in the product was typically low (<1 % w/w).
Spray Drying Process 2
The processing configuration was similar to Process 1, except that spray
drying
was carried out in a Niro PSD-1 extended chamber spray drier equipped with a
two-fluid nozzle
with 1 mm orifice. The following processing conditions were controlled or
monitored:
formulation solution feed rate (2-7.6 kg/hr), processing gas flow rate (35-38
mm H20),
atomization ratio (ratio of atomization gas flow rate to feed rate) (0.9-2.8),
atomization pressure
(0.25-1.5 bar), outlet gas temperature (43-70 C), and inlet gas temperature
(61-134 C)
Post Spray Drying Processing:
At the smaller processing scale, material collection occurred in two areas,
the
cyclone and the bag filter chambers. Typical mean particle sizes resulting
from the Spray Drying
Process 1 ranged from 1 to 30 1AM, with individual particles measuring between
<1 [tm and >100
as sampled from the cyclone collection area. The majority of particles in the
bag filter were
1 [.tm or less, although the particles were highly agglomerated. Under Spray
Drying Process 2
conditions, particles were harvested from the cyclone collection chamber only,
and the typical
mean particle size may be much larger, typically ranging between 5 to 70 [tm.
The spray dried particles were made into granules as follows. The particles
were
blended in a suitable blender (V or Bohle) with microcrystalline cellulose
such as Avicel (a
filler), lactose (a croscarmellose sodium (a disintegrant), colloidal
silicon dioxide (a
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CA 02795550 2012-11-13
glidant), and magnesium stearate (a lubricant). The blended powders were then
roller compacted
into granules, subjected to extragranular lubrication, and filled into
capsules.
A formulation prepared as described above that comprised of 10% (w/w)
suvorexant, 40% HPMCAS-LF, 42.5% lactose monohydrate, 6% croscarmellose
sodium, 0.5%
colloidal silicon dioxide, and 1% magnesium stearate was transferred to
capsules, with each
capsule containing 50 mg of suvorexant. The pharmacokinetic profile of this
composition was
tested in a panel of 3 fasted beagle dogs with a single dose of 1 mg/kg. The
pharmacokinetic
measurements of suvorexant in the blood for a period of 24 hours was as
follows: AUC0_24 is
52.3 19.1 M*hr; Cmax is 6.95 2.23 p,M; and Tmax is 1.0 hr with a range of
1.0-2.0 hr.
For comparison, a formulation containing suvorexant without the polymer or
spray drying process was made and tested, as follows. The non-polymer
formulation contained
25% of suvorexant, 3% croscarmellose sodium, 1% magnesium stearate 35.5%
microcrystalline
cellulose, and 35.5% lactose, and was prepared by roller compaction and
compressed into a
tablet. The pharmacokinetic profile of this composition was measured by
administering a single
5 mg/kg dose to a panel of 3 fasted beagle dogs and then measuring the amount
of suvorexant in
the blood of the dogs for a period of at least 24 hours. The pharmacokinetic
data was as follows:
AUC0_24 is 3.04 1.40 p,M*hr, Cmax is 0.34 0.10 M, and Tmax is 2.0 hr with
a range of 1.0-
2.0 hr. The pharmacokinetics are not as good for the "conventional"
formulation as for the
polymer formulations.
In an embodiment of this invention, formulations of HPMCAS with suvorexant
and an optional surfactant may comprise 4% -40% suvorexant and 0-10%
surfactant, with the
balance of the formulation being HPMCAS.
EXAMPLE 2: PREPARATION OF HOT MELT EXTRUSION FORMULATIONS
The following two formulations were made by hot melt extrusion. Amounts are
expressed as weight %. KollidonVA64 is a copolymer of polyvinylpyrrolidinone
and polyvinyl
acetate having a co-monomer ratio of about 1.2:1. It is also known as
copovidone. It has a glass
transition temperature (Tg) of about 110 C.
(1) suvorexant, 20%; Kollidon VA64, 80%.
(2) suvorexant, 20%; HPMCAS-LG, 80%
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CA 02795550 2012-11-13
Formulation 1
Formulation 1 was made by blending the two components, and then feeding the
mixture into a twin screw extruder. The mixture was made by combining the
KollidonVA64
polymer and suvorexant at room temperature in a Bohle bin blender equipped
with a 2 liter bin.
The pre-extrusion blend was fed into a Thermo Prism 16mm L/D 40:1 Hot Melt
Twin Screw Extruder. The barrel of the extruder had 10 temperature zones
numbered 1-10, with
Zone 1 at the entry end of the barrel and Zone 10 just before the die. Zone 1
was not heated and
has no temperature measurement. Zones 2-10 each have temperature control, and
the
temperatures of each of these zones were measured. The temperature of the die
was not
controlled but can be measured. The feed was introduced into Zone 2 through a
feed throat. The
screws were designed so that mixing occurred across Zones 4 and 5. The mixing
ended
immediately past the vent port. The pre-extrusion mixture was fed into the
feed port of the
extruder at about 10 g/min from a K-Tron twin-screw gravimetric feeder. The
screw speed was
100 rpm. The profile of temperature set points in the extruder for Zones 2-10
was: Zones 2-5,
20 C; Zones 6-10, 130 C. The actual temperatures in these zones were: Zone
2, 22-23 C;
Zone 4, 80 C; Zones 6-10, 180 C;. Zone 10 was initially set at 190 C to
avoid pressure during
startup, and then the temperature set point was lowered to 180 C once the
extrusion began. The
temperature of the molten product exiting from the die was 200 C. There was
no appreciable
buildup of die pressure. The extrudate was clear, and it appeared homogeneous.
