U.S. patent application number 13/925509 was filed with the patent office on 2014-12-25 for use of nk-1 receptor antagonists in pruritus.
The applicant listed for this patent is TIGERCAT PHARMA, INC.. Invention is credited to James W. LARRICK, Andrew J. PERLMAN, Edward F. SCHNIPPER, Xiaoming ZHANG.
Application Number | 20140378521 13/925509 |
Document ID | / |
Family ID | 52001636 |
Filed Date | 2014-12-25 |
United States Patent
Application |
20140378521 |
Kind Code |
A1 |
ZHANG; Xiaoming ; et
al. |
December 25, 2014 |
USE OF NK-1 RECEPTOR ANTAGONISTS IN PRURITUS
Abstract
The invention relates to methods for treating pruritus with an
NK-1 receptor antagonist. The invention further relates to
pharmaceutical compositions comprising NK-1 receptor
antagonist.
Inventors: |
ZHANG; Xiaoming; (Sunnyvale,
CA) ; SCHNIPPER; Edward F.; (Redwood City, CA)
; PERLMAN; Andrew J.; (Stanford, CA) ; LARRICK;
James W.; (Sunnyvale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TIGERCAT PHARMA, INC. |
South San Francisco |
CA |
US |
|
|
Family ID: |
52001636 |
Appl. No.: |
13/925509 |
Filed: |
June 24, 2013 |
Current U.S.
Class: |
514/416 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 45/06 20130101; A61K 31/403 20130101; A61K 31/4035 20130101;
A61K 47/10 20130101; A61K 9/4883 20130101; A61K 9/2054 20130101;
A61K 9/4858 20130101; A61P 17/00 20180101; A61K 9/0053 20130101;
A61K 9/06 20130101 |
Class at
Publication: |
514/416 |
International
Class: |
A61K 31/4035 20060101
A61K031/4035 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. A method of treating chronic pruritus, said method comprising
orally administering
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne or a pharmaceutically acceptable salt or solvate thereof to a
patient in need of such treatment according to a schedule, said
schedule comprising: a) first administering a at least one loading
dose; and b) second administering at least one therapeutically
effect maintenance dose; said maintenance dose is administered
chronically and comprises a dosage from about 0.1 mg to about 7.5
mg.
9. The method according to claim 8, wherein the loading dose is
five times, four times, three times, or two times the maintenance
dose.
10. The method according to claim 9, wherein the loading dose is
three times the maintenance dose.
11. The method according to claim 8, wherein the loading dose is
administered on day 1 and the maintenance dose is administered on
day 2 and thereafter.
12. The method according to claim 8, wherein the loading dose and
the maintenance dose are administered at bedtime.
13. The method according to claim 8, further comprising
administering a second loading dose prior to administering the
maintenance dose.
14. The method according to claim 13, wherein the loading dose is
three times the maintenance dose and the second loading dose is two
times the maintenance dose.
15. (canceled)
16. The method of claim 15, wherein the therapeutically effective
maintenance dose comprises a dosage of 0.25 mg, 1 mg, or 5 mg
administered once a day.
17. (canceled)
18. The method of claim 8, wherein the therapeutically effective
maintenance dose is administered once a day, once every other day,
once every third day, once every fourth day, or once a week.
Description
TECHNICAL FIELD
[0001] The invention relates to methods for treating acute or
chronic pruritus with an NK-1 receptor antagonist. The invention
further relates to pharmaceutical compositions comprising NK-1
receptor antagonist.
BACKGROUND OF THE INVENTION
[0002] Pruritus, or itch, is an uncomfortable skin sensation that
provokes a desire to scratch. Although itch may be acute, for
example, from an insect sting, chronic pruritus originates from
many different causes. It is a seriously debilitating condition,
comparable to chronic pain, which negatively impacts quality of
life.
[0003] Chronic pruritus affects millions of people worldwide,
although solid epidemiological data is very limited. For example,
one study reported that 8-10% of the population of Oslo suffer from
chronic pruritus from all causes (F. Dalgard et al., J. Investig.
Dermatol. Symp. Proc., 2004, 9(2):120-5). Patients with certain
diseases and conditions report high incidences of chronic itch,
including those with psoriasis (78-84%), Hodgkin's disease
(25-35%), dialysis patients (22%), and polycythaemica vera (48%)
(M. Metz and S. Stander, CME Dermatol., 2008; 3(3):124-143).
Chronic pruritus is also a prevalent symptom in cutaneous T-cell
lymphoma (68-93%), a disease that includes mycosis fungoides and
Sezary syndrome (N. Meyer et al., Acta Derm. Venereol., 2010,
90:12-17). Pruritus is the most common dermatological complaint in
elderly patients (S. Beauregard and B. A. Gilchrest, Arch.
Dermatol., 1987, 123:1638-43). Itch is often the side effect of
certain drugs, such as EGF receptor antagonists.
[0004] Antihistamines can sometimes effectively treat itch due to
acute urticaria, but many chronic pruritic diseases respond poorly
to conventional H1 receptor antagonists (Tey H. L. and G.
Yosipovitch; Br. J. Dermatol., 2011, 165(1):5-17). In addition to
marginal efficacy, antihistamines can also cause intolerable
drowsiness. Other current therapies possess various limitations.
For example, anticonvulsants such as gabapentin inhibit spinal
mechanisms in the perception of itch, but their use is limited due
to their slow onset of action (5-6 weeks) (Metz and Stander, 2008).
Opiate receptor antagonists such as naloxone, nalmefene, and
naltrexone decreased pruritus symptoms in patients with liver and
kidney disease, although significant central nervous and
gastrointestinal side effects occurred (Metz and Stander, 2008; N.
V. Bergasa et al., Hepatology, 2006, 44(5):1317-23).
[0005] Substance P, the endogenous ligand for the neurokinin-1
(NK-1) receptor, is a significant mediator of pruritus (T. Andoh et
al., J. Pharmacol. Exp. Ther., 1998, 286:1140-5). Intradermal
injection of substance P elicits an itch sensation in human
subjects, and an associated itch response in mice. The substance
P-induced itch-associated response in mice is not inhibited by
antihistamines (B. Amatya et al., Skin Pharmacol. Physiol., 2010;
23:133-138; C. Weidner et al., J. Invest. Dermatol., 2000,
115:1015-1020). In an experiment designed to study the role of
substance P in pruritus, Ohmura et al. reported that tachykinin
NK-1 receptor antagonist, BIIF 1149 CL, inhibited scratching
behavior in a picrylchloride-induced dermatitis model in NC/Nga
mice (Eur. J. Pharmacol., 2004, 491:191-194; U.S. Patent
Application No. 2003/100565).
