U.S. patent application number 16/563435 was filed with the patent office on 2020-05-21 for method for reducing side effects from administration of phosphodiesterase-4 inhibitors.
This patent application is currently assigned to ARCUTIS, INC.. The applicant listed for this patent is ARCUTIS, INC.. Invention is credited to David W. Osborne, Archie W. THURSTON, JR., Howard WELGUS.
Application Number | 20200155524 16/563435 |
Document ID | / |
Family ID | 70728613 |
Filed Date | 2020-05-21 |
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United States Patent
Application |
20200155524 |
Kind Code |
A1 |
WELGUS; Howard ; et
al. |
May 21, 2020 |
METHOD FOR REDUCING SIDE EFFECTS FROM ADMINISTRATION OF
PHOSPHODIESTERASE-4 INHIBITORS
Abstract
A method for altering the PK profile of a pharmaceutical
formulation containing a PDE-4 inhibitor, such as roflumilast, to
reduce the spike in Cmax. The spike in Cmax is reduced by topically
administering the PDE-4 inhibitor in combination with one or more
phosphate ester surfactants. Reducing the spike in Cmax will reduce
gastrointestinal side effects and result in better patient
compliance.
Inventors: |
WELGUS; Howard; (Ballwin,
MO) ; THURSTON, JR.; Archie W.; (San Diego, CA)
; Osborne; David W.; (Fort Collins, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARCUTIS, INC. |
Westlake Village |
CA |
US |
|
|
Assignee: |
ARCUTIS, INC.
Westlake Village
CA
|
Family ID: |
70728613 |
Appl. No.: |
16/563435 |
Filed: |
September 6, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62768314 |
Nov 16, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 47/10 20130101; A61K 9/06 20130101; A61K 9/0014 20130101; A61K
9/122 20130101; A61K 47/24 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 9/00 20060101 A61K009/00; A61K 9/06 20060101
A61K009/06; A61K 9/12 20060101 A61K009/12; A61K 47/10 20060101
A61K047/10; A61K 47/24 20060101 A61K047/24 |
Claims
1. A method for reducing gastrointestinal side effects in a patient
suffering from gastrointestinal side effects or likely to suffer
from gastrointestinal side effects due to administration of a PDE-4
inhibitor drug, comprising administering to said patient, a
composition comprising a PDE-4 inhibitor drug at a concentration
sufficient to provide a systemic effect of the drug in combination
with a phosphate ester surfactant comprising cetostearyl alcohol,
dicetyl phosphate and ceteth-10 phosphate.
2. The method of claim 1 wherein the composition is administered
topically.
3. The method of claim 1 wherein the PDE-4 inhibitor drug is
selected from the group consisting of apremilast, cilomilast,
crisaborole, ibudilast, piclamilast, roflumilast, and rolipram.
4. The method of claim 3 wherein the PDE-4 inhibitor drug is
roflumilast.
5. The method of claim 1 wherein the composition is in the form of
a semisolid.
6. The method of claim 1 wherein the composition further comprises
diethylene glycol monoethyl ether.
7. The method according to claim 4, wherein said roflumilast is in
an amount of 0.005-2% w/w.
8. The method according to claim 7, wherein said roflumilast is in
an amount of 0.05-1% w/w.
9. The method according to claim 8, wherein said roflumilast is in
an amount of 0.1-0.5% w/w.
10. The method according to claim 3, wherein said roflumilast is in
an amount of 0.3% w/w.
11. The method according to claim 1, wherein said composition is
selected from the group consisting of an oil in water emulsion, a
thickened aqueous gel, a thickened hydroalcoholic gel, a
hydrophilic gel, and a hydrophilic or hydrophobic ointment.
12. The method according to claim 1, wherein said roflumilast
composition further comprises at least one additional component
selected from the group consisting of a solvent, moisturizer,
surfactant or emulsifier, polymer or thickener, anti-foaming agent,
preservative, antioxidant, sequestering agent, stabilizer, buffer,
pH adjusting solution, skin penetration enhancer, film former, dye,
pigment, and fragrance.
13. The method according to claim 1, wherein said roflumilast
composition further comprises an additional active agent selected
from the group consisting of nonsteroidal anti-inflammatory drugs
(NSAIDs), Apremilast, JAK inhibitors, leukotriene inhibitors, mast
cell stabilizers, Anthralin, Azathioprine, Tacrolimus, Coal tar,
Methotrexate, Methoxsalen, Salicylic acid, Ammonium lactate, Urea,
Hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine,
Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters,
Corticosteroids, Corticotropin, Vitamin D analogues, Acitretin,
Tazarotene, Cyclosporine, Resorcinol, Colchicine, bronchodialators,
and antibiotics.
14. The method according to claim 1, wherein said patient is
suffering from asthma or chronic obstructive pulmonary disease
(COPD).
15. The method according to claim 1, wherein said patient is
suffering from an inflammatory condition.
16. The method according to claim 13, wherein said patient is
suffering from atopic dermatitis.
17. The method according to claim 1, wherein the composition is
administered in a semi-solid or a liquid form.
18. The method according to claim 17, wherein the composition is
administered in a form selected from the group consisting of an
emulsion, suspension, ointment, oil, cream, gel, paste, transdermal
patch, spray, and foam.
19. The method according to claim 18, wherein the composition is
administered in the form of a foam.
20. A method for reducing a spike in Cmax resulting from
administration of a PDE-4 inhibitor drug, comprising administering
to said patient, a composition comprising a PDE-4 inhibitor drug at
a concentration sufficient to provide a systemic effect of the drug
in combination with a phosphate ester surfactant, wherein said
phosphate ester surfactant comprises cetostearyl alcohol, dicetyl
phosphate and ceteth-10 phosphate.
21. A composition comprising a PDE-4 inhibitor drug in combination
with a phosphate ester surfactant comprising cetostearyl alcohol,
dicetyl phosphate and ceteth-10 phosphate.
22. The composition according to claim 21, wherein the composition
is in a form selected from the group consisting of an emulsion,
suspension, ointment, oil, cream, gel, paste, transdermal patch,
spray, and foam.
23. The method according to claim 22, wherein the composition is in
the form of a cream or a foam.
Description
CROSS REFERENCE OF RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of the filing date of provisional patent application Ser.
No. 62/768,314 filed Nov. 16, 2018, the disclosure of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention pertains to the field of topical
medications for the treatment of medical disorders. In particular,
the invention pertains to topical formulations containing an active
pharmaceutical ingredient that is an inhibitor of the enzyme
phosphodiesterase-4. The formulations are pharmaceutically
efficacious but have decreased gastrointestinal side effects.
BACKGROUND OF THE INVENTION
[0003] Drugs that inhibit the enzyme phosphodiesterase-4 (PDE-4)
have been found to be useful in the medical treatment of many
medical conditions, most notably psoriatic arthritis, psoriasis,
atopic dermatitis, asthma, and chronic obstructive pulmonary
disease (COPD). Examples of such drugs include apremilast,
cilomilast, crisaborole, ibudilast, piclamilast, roflumilast, and
rolipram. Although these drugs are clinically useful, their use has
been limited at times due to the high incidence of side effects
including diarrhea, weight loss, nausea, headache, back pain,
insomnia, dizziness, flu-like symptoms and decreased appetite, that
are associated with their administration. These side effects,
especially the gastrointestinal side effects, can have a
significant influence on patient compliance.
[0004] Roflumilast
(3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-yl]-benzami-
de) and its active metabolite roflumilast N-oxide
(3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl
1-oxide)benzamide) are described herein as representative members
of the class of drugs that inhibit PDE-4. Roflumilast is known to
be suitable as a bronchial therapeutic agent as well as for the
treatment of inflammatory disorders. Compositions containing
roflumilast are used in human and veterinary medicine and have been
proposed for the treatment and prophylaxis of diseases including
but not limited to: inflammatory and allergen-induced airway
disorders (e.g. bronchitis, asthma, COPD); dermatoses (e.g.
proliferative, inflammatory and allergen induced skin disorders),
and generalized inflammations in the gastrointestinal region
(Crohn's disease and ulcerative colitis). Currently, roflumilast is
administered systemically to treat inflammatory disorders involving
the lungs, such as asthma and chronic obstructive pulmonary disease
(COPD).
[0005] Roflumilast and its synthesis were described in U.S. Pat.
No. 5,712,298 (the "298 patent"), incorporated herein by
reference.* Roflumilast is approved in the United States under the
trade name DALIRESP.RTM. (AstraZeneca Pharmaceuticals LP,
Wilmington, Del.) and in Europe under the trade name DAXAS.RTM.
(Takeda GmbH, Konstanz, Germany). Both DALIRESP.RTM. and DAXAS.RTM.
are administered orally once daily as 500 mcg tablets for treatment
of COPD. * Unless otherwise indicated, references incorporated
herein by reference are incorporated in their entireties for all
purposes.
[0006] Because of the high incidence of gastrointestinal side
effects, including severe nausea and diarrhea, the prescribing
information pertaining to DALIRESP.RTM. instructs that it may be
beneficial to take half of the therapeutically effective dose, 250
mcg, once daily for 4 weeks prior to commencing the therapeutically
effective dose of 500 mcg per day in order to reduce the rate of
treatment discontinuation. The prescribing information for
DAXAS.RTM. does not instruct the patient to take a reduced
non-therapeutically effective dosage prior to taking the
therapeutic dose. However, the prescribing information for
DAXAS.RTM. does report a high incidence of diarrhea, nausea, and
abdominal pain associated with this medication.
[0007] When roflumilast is orally administered, the drug is rapidly
absorbed, resulting in a sharp spike in plasma concentration.
According to documents filed in the FDA, upon initial
administration of a roflumilast tablet, a Cmax (peak plasma
concentration) of 7.34 mcg/I that spiked at a Tmax (time after
administration to reach Cmax) 1 hour after administration occurred
with a 500 mcg tablet and a Cmax of 3.99 mcg/I that spiked at a
Tmax of 1 hour occurred with a 250 mcg tablet. The spike in Cmax
followed a clear dose-response relationship. A similar
dose-response relationship was shown for the occurrence of
gastrointestinal side effects, indicating that these side effects
are associated with the spike in Cmax.
[0008] When multiple doses of oral roflumilast are administered,
exposure follows a `peak to trough` pattern. This results in an
episodic variation in blood levels of drug and continued
gastrointestinal side effects due to the renewed high spike Cmax
levels following each administration of the drug.
[0009] Bolle, U.S. Patent Application Publication No. 2006/0084684
discloses topical formulations of roflumilast, salts of
roflumilast, the N-oxide of roflumilast, and salts of the N-oxide.
Bolle discloses that such formulations are useful to apply to skin
lesions for the local treatment of skin disorders or to administer
topically for the systemic treatment of skin disorders and other
disorders, such as COPD. Bolle discloses that the systemic effect
of topical application of the roflumilast formulations is
comparable to that of an oral dosage form.
[0010] Bolle further discloses, in paragraph 0080 that "Comparison
with oral administration shows that, irrespective of the
composition of the topical preparation, similar Cmax and AUCs and
similar excretions with the urine are achieved."
[0011] Although Bolle does not discuss the incidence of side
effects that occur following topical administration of the
roflumilast formulations, because Cmax with the topical
formulations, irrespective of the composition of the topical
formulation, is similar to that which is obtained with orally
administered formulations, and because side effects are correlated
with Cmax, it would be expected that administration of any of the
topical formulations, irrespective of composition, would cause an
incidence of side effects similar to that caused by orally
administered formulations.