The solid
extruded polymer was then milled using a Fitz Mill with a knife configuration,
Impact forward,
with a 1722-0033 screen at 7500 rpm.
In an alternate procedure, a formulation was made by blending the two
components, and then feeding the mixture into a twin screw extruder. The
mixture was made by
combining the copovidone polymer and suvorexant at room temperature in a bin
blender. The
pre-extrusion blend was fed into a 40/1 L/D twin screw extruder. The extruder
had 12
temperature zones numbered 1-12, with Zone 1 at the entry end of the barrel
and Zone 10 the end
of the barrel sections with zone 11 being an adaptor to change the flow regime
to a single orifice
and zone 12 being a die adaptor. Zone 1 was maintained at low temperatures by
cooling water.
Zones 2-12 each have temperature control, and the temperatures of each of
these zones were
measured. The feed was introduced into Zone 2 through a side stuffer. The
screws were
designed so that a melt seal was formed at zone 3 allowing moisture venting at
zone 4. Mixing
occurred across Zones 6 and 7 allowing further moisture venting at zone 8. The
pre-extrusion
mixture was fed into the feed port of the extruder from a twin-screw
gravimetric feeder. The
screw speed was 300 rpm. The profile of temperature set points in the extruder
for Zones 2-12
was: Zone 2,42 C; Zone 3, 100 C; zone 4, 130 C Zones 5-12, 180 C. The
temperature of the
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CA 02795550 2012-11-13
molten product exiting from the die was 185 C. There was no appreciable build-
up of die
pressure. The extrudate was clear, and it appeared homogeneous. The extruded
material was fed
through counter rotating rolls chilled to 10-12 C to bring the melt below its
glass transition
temperature and form a brittle glass sheet, that was conveyed to a coarse
mill, and broken up into
small pieces. The extrudate was then further milled using an impact mill with
a hammer
configuration with a 0.84 mm screen at mill tip speed of 40-45 m/s.
Formulation 2
Formulation 2 was made using the same procedure as was used for Formulation 1.
The extrusion was carried out under the same general conditions as the
extrusion of Formulation
1. The only change was that the temperature of Zones 6-10 was set to 140 C
and Zone 10 was
initially set at 150 C, before lowering back to 140 C. The temperature of
the molten extrudate
as it exited from the die was 140 C. The die pressure was low. The extrudate
was milled using
the same method as was used for Formulation 1.
EXAMPLE 3: PREPARATION OF TABLET FORMULATIONS
BY HOT MELT EXTRUSION
The formulation composition for making tablets containing 8% of suvorexant are
shown in the following table. In accordance with the present invention, the
compositions can be
varied more broadly.
Component Composition (% w/w)
Suvorexant 8%
Copovidone 32%
Lactose monohydrate 16.5%
Microcrystalline cellulose 33%
Croscarmellose sodium 10%
Magnesium stearate 0.5%
Representative ranges of the amounts of the components that can be used and
their function are as follows: suvorexant (API), 0.5-40%; 5-30% copovidone
(stabilizing
polymer), 0.25-40%; microcrystalline cellulose (filler), 5-95%; lactose
(filler), 5-95%;
croscarmellose sodium (disintegrant), 1-10%; magnesium stearate (lubricant).
Representative
ranges of the amounts of suvorexant and copovidone are 1-40% and 5-90%,
respectively.
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CA 02795550 2012-11-13
In an embodiment of the present invention, substitutes may be used in place of
the
polymers and excipients. For example, where a trade name or brand name is
used, the same
materials having other brand or trade names may also be used: stabilizing
polymer - Eudragits
(acrylate-methacrylate copolymers), PVP, HPC, HPMC, HPMCP, HPMCAS, CAS, CAP,
and
CAT; Surfactants - SDS, Cremophor (various grades), polysorbates (various
grades), Solutol,
Gelucires, Spans (various grades), PEG's; fillers - dicalcium phosphate,
silicified
microcrystalline cellulose, starch, mannitol; disintegrants - crospovidone,
sodium starch
glycolate, calcium silicate, starch; optional colorants - red iron oxide,
yellow iron oxide, black
iron oxide, titanium dioxide, FD&C Blue #2; and optional coating - Opadry I,
Opadry II, Opadry
II HP.