[0006] Aprepitant (Emend.COPYRGT.), an NK-1 receptor antagonist, is
approved by the FDA for use in the prevention of chemically induced
nausea and vomiting (emesis) after chemotherapy. Duval and
Dubertret first reported that oral aprepitant (80 mg daily) had
utility in treating pruritus in three patients with Sezary syndrome
(N. Engl. J. Med., 2009, 361(14):1415-6). Torres et al. disclosed
similar results (J. Am. Acad. Dermatol., 2012; 66(1):e14-5).
Stander et al. conducted a small, open-label study which
demonstrated that aprepitant significantly decreased chronic
pruritus caused by conditions such as atopic diathesis and prurigo
nodularis. In this study, twenty previously untreatable patients
were given a daily dose of 80 mg for 3 to 13 days. Eighty percent
of the patients experienced a considerable reduction in itch
intensity (S. Stander, et al., PLoS One, 2010, 5:6, e10968).
However, Wallengren conducted a follow-up double-blind study based
on Stander's work testing a single dose of topical aprepitant
blended at a 5% concentration in a lipophilic vehicle in patients
suffering from chronic pruritus of various etiologies. Although the
drug was absorbed into the skin, the patients' itch was not
alleviated (J. Wallengren, Arch. Dermatol., 2012,
148(8):957-9).
[0007] Although oral aprepitant is generally well-tolerated, it is
extremely expensive, limiting its use in chronic pruritus (Tey,
2011). Further, aprepitant is a moderate inhibitor as well as an
inducer of CYP3A4 and CYP2C9, indicating that drug-drug
interactions with chemotherapeutic agents and corticosteroids must
be considered (Torres, 2012). Mir and Coriat have suggested that
the risk of drug-drug interactions with aprepitant is high because
it can alter the activity of cytochrome P450 3A4 isoform (CYP-3A4),
an enzyme involved in the metabolism of a range of commonly
prescribed drugs, including tyrosine-kinase inhibitors, either
inducing or inhibiting the CYP-3A4, depending on which drugs are
given concomitantly. Tyrosine-kinase inhibitors do not induce
frequent nausea and emesis; therefore, clinical experience with
concomitant administration of aprepitant and these drugs is scarce.
Furthermore, the pharmacokinetics of tyrosine-kinase inhibitors
varies widely between patients, and drug-drug interactions are
common (O. Mir and R. Coriat, The Lancet, 2012, 13:964-965). Thus,
the need for additional, safe treatments for acute and chronic
pruritus exists.
SUMMARY OF THE INVENTION
[0008] In one aspect, this invention provides a method of treating
pruritus in a patient in need of such treatment comprising
administering to said patient a therapeutically effective amount of
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne or a pharmaceutically acceptable salt or solvate thereof. In one
embodiment, the therapeutically effective amount comprises a dosage
of 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg,
2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20
mg, 25 mg, or 30 mg one or more times a day. In another embodiment,
the therapeutically effective amount comprises a dosage of 0.25 mg,
1 mg, or 5 mg once a day. In a further embodiment, the
therapeutically effective amount comprises a dosage of from about
0.1 mg to about 30 mg or from about 1 mg to about 7.5 mg. In
another embodiment, the therapeutically effective amount is
administered orally in the form of a tablet. In a further
embodiment, the therapeutically effective amount is administered
once a day at bedtime. In another embodiment, the therapeutically
effective amount is administered once a day, once every other day,
once every third day, once every fourth day, or once a week.
[0009] In another aspect, this invention provides a method of
treating pruritus whereby
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoronnethyl)phenyl]ethoxy]-4-(-
4-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1--
one or a pharmaceutically acceptable salt or solvate thereof is
administered orally to a patient in need of such treatment
according to a schedule, wherein a least one loading dose is first
administered, and, second, at least one therapeutically effect
maintenance dose is administered. In one embodiment, the loading
dose is five times, four times, three times, or two times the
maintenance dose. In another embodiment, the loading dose is three
times the maintenance dose. In a further embodiment, the loading
dose is administered on day 1 and the maintenance dose is
administered on day 2 and thereafter. In another embodiment, the
loading dose and the maintenance dose are administered at bedtime.
In another embodiment, the method further comprises administering a
second loading dose prior to administering the maintenance dose. In
one embodiment, the loading dose is three times the maintenance
dose and the second loading dose is two times the maintenance dose.
In a further embodiment, the therapeutically effective maintenance
dose is 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg,
2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15
mg, 20 mg, 25 mg, or 30 mg administered one or more times a day. In
another embodiment, the therapeutically effective maintenance dose
comprises a dosage of 0.25 mg, 1 mg, or 5 mg administered once a
day. In a further embodiment, the therapeutically effective
maintenance dose comprises a dosage from about 0.1 mg to about 30
mg or from about 1 mg to about 7.5 mg. In another embodiment, the
therapeutically effective maintenance dose is administered once a
day, once every other day, once every third day, once every fourth
day, or once a week.
[0010] In one aspect, this invention provides a pharmaceutical
composition for the treatment of pruritus comprising
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne or a pharmaceutically acceptable salt or solvate thereof and a
pharmaceutically acceptable carrier. In one embodiment, the
pharmaceutical composition is formulated as a tablet comprising
Compound 1 or a pharmaceutically acceptable salt or solvate thereof
and one or more diluents, disintegrants, surfactants or lubricants.
In another embodiment, the composition comprises a capsule filled
with a solution comprising Compound 1 or a pharmaceutically
acceptable salt or solvate thereof and an amphiphilic agent. In a
further embodiment, the amphiphilic agent is a fatty acid ester of
glycerol, propylene glycol or sorbitol. In another embodiment, the
pharmaceutical composition comprises 0.10 mg, 0.15 mg, 0.20 mg,
0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of
Compound 1 or a pharmaceutically acceptable salt or solvate
thereof. In another embodiment, the composition comprises 0.25 mg,
1 mg, or 5 mg of Compound 1 or a pharmaceutically acceptable salt
or solvate thereof.
[0011] In another aspect, this invention provides a method of
treating acute or chronic pruritus in a patient in need of such
treatment comprising administering to said patient a
therapeutically effective amount of a pharmaceutical composition
comprising
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne or a pharmaceutically acceptable salt or solvate thereof and a
pharmaceutically acceptable carrier. In one embodiment, the method
involves treatment with a pharmaceutical composition formulated as
a tablet comprising Compound 1 or a pharmaceutically acceptable
salt or solvate thereof and one or more diluents, disintegrants,
surfactants or lubricants. In another embodiment, the method
involves administration of a composition comprising a capsule
filled with a solution comprising Compound 1 or a pharmaceutically
acceptable salt or solvate thereof and an amphiphilic agent. In a
further embodiment, the amphiphilic agent is a fatty acid ester of
glycerol, propylene glycol or sorbitol. In another embodiment, the
method involves treatment with a pharmaceutical composition
comprising 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1
mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,
15 mg, 20 mg, 25 mg, or 30 mg of Compound 1 or a pharmaceutically
acceptable salt or solvate thereof. In another embodiment, the
composition comprises 0.25 mg, 1 mg, or 5 mg of Compound 1 or a
pharmaceutically acceptable salt or solvate thereof.