[0012] Although oral tablets of roflumilast have been
commercialized, topical and parenteral administration require
different formulations due to the low aqueous solubility of the
compound which has been reported to be only 0.53 mg/I at 21.degree.
C. in WO95/01338 (corresponding to the '298 patent and incorporated
herein by reference). This low aqueous solubility has been
problematic for the development of parenteral preparations and
topical emulsions, suspensions, gels or solutions containing water.
In U.S. Pat. No. 9,205,044 (incorporated herein by reference), the
poor water solubility of roflumilast was overcome by using an
alkoxylated fat, specifically polyoxyethylated 12-hydroxystearic
acid, as a co-solvent for parenteral administration. In U.S. Pat.
No. 9,884,050 (incorporated herein by reference), the poor water
solubility of roflumilast was overcome by using hexylene glycol. In
EP 1511516B1 (corresponding to published U.S. application Ser. No.
14/075,035 incorporated herein by reference), the low water
solubility of roflumilast was overcome in topical emulsion (cream)
formulations by formulating with polyethylene glycol 400 (PEG 400)
in concentrations over 62% (w/w) while keeping water weight
percentages under 10%.
[0013] Topical application of potent pharmacological agents like
roflumilast has been found to provide superior delivery and greater
ease of use for patients. The molecular structure of the compound
ultimately dictates the ability of the drug to cross the epithelium
of the tissue to which the product is applied. For topical
application to skin, selection of the components of the formulation
dictates the maximum skin permeation that the formulator can
achieve. Creams, lotions, gels, ointments and foams are just a few
of the more familiar forms of topical products that contain active
pharmaceutical ingredients (API) for application to the skin.
[0014] It would be advantageous to develop and provide a
pharmaceutical formulation containing a PDE-4 inhibitor, such as
roflumilast, that, when administered systemically, in a
therapeutically effective dose, does not result in a spike in Cmax,
while still providing a high AUC, and which, therefore, is
pharmaceutically efficacious but is associated with a decreased
incidence of gastrointestinal side effects.
SUMMARY OF THE INVENTION
[0015] In accordance with the present invention, it has been
discovered that the inclusion of one or more phosphate ester
surfactants in a topical formulation containing a PDE-4 inhibitor
reduces the spike in Cmax while still producing a high AUC. The
reduction in the spike in Cmax reduces gastrointestinal side
effects which will lead to better patient compliance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a line graph comparing the pharmacokinetic (PK)
profile of two formulations of the invention, Formulation 1 and
Formulation 2, and a PK profile of a formulation of the prior art,
Formulation 3.
[0017] FIG. 2 is a graph comparing the slow rise to Cmax of
Formulation 4 (dicetyl phosphate/ceteth-10 phosphate) with the
significantly greater roflumilast Cmax peak values (compared to
trough T=0 plasma concentrations) following dosing with comparative
formulation 5 (potassium cetyl phosphate) and comparative
formulation 6 (Cetostearyl Alcohol and Glyceryl Stearate/PEG-100
Stearate).
[0018] FIG. 3 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 0.15% roflumilast topical cream.
[0019] FIG. 4 is a line graph showing Day 1 and Day 14 PK profiles
after once daily dosing of 0.3% roflumilast topical cream.
[0020] FIG. 5 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 0.5% roflumilast topical cream.
[0021] FIG. 6 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 1.0% roflumilast topical cream.
[0022] FIGS. 7A, 7B and 7C show changes in baseline in Target
Plaque Severity Score and/or Target Plaque Area for 0.15%
roflumilast topical cream and 0.5% roflumilast topical cream.
[0023] FIGS. 8A and 8B show roflumilast and roflumilast N-oxide
plasma concentrations at day 1 and day 28 (pharmacokinetic
population) for 0.15% roflumilast topical cream and 0.5%
roflumilast topical cream.
[0024] FIG. 9 is a line graph showing Day 1 single dose and Day 8
steady state pharmacokinetic profiles for the PDE4 inhibitor
crisaborole after application of once daily Eucrisa.RTM. topical
ointment.
[0025] FIG. 10 is a line graph showing Day 1 single dose PK
profiles after once daily dosing of Crodafos-CES creams containing
either 0.3% crisaborole or 0.3% roflumilast.
DESCRIPTION OF THE INVENTION
[0026] The term "PDE-4 inhibitor" refers to one or more members of
the class of drugs that, when administered to a person, inhibit the
enzyme phosphodiesterase-4. Examples of members of this class of
drug include apremilast, cilomilast, crisaborole, ibudilast,
piclamilast, roflumilast, and rolipram.
[0027] The term "roflumilast" as used in this application refers to
roflumilast, its salts, the N-oxide of roflumilast, and its salts
unless specified otherwise or unless it is clear in context that
reference is to roflumilast itself. The terms "N-oxide of
roflumilast" and "salts of either roflumilast or of the N-oxide of
roflumilast" refer specifically to the N-oxide or salts of either
roflumilast or the N-oxide thereof. Roflumilast is described
herein, both as a representative member of the class of PDE-4
inhibitors and as roflumilast itself, which includes, depending on
context, roflumilast itself, its salts, the N-oxide of roflumilast,
and salts of the N-oxide. Roflumilast formulations can be prepared
by methods known in the art (e.g. see the '298 patent and U.S.
application Ser. No. 14/075,035).
[0028] Roflumilast is a Compound of the Formula (I)
##STR00001##
wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is
3,5-dichloropyrid-4-yl.
[0029] This compound has the chemical name
N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-
-e (INN: roflumilast).
[0030] The term "salts", when referring to roflumilast or the
N-oxide of roflumilast, means a salt as described in paragraphs
[0012] and [0013] of U.S. Patent Application Publication No. US
2006/0084684, the disclosure of which is incorporated herein by
reference.
[0031] It has been unexpectedly discovered that, in direct contrast
to the dogma of the prior art, a pharmaceutical formulation, such
as a topically applied pharmaceutical formulation containing a
PDE-4 inhibitor, such as roflumilast, provides an altered PK
(pharmacokinetic) profile with a reduced Cmax or a reduced
absorption rate to reach Cmax when the formulations contain one or
more phosphate ester surfactants compared to pharmaceutical
formulations containing the PDE-4 inhibitor without a phosphate
ester surfactant(s). In particular, it has been unexpectedly
discovered that a pharmaceutical formulation containing roflumilast
and one or more phosphate ester surfactants, when topically
administered to an individual, provides a systemically effective
level of the PDE-4 inhibitor comparable to, or even greater than,
that achieved with oral administration by slow absorption and
without a Cmax spike of the PDE-4 inhibitor into the
bloodstream.
[0032] In pharmacokinetic terms, a formulation containing a PDE-4
inhibitor drug, such as roflumilast, and a phosphate ester
surfactant, when administered to an individual, such as by applying
topically to the skin of an individual, provides a sufficiently
high Area Under the Curve (AUC) to attain a systemically effective
level of the PDE-4 inhibitor drug without rapidly producing a peak
plasma concentration (Cmax) that is associated with
gastrointestinal side effects. That is, the absorption rate of the
drug to reach Cmax is decreased when the formulation of the present
application is administered, compared with the administration of
formulations of the prior art.
[0033] As used herein, the term "absorption rate to reach Cmax"
means the slope of the PK curve between the administration of a
formulation containing drug until Cmax, or the slope of the PK
curve between a trough and the adjacent peak following serial
multiple dose administrations of the formulation.
[0034] Thus, in contrast to the teachings of the prior art, the
formulations of the present application unexpectedly have a
markedly different PK profile compared to prior art formulations
containing a PDE-4 inhibitor. The formulations of the present
application provide a sufficiently high AUC to attain a
systemically effective level of the PDE-4 inhibitor without
producing a spike in Cmax. The gradual ascent to Cmax obtained
following topical application of the formulations of the present
invention is markedly different from that of prior art
formulations, but the AUC is similar. Additionally, following
multiple doses of the formulation, the PK profile lacks the initial
Cmax spike and the peak to trough pattern that is obtained
following multiple daily dosing with prior art formulations
containing the drug.
[0035] This discovery provides several unexpected advantages.
Primarily, it provides a means for treatment of medical conditions
that are responsive to the administration of a PDE-4 inhibitor,
that minimizes the incidence of undesirable side effects,
especially GI side effects. This in turn leads to greater patient
compliance and reduced incidence of cessation of treatment due to
the development of such side effects.
[0036] Furthermore, because the ascent to Cmax is so slow, and the
Cmax spike is avoided, the formulations of the present invention
can result in higher systemic exposure levels (AUC) than are
possible with prior art formulations and without the side effects
associated with Cmax spike, such as those of the G.I. system. Such
previously unobtainable exposure levels will provide a greater
efficacy in the treatment of diseases.
[0037] Moreover, it has been unexpectedly discovered that,
following the attainment of Cmax after administration, there is a
very flat and prolonged plateau in blood levels of the drug.
Additionally, the PK profile obtained after multiple doses of the
formulation of the present application is extremely and
unexpectedly flat and prolonged with an extremely small peak to
trough fluctuation following administration for 28 days. This
flatness of the PK profile is especially pronounced when the
formulation further contains diethylene glycol monoethyl ether.
[0038] Because the absorption of the PDE-4 inhibitor from the
formulation in an amount required to provide a therapeutic effect
is not dependent on a spike in absorption to provide a high Cmax
and because the absorption of the PDE-4 inhibitor is stable and has
a flat PK profile, an individual user of the formulation may miss a
dose from time to time and still maintain efficacy of the
treatment.
[0039] An important advantage of the formulations of the present
invention is that, because the ascent to Cmax is so slow, and the
Cmax spike is avoided, the formulations of the present invention
permit the obtaining of higher systemic exposure levels (AUC) than
are possible with prior art formulations and without the side
effects associated with Cmax spike, such as those of the G.I.
system. Such previously unobtainable exposure levels will provide a
greater efficacy in the treatment of diseases.
[0040] In a first embodiment, the present invention is a
pharmaceutical formulation for administering a PDE-4 inhibitor drug
to an individual in need thereof.
[0041] According to this embodiment, the pharmaceutical formulation
of the present invention contains one or more PDE-4 inhibitor
drugs. Such PDE-4 inhibitor drugs may include apremilast,
cilomilast, crisaborole, ibudilast, piclamilast, roflumilast,
and/or rolipram. In a preferred embodiment, the formulation
contains roflumilast. The concentration of the PDE-4 inhibitor drug
is that which is sufficient to ameliorate a medical condition that
is responsive to the administration of a PDE-4 inhibitor drug, such
as psoriatic arthritis, psoriasis, atopic dermatitis, asthma and
COPD.
[0042] The formulation further contains one or more phosphate ester
surfactants. Examples of phosphate ester surfactants that may be
included in the formulations of this application include but are
not limited to potassium cetyl phosphate, potassium C9-15 alkyl
phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl
phosphate, potassium C12-14 alkyl phosphate, potassium lauryl
phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate,
C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate,
cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl
phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate,
disodium oleyl phosphate, lauryl phosphate, myristyl phosphate,
octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate,
oleth-3 phosphate, oleyl ethyl phosphate oleyl phosphate,
PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5
ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4
phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10
phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl
phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl
phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4
phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl
phosphate and tristearyl phosphate.