Unit Strength = 10 mg
Component mg/tablet
Suvorexant 10
Polyvinylpyrolidone/Vinyl Acetate Copolymer (Kollidon 40
VA64)
Lactose monohydrate (316 Fast-Flo) 20.625
Microcrystalline cellulose (Avicel PH102) 41.25
Croscarmellose sodium 12.5
Magnesium stearate 0.625
(Core Tablet Weight 125 mg)
Unit Strength = 30 mg
Component mg/tablet
Suvorexant 30
PolyvinylpyrolidoneNinyl Acetate Copolymer (Kollidon 120
VA64)
Lactose monohydrate (316 Fast-Flo) 61.875
Microcrystalline cellulose (Avicel PH102) 123.75
Croscarmellose sodium 37.5
Magnesium stearate 1.875
(Core Tablet Weight 375 mg)
The formulations in the table above were made by hot melt extrusion by the
following procedure. Suvorexant was fed using a Ktron K20 twin screw powder
feeder at
extruder barrel zone 1 through the top feed port of the barrel section (2
kg/hr). Polymer
(Kollidon VA64) was fed using a Ktron K20 twin screw powder feeder at extruder
barrel zone 2
through a twin screw Leistritz side stuffer with top vent port in the barrel
section (8 Kg/hr).
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CA 02795550 2012-11-13
A vent (or two vents) were located at barrel zones 7, 8, and/or 9. These were
ambiently vented to remove water vapor. The remaining barrel sections were
closed. All feeders
are placed on load cells to continuously monitor changes in weight. The barrel
temperature was
at room temperature at zone 1, and the temperatures were at about 130 C at
Zone 3 or 4. Zones
5-10 were heated to about 180 C.
A four hole strand die was used to extrude material onto a chilled roll unit
made
by ThermoElectron. The chilled roll unit used cool water to produce a brittle
sheet of extrudate
that was subsequently chopped up into particles by a "kibbler" (basically a
rotor with
perpendicular pegs that wacks at the brittle sheet that is conveyed to the
rotor).
The particles from the kibbler above were milled using a Fitz mill prior to
downstream processing/tabletting. The milled extrudate was then blended in a
suitable blender
(V or Tote) with microcrystalline cellulose (e.g. Avicel) (a filler), lactose
(a filler), and
croscarmellose sodium (a disintegrant). The blend was then lubricated with
magnesium stearate.
The lubricated blend is compressed into tablets. The compressed tablets may
optionally be
coated.
The pharmacokinetic profile of this composition of suvorexant was tested by
administering a single dose of the formulation at a dose of 5 mg/kg to panels
of 3 fasted beagle
dogs and measuring the concentration of suvorexant in the blood for a period
of at least 24 hours.
The pharmacokinetic measurements of suvorexant were as follows: AUCO-24 (p.M-
hr) 2.82
0.493; Cmax ([1.M) 0.587 0.182; Tmax (hr) 1.0 (0.5-2.0).
The pharmacokinetic profile of this composition of suvorexant was also tested
by
administering a single dose of the formulation to healthy human men. In this
study, this
composition of suvorexant helped to reduce the food effect when a formulation
of suvorexant is
administered with food (such as a high fat meal). In the first treatment
period of this clinical
study, a single, oral dose of this composition of suvorexant (40 mg) was
administered to 7
subjects in a fasted state (following an 8-hour fast), and a single, oral dose
of this composition of
suvorexant (40 mg) was administered to 7 different subjects following a
standard high-fat
breakfast. In the second period of this clinical study, the 7 subjects in each
treatment groups
were crossed over and received the other treatment.
As shown in the following table, AUCo_oo and C. for this composition of
suvorexant remained unchanged after administration with a high fat breakfast
compared to
administration in a fasted state. The fed/fasted GMR and 90% confidence
intervals for AUC0f
were 0.98 (0.90, 1.07). The fed/fasted GMR and 90% confidence intervals for
Cmax were 1.09
(0.90, 1.33). Median T. was 3.0 hours after a high fat breakfast and 2.0 hours
in a fasted state.
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CA 02795550 2012-11-13
Mean apparent terminal ty, when administered after a high fat breakfast was
largely uncharged
compared to administration in a fasted state, with t112 values of 11.8 and
10.9 hours respectively.
Pharmacokinetic Suvorexant Fasted Suvorexant Fed
(Suvorexant Fed/
Parameter
Suvorexant Fasted)
N GM 95% CI
N , GM 95% CI GMR 90% CI
AUCo.. (pM=hr) 12 13.2 (10.60, 12 13.0
(10.43, 0.98 (0.90,
16.42) 16.16) 1.07)
Cum (11M) 13 1.0 (0.79, 13 1.1 (0.86,
1.09 (0.90,
1.22) 1.34) 1.33)
Tmax (hr) 13 2.0 1.0, 4.0 13 3.0 1.0, 6.0
1.5 (1.0,3.0)
Apparent 12 10.9 3.4 12 11.8 3.8 -- --
Terminal tu2 (hr)
(GM: Geometric Mean, GMR: Geometric Mean ratio, CI: Confidence interval)
While the invention has been described and illustrated with reference to
certain
particular embodiments thereof, those skilled in the art will appreciate that
various adaptations,
changes, modifications, substitutions, deletions, or additions of procedures
and protocols may be
made without departing from the spirit and scope of the invention.
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