[0012] Other objects of the invention may be apparent to one
skilled in the art upon reading the following specification and
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0014] FIG. 1 depicts a synthetic scheme for serlopitant, Compound
1.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Unless defined otherwise, 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 application belongs. It
must be noted that as used herein and in the appended claims, the
singular forms "a", "and", and "the" include plural referents
unless the context clearly dictates otherwise.
[0016] Reference will now be made in detail to certain preferred
methods of treatment, compounds and methods of administering these
compounds. The invention is not limited to those preferred
compounds and methods, but rather is defined by the claim(s)
issuing herefrom.
Introduction
[0017] Serlopitant is a neurokinin-1 (NK-1) receptor antagonist.
The present invention provides a method for treating chronic
pruritus and related conditions using serlopitant or a
pharmaceutically acceptable salt or hydrate thereof. Chemically,
the generic name serlopitant refers to the compound of Compound
1:
##STR00001##
[0018] The I.U.P.A.C. name for the compound is
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne. Alternatively, Compound 1 may be named
3-1[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(-
4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one. For
purposes of the present invention, it is understood that any of
these designations for Compound 1 may be interchangeably used and
have the same meaning.
[0019] Serlopitant has previously been disclosed as a neurokinin-1
(NK-1) receptor antagonist, an inhibitor of tachykinin and, in
particular, of substance P (J. Jiang, et al., J. Med. Chem., 2009,
52:3039-3046)). Neurokinin receptors are part of the larger family
of G-protein coupled receptors that elicit many of their effects
via activation of the inositol phosphate signal transduction
pathway. NK-1 receptors are present in both the central and
peripheral nervous system and in vascular endothelial cells, muscle
and cells of the immune system. Compound 1 is unusually selective
(>39,000 fold) for the cloned human NK-1 receptor over the
cloned human NK-2 and NK-3 receptors, as demonstrated using Chinese
hamster ovary cells stably expressing the respective receptors
(Jiang et al., 2009). Jiang et al. showed that serlopitant binds to
the human NK-1 receptor with a K.sub.d of 46 pM and that it
displaces substance P binding at the same receptor with an
IC.sub.50 of 61 pM.
[0020] Compound 1 is a weak reversible inhibitor of human CYP-3A4,
2C8, 2C9, 2C19, 2D6, and 1A2 enzymes, the IC.sub.50 values of which
are 39, 58, 30, 29, 35, and >100 .mu.M, respectively.
Serlopitant did not significantly induce CYP-3A4 mRNA in three
individual preparations of human hepatocytes. These data suggest
that serlopitant will have minimal drug-drug interaction liability
in humans and that any drug-drug interactions will be reduced in
comparison with other NK-1 receptor antagonists. Although
broad-based counter-screening of serlopitant in more than 145
assays identified a number of weak activities between 1 and 10
.mu.M, no assays for which IC.sub.50<1 .mu.M were observed.
Therefore, off-target activities were more than 20000-fold less
potent than hNK-1 activity (Jiang et al., 2009).
[0021] It has been suggested serlopitant and its analogs would be
useful in the prevention and treatment of a variety of clinical
conditions characterized by the presence of an excess of
tachykinin, in particular substance P, activity. Serlopitant has
been disclosed as a treatment for emesis and for urinary
incontinence (U.S. Pat. Nos. 7,217,731, 7,345,083, 7,544,815,
7,645,790, and 7,893,091, the disclosures of which are herein
incorporated by reference; U.S. Published Application Nos. US
2009/0270477, US 2010/0113469, and US 2010/0209496, the disclosures
of which are herein incorporated by reference; and PCT Publication
WO 2007/146224, the disclosure of which is herein incorporated by
reference).
[0022] The safety and tolerability of serlopitant have been
evaluated in several human clinical trials for the treatment or
prevention of with overactive bladder (OAB). In one investigation,
a total of 557 patients with OAB were randomized into this
double-blind, placebo-controlled and active-controlled
(tolterodine), dose-ranging study. Serlopitant at 0.25 and 4 mg
daily significantly reduced the number of daily micturitions
compared with placebo. There were no drug-related serious adverse
experiences and the drug was generally well tolerated. However,
serlopitant did not show a dose response relationship with
micturition frequency, and did not significantly influence the
secondary efficacy end points of urinary urgency, urge incontinence
and total incontinence. Tolterodine was numerically more effective
than serlopitant at all efficacy end points and statistically
significantly more effective than placebo. Serlopitant was not
associated with the adverse experience of dry mouth common in
patients receiving tolterodine, a muscarinic antagonist. (See:
Frenkl, T. L. et al., J. Urology, 2009, 181(4), Suppl. S, p. 676;
Frenkl, T. L. et al., Neurourol. Urodyn., 2009, 28(2):143-144;
Frenkl, T. L. et al., European Urology Supplements, 2009, 8(4):134;
Frenkl, Tara L, et al., J. Urology, 2010, 184(2):616-622.)
Chemical Description of Serlopitant
[0023] 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.
Particularly preferred are 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,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,
2-dimethylamino-ethanol, 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 of
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, ethanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of the present invention are
meant to also include the pharmaceutically acceptable salts.
[0024] The term "solvate" refers to an aggregate that consists of a
solute ion or molecule with one or more solvent molecules.
"Solvates" include hydrates, that is, aggregates of a compound of
interest with water. It will be understood that, as used herein,
references to the compounds of the present invention are meant to
also include the solvates.
[0025] Chemical Synthesis. Serlopitant may be prepared as described
by Jiang et al. (J. Med. Chem. 2009, 52:3039-3046), which is herein
incorporated by reference in its entirety. Alternatively, the
method of Kuethe et al., as described in U.S. Pat. No. 7,544,815,
or Bunda et al., as described in U.S. Pat. No. 7,217,731, both of
which are herein incorporated by reference in their entirety, may
be used.