[0043] The formulation can optionally contain, in addition to the
one or more phosphate ester surfactants, diethylene glycol
monoethyl ether. Diethylene glycol monoethyl ether is also known as
2-(2-ethoxyethoxy)ethanol, or as DEGEE, and is marketed under the
several tradenames, including TRANSCUTOL.RTM. (Gattefosse
Corporation, Paramus, N.J.), CARBITOL.TM. (The Dow Chemical
Company, Midland, Mich.), DIOXITOL.RTM. (Shell Oil Company,
Houston, Tex.), and POLY-SOLV DM (Monument Chemical, Houston,
Tex.).
[0044] DEGEE is often added to topical products as a co-solvent to
increase solubility of the drug in the formulation. Addition of
DEGEE to a topical formulation has also been shown to enhance skin
penetration, i.e. increase Cmax, of topically administered
pharmaceutical actives. See Javadzadeh et al, Chapter 12 pages
195-205, in Percutaneous Penetration Enhancers Chemical Methods in
Penetration Enhancement: Modification of the Stratum Corneum (N.
Dragicevic, H. I. Maibach, eds) Springer-Verlag Berlin Heidelberg
2016.
[0045] The concentration of the PDE-4 inhibitor, such as
roflumilast, in the formulation is that which is sufficient to
obtain a desired systemic pharmacologic effect when the formulation
is applied to the skin of an individual. This concentration will
necessarily differ based on the particular PDE-4 inhibitor
contained within the formulation and the disease or condition to be
treated. In the case of roflumilast, the concentration within the
formulation is typically in the range of 0.001 to 25% w/w, with a
preferred range between 0.01 to 5%, a more preferred range between
0.05 and 1%, and a most preferred range between 0.1 and 0.5%. In a
particular preferred embodiment, the concentration of roflumilast
in the formulation is between 0.05 and 0.5%, such as 0.05%, 0.15%,
0.3%, and 0.5% w/w.
[0046] The concentration of the phosphate ester surfactant in the
formulation is that which is sufficient to produce a stable
emulsion having uniform globule size. If desired, lower
concentrations of the phosphate ester surfactant may be combined
with other emulsifiers to produce a stable emulsion having uniform
globule size. The phosphate ester surfactant may also increase the
solubility of the roflumilast in the cream. The concentration of
the phosphate ester surfactant generally may be any concentration
between 1.0% to 25% w/w. The preferred concentration can be
different for different administration forms. In a preferred
embodiment, when the formulation is a cream or ointment, the
concentration of the phosphate ester surfactant is between 2.5% and
20%, with a more preferred concentration range between 5% and 15%,
and a most preferred concentration being about 10% w/w. When the
formulation is in the form of a foam, the concentration is
preferably between 1.0%-10%, more preferably between 1.0%-10%, and
most preferably 2%.
[0047] The concentration of the diethylene glycol monoethyl ether,
if present, in the formulation is that which is sufficient to
dissolve the active pharmaceutical ingredient. Diethylene glycol
monoethyl ether may also enhance the skin penetration of the
roflumilast. Generally, the concentration of the diethylene glycol
monoethyl ether is between 5% and 50% w/w, with a preferred range
of concentrations between 10% and 40% w/w, a more preferred range
between 15% and 30% w/w, and a particular preferred concentration
being about 15-25% w/w. Likewise, water is formulated as about
20-90% (w/w) in topical products. For blends of DEGEE and water the
ratio can range from 1:10 to 20:1. Preferably the DEGEE:water ratio
is 1:4 to 9:1 in a formulation containing roflumilast. Generally,
DEGEE-water blends can be used to dissolve up to 2.0% roflumilast
(in the finished product) or preferably up to 0.5% roflumilast (in
the finished product).
[0048] The formulation for topical application to the skin is
preferably a semi-solid dosage form that is cosmetically acceptable
for use on the skin and which is easily spreadable on the skin.
Examples of such semi-solid dosage forms include emulsions,
ointments, creams, gels, and pastes. The formulation may
alternatively be in a form other than a semi-solid dosage form,
such as a liquid, which may be administered as a spray, or a foam.
Preferably, a formulation for topical administration is in one of
the following forms:
[0049] An oil-in-water emulsion: The topical product may be an
emulsion comprising a discrete hydrophobic phase and a continuous
aqueous phase that includes the DEGEE-water blend and optionally
one or more polar hydrophilic excipients as well as solvents,
co-solvents, salts, surfactants, emulsifiers, and other components.
These emulsions may include water-soluble or water-swellable
polymers that help to stabilize the emulsion.
[0050] A water-in-oil emulsion: The compositions may be
formulations in which roflumilast is incorporated into an emulsion
that includes a continuous hydrophobic phase and an aqueous phase
that includes the DEGEE-water blend and optionally one or more
polar hydrophilic carrier(s) as well as salts or other components.
These emulsions may include oil-soluble or oil-swellable polymers
as well as one or more emulsifier(s) that help to stabilize the
emulsion.
[0051] For both oil-in-water and water-in-oil emulsions, order of
addition may be important. Roflumilast can be added pre-dissolved
in the continuous aqueous phase containing the DEGEE-water blend.
Likewise, roflumilast can be pre-dissolved in the hydrophobic
discrete phase of the emulsion that is then mixed with the
DEGEE-water blend and optional hydrophilic excipients that do not
contain the active ingredient. Roflumilast can be pre-dissolved in
both the oil phase and water phase of the emulsion or added
pre-dissolved in DEGEE or a DEGEE-water blend after the emulsion
has been formed. Some emulsions undergo phase inversion over a
specific temperature range during cooling of the emulsion. Thus,
roflumilast may be added to a water-in-oil emulsion above the phase
inversion temperature, with the final drug product being an
oil-in-water emulsion at controlled room temperature, or vice
versa.
[0052] Thickened aqueous gels: These systems include the
DEGEE-water blend with dissolved roflumilast and optionally one or
more polar hydrophilic carrier(s) such as hexylene glycol which has
been thickened by suitable natural, modified natural, or synthetic
thickeners as described below. Alternatively, the thickened aqueous
gels can be thickened using suitable polyethoxylate alky chain
surfactants or other nonionic, cationic, or anionic systems.
[0053] Thickened hydroalcoholic gels: These systems include the
DEGEE-water-alcohol blend with dissolved roflumilast and optionally
one or more polar hydrophilic carrier(s) such as hexylene glycol as
the polar phase which has been thickened by suitable natural,
modified natural, or synthetic polymers such as described below.
Alternatively, the thickened hydroalcoholic gels can be thickened
using suitable polyethoxylate alky chain surfactants or other
nonionic, cationic, or anionic systems. The alcohol can be ethanol,
isopropyl alcohol or other pharmaceutically acceptable alcohol.
[0054] A hydrophilic or hydrophobic ointment: The compositions are
formulated with a hydrophobic base (e.g. petrolatum, thickened or
gelled water insoluble oils, and the like) and optionally have a
minor amount of the DEGEE-water blend with dissolved roflumilast.
Hydrophilic ointments generally contain one or more surfactants or
wetting agents.
[0055] In addition to the PDE-4 inhibitor, such as roflumilast, and
phosphate ester surfactant, with or without the optional diethylene
glycol monoethyl ether, the formulation may contain additional
excipients commonly present in such dosage forms. Such excipients
will vary depending on the type of the dosage form and the desired
characteristics.
Solvents
[0056] Compositions of the present invention may include one or
more solvents or co-solvents to obtain the desired level of active
ingredient solubility in the product. The solvent may also modify
skin permeation or activity of other excipients contained in a
topical product. Solvents include but are not limited to acetone,
ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate,
diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl
sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate,
isopropyl myristate, N-methyl pyrrolidinone, propylene glycol and
SD alcohol.
Moisturizers
[0057] Compositions of the present invention may include a
moisturizer to increase the level of hydration. For emulsions, the
moisturizer is often a component of the discrete or continuous
hydrophobic phase. The moisturizer can be a hydrophilic material
including humectants or it can be a hydrophobic material including
emollients. Suitable moisturizers include but are not limited
to:1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol,
glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl
alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa
butter, coconut oil, cyclomethicone, dimethicone, docosanol,
ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate,
glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl
palmitate, glycol distearate, glycol stearate, isostearic acid,
isostearyl alcohol, lanolin, mineral oil, light mineral oil,
lanolin, limonene, medium-chain triglycerides, menthol, myristyl
alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate,
olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W,
sorbitol, stearic acid, stearyl alcohol, and urea.
Surfactants and Emulsifiers
[0058] Compositions according to the present invention can
optionally include one or more surfactants to emulsify the
composition and to help wet the surface of the active ingredients
or excipients. As used herein the term "surfactant" means an
amphiphile (a molecule possessing both polar and nonpolar regions
which are covalently bound) capable of reducing the surface tension
of water and/or the interfacial tension between water and an
immiscible liquid. Surfactants include but are not limited to alkyl
aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate,
apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride,
Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearyl
alcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10
phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide
ether sulfate, cocamine oxide, coco betaine, coco diethanolamide,
coco monoethanolamide, coco-caprylate/caprate, dicetyl phosphate,
disodium cocoamphodiacetate, disodium laureth sulfosuccinate,
disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate,
disodium oleamido monoethanolamine sulfosuccinate, docusate sodium,
laureth-2, laureth-23, laureth-4, lauric diethanolamide, lecithin,
mehoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose
sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100
stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate,
PEG-15 cocamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl
glucose sesqustearate, PEG-22 methyl ether, PEG-25 propylene glycol
stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45/dodecyl glycol
copolymer, PEG-5 oleate, PEG-50 Stearate, PEG-54 hydrogenated
castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil,
PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate,
Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124,
poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237
poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohols,
polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether,
polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl
6 and polyoxyl 32, polyoxyl glyceryl stearate, polyoxyl stearate,
polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,
polysorbate 80, PPG-26 oleate, PROMULGEN.TM. 12, propylene glycol
diacetate, propylene glycol dicaprylate, propylene glycol
monostearate, sodium xylene sulfonate, sorbitan monooleate,
sorbitan monopalmitate, sorbitan monostearate, steareth-2,
steareth-20, steareth-21, steareth-40, tallow glycerides, and
emulsifying wax.
[0059] Suitable phosphate ester surfactants include but are not
limited to potassium cetyl phosphate, potassium C9-15 alkyl
phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl
phosphate, potassium C12-14 alkyl phosphate, potassium lauryl
phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate,
C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate,
cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl
phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate,
disodium oleyl phosphate, lauryl phosphate, myristyl phosphate,
octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate,
oleth-3 phosphate, oleyl ethyl phosphate oleyl phosphate,
PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5
ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4
phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10
phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl
phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl
phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4
phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl
phosphate and tristearyl phosphate.
Polymers and Thickeners
[0060] For certain applications, it may be desirable to formulate a
topical product that is thickened with soluble, swellable, or
insoluble organic polymeric thickeners such as natural and
synthetic polymers or inorganic thickeners including but not
limited to acrylates copolymer, carbomer 1382, carbomer copolymer
type B, carbomer homopolymer type A, carbomer homopolymer type B,
carbomer homopolymer type C, caroboxy vinyl copolymer,
carboxymethylcellulose, carboxypolymethylene, carrageenan, guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
microcrystalline wax, and methylcellulose.
[0061] The formulation may contain one or more thickening agent to
provide viscosity so that the formulation may be provided in the
form of a semisolid, such as a lotion, gel, cream, or ointment.
Examples of suitable thickening agents include but are not limited
to soluble, swellable, or insoluble organic polymeric thickeners
such as natural and synthetic polymers or inorganic thickeners
including but not limited to acrylates copolymer, carbomer 1382,
copolymer type B, carbomer homopolymer type A, homopolymer type B,
carbomer homopolymer type C, carboxypolymethylene, carrageenan,
guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
microcrystalline wax, acacia, alginic acid, bentonite, carbomers,
also known as carboxy vinyl polymers, such as sold under the
tradename Carbopol.RTM. (Lubrizol, Wickliffe, Ohio),
carboxymethylcellulose, ethylcellulose, gelatin,
hydroxyethylcellulose, hydroxypropyl cellulose, magnesium aluminum
silicate, methylcellulose, poloxamers, polyvinyl alcohol, sodium
alginate, tragacanth, and xanthan gum. The thickening agent may
reside in the oil or lipophilic portion of the formulation.
Examples of suitable lipophilic thickening agents include cetyl
alcohol, stearyl alcohol, glyceryl stearate, white beeswax,
microcrystalline wax, hydrogenated polyisobutane polymers, and
emulsifying wax.
Additional Components
[0062] Compositions according to the present invention may be
formulated with additional components such as fillers, carriers and
excipients conventionally found in cosmetic and pharmaceutical
topical products. Additional components include but are not limited
to foaming agents, propellants, preservatives, antioxidants,
sequestering agents, stabilizers, buffers, pH adjusting solutions,
skin penetration enhancers, chelating agents, film formers, dyes,
pigments, fragrances and other excipients to improve the stability
or aesthetics of the product. In a preferred embodiment, hexylene
glycol is added to inhibit changes in particle size distribution
over the shelf life of the composition. Hexylene glycol can be
added between 0.1% and 20% on a weight/weight basis, preferably
between 0.25% and 8% on a weight/weight basis and most preferably
between 0.5% and 2% on a weight/weight basis.
[0063] The formulation may contain other pharmaceutically
acceptable excipients if desired. For example, the formulation may
contain a humectant such as glycerin, sorbitol, hexylene glycol,
urea, or propylene glycol. The formulation may contain an emollient
such as petrolatum, lanolin, mineral oil, light mineral oil,
stearic acid, cyclomethicone, or dimethicone. Additional optional
excipients include stabilizers, foaming agents, preservatives such
as methylparaben, pH adjusting agents such as sodium hydroxide,
chelating agents such as EDTA and its salts, and buffers.
[0064] In one preferred embodiment, the roflumilast is in the form
of an aerosolized foam which is particularly suitable for
application to the scalp. Any suitable propellant can be used to
prepare the aerosolized foam. Particularly preferred propellants
are Isobutane A-31, Aeropin 35, Butane 48, Dimethyl
Ether/N-Butane-(53/47), Propane/Iso-Butane/N-Butane,
Propane/Isobutane-A70, and Propane/Isobutane A-46, N-Butane
(A-17.
Additional Active Agents
[0065] Compositions according to the present invention may be
formulated with additional active agents depending on the condition
to be treated. The additional active agents include but are not
limited to NSAIDs (e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen),
Apremilast, JAK inhibitors (e.g. Tofacitinib, Ruxolitinib,
Oclacit), leukotriene inhibitors (e.g. Zileuton, Zafirlukast,
Montelukast), mast cell stabilizers (e.g. Nedocromil, Cromolyn
sodium, Ketotifen, Pemirolast), Anthralin (dithranol),
Azathioprine, Tacrolimus, Coal tar, Methotrexate, Methoxsalen,
Salicylic acid, Ammonium lactate, Urea, Hydroxyurea,
5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine,
Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g.
Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone,
Mometasone, Triamcinolone, Fluocinolone, Fluocinonide,
Flurandrenolide, Diflorasone, Desonide, Desoximetasone,
Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone,
Methylprednisolone, Prednicarbate, Prednisone), Corticotropin,
Vitamin D analogues (e.g. calcipotriene, calcitriol), Acitretin,
Tazarotene, Cyclosporine, Resorcinol, Colchicine, bronchodialators
(e.g. beta-agonists, anticholinergics, theophylline), and
antibiotics (e.g. erythromycin, ciprofloxacin, metronidazole).
Administration and Dosage
[0066] Suitable pharmaceutical dosage forms include but are not
limited to emulsions, suspensions, sprays, oils, ointments, fatty
ointments, creams, pastes, gels, foams transdermal patches, and
solutions.
[0067] The composition preferably contains roflumilast, salts of
roflumilast, the N-oxide of roflumilast or salts thereof in an
amount of 0.005-2% w/w, more preferably 0.05-1% w/w, and most
preferably 0.1-0.5% w/w per dosage unit. The topical formulation
containing the PDE-4 inhibitor, such as roflumilast, is applied to
the skin in an amount that is sufficient to obtain the desired
pharmacologic effect, which typically is to ameliorate the signs
and/or symptoms of a medical disorder. The amount of the
formulation that is applied may vary depending on the PDE-4
inhibitor that is contained within the formulation, the
concentration of the PDE-4 inhibitor within the formulation, and
the frequency in which the formulation is applied. Generally, the
formulation is applied with a frequency between weekly to several
times daily, preferably between every other day to three times
daily, and most preferably one or two times daily.
[0068] The formulation containing the PDE-4 inhibitor may be used
in veterinary and in human medicine to treat a systemic medical
condition that is ameliorated by or responsive to systemic
administration of a PDE-4 inhibitor such as roflumilast.
Non-limiting examples of such medical conditions include but are
not limited to acute and chronic airway disorders such as
bronchitis, allergic bronchitis, asthma, and COPD; proliferative,
inflammatory and allergic dermatoses such as psoriasis, scalp
psoriasis, or inverse psoriasis, irritant and allergic contact
eczema, hand eczema, atopic dermatitis, seborrheic dermatitis,
lichen simplex, sunburn, aphthous ulcers, lichen planus, vitiligo,
pruritus in the genital or anal regions, alopecia areata,
hypertrophic scars, discoid lupus erythematosus, follicular and
extensive pyodermas, endogenous and exogenous acne, acne rosacea,
disorders which are based on an excessive release of TNF and
leukotrienes, disorders of the heart which can be treated by PDE
inhibitors, inflammations in the gastrointestinal system or central
nervous system, disorders of the eye, disorders which can be
treated by the tissue-relaxant action of PDE inhibitors and other
proliferative, inflammatory and allergic skin disorders; and immune
mediated diseases such as arthritis including rheumatoid arthritis,
rheumatoid spondylitis, osteoarthritis, and psoriatic
arthritis.
[0069] The formulation for topical application containing the PDE-4
inhibitor, such as roflumilast, may be prepared by processes
typically used in the field of manufacture of pharmaceutical
formulations for topical application. In order to make a
single-phase formulation, such as a liquid, the constituents of the
formulation may be combined and mixed until a homogenous solution
or suspension of the active ingredient is obtained. In order to
make a multiphase formulation such as an emulsion, for example, the
components of the aqueous phase and of the oil phase may be
separately combined and mixed until homogenous solutions are
obtained and then the aqueous solution and the oil solution may be
combined and mixed, such as by shear mixing, to form the
formulation. The one or more drug actives may be dissolved
(molecularly dispersed), complexed, or associated with an excipient
or other active, or may be particulate (amorphous or crystalline).
The oil phase may be added to the water phase, or the water phase
may be added to the oil phase. The phases may be combined and
mixed, such as at elevated temperatures of 50-90.degree. C. or at
room temperature, that is between 20-30.degree. C., or at a
temperature between room temperature and the elevated
temperatures.
[0070] The following examples are provided to enable those of
ordinary skill in the art to make and use the methods and
compositions of the invention. These examples are not intended to
limit the scope of what the inventors regard as their invention.
Additional advantages and modifications will be readily apparent to
those skilled in the art.
[0071] In the following examples roflumilast is utilized as a
representative example of a PDE-4 inhibitor drug. Also, in the
following examples, Crodafos.TM. CES (Croda Inc., Edison, N.J.),
containing the phosphate ester surfactants dicetyl phosphate and
ceteth-10 phosphate, is utilized as a representative example of a
phosphate ester surfactant.
Example 1--Formulations According to the Invention and of the Prior
Art
[0072] A first formulation of the invention, hereafter referred to
as Formulation 1, was made by combining roflumilast with a
phosphate ester surfactant and water. The formulation was buffered
with NaOH to obtain a pH of 6.5.
[0073] A second formulation of the invention, hereafter referred to
as Formulation 2, was made by combining the above constituents and
adding diethylene glycol monoethyl ether. This formulation was
buffered with NaOH to obtain a pH of 6.5.
[0074] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 3, was made by combining
roflumilast with diethylene glycol monoethyl ether. This
formulation was gelled with hydroxylpropyl cellulose so that it
would have a similar viscosity and spread on the skin like the two
phosphate ester surfactant emulsion Formulations 1, and 2. This
semisolid formulation was likewise buffered with NaOH to obtain a
pH of 6.5.
[0075] The compositions of these formulations are shown below in
table 1.
TABLE-US-00001 TABLE 1 Comparative Formulation 1 Formulation 2
Formulation 3 Roflumilast 0.15% w/w 0.15% w/w 0.15% w/w Crodafos
CES 10.0% w/w 10.0% w/w cetostearyl alcohol dicetyl phosphate
ceteth-10 phosphate Diethylene Glycol 25.0% w/w 25.0% w/w Monoethyl
Ether, NF Hydroxypropyl 0.5% w/w Cellulose 1N NaOH, NF q.s. ad pH
6.5 q.s. ad pH 6.5 q.s. ad pH 6.5 Purified Water, USP q.s. ad 100%
q.s. ad 100% q.s. ad 100%
Example 2--Single Dose Testing of Formulations of Example 1
[0076] Male and female swine (Gottingen Minipig.RTM. breed)
(Marshall BioResources, North Rose, N.Y.) were ordered to weigh 8
to 12 kg at arrival. On the day prior to administration of one of
the topical cream semisolid formulations of Example 1 containing
0.15% roflumilast, the hair was clipped from the back of each
animal. The pigs were sedated for the shaving procedure. Care was
taken to avoid abrading the skin.
[0077] Two (2) grams of one of the cream formulations of Example 1
for each kg of pig weight was distributed over the clipped skin
area by gentle inunction with a glass stirring rod or
stainless-steel spatula. The cream formulation was applied evenly
with a thin, uniform film beginning at the scapular region and
moving caudally over the test site. The width of the test site area
was bilaterally divided by the spine. Six pigs (3 males and 3
females) were administered a single dose of the Formulation 2.
Blood was sampled from the anterior vena cava through the thoracic
inlet or other suitable vein pre-dose (time=0) and at 1, 2, 4, 8
and 24 hours post dose administration. A one-week wash out (no
product dosed) was sufficient to reduce plasma levels of
roflumilast to zero as verified by the pre-dose (time=0) sample.
After the wash out period, a single dose of formulation 1 was
applied. After a second one-week wash out period, a single dose of
Formulation 3 was applied. Blood samplings were the same for all
three groups. The results are shown graphically in FIG. 1.