[0026] The method of Kuethe et al. is depicted in FIG. 1. Briefly,
commercially available 4-fluorophenylacetic acid (2) (Sigma-Aldrich
Co. LLC, St. Louis, Mo.) is reacted with thionyl chloride in
DMF/toluene to yield acid chloride (3). The acid chloride (3) is
then reacted with the hydrochloride salt of the Weinreb amine
(CH.sub.3NHOCH.sub.3.HCl) in the presence of sodium hydroxide to
give 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide (4). A vinyl
Grignard reaction converts (4) to 1-(4-fluorophenyl)but-3-en-2-one
(5). TES dienyl ether (6) is produced from the reaction of (5) with
chlorotriethylsilane (TESCl) in the presence of
iPr.sub.2NEt.sub.2.
[0027] Commercially available furrieryl chloride and two
equivalents of (-)-menthol (both Sigma-Aldrich) are reacted to
yield di-(-)-menthylfumarate (7). A Diels-Alder reaction between
(6) and (7) produces (8). Any E-isomer of the diene (<5%) that
is present does not react in the Diels-Alder reaction. Deprotection
and epimerization of (8) in acid gives (9). The desilylation of (8)
initially gave a mixture of 2,3-cis- and 2,3-trans-ketones, which,
driven by crystallization of desired (9), isomerized to the
predominantly trans compound. Reduction of (9) with lithium
tri-t-butoxy aluminum hydride (Li(t-BuO).sub.3AlH), followed by
lithium aluminum hydride (LiAlH.sub.4), produces triol (10), which
is then protected with n-propyl sulfonyl chloride
(nPrSO.sub.2Cl.sub.2) to give (11).
[0028] S-BTBA ((S)-1-[3,5-bis(trifluoromethyl)]phenylethanol)) (12)
is reacted with trichloroacetonitrile (Sigma-Aldrich) in the
presence of base 1,8-diazabicycloundec-7-ene (DBU) to produce
imidate (13). HBF.sub.4 is used to catalyze the reaction of (11)
with (13) to yield ether (14). Treatment with allylamine and
bis-propylsulfonate cyclizes (14) to allylamine-protected
pyrrolidine (15). Removal of the allyl protecting group with
thiosalicylic acid and 1,4-bis(diphenylphosphino)butane (dppb),
followed by bis(dibenzylideneacetone)palladium
(Pd.sub.2(dba).sub.3) and isolation with acetic acid gives
crystalline (16). Finally, (16) is reacted with
1,3-cyclopentanedione (Sigma-Aldrich) in isopropyl alcohol to give
Compound 1. Compound 1 is a white to off-white powder. It is freely
soluble in methanol, soluble in ethanol, slightly soluble in
isopropyl acetate, sparingly soluble in isopropyl alcohol, ethyl
acetate, and acetonitrile, and insoluble in water.
Pharmaceutical Compositions
[0029] Compositions containing serlopitant or a pharmaceutically
acceptable salt or solvate thereof as the active ingredient may be
advantageously used to treat chronic pruritus. While it is possible
for serlopitant or a pharmaceutically acceptable salt or solvate
thereof to be administered alone, it is preferable to present it as
a formulation. The compositions, or dosage forms, may be
administered or applied singly, or in combination with other
agents. The formulations may also deliver serlopitant to a patient
in combination with another pharmaceutically active agent.
[0030] The term "composition" as used herein is intended to
encompass a product comprising specified ingredients in
predetermined amounts or proportions, as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. This term in relation to
pharmaceutical compositions is intended to encompass a product
comprising one or more active ingredients, and an optional
pharmaceutically acceptable carrier comprising inert ingredients,
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. In general, 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
process or condition of diseases. 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. Said compositions are prepared
according to conventional mixing, granulating, or coating methods,
respectively, and contain about 0.1 to 75%, preferably about 1 to
50%, of the active ingredient.
[0031] 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.
Pharmaceutical compositions intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may 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.
[0032] Tablets 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, cornstarch, 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. A tablet may be made by compressing or
molding the active ingredient optionally with one or more
pharmaceutically acceptable ingredients. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as a powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active, or dispensing agent. Molded tablets may be made by molding,
in a suitable machine, a mixture of the powdered active ingredient
and a suitable carrier moistened with an inert liquid diluent.
[0033] 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. In particular, a pharmaceutical
composition of the present invention may comprise a liquid-filled
capsule dosage form in which the active ingredient is in solution
in certain combinations of liquid and semi-solid excipients. In one
embodiment, the invention is directed to a solution comprising the
active agent
3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-
-fluorophenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one
(Compound 1) or a pharmaceutically acceptable salt or solvate
thereof, and an amphiphilic agent, said amphiphilic agent being a
fatty acid ester of glycerol, propylene glycol or sorbitol, as
described in U.S. Published Application No. 2010/0209496 (Dakou et
al.), which is herein incorporated by reference in its entirety.
Preferably, the amphiphilic agent consists essentially of mono- and
di-glycerides of C8 to C12 saturated fatty acids and mixtures
thereof.
[0034] Compositions for oral administration may also be formulated
as aqueous suspensions containing the active ingredient in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Oily suspensions may be formulated by suspending the
active ingredient in a suitable oil. Oil-in-water emulsions may
also be employed. 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.
[0035] The active ingredient of the present invention may be
administered in an oral sustained release formulation. "Sustained
release" refers to release of an active agent from a dosage form at
a rate effective to achieve a therapeutic amount of the agent, or
active metabolite thereof, in the systemic blood circulation over a
prolonged period of time relative to that achieved by oral
administration of a conventional formulation of the agent. Release
of the agent occurs over an extended period of hours, for example,
over a period of at least 6 hours, over a period of at least 8
hours, over a period of at least 12 hours, or over a period of at
least 24 hours.
[0036] Suitable topical formulations and dosage forms include
ointments, creams, gels, lotions, pastes, and the like, as
described in Remington: The Science and Practice of Pharmacy
(21.sup.st Edition, University of the Sciences in Philadelphia,
2005). Ointments are semi-solid preparations that are typically
based on petrolatum or other petroleum derivatives. The specific
ointment base to be used, as will be appreciated by those skilled
in the art, is one that will provide for optimum drug delivery,
and, preferably, will provide for other desired characteristics as
well, e.g., emolliency or the like. Creams are viscous liquids or
semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant. Gels are semisolid, suspension-type systems.
Single-phase gels contain organic macromolecules (polymers)
distributed substantially uniformly throughout the carrier liquid,
which is typically aqueous, but also, preferably, contain an
alcohol such as ethanol or isopropanol and, optionally, an oil. In
order to prepare a uniform gel, dispersing agents such as alcohol
or glycerin can be added, or the gelling agent can be dispersed by
trituration, mechanical mixing or stirring, or combinations
thereof. Lotions are preparations to be applied to the skin surface
without friction, and are typically liquid or semiliquid
preparations in which solid particles, including the active agent,
are present in a water or alcohol base. Lotions are usually
suspensions of finely divided solids and will typically contain
suspending agents to produce better dispersions as well as
compounds useful for localizing and holding the active agent in
contact with the skin. Pastes are semisolid dosage forms in which
the active agent is suspended in a suitable base. Depending on the
nature of the base, pastes are divided between fatty pastes or
those made from single-phase aqueous gels.