[0078] As shown in FIG. 1, pigs dosed with Comparative Formulation
3 of the prior art showed a rapid spike to Cmax within 3 hours of
dosing. In contrast, pigs dosed with Formulation 1 of the invention
containing the phosphate ester surfactant Crodafos CES showed
little or no spike to Cmax. Pigs dosed with Formulation 2 of the
invention containing both a phosphate ester surfactant and
diethylene glycol monoethyl ether, like those dosed with
Formulation 1, showed a reduced spike to Cmax as compared to
Formulation 3. However, the higher Cmax obtained with Formulation 2
was higher than that for Formulation 1.
[0079] The PK data results in the graph of FIG. 1 show that the
single dose PK profile data for the formulation containing
phosphate ester surfactants lacks a significant spike to Cmax and
has a low Cmax of 0.36 ng/mL, while maintaining a mean plasma
concentration of 0.34 ng/ml through the 4 hour sample point. This
is in contrast to PK data for the DEGEE formulation that rapidly
raises to a Cmax of 0.85 ng/ml at 2 hours and then just as quickly
drops to 0.57 ng/mL at 4 hours. When the phosphate ester surfactant
is added to DEGEE the formulation of the invention, it lacks a
significant spike to Cmax and has a low Cmax, while maintaining
AUC, in contrast to PK data for the DEGEE formulation which does
not contain phosphate ester surfactants. This PK data is especially
surprising in view of the fact that the prior art (Bolle) teaches
that Cmax and AUC are similar for topical preparations containing
roflumilast, irrespective of the composition of the topical
formulation. In contrast to what one would expect based on the
teachings of the prior art, Formulation 1, containing phosphate
ester surfactant, lacks a significant spike to Cmax. Moreover, the
mean plasma concentration of 0.34 ng/ml was maintained throughout
the 4 hour sample point. In contrast, Formulation 3 containing
diethylene glycol monoethyl ether but lacking a phosphate ester
surfactant, showed a rapid spike rise to Cmax of 0.85 ng/ml at two
hours. When a phosphate ester surfactant was utilized in
combination with diethylene glycol monoethyl ether, Formulation 2
administration produced no significant spike to Cmax and had a Cmax
between those obtained with Formulations 1 and 3, while maintaining
AUC.
Example 3--Formulation of the Invention and a Formulation of the
Closest Prior Art
[0080] A third embodiment of the invention, hereafter referred to
as Formulation 4, was made by combining roflumilast at a
concentration of 0.3% w/w with a phosphate ester surfactant and
water. The formulation was buffered with NaOH to obtain a pH of
5.5. This formulation is similar to Formulation 1 except that the
concentration of roflumilast is 0.3% rather than 0.15% and the
emulsion is buffered to a pH value of 5.5 rather than a pH value of
6.5.
[0081] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 5, was made by combining
roflumilast at a concentration of 0.3% containing a phosphate ester
surfactant, a polyoxyl stearyl ether surfactant and diethylene
glycol monoethyl ether, as well as other excipients. This
formulation is a cream formulation containing a frequently used
phosphate ester surfactant that is not Crodafos CES.
[0082] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 6, was made by combining
roflumilast at a concentration of 0.2%. This formulation is that of
the closest prior art known to the inventors and is disclosed in
Example 3 of Bolle et al, U.S. Patent Application No. US
2006/0084684.
[0083] The compositions of these formulations are shown below in
Table 2.
TABLE-US-00002 TABLE 2 Comparative Comparative Formulation 4
Formulation 5 Formulation 6 Roflumilast 0.3% w/w 0.3% w/w 0.2% w/w
Petrolatum, USP -- 10.0% w/w -- Isopropyl Palmitate, -- 5.0% w/w --
NF Medium-Chain -- -- 25.0% w/w Triglycerides Crodafos CES 10.0%
w/w -- -- cetostearyl alcohol (6-8% w/w) dicetyl phosphate (1-2%
w/w) ceteth-10 phosphate (1-2% w/w) Potassium Cetyl 2.0% w/w
Phosphate Cetostearyl Alcohol 6.0% w/w 5.0% w/w Polyoxyl Stearyl
Ether 2.0% w/w Glyceryl Stearate/ -- 5.0% w/w PEG-100 Stearate
Diethylene Glycol -- 25.0% w/w -- Monoethyl Ether, NF Hexylene
Glycol, NF -- 2.0% w/w -- Methylparaben, NF -- 0.20% w/w --
Propylparaben, NF -- 0.050% w/w -- 1N NaOH, NF q.s. ad pH 5.5 q.s.
ad pH 5.5 -- Purified Water, USP q.s. ad 100% q.s. ad 100% q.s. ad
100% *The exact ratio of cetostearyl alcohol to dicetyl phosphate
to cetheth-10 phosphate in Crodafos CES is consistent between
batches of product but is not publicly disclosed by the
manufacturer (Croda). The safety data sheet for Crodafos CES states
that this emulsifier is composed of 60-80% cetostearyl alcohol,
10-20% dicetyl phosphate and 10-20% cetheth-10 phosphate. To
emphasize the similarity in composition between Formulation 4
(phosphate-ester surfactant blend) and Comparative Formulation 5
(phosphate ester and nonionic surfactant blend) and Comparative
Formulation 6 (nonionic surfactant blend), the cetostearyl alcohol
portion of Crodafos CES is listed separately from the surfactant
portion of Crodafos CES in Table 2. Glyceryl Stearate/PEG-100
Stearate is the nomenclature used by the US Food and Drug
Administration to describe the nonionic emulsifier blend sold using
the tradename Arlacel .RTM. 165 and Tego Care .RTM. 150.
Medium-Chain Triglycerides is the nomenclature used by the US Food
and Drug Administration to describe the cosmetic ingredient
Capryli/Capric Triglyceride which is sold using tradenames
including Miglyol .RTM. 812 and Crodamol .RTM. GTCC.
Example 4--14-Day Dose Testing of Formulations of Example 3
[0084] Male and female swine (Gottingen Minipig.RTM. breed) are
ordered to weigh 8 to 12 kg at arrival. On the day prior to
administration of one of the topical cream semisolid formulations
of Example 3, the hair is clipped from the back of each animal. The
pigs are sedated for the shaving procedure. Care is taken to avoid
abrading the skin.
[0085] Two (2) grams of one of the cream formulations of Example 3
for each kg of pig weight is distributed over the clipped skin area
by gentle inunction with a glass stirring rod or stainless-steel
spatula. The cream formulation is applied evenly with a thin,
uniform film beginning at the scapular region and moving caudally
over the test site. The width of the test site area is bilaterally
divided by the spine. Eighteen pigs are divided into 3 groups of
six pigs (3 males and 3 females) and the pigs of each group were
dosed with one of the formulations 4, 5, or 6. Blood is sampled
from the anterior vena cava through the thoracic inlet or other
suitable vein pre-dose (time=0) and at 1, 2, 4, 8 and 24 hours post
dose administration. The results are shown graphically in FIG.
2.
[0086] As shown in FIG. 2, pigs dosed with Formulation 5 of the
prior art show a rapid spike to a Cmax value of 6.6 ng/mL at 1 hour
after the 14.sup.th consecutive daily dose. In contrast, pigs dosed
with Formulation 4 of the invention containing the phosphate ester
surfactant Crodafos CES show little or no spike to Cmax.
[0087] The results show in the graph of FIG. 2, that the steady
state PK profile data after 14 days of once daily dosing for the
formulation of the invention lacks a significant spike to Cmax and
has a low Cmax, while maintaining AUC, in contrast to PK data for
the prior art formulation or a formulation using a phosphate ester
surfactant that was not Crodafos CES. These results are especially
surprising in view of the fact that the prior art (Bolle) teaches
that Cmax and AUC are similar for topical preparations containing
roflumilast, irrespective of the composition of the topical
formulation.
Example 5--Testing for Multiple Dose Pharmacokinetics Compared to
Prior Art
[0088] A fourth formulation of the invention is shown in Table 3,
hereafter referred to as Formulation 7, was made by combining the
above constituents and adding diethylene glycol monoethyl ether, as
well as other ingredients to create a complete formulation. This
formulation was buffered with NaOH to obtain a pH of 5.5. The
qualitative and quantitative composition of Formulation 7 varies
only in the amount of roflumilast added to the cream. As a fraction
of 1% roflumilast is added, a fraction of 1% of water is removed
from the cream.
TABLE-US-00003 TABLE 3 Formulation 7 Roflumilast 0.15, 0.3, 0.5 or
1.0% w/w Petrolatum, USP 10.0% w/w Isopropyl Palmitate, NF 5.0% w/w
Crodafos CES 10.0% w/w cetostearyl alcohol (6-8% w/w) dicetyl
phosphate (1-2% w/w) ceteth-10 phosphate (1-2% w/w) Diethylene
Glycol Monoethyl Ether, 25.0% w/w NF Hexylene Glycol, NF 2.0% w/w
Methylparaben, NF 0.20% w/w Propylparaben, NF 0.050% w/w 1N NaOH,
NF q.s. ad pH 5.5 Purified Water, USP q.s. ad 100%
[0089] Male and female swine (Gottingen Minipig.RTM. breed) were
ordered to weigh 8 to 12 kg at arrival. On the day prior to
administration of a topical cream containing roflumilast, the hair
was clipped from the back of each animal. The pigs were sedated for
the shaving procedure. Care was taken to avoid abrading the
skin.
[0090] Two (2) grams of the cream Formulation 7 having varying
concentrations of roflumilast, for each kg of pig weight was
distributed over the clipped skin area by gentle inunction with a
glass stirring rod or stainless-steel spatula. The cream was
applied evenly with a thin, uniform film beginning at the scapular
region and moving caudally over the test site. The width of the
test site area was bilaterally divided by the spine. Twenty pigs
(10 males and 10 females) were dosed with 1% roflumilast cream,
twelve pigs (6 males and 6 females) were dosed with 0.5%
roflumilast cream, and twelve pigs (6 males and 6 females) were
dosed with 0.15% roflumilast cream, each dosed daily for 28 days.
Six pigs (3 males and 3 females) were each dosed daily with 0.3%
roflumilast cream (formulation 7) for 14-days. Blood was sampled
from a suitable vein pre-dose (time=0), and at times 1, 2, 4, 8 and
24 hours post dose administration on day 1 and day 28 (or day 14
for 0.3% roflumilast) of dosing. The results are shown graphically
in FIG. 3 (0.15% roflumilast cream), in FIG. 4 (0.3% roflumilast),
in FIG. 5 (0.5% roflumilast cream), and in FIG. 6 (1.0% roflumilast
cream) and in tabular form in Table 4.
[0091] As shown in each of FIGS. 3 to 6, the gradual ascent to Cmax
is evident from the day 1 pharmacokinetic profile. What is most
striking and surprising about the data shown in FIGS. 3 to 6 is the
very flat and prolonged plateau in blood levels of the drug
following Cmax in the day 28 or day 14 (0.3% roflumilast cream)
pharmacokinetic profile, after reaching steady state drug
delivery.
TABLE-US-00004 TABLE 4 Trough (T = 0) Peak or Cmax Topical Product
Dosed (ng/mL) (ng/mL) 0.15% Roflumilast Cream 4.5 (females) 4.9
(females) (FIG. 3--Steady State Day 28) 5.0 (males) 5.0 (males)
0.3% Roflumilast Cream 3.7 (females) 4.5 (females) (FIG. 4--Steady
State Day 14) 6.6 (males) 6.6 (males) 0.5% Roflumilast Cream 8.5
(females) 10.7 (females) (FIG. 5--Steady State Day 28) 6.7 (males)
8.2 (males) 1% Roflumilast Cream 16.3 (females) 16.3 (females)
(FIG. 6--Steady State Day 28) 8.4 (males) 10.0 (males)
[0092] Likewise, the data of Table 4 show an extremely small
variation in blood concentration between the trough and peak (Cmax)
following the attainment of steady state for each of the four
concentrations of roflumilast when the formulation of the present
invention is topically applied.
Example 6--Clinical Study in Subjects with Plaque Psoriasis
Study Design
[0093] ARQ-151 is a topical cream which contains roflumilast. This
phase 1/2a clinical trial enrolled two cohorts: Cohort 1 evaluated
a single administration of ARQ-151 cream 0.5% and Cohort 2
evaluated ARQ-151 cream 0.5% or 0.15% applied once daily for 28
days. In Cohort 1, subjects applied ARQ-151 cream 0.5% to 25
cm.sup.2 of psoriatic plaque(s). Subjects were screened (Visit 1),
returned to the clinic for treatment (Visit 2) and PK blood draws,
had a follow-up visit at 24 hours after the baseline visit for a PK
blood draw (Visit 3), and received a follow-up telephone contact
for safety evaluation 7 days after Visit 3. Subjects enrolled in
Cohort 1 could be enrolled in Cohort 2 if they met eligibility
criteria; subjects from Cohort 1 who rolled into Cohort 2 had all
of their plaque(s) treated in Cohort 2 up to 5% body surface area
(BSA).
[0094] Cohort 2 used a parallel-group, double-blind,
vehicle-controlled study design. Subjects were randomly assigned in
a 1:1:1 ratio to ARQ-151 cream 0.5%, ARQ-151 cream 0.15%, or a
matched vehicle, which was applied to all psoriatic plaques (except
on the face, intertriginous areas, scalp, palms, and soles) up to
an application area of 5% BSA. Subjects in Cohort 2 had screening
and baseline visits, follow-up visits at weeks 1, 2, 3, and 4, an
additional visit at day 29 for a final pharmacokinetic sample
collection, and a follow-up telephone call for safety evaluation at
week 5.
[0095] Cohort 1 received open-label treatment, without assignment
or blinding. Assignment to treatment arm in Cohort 2 was performed
using a computer-generated randomization list. Randomization was
generated using SAS by an unblinded Premier Research statistician
who was otherwise not involved in study conduct. The block size was
3; 72 total blocks were used. Everyone was blinded to
treatment.
[0096] This study was conducted in accordance with the principles
of the Declaration of Helsinki and Good Clinical Practice. The
protocol was approved by Research Review Board, Inc., Richmond
Hill, ON, Canada for all sites. All subjects provided written
informed consent prior to initiation of any study-specific
procedures. This trial was registered under ClinicalTrials.gov #
NCT03392168.
Manufacture of ARQ-151 Cream (Formulation 7)
[0097] A target amount of 480 grams sterile water for
irrigation-USP was accurately weighed into a 1000 ml glass beaker
and 20 grams of sodium hydroxide pellets-NF was added and mixed
using a stir bar until complete dissolution. This solution was set
aside and labeled 1 N Sodium Hydroxide.
[0098] Target weights pf 1,000 grams white petrolatum-USP, 500
grams isopropyl palmitate-NF, and 1,000 grams of phosphate-ester
self-emulsifying wax (CRODAFOS.TM. CES) were weighed into a 4 L
glass beaker and heated on a hot plate to 75.degree. C. to
80.degree. C. while mixing with a propeller mixer. The mixture was
labeled Oil Phase and was maintained at 75.degree. C. to 80.degree.
C.
[0099] To the Main Manufacturing Vessel (a 20 L stainless steel
vessel) a target weight of 4,225 grams of sterile water for
irrigation-USP and a target weight 300 grams 1N sodium hydroxide
were added and heated on a hot plate to 75.degree. C. to 80.degree.
C. This was recorded as the Aqueous Phase and was maintained at
75.degree. C. to 80.degree. C.
[0100] Target weights of 2,400 grams of Transcutol P-NF, 200 grams
of hexylene glycol-NF, 20.0 grams of methylparaben-NF, and 5.0
grams of propylparaben NF were accurately weighed into a 7 L
stainless steel beaker and propeller mixed until a clear
homogeneous solution was obtained. Sufficient potency corrected
roflumilast was added to this solution to obtain either a 0.15%
roflumilast cream or a 0.5% roflumilast cream and this was labeled
the API Phase.
[0101] The Oil Phase that was maintained at 75.degree. C. to
80.degree. C. was slowly added to the Aqueous Phase maintained at
75.degree. C. to 80.degree. C. in the Main Manufacturing Vessel
with homogenizer mixing until a smooth, homogeneous cream was
obtained. Using propeller mixing, the cream was cooled to
45.degree. C. to 50.degree. C. The API Phase was slowly added to
the cream in the main manufacturing vessel and was mixed with the
homogenizer. The pH of the finished cream was measured and adjusted
to within the pH range of 5.1 to 5.9 using 1 N Sodium Hydroxide or
Diluted Hydrochloric Acid, 10% (w/v)-NF. After bulk product
release, the cream was filled into aluminum 3/4''.times.33/4'' #16
sealed white tubes and the tubes crimped to provide the primary
container closure system.
Patients
[0102] To be eligible for enrollment in Cohort 1, subjects had to
be 18 years of age with 25 cm.sup.2 of chronic plaque psoriasis. To
be eligible for enrollment in Cohort 2, subjects also had to have
chronic plaque psoriasis of 6 months duration covering 0.5% to 5.0%
of total BSA excluding the face, scalp, intertriginous areas,
palms, and soles. Subjects needed to have at least 1 (and up to 3)
target plaque(s).gtoreq.9 cm.sup.2 in size with a Target Plaque
Severity Score (TPSS).gtoreq.4. Target plaques could be located
anywhere on the body (excluding the face, scalp, intertriginous
areas, palms, and soles), including the knees and elbows. Key
exclusion criteria included: non-plaque forms of psoriasis,
drug-induced psoriasis, skin conditions that would interfere with
study assessments, known allergies to excipients in ARQ-151 cream,
hypersensitivity to PDE-4 inhibitors, inability to discontinue use
of strong P-450 cytochrome inducers or P-450 cytochrome inhibitors,
inability to refrain from use of a tanning bed, inability to
discontinue systemic or topical therapies for the treatment of
psoriasis, active infection requiring oral or intravenous
antibiotics, antifungal, or antiviral agents within 7 days of
baseline, or current or history of cancer within 5 years except for
fully excised skin basal cell carcinoma, cutaneous squamous cell
carcinoma, or cervical carcinoma.
Treatments and Application
[0103] Formulation 7, also known as ARQ-151 cream, contained 0.5%
or 0.15% roflumilast. Vehicle contained all ingredients in the
ARQ-151 cream except roflumilast. In Cohort 1, ARQ-151 cream 0.5%
was applied in the clinic to 25 cm.sup.2 of psoriatic plaque(s). In
Cohort 2, all psoriatic lesions up to 5% BSA (except for those on
the face, scalp, intertriginous areas, palms, and soles) were
treated at home by subjects. Subjects were instructed by study
staff on proper dosing and administration of ARQ-151 cream and
vehicle.
Study Assessments
[0104] Assessments of efficacy (Cohort 2 only), pharmacokinetics
(both cohorts), and safety (both cohorts) were conducted. The
primary and secondary efficacy endpoints were calculated based on
the product of Target Plaque Severity Score (TPSS) and Target
Plaque Area (TPA). The TPSS was determined for each target plaque
on each subject as the sum of erythema, thickness, and scaling
scores, each rated on a scale of 0 (none) to 4 (very severe) and
was identical to the severity scoring used in the PASI. TPA
(cm.sup.2) was determined by multiplying the longest diameter (cm)
of the target plaque by the widest perpendicular diameter (cm).
Thus, the product of TPSS.times.TPA was roughly analogous to a PASI
for the treated plaque. TPSS and TPA assessments were conducted at
screening, baseline, and weeks 1, 2, 3, and 4. Optional photography
was performed at 4 centers at baseline and Visits 2, 3, 4, and
6.
[0105] Pharmacokinetic profiles for roflumilast and its active
metabolite roflumilast N-oxide12 were determined from plasma. Blood
samples for pharmacokinetic analyses were collected on day 1 at 1,
2, 4, and 6 hours after ARQ-151 application. On day 28, samples
were collected before dosing (trough level) and at 1, 2, 4, 6, and
24 hours after application.
[0106] Safety endpoints included the type and incidence of
treatment-emergent adverse events (TEAEs) and serious adverse
events (SAEs); application site reactions; and changes in physical
examinations, vital signs, electrocardiograms, and clinical
laboratory parameters. Safety was assessed at all study visits and
at telephone follow-up. Skin irritation was assessed on days 1 and
2 for Cohort 1 and at baseline and visits 3, 4, 5, and 6 for Cohort
2. Skin irritation was evaluated using a scale developed by Berger
and Bowman13 ranging from 0 (no evidence of irritation) to 7
(strong reaction spreading beyond application site). Additionally,
other clinical signs of irritation were scored on an `A` (slight
glazed appearance) to `F` (small petechial erosions and/or scabs)
scale. An additional safety endpoint was the results from the
Depressive Symptomatology Questionnaire, 14 which was administered
at screening, week 2, and week 4. The questionnaire is a 16-item
inventory of depressive symptoms, with each item scored on a range
of 0 to 3. Depression severity is based on score category, where
total score 5 represents no depression; 6-10 represents mild
depression; 11-15 represents moderate depression; 16-20 represents
severe depression; and 21 represents very severe depression.
Statistical Considerations
[0107] For Cohort 2, a sample size of 24 subjects per arm (72 total
subjects) was estimated to provide 80% power to detect a difference
of 23% in the mean percentage change from baseline in the primary
endpoint between the ARQ-151 cream and matching vehicle arm. This
estimation was based on a 1-way analysis of variance at the
.alpha.=0.025 significance level. To accommodate a 16% drop-out
rate, the total sample size was increased to 84 subjects.
[0108] TEAEs were coded using the Medical Dictionary for Regulatory
Activities (MedDRA) version 20.1, and severity was graded on a
5-point scale of Grade 1 (mild), Grade 2 (moderate), Grade 3
(severe), Grade 4 (life-threatening consequences), or Grade 5
(death related to AE).
[0109] Pharmacokinetic parameters were calculated using the plasma
concentration values of roflumilast and roflumilast N-oxide (ng/mL)
at each nominal time point with Phoenix WinNonlin (v8.0) using
standard noncompartmental analysis. The area under the
concentration time curve (AUC) was estimated using the linear
trapezoidal linear interpolation method. The maximum plasma
concentration (Cmax) and time to reach maximum concentration (Tmax)
were based on direct assessment. Sample concentration values
reported to be below the limit of quantification (BLQ; <0.100
ng/mL) were ignored.
[0110] The primary efficacy endpoint was the difference in mean
percentage change from baseline at week 4 in the product of
TPSS.times.TPA between each dose of ARQ-151 cream and vehicle
control. The primary efficacy endpoint was analyzed using a mixed
model for repeated measures with center within country, treatment,
study visit, and treatment-by-study-visit interaction as fixed
effects and baseline TPSS.times.TPA score as a covariate. Mean
differences between visit value and baseline were calculated for
each treatment. Mean percentage change from baseline for each
ARQ-151 dose and corresponding vehicle were compared using an
unstructured covariance structure unless the model did not
converge; in that case the appropriate covariance structure was
investigated. The Bonferroni method was used to control for
multiplicity, where the significance level for each of pairwise
comparisons of active vs placebo was at .alpha.=0.025.