[0037] Various additives, known to those skilled in the art, may be
included in the topical formulations. For example, solvents,
including relatively small amounts of alcohol, may be used to
solubilize certain drug substances. Other optional additives
include opacifiers, antioxidants, fragrance, colorant, gelling
agents, thickening agents, stabilizers, surfactants and the like.
Other agents may also be added, such as antimicrobial agents, to
prevent spoilage upon storage, i.e., to inhibit growth of microbes
such as yeasts and molds. For those drugs having an unusually low
rate of permeation through the skin or mucosal tissue, it may be
desirable to include a permeation enhancer in the formulation. The
formulation may also contain irritation-mitigating additives to
minimize or eliminate the possibility of skin irritation or skin
damage resulting from the drug, the enhancer, or other components
of the dosage form. The formulations may also contain ether
physiologically acceptable excipients or other minor additives,
such as fragrances, dyes, emulsifiers, buffers, cooling agents
(e.g. menthol), antibiotics, stabilizers or the like. In some
instances, one component may serve more than one function.
[0038] The concentration of the active agent in a topical
formulation can vary a great deal, and will depend on a variety of
factors, including the disease or condition to be treated, the
nature and activity of the active agent, the desired effect,
possible adverse reactions, the ability and speed of the active
agent to reach its intended target, and other factors within the
particular knowledge of the patient and physician. The formulations
will typically contain on the order of about 0.1 wt % to 50 wt %
active agent, preferably about 0.1 wt % to 5 wt % active agent,
optimally about 5 wt % to 20 wt % active agent.
[0039] The pharmaceutical compositions of the present invention may
be formulated as a depot formulation for administration via
intramuscular or subcutaneous injection. Depot formulations are
efficient, well-tolerated, sustained or delayed release
compositions of the active ingredient that are therapeutically
effective for a number of weeks, such as at least one week, at
least two weeks, at least three weeks, at least four weeks, at
least five weeks, or at least six weeks or more. In addition to the
active agent, additional ingredients may be used in the depot
formulations of the present invention including surfactants,
solubilizers, emulsifiers, preservatives, isotonicity agents,
dispersing agents, wetting agents, fillers, solvents, buffers,
stabilizers, lubricants, and thickening agents. A combination of
additional ingredients may also be used. The amount of the active
ingredient in a depot formulation will depend upon the severity of
the pruritus being treated.
[0040] The compositions of the present invention may be presented
in unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy. The term "unit dosage form" is taken
to mean a single dose wherein all active and inactive ingredients
are combined in a suitable system, such that the patient or person
administering the drug to the patient can open a single container
or package with the entire dose contained therein, and does not
have to mix any components together from two or more containers or
packages. Typical examples of unit dosage forms are tablets or
capsules for oral administration. These examples of unit dosage
forms is not intended to be limiting in any way, but merely to
represent typical examples in the pharmacy arts of unit dosage
forms.
[0041] The compositions of the present invention may also be
presented as a kit, whereby two or more components, which may be
active or inactive ingredients, carriers, diluents, and the like,
are provided with instructions for preparation of the actual dosage
form by the patient or person administering the drug to the
patient. Such kits may be provided with all necessary materials and
ingredients contained therein, or they may contain instructions for
using or making materials or components that must be obtained
independently by the patient or person administering the drug to
the patient.
Pruritus
[0042] Pruritus is a physiological perception within the sensory
neuronal network in the skin which, along with pain and physical or
mechanical stimuli, can serve as a warning system against potential
bodily threats. Itching is an unpleasant sensation that can lead to
scratching, but is independent of pain. The International
Federation for the Study of Itch (IFSI) defines chronic pruritus
(as opposed to acute pruritus) as itching that lasting six weeks or
longer (S. Stander et al., Acta Derm. Venereol., 2007,
87(4):291-4). Several factors in and on the skin can activate the
sensory nerve fibers or modulate their activity and thus trigger,
suppress, or exacerbate itching. Physical stimuli such as cold and
heat modulate the perception of itching; painful heat and cold can
significantly diminish it, while moderate cold intensifies it
(Valet et al., J. Invest. Dermatol., 2008, 128(2):426-33.).
Mechanical factors such as rubbing or scratching the skin can
briefly suppress itching by activating nerve fibers that
selectively activate and de-activate certain areas of the brain
(Yosipovitch et al., J. Invest. Dermatol., 2008,
128(7):1806-11).
[0043] Chronic pruritus can seriously diminish the quality of life
in its sufferers as it can be intractable and incapacitating. It is
a seriously debilitating condition, comparable to chronic pain,
which can lead to frustration, desperation and depression.
Moreover, chronic scratching often produces open skin lesions,
subject to primary or secondary infection, scarring and potential
disfigurement. Chronic pruritus is often an indication of
underlying disease and is always present in diseases such as
urticaria and atopic dermatitis. Diagnosis of the underlying
disease is desirable and clinical presentation, patient history,
and patient self-evaluation form important parts of such
diagnosis.
[0044] According to Arbeitsgemeinschaft der Wissenschaftlichen
Medizinischen Fachgesellschaften (AWMF) (Association of the
Scientific Medical Societies of Germany) guidelines, diseases and
disorders with chronic pruritus as a symptom may be classified by
whether the skin is inflamed or not inflamed (S. Stander, Clin.
Exp. Dermatol., 2006, 31(6):762-7). The IFSI further characterizes
pruritus as dermatologic, systemic, neurogenic, psychogenic, mixed
and other. Chronic pruritus on non-inflamed skin may result from
dermatological diseases, including atopic diathesis, asteatosis,
porphyria, suburticarial stages of solar injury, cholinergic,
adrenergic urticaria, initial stage of mastocytosis, bullous
pemphigoid, and Duhring's disease (dermatitis herpetiformis); from
endocrine and metabolic disorders, such as chronic renal
insufficiency and the dialysis needed treat it, hepatopathies with
cholestasis, diabetes mellitus, malabsorption disorders, anorexia,
gluten-enteropathies, hyperthyroidism, hypothyroidism,
hyperparathyroidism, and perimenopausal pruritus; from infections
including HIV infection, parasites, Helicobacter pylori, and
helminth-related; from hemotological and lymphoproliferative
diseases such as iron deficiency, polycythaemica vera,
hypereosinophilia syndrome, myelodysplastic syndrome, Hodgkin's
disease, non-Hodgkin's lymphoma, plasmocytoma, and systemic
mastocytosis; from solid malignant tumors including cervical,
breast, prostate or large intestinal cancer, and carcinoid tumors;
from neurological disorders such as brachioradial pruritus,
notalgia paraesthetica, post-zoster neuralgia, vulvodynia,
neuropathies of various origin, multiple sclerosis, tumors,
abscesses, underperfusion, infarctions involving the CNS/spinal
cord; from psychogenic disorders such as depression, schizophrenia,
and tactile hallucinations; and from intrahepatic cholestasis in
pregnant women (pruritus gravidarum).