[0111] Secondary efficacy endpoints included the difference in mean
percentage change from baseline at weeks 1, 2, and 3 in composite
TPSS.times.TPA score, TPSS, and TPA between each dose of ARQ-151
cream and vehicle control. Statistical analyses of secondary
efficacy endpoints were the same as those used for the primary
endpoint, except no adjustments for multiplicity were used and all
analyses were conducted at the .alpha.=0.05 level.
[0112] In a post hoc analysis, the percentage of subjects with 75%
and 90% improvement from baseline in TPSS.times.TPA (75% responders
and 90% responders) at each study visit through week 4 were also
evaluated.
[0113] Safety analyses were conducted with the safety population,
which comprised all subjects who received at least 1 dose of study
drug and were based on treatment received. Pharmacokinetic analyses
were conducted with the pharmacokinetic population, which included
all subjects who consented for sampling and received active drug
with sufficient plasma concentrations of roflumilast to define a
profile. Efficacy analyses were conducted with the modified
intent-to-treat population, which was composed of all subjects in
Cohort 2 who received 1 dose of study drug and had 1 post-baseline
efficacy evaluation.
[0114] No imputation was used for missing data. Data processing,
tabulation of descriptive statistics, calculation of inferential
statistics, and graphical representations (except for PK parameter
estimation) were performed primarily using SAS (release 9.4). All
PK parameter estimations were performed using WinNonlin.RTM.
version 6.4 or later.
[0115] Results
Patients
[0116] Subjects were recruited from 7 study sites in Canada and
from 1 site in the US between Dec. 5, 2017 (first patient enrolled)
and May 2, 2018 (last follow-up visit). Eight subjects enrolled in
Cohort 1, and 89 subjects enrolled in Cohort 2, including subjects
randomly assigned to ARQ-151 cream 0.5% (N=30), ARQ-151 cream 0.15%
(N=28), and vehicle (N=31). All subjects in Cohort 1 received
treatment and completed the study, and 6 also participated in
Cohort 2. Four subjects in Cohort 2 discontinued early from the
study because of loss to follow-up (n=3) or other reasons (n=1).
There were no discontinuations due to AEs. The safety populations
comprised all 8 subjects in Cohort 1 and all 89 subjects in Cohort
2. The PK population included 20 subjects who received Formulation
7 (ARQ-151 cream) 0.5% and 22 subjects who received Formulation 7
(ARQ-151 cream) 0.15%. The efficacy population comprised all
subjects in Cohort 2.
[0117] The mean age (standard deviation [SD]) was 51.6 (16.9) years
for Cohort 1 and mean age ranged from 47.5 to 55.3 years across
Cohort 2 treatment arms (Table 5). Most subjects were white. The
average BSA of involvement was .about.2% in all treatment groups.
Of the 89 subjects enrolled in Cohort 2, 35 (39.3%) had target
plaques located on the knees, elbows, or both.
TABLE-US-00005 TABLE 5 Subject Characteristics (Safety Population)
Cohort 1 Cohort 2 ARQ-151 ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle
(N = 8) (N = 30) (N = 28) (N = 31) Age, mean years (SD) 51.6 (16.9)
49.9 (15.9) 55.3 (13.2) 47.5 (14.7) Sex, n (%) Male 1 (12.5) 16
(53.3) 19 (67.9) 18 (58.1) Female 7 (87.5) 14 (46.7) 9 (32.1) 13
(41.9) Race, n (%) 8 (100) 25 (83.3) 24 (85.7) 22 (71.0) White 0 2
(6.7) 2 (7.1) 8 (25.8) Asian 0 2 (6.7) 2 (7.1) 0 Black/African 0 1
(3.3) 0 1 (3.2) American Other Psoriasis-affected BSA, NC 3.06
(1.39) 2.73 (1.32) 2.21 (1.05) mean m.sup.2 (SD) BSA, body surface
area; NC, not collected; SD, standard deviation.
Efficacy Results
[0118] The primary efficacy endpoint was met: the mean percentage
change from baseline in TPSS.times.TPA at week 4 was significantly
different from vehicle for ARQ-151 cream 0.5% (P=0.0007) and
ARQ-151 cream 0.15% (P=0.0011) (FIG. 7A). For both concentrations
of ARQ-151 cream, 66%-67% improvement from baseline was observed in
the primary endpoint after 4 weeks of treatment vs 38% for vehicle,
based on least square (LS) mean percentage change from baseline.
Statistical separation from vehicle was reached for both drug
product concentrations as early as week 2 of treatment, and the
difference between drug product and vehicle continued to increase
through week 4. Both Formulation 7, ARQ-151 cream 0.5% and 0.15%
showed similar efficacy in this primary endpoint throughout the
study duration.
[0119] Secondary efficacy endpoints of change from baseline in TPSS
(FIG. 7B) and change from baseline in TPA (FIG. 7C) were
statistically significantly different between ARQ-151 at both
active concentrations and vehicle after 4 weeks of treatment. For
both active concentrations of ARQ-151 vs vehicle, change from
baseline in TPSS, but not TPA, reached statistical significance as
early as 2 weeks.
[0120] Patients receiving Formulation 7, ARQ-151 cream 0.5% and
0.15% and vehicle after 4 weeks of treatment were compared to
baseline, along with their respective TPSS.times.TPA scores. Of
note, the vehicle-treated subjects seemed to have improvement
mainly in the appearance of scaling (predictable for an emollient
cream). Both subjects receiving ARQ-151 cream 0.5% and 0.15% show
examples of substantial improvement in the elbows or knees, which
can be treatment-resistant areas of psoriasis. Indeed, 39.3% of
subjects had target plaques on the elbows and/or knees.
[0121] In a post hoc analysis, 75% responder rates (75% improvement
from baseline in TPSS.times.TPA) at week 4 were also evaluated. In
the ARQ-151 cream 0.5% group, 10 subjects (35.7%) achieved this
level of improvement (P=0.0090), and in the ARQ-151 cream 0.15%
group, 7 subjects (25.9%) were 75% responders (P=0.0700). There
were two 75% responders in the vehicle group. In this same
analysis, 90% responder rates at week 4 were also evaluated. In the
ARQ-151 cream 0.5% group, 4 subjects (14.3%) achieved this level of
improvement, and in the ARQ-151 cream 0.15% group, 3 subjects
(11.1%) were 90% responders; however, none of the 90% responder
rates was statistically significant. There was one 90% responder in
the vehicle group.
Pharmacokinetic Results
[0122] In Cohort 1, limited evidence of systemic plasma exposure to
roflumilast or roflumilast N-oxide was observed after a single
topical administration of ARQ-151 0.5% to 25 cm.sup.2 of psoriatic
plaques (data not shown). In Cohort 2, systemic plasma exposure to
roflumilast and roflumilast N-oxide was observed following single
or multiple applications of Formulation 7 (ARQ-151) to psoriatic
plaques covering 0.5% to 5% BSA (Table 8, FIG. 8A for 0.5%
Formulation 7, ARQ-151 cream and FIG. 8B for 0.15% Formulation 7,
ARQ-151 cream). On day 1, roflumilast but not roflumilast N-oxide
exposure appeared to increase in a dose-dependent manner. At day
28, the plasma concentration vs time profiles were relatively flat
(very small peak to trough differences) suggesting that roflumilast
and roflumilast N-oxide exposure achieved steady state and appeared
to increase in a dose-dependent manner. The ratio of N-oxide to
roflumilast after topical administration ranged from 4.7 to 5.9,
compared with 12 after oral administration of roflumilast, the
latter being higher due to increased contribution from first pass
metabolism.
[0123] As shown in FIGS. 8A and 8B, when roflumilast is formulated
in a cream containing the phosphate ester surfactant Crodafos CES,
the gradual ascent to Cmax is evident in the single dose and
steady-state pharmacokinetic profile. As shown in FIGS. 8A and 8B,
there is a very flat and prolonged plateau in blood levels of the
drug following Cmax for the 24-hours following the first
application of 0.15% or 0.5% Formulation 7 (ARQ-151 cream) in human
subjects. The pharmacokinetic profile of roflumilast after dosing
the skin with Formulation 7 has the same low rise to Cmax shape
when applied to humans or pigs.
TABLE-US-00006 TABLE 6 Pharmacokinetic Parameters (Pharmacokinetic
Population; Cohort 2) ARQ-151 ARQ-151 0.5% 0.15% Day 1 Roflumilast
AUC.sub.0-last, mean h .times. ng/mL 4.37 (5.84) [10] 2.34 (2.56)
[7] (SD) [n] C.sub.max, mean ng/mL 1.38 (2.26) [10] 0.578 (0.468)
[7] (SD) [n] T.sub.max, mean h {minimum, 3.20 {1.00, 6.00} [10]
.sup. 3.71 {1.00, 6.00} [7] .sup. maximum} [n] Roflumilast N-oxide
AUC.sub.0-last, mean h .times. ng/mL 2.61 (2.13) [4] 3.18 (2.54)
[2] (SD) [n] C.sub.max, mean ng/mL 0.965 (0.858) [4] 1.07 (0.950)
[2] (SD) [n] T.sub.max, mean h [minimum, 6.00 {6.00, 6.00} [4]
.sup. 6.00 {6.00, 6.00} [2] .sup. maximum] [n] Day 28 Roflumilast
AUC.sub.0-last, mean h .times. ng/mL 29.2 (19.9) [20] 24.4 (22.8)
[21] (SD) [n] C.sub.max, mean ng/mL 1.48 (0.978) [20] 1.30 (1.06)
[21] (SD) [n] T.sub.max, mean h [minimum, 3.70 {0.00, 24.0} [20]
.sup. 4.95 {0.00, 24.0} [21] .sup. maximum] [n] Roflumilast N-oxide
AUC.sub.0-last, mean h .times. ng/mL 172 (116) [20] 127 (119) [22]
(SD) [n] C.sub.max, mean ng/mL 8.41 (5.54) [20] 6.11 (5.53) [22]
(SD) [n] T.sub.max, mean h [minimum, 8.25 {0.00, 24.0} [20] .sup.
8.59 {0.00, 24.0} [22] .sup. maximum] [n] AUC.sub.0-last, area
under the concentration time curve until the last measurable time
point; C.sub.max, maximum plasma concentration; T.sub.max, time to
maximum plasma concentration.
Safety Results
[0124] In Cohort 1, only 1 subject reported a TEAE, which was
considered unrelated to treatment (Table 9). In Cohort 2, the
percent of TEAEs in the 0.15% group was lower than in the 0.5% or
vehicle groups (7.1% vs 23.3% and 25.8%, respectively, for
treatment-related TEAEs; and 25% vs 40% and 35.5%, respectively,
for all TEAEs) (Table 9); all were mild or moderate in severity. No
SAE was reported in this study, and no subject discontinued from
the study because of a TEAE. All treatment-related TEAEs were
associated with the application site, accounting for 17 events.
Application site TEAEs were generally mild in severity and number
(16 events were mild and 1 event was moderate) and showed no
consistent differences between drug product and vehicle. No changes
in physical examinations, vital signs, electrocardiograms, or
clinical laboratory parameters were considered clinically
meaningful. There were no clinically significant differences in
weight changes between treatment groups. One subject in the 0.5%
treatment group reported a single episode of nausea of moderate
severity, but no further episodes in the remaining 3 weeks of the
study. No subjects reported vomiting or diarrhea. No signs of skin
irritation (dermal reactions) were noted in Cohort 1. For Cohort 2,
mean (SD) dermal reaction scores at baseline for ARQ-151 cream
0.5%, 0.15%, and vehicle were 0.2 (0.5), 0.0 (0.2), and 0.2 (0.4),
respectively, and at week 4 were 0.1 (0.5), 0.0 (0.0), and 0.1
(0.4).
TABLE-US-00007 TABLE 7 Summary of Safety (Safety Population) Cohort
1 Cohort 2 ARQ-151 ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle (N = 8)
(N = 30) (N = 28) (N = 31) Subjects with, n (%): .gtoreq.1 TEAE 1
(12.5) 12 (40.0) 7 (25.0) 11 (35.5) Treatment-related 0 7 (23.3) 2
(7.1) 8 (25.8) TEAE TEAE leading to 0 0 0 0 discontinuation SAE 0 0
0 0 Maximum severity of TEAEs, n (%) Mild 0 7 (23.3) 3 (10.7) 6
(19.4) Moderate 1 (12.5) 5 (16.7) 4 (14.3) 5 (16.1) Application
site TEAEs, n (%) Erythema 0 4 (13.3) 1 (3.6) 4 (12.9) Pain 0 2
(6.7) 1 (3.6) 5 (16.1) Edema 0 1 (3.3) 0 1 (3.2) Papules 0 1 (3.3)
0 1 (3.2) Pruritus 0 1 (3.3) 1 (3.6) 0 SAE, serious adverse event;
TEAE, treatment-emergent adverse event.
[0125] Discussion
[0126] In this phase 1/2a clinical trial, Formulation 7 (ARQ-151
cream) 0.5% and 0.15% was well tolerated, safe, and effective for
the treatment of chronic plaque psoriasis. Formulation 7 (ARQ-151
cream) at both doses tested demonstrated strong efficacy as shown
by statistically significant reductions in plaque severity and size
compared to vehicle.
[0127] Statistically significant efficacy of ARQ-151 (Formulation 7
containing 0.15% or 0.5% roflumilast) as compared to vehicle in the
primary study endpoint was observed with both active doses as early
as 2 weeks after initiation of treatment, and differences between
ARQ-151 and vehicle continued to increase through the last visit at
4 weeks. LS mean TPSS.times.TPA values decreased 38% with vehicle
over the course of the study; the preponderance of this effect
occurred during week 1 of treatment, which was likely contributed
to by apparently decreased scaling to the observer's eye caused by
the emollient cream. There was no difference in efficacy between
ARQ-151 cream 0.5% and 0.15% in the primary endpoint (percentage
change from baseline in TPSS.times.TPA) at week 4. However, the 75%
responder rates at week 4 suggested the 0.5% cream was somewhat
more efficacious (35.7%; P=0.0090 vs vehicle) than the 0.15%
concentration (25.9%; P=0.0700). With both active drug
concentrations after 4 weeks of dosing, TPSS.times.TPA values were
already reduced by 66%-67% from baseline based on LS means.
However, TPSS.times.TPA did not plateau in subjects treated with
ARQ-151, suggesting that a longer duration of treatment might
provide even greater efficacy.
[0128] The TPSS.times.TPA endpoint was chosen to be analogous to
whole-body Psoriasis Area and Severity Index (PASI) measurements.
Both use the same plaque severity scale, which was applied to 1-3
target lesions in the current study vs the entire body with PASI.
The TPA `area` function is different from the area of plaque
involvement assessment in PASI, but we would propose that the
product of TPSS.times.TPA provides an analogous assessment of
`target plaque(s)` to PASI for the entire body. Based on this
assumption, the efficacy of topical ARQ-151 after 4 weeks of dosing
(with 35.7% of subjects reaching 75% improvement for the 0.5%
cream) may be comparable to that of the class 1 steroid
betamethasone dipropionate 0.064% (32.7% PASI 75 response rate
after 4 weeks of dosing) in the phase 3 studies of
Taclonex.RTM..
[0129] The safety profile of Formulation 7 (ARQ-151 cream) at both
0.5% and 0.15% was similar to vehicle, which is explained, at least
in part, by the pharmacokinetic findings. When administered orally
for COPD, roflumilast may be associated with gastrointestinal side
effects (diarrhea, nausea), headache, and weight loss in a minority
of patients. Typically, clinical development of PDE-4 inhibitors
for oral use has been limited by gastrointestinal effects such as
nausea and vomiting. Indeed, nausea, vomiting, and weight loss are
believed to be mediated at the level of the brain. In contrast to
oral administration, topical administration of roflumilast in our
study was associated with a slow ascent to maximum plasma
concentrations over multiple days, and a flat exposure to
roflumilast and its active metabolite roflumilast N-oxide
throughout the dosing period (i.e. C.sub.max.about.C.sub.min across
dosing interval). The lack of nausea and vomiting seen in the
present study could possibly be attributed the lack of `peak to
trough` C.sub.max variation; lower C.sub.max values than observed
following oral administration; or bypassing of the gastrointestinal
tract with topical administration
[0130] PDE-4 inhibition represents a validated mechanism of action
for oral psoriasis therapy, but a new mechanism of action for
topical psoriasis therapy. Patients with mild to moderate disease
represent the majority of the psoriasis population. This patient
population has not benefited from the recent introduction of
biologic therapies, which are used in patients with more severe
disease. However, it is not surprising that PDE-4 inhibition is an
effective modality for the treatment of psoriasis. Apremilast was
approved for the oral treatment of psoriasis in 2014. Crisaborole
is currently approved at a 2% concentration for the treatment of
atopic dermatitis. Roflumilast is a highly potent PDE-4 inhibitor,
exhibiting half maximal inhibitory concentration (IC.sub.50) values
of both roflumilast and roflumilast N-oxide for the different PDE-4
isoforms and subtypes at subnanomolar potency. Rolumilast is 50- to
300-fold more potent than either apremilast or crisaborole against
the different PDE-4 isoforms and subtypes. The oral dose of
roflumilast, at only 0.5 mg per day, is reflective of this
extremely high potency.
Example 7--Crisaborole Single and Multiple Dose Human
Pharmacokinetics
[0131] As stated in the Eucrisa.RTM. package insert (Pfizer Labs,
New York, N.Y.) 2% crisaborole, a PDE4 inhibitor, is formulated as
a topical ointment composed of white petrolatum, propylene glycol,
mono- and diglycerides, paraffin, butylated hydroxytoluene and
edetate calcium disodium. This formulation does not contain a
phosphate ester surfactant.
[0132] Atopic dermatitis patients having 25% or greater body
surface area of diseased skin applied Eucrisa.RTM. ointment once
daily. Single dose (day 1) pharmacokinetics for crisaborole, the
PDE4 inhibitor active in Eucrisa.RTM., were published in the
non-confidential portion of the Summary Basis of Approval (SBOA)
and are reproduced in FIG. 9. For the same patients, steady-state
pharmacokinetic data for crisaborole were obtained on day 8 after
once daily treatment with Eucrisa.RTM.. This steady state
pharmacokinetic data was obtained from the Eucrisa.RTM. SBOA and is
reproduced in FIG. 9. As seen, the PDE4 inhibitor crisaborole, when
dosed from a commercialized topical ointment, rapidly rises to a
Cmax spike at 4 hours and then drops to near pre-dose levels within
24-hours of once daily dosing. This high Cmax spike of the PDE4
inhibitor occurs after a single topical application and after
steady-state dosing of once daily ointment applications.
Example 8--Single Dose Pharmacokinetics of Crisaborole Delivered
from a Crodafos CES Cream Compared to Delivery of Roflumilast from
the Same Cream
[0133] Crisaborole (0.3% w/w) was formulated as cream Formulation 8
by combining Crodafos CES (a commercial blend of cetostearyl
alcohol, dicetyl phosphate and ceteth-10 phosphate), diethylene
glycol monoethyl ether, as well as other ingredients to create a
complete marketable formulation. Formulation 8 has the same
excipients in the same ratios as Formulation 7 of this invention.
The only difference between the two formulations is that
Formulation 8 contains 0.3% crisaborole as the PDE-4 inhibitor drug
active and Formulation 7 contains 0.3% roflumilast as the PDE-4
inhibitor drug active. Both formulations were buffered with NaOH to
obtain a pH of 5.5.
TABLE-US-00008 TABLE 8 Ingredient Formulation 7 Formulation 8 PDE4
Inhibitor 0.3% 0.3% w/w Roflumilast Crisaborole Petrolatum, USP
10.0% w/w 10.0% w/w Isopropyl Palmitate, NF 5.0% w/w 5.0% w/w
Crodafos CES 10.0% w/w 10.0% w/w cetostearyl alcohol (6-8% w/w)
(6-8% w/w) dicetyl phosphate (1-2% w/w) (1-2% w/w) ceteth-10
phosphate (1-2% w/w) (1-2% w/w) Diethylene Glycol Monoethyl Ether,
25.0% w/w 25.0% w/w NF Hexylene Glycol, NF 2.0% w/w 2.0% w/w
Methylparaben, NF 0.20% w/w 0.20% w/w Propylparaben, NF 0.050% w/w
0.050% w/w 1N NaOH, NF q.s. ad pH 5.5 q.s. ad pH 5.5 Purified
Water, USP q.s. ad 100% q.s. ad 100%
Male and female swine (Gottingen Minipig.RTM. breed) were ordered
to weigh 8 to 12 kg at arrival. On the day prior to administration
of a topical cream containing roflumilast, the hair was clipped
from the back of each animal. The pigs were sedated for the shaving
procedure. Care was taken to avoid abrading the skin.
[0134] Two (2) grams of the cream Formulation 8 (containing 0.3%
crisaborole) for each kg of pig weight was distributed over the
clipped skin area by gentle inunction with a glass stirring rod or
stainless-steel spatula. The cream was applied evenly with a thin,
uniform film beginning at the scapular region and moving caudally
over the test site. The width of the test site area was bilaterally
divided by the spine. Twelve pigs (6 males and 6 females) were
dosed once with 0.3% crisaborole cream (formulation 8). Six pigs (3
males and 3 females) were dosed once with 0.3% roflumilast
(formulation 7). Blood was sampled from a suitable vein pre-dose
(time=0), and at times 1, 2, 4, 8 and 24-hours post dose
administration. The single dose results for these two PDE-4
inhibitors are shown graphically in FIG. 10
[0135] As shown in FIG. 10, when a PDE-4 inhibitor is formulated in
a cream containing the phosphate ester surfactant Crodafos CES, the
gradual ascent to Cmax is evident in the single dose
pharmacokinetic profile. What is most striking and surprising about
the data shown in FIG. 10 is the very flat and prolonged plateau in
blood levels of the drug following Cmax for the 24-hours following
the first application of 0.3% crisaborole cream in the pig. The
pharmacokinetic profile of the PDE4 inhibitors roflumilast and
crisaborole have the same low rise to Cmax shape when delivered
from the same Crodafos CES cream formulation. This low rise to Cmax
PK profile is not seen with topical formulations of roflumilast or
crisaborole when topically applied in formulations the do not
contain Crodafos CES.
[0136] Further modifications, uses, and applications of the
invention described herein will be apparent to those skilled in the
art. It is intended that such modifications be encompassed in the
following claims.
* * * * *