[0045] Chronic pruritus on inflamed skin may be observed in
patients with inflammatory skin disease including, but not limited
to, atopic dermatitis, allergic, irritant contact dermatitis,
exsiccation dermatitis, nummular and dyshidrotic dermatitis, lichen
planus, lichen sclerosus et atrophicus, polymorphous light eruption
psoriasis, Grover's disease, mucinosis, mastocytosis, and
urticaria; infectious skin diseases such as mycoses, bacterial and
viral infections, scabies, pediculosis, insect bites, and
folliculitides; autoimmune skin diseases including Bullous skin
disorders, especially dermatitis herpetiformis (Duhring's disease),
and bullous pemphigoid; genodermatoses such as Darier's disease,
and Hailey-Hailey disease; pregnancy-related skin diseases
including polymorphic eruption of pregnancy (PEP, formerly known as
PUPPP), atopic eruption of pregnancy, and pemphigoid gestationis;
and neoplasias such as cutaneous T-cell lymphoma (especially the
erythrodermic form).
[0046] Prurigo nodularis (PN), or nodular prurigo, is a
particularly severe form of chronic itching that may treated by
methods and compositions of the present invention. Characterized by
itchy, excoriated, lichenified papules and nodules, PN can occur at
any age, but most often presents in middle-aged and elderly
patients on their arms and legs (E. Weisshaar and S. Stander, Acta
Derm. Venereol., 2012, 92:532-533). The etiology of PN is unknown,
but it usually occurs in patients with a personal or family history
of atopic dermatitis, and often with concomitant medical conditions
such as hepatic or renal function, local trauma or insult to the
skin, infection, and HIV or other immunodeficiencies. PN may result
in permanent changes to the skin, including nodular
lichenification, hyperkeratosis, hyperpigmentation, and skin
thickening.
Therapeutic Administration and Doses
[0047] The terms "administration of" or "administering a" compound
should be understood to mean providing a compound of the invention
to the individual in need of treatment in a form that can be
introduced into that individuals body in a therapeutically useful
form and therapeutically effective amount, including, but not
limited to, oral dosage forms, such as tablets, capsules, syrups,
suspensions, and the like.
[0048] The terms "treat", "treating" and "treatment" of chronic
pruritus all refer to reducing the frequency of symptoms of acute
or chronic pruritus (including eliminating them entirely), avoiding
the occurrence of acute or chronic pruritus and/or reducing the
severity of symptoms of acute or chronic pruritus.
[0049] The term "therapeutically effective amount" refers to a
sufficient quantity of the compounds of the present invention, in a
suitable composition, and in a suitable dosage form to treat the
noted disease conditions. The "therapeutically effective amount"
will vary depending on the compound, the severity of the condition
causing the pruritus, and the age, weight, etc., of the patient to
be treated.
[0050] The term "loading dose" refers to the amount of the
compounds or compositions of the present invention that is often
larger than subsequent doses, administered for the purpose of
establishing a therapeutic level of the drug. More generally, a
loading dose is the amount of Compound I, or a pharmaceutically
acceptable salt or solvate thereof, administered to a patient with
pruritus given sometime after presentation but before initiation of
one or more maintenance doses. Alternatively, a loading dose refers
to one or a series of doses that may be given at the onset of
therapy to achieve a target concentration of an active ingredient
quickly.
[0051] The present methods for treatment of pruritus require
administration of serlopitant, or a pharmaceutical composition
containing serlopitant, to a patient in need of such treatment. The
compound and/or pharmaceutical compositions are preferably
administered orally. Various delivery systems are known, (e.g.,
encapsulation in liposomes, microparticles, microcapsules,
capsules, etc.) can be used to administer a serlopitant compound
and/or composition. The compound and/or pharmaceutical compositions
may be delivered via sustained release dosage forms.
[0052] The amount of serlopitant, a pharmaceutically acceptable
salt or solvate thereof, that will be effective in the treatment
pruritus in a patient will depend on the specific nature of the
condition, and can be determined by standard clinical techniques
known in the art. In addition, in vitro or in vivo assays may
optionally be employed to help identify optimal dosage ranges. The
specific dose level for any particular individual will depend upon
a variety of factors including the activity of the composition, the
age, body weight, general physical and mental health, genetic
factors, environmental influences, sex, diet, time of
administration, route of administration, rate of excretion, and the
severity of the pruritus being treated.
[0053] Preferably, the dosage forms are adapted to be administered
to a patient three, two or one time a day. More preferably, a
therapeutically effective amount is taken once per day.
Alternatively, a dose may be taken every other day, every third
day, every fourth day or once a week.
[0054] Doses may be taken at any time convenient to the patient.
However, to minimize side effects such as dizziness or drowsiness,
a daily dose may be taken at bedtime. NK-1 receptor antagonists
have been shown to cause drowsiness in human clinical trials for
uses other than treating pruritus. For example, Ratti at al.
reported as much as a doubling in the incidence of somnolence vs.
placebo in patients treated with casopitant for major depressive
disorder (J. Clin. Psychopharmacol., 2011, 31:727-733). Somnolence
was also seen in a similar clinical trial testing NK-1 receptor
antagonist L-759274 as an anti-depressant (M. S. Kramer et al.,
Neuropsychopharm., 2004, 29:385-392). Thus, in one embodiment of
the present invention, serlopitant is administered before the
patient goes to bed.
[0055] Dosing may be provided alone or in combination with other
drugs and may continue as long as required for effective treatment
pruritus. For example, the compounds of the present invention may
be administered in combination with another substance that has a
complimentary effect to the tachykinin and substance P inhibitory
effect of the present invention. Appropriate compounds include
other NK-1 receptor antagonists such as, but not limited to,
casopitant (GW679769), L-759274, L-733060, CP122,721, BIIF 1149CL,
DNK333, M516102, ezlopitant, rolapitant, orvepitant, LY-686017,
Ianepitant (LY-303870), maropitant, vestipitant, vofopitant,
aprepitant, fosaprepitant, AV-818, and TA-5538.
[0056] Dosage ranges of compounds of the present invention for oral
administration may be stated in terms of amount of drug
administered per time period. A certain amount of active ingredient
may be given one or more times a day as appropriate according to
the factors described above. For example, doses may be taken once a
day, twice a day, three times a day, four times a day, or more.
Suitable dosages range from about 0.1 mg to about 30 mg, and
preferably, from about 1 mg to about 7.5 mg. Suitable dosages are
typically 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1
mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,
15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 100 mg or 200 mg
one or more times a day. Preferably, a dose of 0.25 mg, 1 mg or 5
mg is administered once a day.
[0057] Alternatively, suitable dosage ranges of compounds of the
present invention for oral administration are generally about 0.001
mg to about 500 mg of drug per kilogram body weight, preferably
from about 0.1 mg to about 200 mg of drug per kilogram body weight,
and more preferably about 1 to about 100 mg/kg-body wt. per day.
Dosage ranges may be readily determined by methods known to the
skilled artisan. The amount of active ingredient that may be, for
instance, combined with carrier materials to produce a single
dosage form will vary depending upon the patient treated and the
particular mode of administration. Dosage unit forms will generally
contain between about 0.25 mg to about 500 mg of active
ingredient.
[0058] In cases in which longer-term persistence of active drug is
desirable, for example but not limited to, in the treatment of
chronic pruritus, a dosing schedule is used where a loading dose is
administered, followed by either (i) a second loading dose, or
doses, and a maintenance dose (or doses), or (ii) a maintenance
dose or doses, without a second loading dose, as determined to be
appropriate by one skilled in the art. The schedule for
administration of the loading and maintenance doses may be
determined based upon the individual requirements of a particular
patient. In one embodiment of the present invention, one loading
dose is administered, followed by administration of a
therapeutically effective maintenance dose after an appropriate
interval, such as after one day. In another embodiment, a loading
dose is administered on day 1, a second loading dose on day 2, and
the maintenance dose is administered on day 3 and thereafter for
the duration of therapy. The loading dose may be five, four, three
or two times the maintenance dose. Preferably, the loading dose is
three times the maintenance dose.
Determination of Therapeutic Effectiveness
[0059] The effectiveness of compositions of the present invention
can be tested in experimental animal models of pruritus known to
those skilled in the art. For example, various mouse models have
been utilized to evaluate treatments for itching. Tsukumo et al.
describe a model in which
4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) induces
chronic dermatitis with an associated itch response in BALB/c mice
that can be used to determine whether an anti-pruritic treatment is
effective (J. Pharmacol. Sci., 2010, 113:255-262). Costa et al.
report a similar model in which Phoneutria nigriventer spider venom
is used as the itch inducer (Vascul. Pharmacol., 2006,
45(4):209-14). Analogously, Ohmura et al. use picrylchloride in
NC/Nga mice to stimulate scratching behavior (Eur. J. Pharmacol.,
2004; 491:191-194). Essentially, itching is induced in the subject
animal with an irritating agent, the test compound or a placebo is
administered, and the animal observed under controlled conditions.
Scratching behavior is quantified and analyzed using standard
statistical techniques. A test compound is considered effective if
either continuous or severe scratching is suppressed.
[0060] The efficacy of the methods and compositions of the present
invention in the treatment of acute and chronic pruritus can also
optionally be evaluated in human clinical trials conducted under
appropriate standards and ethical guidelines as set forth by the
U.S. Food and Drug Administration (FDA). After the general safety
of a drug is determined in Phase I clinical trials conducted in
healthy volunteers, Phase II trials assessing the safety and
efficacy of the drug in patients with the condition being treated
are conducted. Typically, such trials are double-blinded and
placebo-controlled, and may be dose-ranging. Phase III studies
gather more information about safety and effectiveness by studying
different populations and different dosages and by using the drug
in combination with other drugs.
[0061] Because amelioration of pruritus is subject to a patient's
own perceptions, it can be difficult to evaluate with typical
clinical endpoints. However, two standardized assessment tools have
been created and may be used in clinical trials demonstrating the
utility of the present invention. The Visual Analog Scale (VAS) is
the most commonly used tool to evaluate the intensity of pruritus
(N. Q. Phan et al., Acta Derm. Venereal., 2012; 92:502-507). The
VAS is a graphic tool with a 100-mm horizontal line with the left
end labeled "no symptom" and the right end labeled "worst
imaginable symptom". The patient is asked to draw a vertical line
to indicate the horizontal scale at a point that corresponded to
the intensity of the symptom. The length from the left end to the
vertical mark made by the patient is measured in millimeters.
Separation in one-hundredths is regarded as sufficiently sensitive
(R. C. Aitken, Proc. R. Soc. Med., 1969, 62:989-993). The results
may be analyzed using standard statistical techniques known to
those skilled in the art.
[0062] In addition to the VAS, the Dermatology Life Quality Index
(DLQI) may be used to evaluate the efficacy of a chronic pruritus
treatment. The DLQI, a self-administered general dermatology
quality of life questionnaire, was originally developed and
published in a dermatology clinic at University Hospital of Wales
(A. Y. Finlay and G. K. Khan, Clin. Exper. Derm., 1994,19:210-216).
Independent studies have verified that the DLQI is an easy and
efficient method for assessing quality of life in dermatology
patients (H. B. Hahn et al., J. Am. Acad. Dermatol., 2001,
45(1):44-8). A current version of the simple, ten-question
validated questionnaire, with instructions for use and scoring is
available from the School of Medicine, Cardiff University, Wales,
UK (world wide web URL dermatology.org.uk/quality/).
[0063] The following examples are offered by way of illustration
and not by way of limitation.
EXAMPLES
[0064] All of the inactive pharmaceutical ingredients in the
examples below comply with United States Pharmacopeia and The
National Formulary requirements and are tested and released
according to the monograph for each ingredient specified in the
USP/NF compendium.
Example 1
Preparation of Serlopitant Tablets
[0065] Serlopitant,
3-[(3aR,4R,5S,7aS)-5-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-4-(4-
-fluorophenyl)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]cyclopent-2-en-1-o-
ne, Compound 1, may be formulated as a tablet for oral use. Table 1
shows the qualitative/quantitative composition of exemplary
dosages. Minor variations in the excipient quantities (+/-10%) may
occur during the drug development process.
TABLE-US-00001 TABLE 1 Components Function % of composition
Compound 1 Active agent 1-6% Microcrystalline cellulose Diluent
50-60% Mannitol Diluent 20-30% Croscarmellose Sodium Disintegrant
1-3% Colloidal silica Disintegrant 0.25-0.5% Sodium Lauryl Sulfate
Surfactant 5-6% Magnesium Stearate Lubricant 0.25-2% Total Tablet
Composition 100%.sup.
[0066] Tablet potencies of 0.25, 1 and 5 mg are prepared as a
compressed tablet formulation. The tablet manufacturing process is
the same for all proposed potencies. The process consists of the
following steps: 1) Compound 1, mannitol and sodium lauryl sulfate
are blended; 2) the remaining mannitol is added to the blender and
mixed; 3) microcrystalline cellulose, croscarmellose sodium, and
colloidal silica are added to the blender containing the mixture
above to complete the mixing and the blend is de-agglomerated if
necessary; 4) the blend is lubricated with magnesium stearate which
has been previously screened, if necessary; 5) the lubricated blend
is roller compacted and milled, and then lubricated with magnesium
stearate, which has been previously screened, if necessary; and 6)
the mixture is then compressed into tablets of the appropriate
weight.
Example 2
Preparation of Serlopitant Capsules
[0067] Serlopitant (Compound 1) may also be supplied to the clinic
as liquid-filled capsules. Table 2 shows the
qualitative/quantitative composition of exemplary dosages. Minor
variations in the excipient quantities (+/-10%) may occur during
the drug development process.
TABLE-US-00002 TABLE 2 Unit Strength Components Function 0.25 mg 1
mg 4 mg Capsule Fill Compound 1 Active agent 0.25 mg 1 mg 4 mg
Mono- & Di-glycerides Solubilizer 399 mg 398.6 mg 395.6 mg
Butylated Hydroxyanisole Antioxidant 0.40 mg 0.40 mg 0.40 mg
Capsule Shell #0 White Opaque Hard Gelatin Capsule shell 96 mg** 96
mg** 96 mg** Capsule* Gelatin*** Banding -- -- -- component
Polysorbate 80*** Banding -- -- -- component *Capsules are provided
by Capsugel (Morristown, NJ) and contain gelatin and titanium
dioxide **Approximate weight of empty capsule shell ***As needed to
seal the capsule shells
[0068] The formulation is prepared by dissolving the drug substance
in mono- and di-glycerides. Furthermore, 0.1 wt % butylated
hydroxyanisole is added as an antioxidant. Initial capsule
strengths are dispensed into hard gelatin capsules and sealed by
spraying with a 1:1 (wt/wt) water:ethanol solution. Subsequent
potencies including 0.25, 1, and 4 mg are dispensed into hard
gelatin capsules and sealed with a band of gelatin/polysorbate 80.
Corresponding placebo formulations are prepared in a similar
manner, but without the addition of the drug substance and the
antioxidant.
[0069] The capsule manufacturing process is the same for all
potencies. The process consists of the following steps: 1) the
mono- and di-glycerides excipient is melted at 40.degree. C., if
necessary; 2) the mono- and diglycerides are added to an
appropriately sized, jacketed vessel and mixing is initiated; 3)
the butylated hydroxyanisole is added to the mono- and
di-glycerides and mixed until dissolved (minimum of 10 min); 4)
Compound 1 is slowly added to the mixture and mixed until dissolved
(visual confirmation); 5) the solution is filled into hard gelatin
capsules; 6) the filled capsules are sealed with a mixture of
gelatin and polysorbate 80; 7) the sealed capsules are allowed to
dry overnight and then the capsules are visually inspected for
leaking; 8) the acceptable capsules may be weighed sorted, if
necessary; and 9) the finished product is then packaged in
appropriate containers.
Example 3
Clinical Study of Serlopitant in Chronic Pruritus
[0070] A well-controlled human clinical trial testing the efficacy
of three dosages of serlopitant in the treatment of chronic
pruritus is conducted in accordance with the ICH Guidelines for
Good Clinical Practices, the U.S. Code of Federal Regulations, the
Health Insurance Portability and Accountability Act (HIPAA), and
any local regulatory requirements. The study is a Phase II
randomized, double-blind, parallel group, placebo-controlled,
multicenter trial designed to test the efficacy and safety of
several doses of serlopitant versus placebo in patients with
chronic pruritus. The study patient population includes adult,
males or females, 18 to 72 years of age. The patients must be
previously diagnosed with chronic pruritus caused by any etiology,
except uremia, hepatic failure, cancer or cancer therapy, with
chronic pruritus defined as greater than 6 weeks of itching and a
VAS score of greater than 7.
[0071] Patients are randomized to receive either placebo or one of
three doses of active agent. Patients take active drug or placebo
once daily by mouth for a total of 2 to 8 weeks. The maximum study
duration for each subject is approximately 14 weeks and includes a
screening period of up to 2 weeks, a treatment period of 2-8 weeks,
and a follow-up period of up to 4 weeks. The study parameters are
summarized in Table 3.
TABLE-US-00003 TABLE 3 Study Title: Phase II Study of Serlopitant
In Patients with Chronic Pruritus Development Phase: Phase II Study
Objectives: Dose finding, efficacy and safety Study Design:
Multicenter, double blind, parallel group, dose finding Sample
Size: 80-240 subjects evaluable for analysis Study Population:
Patients with chronic pruritus (over 6 weeks duration) unresponsive
to standard treatment Investigational Product: Oral daily tablet
Dosage and frequency: Day 1: loading dose of 3 times of drug dose
(0.25 mg, 1 mg, or 5 mg), followed by Drug A, Drug B, or Drug C
Drug A: 0.25 mg serlopitant daily for 2 to 8 weeks Drug B: 1 mg
serlopitant daily for 2 to 8 weeks Drug C: 5 mg serlopitant daily
for 2 to 8 weeks Reference Product(s): None Control Product(s):
Matching placebo daily for 2 to 8 weeks Efficacy Evaluation
Criteria: Efficacy is measured daily by patient diary. Patients
record pruritus level on a 10 point VAS scale. Clinical response is
measured by a change in VAS score between the active agent and the
placebo. Secondary endpoints will include measures of the
Dermatology Life Quality Index (DLQI), lesion healing, and patient
and physician global assessments. Safety Evaluation Criteria: All
local and systemic adverse events observed by or reported to the
investigators are evaluated. The intensity, duration, and causal
relationship to the study product are rated for all adverse events.
Statistical Methods: The primary study endpoint is the difference
in VAS score at baseline and on treatment between placebo and
active agent. Study Sites: Multicenter
[0072] Additional clinical trials according to a similar design may
be conducted to test different dosage levels of the active
ingredient or to differentiate between optimal doses or dosing
schedules. Further, the efficacy of the drug in specific
populations, such as the elderly, children, or patients with
uremia, hepatic failure, cancer or patients undergoing cancer
therapy, may be determined in additional clinical trials conducted
in a similar fashion.
[0073] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application were
specifically and individually indicated to be incorporated by
reference.
[0074] From the foregoing it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *