U.S. patent application number 17/155679 was filed with the patent office on 2021-06-03 for roflumilast formulations with an improved pharmacokinetic profile.
This patent application is currently assigned to ARCUTIS BIOTHERAPEUTICS, INC.. The applicant listed for this patent is ARCUTIS BIOTHERAPEUTICS, INC.. Invention is credited to David W. OSBORNE, Archie THURSTON, Howard WELGUS.
Application Number | 20210161870 17/155679 |
Document ID | / |
Family ID | 1000005389347 |
Filed Date | 2021-06-03 |
United States Patent
Application |
20210161870 |
Kind Code |
A1 |
WELGUS; Howard ; et
al. |
June 3, 2021 |
ROFLUMILAST FORMULATIONS WITH AN IMPROVED PHARMACOKINETIC
PROFILE
Abstract
An improved a method of treating a patient having a disorder
responsive to PDE-4 inhibition by administering roflumilast. The
improvement involves administering the roflumilast topically in a
composition having a roflumilast release profile that produces in
the patient a flattened plasma concentration time curve and a
reduced Cmax relative to oral administration of a PDE4-inhibiting
amount of roflumilast. Such disorders include inflammatory
disorders such as inflammatory dermatoses, including psoriasis,
atopic dermatitis and seborrheic dermatitis. Such disorders also
include inflammatory diseases in a variety of organs, especially
the lungs (asthma, COPD). Because of reduced side effects with
topical administration due to the improved pharmacokinetics (PK)
characteristics, it may be possible to provide higher systemic
exposures (AUCs) with topical administration, resulting in greater
therapeutic efficacy than with the oral route of
administration.
Inventors: |
WELGUS; Howard; (Ballwin,
MO) ; THURSTON; Archie; (San Diego, CA) ;
OSBORNE; David W.; (Fort Collins, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARCUTIS BIOTHERAPEUTICS, INC. |
Westlake Village |
CA |
US |
|
|
Assignee: |
ARCUTIS BIOTHERAPEUTICS,
INC.
Westlake Village
CA
|
Family ID: |
1000005389347 |
Appl. No.: |
17/155679 |
Filed: |
February 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17102056 |
Nov 23, 2020 |
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17155679 |
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16136804 |
Sep 20, 2018 |
10940142 |
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17102056 |
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15848505 |
Dec 20, 2017 |
10105354 |
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16136804 |
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15676356 |
Aug 14, 2017 |
9884050 |
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15848505 |
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15616409 |
Jun 7, 2017 |
9895359 |
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15676356 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/145 20130101;
C09K 15/06 20130101; A61K 45/06 20130101; A61K 9/0014 20130101;
A61K 9/06 20130101; A61K 31/44 20130101; A61K 47/10 20130101 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 9/06 20060101 A61K009/06; A61K 9/14 20060101
A61K009/14; A61K 45/06 20060101 A61K045/06; C09K 15/06 20060101
C09K015/06 |
Claims
1. A method of treating a patient having a disorder responsive to
phosphodiesterase-4 inhibition by administering a therapeutically
effective phosphodiesterase-4-inhibiting amount of roflumilast,
wherein the improvement comprises: administering the roflumilast
topically in a composition having a roflumilast release profile
that produces in the patient a flattened plasma concentration time
curve and a reduced Cmax relative to oral administration of a
therapeutically effective phosphodiesterase-4-inhibiting amount of
roflumilast in an oral composition marketed under the trademark
DALIRESP.RTM..
2. The method of claim 1, wherein said composition comprises
0.1-0.5% w/w of roflumilast.
3. The method of claim 1, wherein said release profile produces in
the patient a delayed Tmax relative to oral administration of a
phosphodiesterase-4-inhibiting amount of roflumilast in an oral
composition marketed under the trademark DALIRESP.RTM..
4. The method of claim 1, wherein the composition is in the form of
a cream or foam.
5. The method according to claim 1, wherein said method produces a
higher area under the curve (AUC) relative to oral administration
of an inflammatory disease-treating effective amount of roflumilast
in an oral composition marketed under the trademark
DALIRESP.RTM..
6. The method according to claim 1, wherein said disorder
responsive to phosphodiesterase-4 inhibition is asthma or chronic
obstructive pulmonary disease COPD.
7. A method of treating a patient suffering from an inflammatory
dermatosis with an inflammatory dermatosis-treating effective
amount of roflumilast, wherein the improvement comprises:
administering the roflumilast topically in a composition having a
roflumilast release profile that produces in the patient a
flattened plasma concentration time curve and a reduced Cmax
relative to oral administration of an inflammatory
dermatosis-treating effective amount of roflumilast in an oral
composition marketed under the trademark DALIRESP.RTM..
8. The method of claim 5, wherein said composition comprises
0.1-0.5% w/w of roflumilast.
9. The method of claim 5, wherein said release profile produces in
the patient a delayed Tmax relative to oral administration of an
inflammatory dermatoses-treating effective amount of roflumilast in
an oral composition marketed under the trademark DALIRESP.RTM..
10. The method of claim 5, wherein the composition is in the form
of a cream or foam.
11. A method of treating a patient suffering from psoriasis with a
psoriasis-treating effective amount of roflumilast, wherein the
improvement comprises: administering the roflumilast topically in a
composition having a roflumilast release profile that produces in
the patient a flattened plasma concentration time curve and a
reduced Cmax relative to oral administration of a
psoriasis-treating effective amount of roflumilast in an oral
composition marketed under the trademark DALIRESP.RTM..
12. The method of claim 11, wherein said composition comprises
0.1-0.5% w/w of roflumilast.
13. The method of claim 11, wherein said release profile produces
in the patient a delayed Tmax relative to oral administration of a
psoriasis-treating effective amount of roflumilast in an oral
composition marketed under the trademark DALIRESP.RTM..
14. The method of claim 11, wherein the composition is in the form
of a cream or foam.
15. The method according to claim 11, wherein said method is
suitable for the treatment of psoriasis patients as young as 2
years old.
16. A method of treating a patient suffering from atopic dermatitis
with an atopic dermatitis-treating effective amount of roflumilast,
wherein the improvement comprises: administering the roflumilast
topically in a composition having a roflumilast release profile
that produces in the patient a flattened plasma concentration time
curve and a reduced Cmax relative to oral administration of an
atopic dermatitis-treating effective amount of roflumilast in an
oral composition marketed under the trademark DALIRESP.RTM.
17. The method of claim 16, wherein said composition comprises
0.1-0.5% w/w of roflumilast.
18. The method of claim 16, wherein said release profile produces
in the patient a delayed Tmax relative to oral administration of an
atopic dermatitis-treating effective amount of roflumilast in an
oral composition marketed under the trademark DALIRESP.RTM..
19. The method of claim 16, wherein the composition is in the form
of a cream or foam.
20. The method according to claim 16, wherein said method is
suitable for the treatment of atopic dermatitis patients as young
as 3 months.
21. A method of treating a patient suffering from seborrheic
dermatitis with a seborrheic dermatitis-treating effective amount
of roflumilast, wherein the improvement comprises: administering
the roflumilast topically in a composition having a roflumilast
release profile that produces in the patient a flattened plasma
concentration time curve and a reduced Cmax relative to oral
administration of an atopic dermatitis-treating effective amount of
roflumilast in an oral composition marketed under the trademark
DALIRESP.RTM..
22. The method of claim 21, wherein said composition comprises
0.1-0.5% w/w of roflumilast.
23. The method of claim 21, wherein said release profile produces
in the patient a delayed Tmax relative to oral administration of an
atopic dermatitis-treating effective amount of roflumilast in an
oral composition marketed under the trademark DALIRESP.RTM..
24. The method of claim 21, wherein the composition is in the form
of a cream or foam.
25. A method of treating a patient having a disorder responsive to
phosphodiesterase-4 inhibition by administering a
phosphodiesterase-4-inhibiting amount of roflumilast, wherein the
improvement comprises: administering the roflumilast topically in a
composition having a roflumilast release profile that produces in
the patient a flattened plasma concentration time curve and a
reduced Cmax relative to oral administration of a
phosphodiesterase-4-inhibiting amount of roflumilast marketed under
the trademark DALIRESP.RTM., wherein the
phosphodiesterase-4-inhibiting amount of roflumilast is sufficient
to reduce the severity, duration and/or recurrence of said
disorder.
26. A method of treating a patient having a disorder responsive to
phosphodiesterase-4 inhibition by administering a therapeutically
effective amount of roflumilast, wherein the improvement comprises:
administering the roflumilast topically in a composition having a
roflumilast release profile that results in reduced psychiatric
adverse reactions and weight loss relative to oral administration
of a therapeutically effective amount of roflumilast marketed under
the trademark DALIRESP.RTM..
Description
[0001] This application is a continuation in part of U.S. Ser. No.
17/102,056 filed Nov. 23, 2020, which is a continuation of U.S.
Ser. No. 16/136,804 filed Sep. 20, 2018, which is a continuation of
U.S. Ser. No. 15/848,505 filed Dec. 20, 2017, which issued as U.S.
Pat. No. 10,105,354 on Oct. 23, 2018, which is a continuation of
U.S. Ser. No. 15/676,356 filed Aug. 14, 2017, which issued as U.S.
Pat. No. 9,884,050 issued on Feb. 6, 2018, which is a divisional of
U.S. Ser. No. 15/616,409 filed Jun. 7, 2017, which issued as U.S.
Pat. No. 9,895,359, issued Feb. 20, 2018, the disclosures of which
are incorporated herein in their entirety by reference.
FIELD OF THE INVENTION
[0002] The invention pertains to methods for treating a patient
having a disorder that is responsive to treatment with PDE-4
inhibition by the topical administration of a roflumilast
formulation having a roflumilast release profile that produces in
the patient a flattened plasma concentration time curve and a
reduced Cmax relative to administration of an equivalent amount of
roflumilast in an oral composition. The methods of treatment of
this invention provide a sufficiently high area under the
plasma-roflumilast concentration curve (AUC) to attain a
systemically effective level of roflumilast without rapid-onset
peak plasma concentration (Cmax) (i.e., short Tmax). It has been
discovered that these pharmacokinetic characteristics result in a
reduction of undesirable side effects associated with oral
roflumilast therapy.
BACKGROUND OF INVENTION
[0003] 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 including
psoriasis, seborrheic dermatitis, and atopic dermatitis), and
generalized inflammations in the gastrointestinal region (Crohn's
disease and ulcerative colitis). Currently, roflumilast is approved
for systemic administration (oral) to treat inflammatory disorders
involving the lungs, such as chronic obstructive pulmonary disease
(COPD).
[0004] Roflumilast and its synthesis were described in U.S. Pat.
No. 5,712,298 (the "'298 patent"), incorporated herein by
reference.* It has long been recognized that pharmaceutical
compounds having phosphodiesterase (PDE)-inhibiting properties,
such as roflumilast, are useful for treating inflammatory
disorders, including inflammatory dermatoses, such as psoriasis and
atopic dermatitis ('298 patent, col 11 lines 52-61) and other
chronic inflammatory and allergen-induced dermatoses. For treatment
of such dermatoses, roflumilast emulsions, suspensions, gels or
solutions for topical application have been described ('298 patent,
col 12, lines 37-64). Although oral tablets of roflumilast have
been commercialized, the low aqueous solubility of the compound has
been reported to be only 0.53 mg/l at 21.degree. C. in WO95/01338
(corresponding to the '298 patent and incorporated herein by
reference in its entirety). 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 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%. * Unless otherwise indicated, references
incorporated herein by reference are incorporated in their
entireties for all purposes.
[0005] Topical application of potent pharmacological agents like
roflumilast for treating skin diseases has been found to provide
superior delivery, lower systemic exposure 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. To
assure consistent delivery of the API into or across the skin, it
must remain either: 1) dissolved over the shelf life of the topical
product, or 2) suspended as particles having unchanged crystal
habit and unchanged particle size distribution over the shelf life
of the topical product.
[0006] The ability of a dissolved active ingredient to permeate the
barrier of the skin is determined by its molecular structure. A
well-known relationship between molecular structure and skin
penetration is that increasing molecular weight decreases the rate
that an active crosses the skin (J D Bos, M M Meinardi, Exp
Dermatol. 2000 June; 9(3):165-9). Another well-understood
relationship is that increasing the octanol-water partition
coefficient of a hydrophilic active initially increases the rate
that an active permeates the skin, but then decreases skin
permeation once the active becomes too lipophilic to partition out
of the stratum corneum and into the lower layers of the epidermis
(D. W. Osborne and W. J. Lambert, Prodrugs for Dermal Delivery, K.
B. Sloane ed., Marcel Dekker, New York 163-178 (1992)). The optimal
octanol-water partition coefficient is usually at log P values of
2-3. The rate that an active ingredient crosses into the viable
epidermis can be further modified based on the composition of the
topical product. Final pH of the formulation may be critical,
because dissolved ionized active ingredients typically do not
permeate the skin as effectively as active ingredients that do not
carry a charge (N. Li, X. Wu, W. Jia, M. C. Zhang, F. Tan, and J
Zhang. Drug Dev Indust Pharm 38(8)985-994). Functional ingredients
such as skin penetration enhancers (D. W. Osborne and J. J. Henke,
Pharmaceutical Technology 21(11)58-66 (1997)) can be added to the
topical product to increase skin permeation. For a dissolved active
in the topical product, the closer the drug concentration is to the
amount of active required to saturate the drug product, the greater
the thermodynamic driving force of the active to cross the skin,
i.e. the greater the skin flux of the active. The scientific
literature guides formulators on how to increase penetration
through the polar route, the nonpolar route, and the intercellular
lipid pathway or transfollicular penetration. While these theories
and mechanisms are sometimes conflicting, it is generally accepted
that the most consistent skin permeation of a drug from a topical
product occurs when the active ingredient is dissolved in the
formulation. For this reason, formulators generally avoid
developing a topical product that will have particles or crystals
of the active ingredient precipitate during storage according to
labeled storage instructions. Precipitation of the active
ingredient can occur for various reasons. Particular active
ingredients, when formulated with particular pharmaceutical
excipients will tend to form supersaturated solutions. At the time
of manufacture, all of the active ingredient will be in solution.
After days, weeks, or months, this metastable topical product will
equilibrate and active ingredient particles will form. If a topical
product contains a volatile solvent such as ethanol, then
evaporation of the solvent upon storage could result in
precipitation of the active ingredient. A less soluble polymorph
(Pudipeddi and Serajuddin, J. Pharm. Sci., 94(5) 929-939 (2005))
may nucleate in the topical product and form active ingredient
particles that will not re-dissolve. Other products may be
formulated too close to the saturation limit of the active
ingredient with the result that minor shifts in storage
temperatures will cause precipitation. It should be noted that the
dramatic temperature shifts that can occur during shipping are
expected to cause the reversible precipitation of the active
ingredient. Regardless of the reason, irreversible precipitation of
the active ingredient during storage of a topical product can have
profound effects on the bioavailability and efficacy of a topical
product, because only dissolved active ingredients can penetrate
into intact stratum corneum, the outermost layer of epithelium of
the skin.
[0007] For a suspended active ingredient, properties in addition to
molecular structure influence skin permeation. The ratio of
dissolved to suspended active ingredient can have a significant
influence on the amount of active delivered after topical
application. It has been shown that optimal drug delivery can be
achieved for particular drugs and particular diseases by utilizing
a topical composition that includes a dissolved active ingredient
that has the capacity to permeate the stratum corneum layer of the
epidermis and become available systemically, along with an active
ingredient in a microparticulate state that does not readily cross
the stratum corneum of the epidermis (U.S. Pat. No. 5,863,560
hereby incorporated by reference). Another property of a suspended
active ingredient that affects its delivery is the distribution of
suspended particle size. It has been shown that a 6 micron particle
will target the hair follicle and penetrate to a depth of 500
micrometers in a terminal hair. For a suspended particle of 0.75
microns to 1.5 microns in size, the particle penetrates the
terminal hair shaft to a depth of 800 micrometers (A Patzelt, F
Knorr, U Blume-Peytavi, W Sterry, J Lademann, Drug Discovery Today:
Disease Mechanisms, 5(2)2008 pages e173-e181). Thus, for suspended
active ingredients, skin permeability depends on the following
properties: 1) molecular structure of dissolved active ingredient,
2) particulate/crystalline structure of the suspended active
ingredient, 3) particle size of the suspended active ingredient,
and 4) particle size distribution of the suspended active
ingredient. The ability of a topical product composition to modify
the skin permeation is similar for suspended active ingredients and
dissolved active ingredients. Because skin permeability is
dependent on additional properties of the suspended active
ingredients, consistent delivery from topical products containing
suspended actives is more difficult to maintain than for topical
products containing only dissolved active ingredients.
[0008] Consistent delivery of a suspended active ingredient from a
topical product is assured by formulation into a product in which
the suspended particles do not significantly change in size or
amount over the shelf life of the product. Change over time in the
ratio of dissolved active ingredient to particulate active
ingredient can dramatically change the skin permeation of the
active ingredient. The same mechanisms described above
(supersaturation, temperature changes, evaporation, polymorphic
transformation) that can cause precipitation of dissolved active
ingredients can alter the dissolved-to-particulate ratio for
suspended active ingredients. Change over time in the particle size
or particle size distribution of the dispersed active ingredient
can also dramatically change the skin permeation of the active
ingredient. Sometimes this change in particle size or particle size
distribution can be explained by Ostwald ripening of the particles.
Ostwald ripening occurs when small particles in the topical product
dissolve and redeposit onto larger particles suspended in the same
container of topical product. Over time this phenomenon shifts the
particle size distribution toward larger particles at the expense
of the smaller particles. Ostwald ripening and precipitation of a
less soluble polymorph are two major problems in developing topical
products containing suspended actives.
[0009] In addition to crystal growth and changes in particle size
which can dramatically change the skin permeation of roflumilast,
successful treatment can be also affected by side effects which can
lead to treatment discontinuation. The prescribing information
pertaining to DALIRESP.RTM. (oral roflumilast tablets marketed in
the U.S.) warns of psychiatric adverse reactions (insomnia,
anxiety, depression, suicidal ideation and suicidal behavior),
weight loss and gastrointestinal side effects when patients are
treated with 500 mcg once daily. 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 so as to reduce the rate of treatment discontinuation. The
prescribing information for DAXAS.RTM. (oral roflumilast tablets
marketed outside the U.S.) 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.
[0010] 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, suggesting a possibility that these
side effects are associated with the spike in Cmax.
[0011] When multiple doses of oral roflumilast are administered,
exposure follows a "peak to trough" pattern. This pattern results
in an episodic variation in blood levels of drug and continued
gastrointestinal side effects.
[0012] 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. 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."
[0013] 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 and Tmax, it would be expected that administration of the
topical formulations of Bolle would cause an incidence of side
effects similar to that caused by orally administered
formulations.
[0014] 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/l 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 EP
151151681 (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%.
[0015] 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.
[0016] A need exists for a method of treating patients having PDE-4
inhibitor responsive disorders with roflumilast, that results in a
therapeutically effective systemic 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 side effects. Indeed, the absence or reduced side
effects allow for therapeutic doses to be administered that provide
higher systemic exposures (AUCs) than are possible orally and with
greater disease efficacy.
SUMMARY OF THE INVENTION
[0017] In accordance with the present invention, an improved method
of treating a patient having a disorder responsive to PDE-4
inhibition by administering a PDE-4-inhibiting amount of
roflumilast, involves administering the roflumilast topically in a
composition having a roflumilast release profile that produces in
the patient a flattened plasma concentration time curve and a
reduced Cmax relative to oral administration of a PDE4-inhibiting
amount of roflumilast. Such disorders include inflammatory
disorders such as inflammatory dermatoses, including psoriasis,
atopic dermatitis and seborrheic dermatitis. As used herein, a
disorder is responsive to PDE-4 inhibition if such inhibition
results in a prevention of the disorder or a diminution of its
severity, duration or recurrence, such disorders also include
inflammatory diseases in a variety of organs, especially the lungs
(asthma, COPD). Because of reduced side effects with topical
administration due to the above-described pharmacokinetics (PK)
findings, it may be possible to provide higher systemic exposures
(AUCs) with topical administration, resulting in greater
therapeutic efficacy than with the oral route of
administration.
[0018] In a preferred embodiment, the topically applied composition
contains from about 0.1% w/w to about 0.5% w/w roflumilast. In a
preferred embodiment, the topically applied composition is in the
form of a cream or a foam.
[0019] In a preferred embodiment, the composition has a roflumilast
release profile that results in a reduced Cmax, longer Tmax and
flattened plasma concentration time curve relative to that achieved
with oral administration of an effective amount of roflumilast in
an oral composition marketed under the trademarks DALIRESP.RTM. and
DAXAS.RTM..
[0020] It has been discovered that topical roflumilast compositions
having the above-described PK properties produce reduced
gastrointestinal, psychiatric, and weight loss side effects as
compared to prior art orally administered compositions.
[0021] Thus, in another embodiment, the present invention provides
a method of treating a patient suffering from a disorder that can
be treated by PDE-4 inhibition that comprises: administering a
topical pharmaceutical composition comprising 0.5% w/w of
roflumilast and a pharmaceutically acceptable carrier, wherein
administration of said composition results in reduced
gastrointestinal and other side effects relative to oral
administration of roflumilast in a composition of roflumilast
marketed under the trademark DALIRESP.RTM. or DAXAS.RTM..
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The patent or application file contains at least one figure
executed in color. Copies of this patent or patent application
publication with color figures will be provided by the Office upon
request and payment of the necessary fee.
[0023] FIG. 1 shows Sample 19-2 "dry" roflumilast crystals from
ferrer-Interquim S.A. Batch A14367P, the drug substance used in all
the examples in this specification. The roflumilast crystals are
0.01 mm-0.02 mm in length.
[0024] FIG. 2 shows Sample 20-3 roflumilast crystals suspended in
equimolar hexylene glycol:water solution after storage for six
weeks at room temperature under 10.times. power. The roflumilast
crystals are 0.01 mm-0.02 mm in length.
[0025] FIG. 3 shows Sample 20-2 roflumilast crystals suspended in
equimolar diethylene glycol monoethyl ether:water solution after
storage for six weeks at room temperature. The roflumilast crystals
are 0.04 mm-0.20 mm in length and 0.01 mm-0.02 mm in width.
[0026] FIG. 4 shows Sample 20-3 roflumilast crystals suspended in
equimolar hexylene glycol:water solution after storage for six
weeks at room temperature under 4.times. power. The roflumilast
crystals are 0.01 mm-0.02 mm in length.
[0027] FIG. 5 shows Sample 21-2 roflumilast crystals suspended in
equimolar ethanol:water solution after storage for six weeks at
room temperature. The roflumilast crystals are 0.05 mm-0.25 mm in
length and 0.02 mm in width.
[0028] FIG. 6 shows Sample 21-3 roflumilast crystals suspended in
equimolar PEG 400:water solution after storage for six weeks at
room temperature. The roflumilast crystals are 0.05 mm-0.07 mm in
length and 0.02 mm in width.
[0029] FIG. 7 shows Sample 21-4 roflumilast crystals suspended in
equimolar DMSO:water solution after storage for six weeks at room
temperature. The roflumilast crystals are 0.10 mm-0.67 mm in length
and 0.02 mm-0.10 mm in width.
[0030] FIG. 8 shows Sample 21-5 roflumilast crystals suspended in
equimolar propylene glycol:water solution after storage for six
weeks at room temperature. The roflumilast crystals are 0.20
mm-1.60 mm in length and 0.02 mm in width.
[0031] FIG. 9 shows Sample 20-1 roflumilast crystals suspended in
equimolar NMP:water solution after storage for six weeks at room
temperature. The roflumilast crystals are 0.10 mm-1.55 mm in length
and 0.02 mm-0.13 mm in width.
[0032] FIG. 10 shows Sample 21-1 roflumilast crystals suspended in
HG:NMP:Water (water mole fraction=1.2) solution after storage for
six weeks at room temperature. The roflumilast crystals are 0.02
mm-0.04 mm in length and 0.02 mm in width.
[0033] FIGS. 11A and 11B show roflumilast particles precipitated in
a cream composition after one freeze thaw cycle. FIG. 11a shows
Sample 36-1 roflumilast particles precipitated in a cream
composition with diethylene glycol monoethyl ether (DEGEE) and
without hexylene glycol. The three largest roflumilast particles
were measured (0.07 mm.times.0.09 mm; 0.06 mm.times.0.06 mm; and
0.10 mm.times.0.05 mm) and found to have a mean surface area of
5,000 square microns. FIG. 11b shows Sample 36-2 roflumilast
particles precipitated in a cream composition with both diethylene
glycol monoethyl ether (DEGEE) and hexylene glycol. The three
largest roflumilast particles were measured (0.05 mm.times.0.03 mm;
0.05 mm.times.0.03 mm and 0.05 mm.times.0.03 mm) and found to have
a mean surface area of 1,500 square microns.
[0034] FIG. 12 is a line graph comparing the pharmacokinetic (PK)
profile of two formulations of the invention, Formulation 3 and
Formulation 4, and a PK profile of a formulation of the prior art,
Formulation 5.
[0035] FIG. 13 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).
[0036] FIG. 14 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 0.15% roflumilast topical cream.
[0037] FIG. 15 is a line graph showing Day 1 and Day 14 PK profiles
after once daily dosing of 0.3% roflumilast topical cream.
[0038] FIG. 16 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 0.5% roflumilast topical cream.
[0039] FIG. 17 is a line graph showing Day 1 and Day 28 PK profiles
after once daily dosing of 1.0% roflumilast topical cream.
[0040] FIGS. 18A, 18B and 18C 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.
[0041] FIGS. 19A and 19B 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.
[0042] FIGS. 20A and 20B are line graphs showing day 1 and day 8 PK
profiles after once daily dosing of Crodafos-CES creams containing
either 0.3% crisaborole or 0.3% roflumilast.
[0043] FIG. 21 is a line graph comparing roflumilast plasma
concentration over time after 500 mcg once daily oral roflumilast
(closed circles) and topical 0.5% ARQ-151 cream (closed squares)
0-24 hours on day 28 of once a day dosing. The oral roflumilast
data (closed circles) was extracted from a plot in the publication
T. D Bethke and G. Lahu, 2011, Int J of Clin Pharm and Ther,
49(1):51-57. [n=20 subjects; Time=0 (day 28 pre-dose blood draw)
1.33 ng/mL; Time=1.0 hour 1.34 ng/mL; Time=2.0 hour 1.26 ng/mL;
Time=4.0 hour 1.18 ng/mL; Time=6.0 hour 1.25 ng/mL; Time=24.0 hour
1.15 ng/mL].
DETAILED DESCRIPTION OF THE INVENTION
[0044] 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 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).
[0045] Roflumilast is a compound of the formula (I)
##STR00001##
wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is
3,5-dichloropyrid-4-yl.
[0046] This compound has the chemical name
N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-
-e (INN: roflumilast).
[0047] 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.
[0048] Hexylene glycol (PharmaGrade. USP/NF) is
2-methyl-2,4-pentanediol of the formula (II).
##STR00002##
[0049] One aspect of present invention is directed to the addition
of hexylene glycol to a roflumilast-containing pharmaceutical
composition that contains a pharmaceutically acceptable solvent,
including water, to inhibit growth of roflumilast crystals in the
composition. For topical products designed to contain suspended
roflumilast particles or crystals, the addition of hexylene glycol
to a composition containing roflumilast, will inhibit (i.e.,
prevent or substantially reduce in comparison to compositions that
do not contain a hexylene glycol) changes in particle size
distribution over the shelf life of the product and assure
consistent bioavailability. For topical products designed to have
roflumilast completely dissolved, hexylene glycol inhibits the
growth of precipitated roflumilast particles.
[0050] Drug products that have fully dissolved drug substance for
the labeled storage conditions over product shelf life will have
the active precipitate if the product is formulated to maintain
significant thermodynamic driving force. Typical storage conditions
for a topical pharmaceutical cream are: Store at room temperature:
60.degree. F./15.degree. C.-80.degree. F./26.degree. C. Do not
freeze. It is understood by product development scientists and
regulatory agency reviewers that a topical product will not always
be stored over this temperature range. Therefore, the FDA requires
that all topical products undergo freeze-thaw cycling and
temperature excursion studies. The active is neither required nor
expected to remain in solution when the product is exposed to
temperatures of -20.degree. C., dramatically below 15.degree. C.
(60.degree. F.) of the labeled storage condition. Since topical
products containing completely dissolved drug are usually
formulated near saturation, i.e. near maximum thermodynamic driving
force, most topical products experience precipitation of the active
ingredient during freeze-thaw cycling or temperature excursion
studies. The addition of hexylene glycol prevents crystal growth of
roflumilast when precipitation occurs due to temperature excursions
below the labeled storage conditions. Inhibiting crystal growth
assures that any precipitated active will quickly return to being
completely dissolved once the product is returned to controlled
room temperature. The prompt return of the precipitated roflumilast
to a fully dissolved state assures consistent, reproducible
bioavailability, efficacy and safety of the topically applied
product. 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.
[0051] The topical roflumilast product formulations that benefit
from the addition of hexylene glycol include but are not limited to
aerosols, foams, sprays, emulsions (which can also be called
creams, lotions, or ointments), gels (two phase or single phase),
liquids, ointments, pastes, shampoos, suspensions, and systems.
These are the tier two terms within compendia taxonomy for dosage
forms containing pharmaceutical active ingredients (US Pharmacopeia
<1151>).
[0052] In a second aspect of the present invention, 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 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 roflumilast 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.
[0053] In pharmacokinetic terms, a formulation containing
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 roflumilast 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.
[0054] 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.
[0055] 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 roflumilast. The formulations of the present application
provide a sufficiently high AUC to attain a systemically effective
level of roflumilast 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.
[0056] This discovery provides several unexpected advantages.
Primarily, it provides a means for treatment of medical conditions
that are responsive to the administration of roflumilast, while
minimizing 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.
[0057] Furthermore, because the ascent to Cmax is relatively slow,
and a rapid 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 a 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.
[0058] 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.
[0059] Because the absorption of roflumilast 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 roflumilast is stable and has a flat PK
profile, an individual user of a formulation producing such a PK
profile may miss one or more doses from time to time and still
maintain efficacy of the treatment.
[0060] An important advantage of the present invention is that, a
slow ascent to Cmax without a concomitant Cmax spike 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.
[0061] A pharmaceutical formulation of the present invention
contains roflumilast in a concentration 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. The
concentration of 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 type of
formulation and the disease or condition to be treated. The
concentration of roflumilast 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.
[0062] The formulation may contain a means for inhibiting crystal
growth and changes in particle size distribution which can be
hexylene glycol. The formulation may further contain a means for
providing a sufficiently high AUC to attain a systemically
effective level of roflumilast without producing a spike in Cmax,
which can be 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.
[0063] 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%.
[0064] The formulation can optionally contain, a means for
increasing the solubility of roflumilast, which can be 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.).
[0065] 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 D. W. Osborne and J. Musakhanian, "Skin
Penetration and Permeation Properties of TRANSCUTOL.RTM.--Neat or
Diluted Mixtures", AAPS Pharm SciTech. 19(8):3512-3533 (2018) DOI:
10.1208/s12249-018-1196-8; and 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.
[0066] 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).
[0067] 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:
[0068] An oil-in-water emulsion: The product may be formulations in
which hexylene glycol is added to an emulsion comprising a discrete
phase of a hydrophobic component and a continuous aqueous phase
that includes water 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.
[0069] 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.
[0070] 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.
[0071] 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 such as described below. Alternatively, the thickened
aqueous gels can be thickened using suitable polyethoxylate alky
chain surfactants or other nonionic, cationic, or anionic
systems.
[0072] Thickened Hydroalcoholic gels: These systems include a blend
of water and alcohol 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.
[0073] Hydrophilic gels: These are systems in which the continuous
phase includes at least one water soluble or water dispersible
hydrophilic component other than water. The formulations may
optionally also contain water up to 60% by weight. Higher levels
may be suitable in some compositions. Suitable hydrophilic
components include one or more glycols such as polyols such as
glycerin, propylene glycol, butylene glycols, polyethylene glycols
(PEG), random or block copolymers of ethylene oxide, propylene
oxide, and/or butylene oxide, polyalkoxylated surfactants having
one or more hydrophobic moieties per molecule, silicone copolyols,
blend of ceteareth-6 and stearyl alcohol as well as combinations
thereof, and the like.
[0074] 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 having a
minor amount of a water soluble phase. Hydrophilic ointments
generally contain one or more surfactants or wetting agents
Solvents
[0075] Compositions according to the present invention may include
a means for obtaining the desired level of active ingredient
solubility in the topical product which can be one or more solvents
or co-solvents. The solvent may also modify skin permeation or the
activity of other excipients contained in the formulation. Means
for obtaining the desired level of active ingredient solubility in
the topical product 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, polyethylene glycol,
glycerol, propylene glycol and SD alcohol.
Moisturizers
[0076] Compositions according to 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, urea and stearyl alcohol.
Surfactants and Emulsifiers
[0077] Compositions according to the present invention optionally
can include one or more surfactants to emulsify the composition and
to help wet the surface of the actives 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 immisicible 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,
methoxy 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.
[0078] Phosphate ester surfactants can also act as a means for
reducing a spike in Cmax while producing an AUC sufficient to
attain a systemically effective level of roflumilast. 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
[0079] For certain applications, it may be desirable to formulate a
product that is thickened with soluble, swellable, or insoluble
organic polymeric thickeners such as natural and synthetic polymers
or inorganic thickeners such as acrylates copolymer, carbomer 1382,
carbomer copolymer type B, carbomer homopolymer type A, carbomer
homopolymer type B, carbomer homopolymer type C, carboxy vinyl
copolymer, carboxymethylcellulose, carboxypolymethylene,
carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose, microcrystalline wax, and methylcellulose.
[0080] 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
[0081] 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 including but not limited
to foaming agents, propellants preservatives (e.g. p-hydroxybenzoic
esters, benzyl alcohol, phenylmercury salts, chlorocresol),
antioxidants, sequestering agents, stabilizers, buffers, pH
adjusting solutions, skin penetration enhancers, film formers,
dyes, pigments, diluents, bulking agents, fragrances and other
excipients to improve the stability or aesthetics of the product,
may be added to the composition.
[0082] 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.
[0083] 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
[0084] Compositions according to the present invention may be
formulated with additional active agents depending on the condition
being treated. The additional active agents include but are not
limited to NSAIDs (e.g. Aspirin, Ibuprofen, Ketoprofen, Naproxen),
Apremilast and other PDE4 inhibitors, 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), purine synthesis inhibitors (e.g. Azathioprine), 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), retinoids (e.g., Acitretin, Tazarotene), calcineurin
inhibitors (eg, cyclosporine, tacrolimus, pimecrolimus),
Resorcinol, Colchicine, bronchodilators (e.g. beta-agonists,
anticholinergics, theophylline), and antibiotics and other
anti-infectives (e.g. erythromycin, ciprofloxacin, metronidazole,
and anti-fungals such as miconazole and terbinafine).
Administration and Dosage
[0085] 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 (e.g. injectable, oral).
[0086] 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.
[0087] The composition preferably contains a means for inhibiting
crystal growth and changes in particle size which is preferably
hexylene glycol in an amount of between 0.1% and 20% w/w, more
preferably between 0.25% and 8% w/w and most preferably between
0.5% and 2% w/w.
[0088] The composition preferably contains one or more phosphate
ester surfactants. The concentration of the phosphate ester
surfactant generally may be any concentration between 1.0% to 25%
w/w.
[0089] The composition preferably contains a component for
increasing the solubility of roflumilast, which is preferably
diethylene glycol monoethyl ether. The concentration of the
diethylene glycol monoethyl ether may be any concentration between
5% and 50% w/w.
[0090] The topical formulation containing 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 concentration
of roflumilast within the formulation, and the frequency with 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.
[0091] The formulation containing roflumilast 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 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 and other varieties of eczema, hand eczema,
atopic dermatitis, seborrheic dermatitis, lichen simplex chronicus,
sunburn, aphthous ulcers, lichen planus, vitiligo, pruritus in the
genital, anal or other body 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 (including the liver)
or central nervous system, disorders of the eye, disorders which
can be treated by the tissue-relaxant action of roflumilast and
other proliferative, inflammatory and allergic skin disorders; and
immune mediated diseases such as arthritis including rheumatoid
arthritis, rheumatoid spondylitis, osteoarthritis, and psoriatic
arthritis.
[0092] The systemic dose of a drug administered topically depends
on the concentration in the formulation, on the surface area to
which the drug is applied and on the disease/anatomical site being
treated. For example, the thick plaques of psoriasis decrease the
systemic dose, but cracks and fissures in and around the plaques
provide a shunt pathway to increase the systemic dose. These
effects tend to cancel each other out so that the systemic dose
found after topically treating psoriasis patients over similar Body
Surface Areas (% BSA) is similar to the systemic dose obtained in
treating normal volunteers. This also results in psoriatic patients
tending to have the same systemic dose throughout treatment
duration even though their disease is steadily resolving to become
clear or nearly clear. When skin afflicted with atopic dermatitis
(AD) is treated, there is a much higher systemic dosing for three
reasons: (1) AD skin has an inherent skin barrier defect that
always results in a higher systemic dose after topical treatment,
(2) higher % BSA areas require treatment in AD (>20% BSA)
compared to psoriasis (on average 7% BSA) because AD covers more of
the body's skin surface area than psoriasis, and 3) psoriasis is
primarily a disease of adults while AD is a disease in children.
The ratio of skin surface area to body weight is higher in a child
compared to an adult.
[0093] Pediatric dosing of topical products such as roflumilast
cream is much simpler than oral tablets because topical creams do
not have rigid dose units, and for children too young to
self-administer product, the product does not need to be
reformulated for a caregiver to administer the product. The
challenge in topically dosing children is that the ratio of skin
surface area to body weight changes dramatically from birth to
adulthood. This is a major concern when dosing neonates with
topical products, but of less concern when dosing children who are
at least 3-months old and proportionately less concern when dosing
pediatric patients 2 years or older. The ratio of surface area to
body weight for pediatric patients compared to an adult is shown
below. The greater ratio of skin surface area to body weight
corresponds to a lower volume of distribution within the pediatric
population after topical administration of the drug product. While
the stratum corneum is intact shortly after birth (<1 month),
the way human skin stores, and transports water becomes adult-like
only after the first year of life (Batchelor, et al., Formulations
for children: problems and solutions, British Journal of Clinical
Pharmacology, 79:3, pp. 405-418 2013. At two years of age, the
stratum corneum is still thinner compared to an adult (10 .mu.m
compared to 12 .mu.m) and thus barrier function is slightly
diminished (Walters, et al., Developmental Changes in Skin Barrier
and Structure during the First 5 years of Life, Skin Pharmacol
Physiol, 29:111-118, 2016). By the time a child reaches 3-5 years
of age the skin barrier is similar to that of an adult.
Average (50 Percentile) BSA and Body Weights in Young Children
TABLE-US-00001 [0094] Patient Skin Surface Body Ratio Child Age
Area Weight to Adult{circumflex over ( )} Neonate 2,100 cm.sup.2
3.4 kg 2.4 3-months 3,400 cm.sup.2 6 kg 2.2 2-years 5,000 cm.sup.2
12.4 kg 1.6 of 66 kg and BSA of 17,000 cm.sup.2
[0095] The lower volume of distribution in the very young pediatric
population compared to an adult results in children experiencing a
higher systemic dose compared to an adult administered the exact
same drug concentration applied over the same body surface area
afflicted with the same severity of skin disease. A higher systemic
dose in children can lead to an increase in adverse events such as
psychiatric, weight loss and gastrointestinal side effects. The
present formulations for topical application are suitable for
administration to atopic dermatitis patients as young as 3 months
and psoriasis patients as young as 2 years of age due to a
roflumilast release profile that produces a flattened plasma
concentration time curve and a reduced Cmax thereby decreasing
adverse events in pediatric populations.
[0096] The formulation for topical application containing
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.
[0097] 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 inventor regards as the invention.
Additional advantages and modifications will be readily apparent to
those skilled in the art.
[0098] 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 phosphate ester surfactants.
Example 1
[0099] A few mg of roflumilast API (Batch A14367P from Interquim
S.A.) dry powder was tapped onto a microscope slide, a coverslip
was moved into place and crystal habit and particle size of the API
were examined using polarized light microscopy using a 10.times.
objective (FIG. 1, microscope sample 19-2).
[0100] 0.0092 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial. An equimolar
blend of hexylene glycol (lot 1AC0818, Spectrum) and distilled
water was added dropwise with mixing to the vial containing
roflumilast to produce a suspension of roflumilast in excess of the
solubility limit. An equimolar blend is 86.7% hexylene glycol and
13.3% water on a weight/weight percent basis. After mixing each
addition of hexylene glycol:water blend, the tightly capped vial
was returned to a water bath set at 25.degree. C. It required
0.7962 grams of equimolar Hexylene Glycol:Water blend to completely
dissolve the 0.0092 grams of roflumilast and give a 1.14%
roflumilast in equimolar Hexylene Glycol:Water (wt/wt %) solution.
0.0064 grams of roflumilast was added to this sample (labeled 12-3)
to form a finely dispersed suspension at 25.degree. C. and the vial
was then stored undisturbed at about 15-18.degree. C., protected
from the light for six weeks. A sample of the roflumilast crystals
was removed from the vial, placed on a microscope slide (with
coverslip) and then examined using polarized light microscopy using
a 10.times. objective (FIG. 2, microscope sample 20-3).
[0101] 0.0111 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial. An equimolar
blend of diethylene glycol (DEGEE) (Transcutol P, lot 146063,
Gattefosse) and distilled water was added dropwise with mixing to
the vial containing roflumilast to produce a suspension of
roflumilast in excess of the solubility limit. An equimolar blend
is 88.3% DEGEE and 11.7% water on a weight/weight percent basis.
After mixing each addition of DEGEE:water blend, the tightly capped
vial was returned to a water bath set at 25.degree. C. It required
0.2477 grams of equimolar DEGEE:Water blend to completely dissolve
the 0.0111 grams of roflumilast and give a 4.29% roflumilast in
equimolar DEGEE:Water (wt/wt %) solution. This sample (labeled
13-1) was a solution of roflumilast at 25.degree. C. and the vial
was then stored undisturbed at about 15-18.degree. C., protected
from the light for six weeks. Roflumilast crystals precipitated due
to the cooler storage temperature. A sample of the roflumilast
crystals was removed from the vial, placed on a microscope slide
(with coverslip) and then examined using polarized light microscopy
using a 10.times. objective (FIG. 3, microscope sample 20-2).
Example 2
[0102] 0.0092 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial. An equimolar
blend of hexylene glycol (lot 1AC0818, Spectrum) and distilled
water was added dropwise with mixing to the vial containing
roflumilast to produce a suspension of roflumilast in excess of the
solubility limit. An equimolar blend is 86.7% hexylene glycol and
13.3% water on a weight/weight percent basis. After mixing each
addition of hexylene glycol:water blend, the tightly capped vial
was returned to a water bath set at 25.degree. C. It required
0.7962 grams of equimolar Hexylene Glycol:Water blend to completely
dissolve the 0.0092 grams of roflumilast and give a 1.14%
roflumilast in equimolar Hexylene Glycol:Water (wt/wt %) solution.
0.0064 grams of roflumilast was added to this sample (labeled 12-3)
to form a finely dispersed suspension at 25.degree. C. and the vial
was then stored undisturbed at about 15-18.degree. C., protected
from the light for six weeks. A sample of the roflumilast crystals
was removed from the vial, placed on a microscope slide (with
coverslip) and then examined using polarized light microscopy using
a 4.times. objective (FIG. 4, microscope sample 20-3).
[0103] 0.0260 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial. 1.0705 grams of
an ethanol:water blend (Everclear which is 74.98% ethanol and
25.02% water on a weight/weight percent basis or 95% alcohol by
volume) was added to produce a dispersion of roflumilast in an
ethanol:water blend in excess of the solubility limit. This sample
(labeled as "Alc" page 2) was then stored undisturbed at about
15-18.degree. C., protected from the light for six weeks. A sample
of the roflumilast crystals was removed from the vial, placed on a
microscope slide (with coverslip) and then examined using polarized
light microscopy using a 4.times. objective (FIG. 5, microscope
sample 20-3).
[0104] 0.0180 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial. Polyethylene
glycol 400 (lot 1DE0880, Spectrum) was added dropwise with mixing
to the vial containing roflumilast to produce a suspension of
roflumilast in excess of the solubility limit. After mixing each
addition of polyethylene glycol 400, the tightly capped vial was
returned to a water bath set at 25.degree. C. It required 0.5486
grams of propylene glycol 400 to completely dissolve the 0.0180
grams of roflumilast and give a 3.18% roflumilast in polyethylene
glycol 400 solution. This sample (labeled as "PEG 400" page 1) was
a solution at 25.degree. C. and was then stored undisturbed at
about 15-18.degree. C., protected from the light for six weeks.
Roflumilast crystals precipitated due to the cooler storage
temperature. A sample of the roflumilast crystals was removed from
the vial, placed on a microscope slide (with coverslip) and then
examined using polarized light microscopy using a 4.times.
objective (FIG. 6, microscope sample 21-3).
[0105] 0.0103 grams of roflumilast (Batch A14367P from Interquim
S.A.) was weighed into a liquid scintillation vial and mixed with
0.2501 grams of dimethyl sulfoxide (lot US150, Gaylord Chemical) to
give a 28.5% solution of roflumilast at 25.degree. C. This sample
(labeled as "DMSO" page 2) was then stored undisturbed at about
15-18.degree. C., protected from the light for six weeks. A sample
of precipitated roflumilast crystals was removed from the vial,
placed on a microscope slide (with coverslip) and then examined
using polarized light microscopy using a 4.times. objective (FIG.
7, microscope sample 21-4).
[0106] 0.0061 grams of roflumilast (Batch A14367P from Interquim
S.A.), 1.9332 grams of propylene glycol (lot 1 EC0004, Spectrum)
and 0.2335 grams distilled water was mixed to initially form a
clear solution at 25.degree. C. The composition of the sample was
0.28% roflumilast, 88.97% propylene glycol and 10.75% water on a
weight/weight % basis. After 105 minutes of storage at 25.degree.
C. a "dusting" of fine roflumilast crystals were observed on the
bottom of the vial. Six days later additional crystals had settled
to the bottom of the vial. This sample (labeled 7-2) was then
stored undisturbed at about 15-18.degree. C., protected from the
light for six weeks. A sample of precipitated roflumilast crystals
was removed from the vial, placed on a microscope slide (with
coverslip) and then examined using polarized light microscopy using
a 4.times. objective (FIG. 8, microscope sample 21-5).
Example 3
[0107] Dramatically greater roflumilast crystalline growth was
observed in an equimolar N-methyl pyrrolidone:water solution
containing roflumilast in excess of drug saturation compared to a
12:4:3 (wt/wt/wt) blend of hexylene glycol:N-methyl
pyrrolidone:water (1.2 mole fraction of water) solution having
roflumilast added in excess of the solubility limit.
[0108] 0.0202 grams of roflumilast (Batch A14367P from Interquim
S.A.) was mixed with 0.0682 grams of equimolar
N-Methyl-2-pyrrolidone:water blend in a liquid scintillation vial.
An equimolar blend is 84.5% N-Methyl-2-pyrrolidone (lot SYYN-HJ,
TCI) and 15.5% water on a weight/weight percent basis. The 22.85%
roflumilast in equimolar N-Methyl-2 pyrrolidone:water was
completely dissolved at 25.degree. C. This sample (labeled 13-2)
was then stored undisturbed at about 15-18.degree. C., protected
from the light for six weeks. Roflumilast crystals precipitated due
to the cooler storage temperature. A sample of the roflumilast
crystals was removed from the vial, placed on a microscope slide
(with coverslip) and then examined using polarized light microscopy
using a 4.times. objective (FIG. 10, microscope sample 20-1).
[0109] A 0.8152 gram sample of 3.6% roflumilast (Batch A14367P from
Interquim S.A.), 60.8% hexylene glycol (lot 1AC0818, Spectrum),
20.0% N-Methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and 15.6% distilled
water was mixed on a weight/weight percent basis. This sample
(labeled 13-4) was a finely dispersed suspension of roflumilast at
25.degree. C. The sample was then stored undisturbed at about
15-18.degree. C., protected from the light for six weeks. A sample
of the roflumilast crystals was removed from the vial, placed on a
microscope slide (with coverslip) and then examined using polarized
light microscopy using a 4.times. objective (FIG. 11, microscope
sample 21-1).
Example 4
[0110] Roflumilast creams were prepared according to the following
formulations.
TABLE-US-00002 Formulation 1 (comparative) Roflumilast 0.5% w/w
White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos
CES 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25%
w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water
q.s. ad 100 (49.25%)
TABLE-US-00003 Formulation 2 Roflumilast 0.5% w/w White Petrolatum
10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w
Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether
(Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05%
w/w Purified Water q.s. ad 100 (47.25%)
[0111] After preparation, 0.4222 grams of formulation 1 was sealed
in a 1.0 mL CryoTube.TM. vial and labeled as 36-1. Likewise, 0.3961
grams of formulation 2 was sealed in a 1.0 mL CryoTube.TM. vial and
labeled as 36-2. The two CryoTube.TM. vials were secured in an
envelope end-to-end and placed in the freezer for 17.5 hours.
Quickly upon removal from the freezer, a microscopic slide was
prepared of each sample and after "thawing" the sample to room
temperature (18.degree. C.) a photomicrograph image was captured to
characterize differences in precipitated roflumilast crystal
growth. See FIGS. 11A and 11B.
Example 5
Formulations According to the Invention and of the Prior Art
[0112] A formulation of the invention, hereafter referred to as
Formulation 3, 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.
[0113] A formulation of the invention, hereafter referred to as
Formulation 4, 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.
[0114] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 5, 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 3, and 4. This
semisolid formulation was likewise buffered with NaOH to obtain a
pH of 6.5.
[0115] The compositions of these formulations are shown below in
Table 1.
TABLE-US-00004 TABLE 1 Comparative Formulation 3 Formulation 4
Formulation 5 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 6--Single Dose Testing of Formulations of Example 5
[0116] 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 5 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.
[0117] Two (2) grams of one of the cream formulations of Example 5
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 4.
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 washout period, a single dose of formulation 3 was
applied. After a second one-week washout period, a single dose of
Formulation 5 was applied. Blood samplings were the same for all
three groups. The results are shown graphically in FIG. 12.
[0118] As shown in FIG. 12, pigs dosed with Comparative Formulation
5 of the prior art showed a rapid spike to Cmax within 3 hours of
dosing. In contrast, pigs dosed with Formulation 3 of the invention
containing the phosphate ester surfactant Crodafos CES showed
little or no spike to Cmax. Pigs dosed with Formulation 4 of the
invention containing both a phosphate ester surfactant and
diethylene glycol monoethyl ether, like those dosed with
Formulation 3, showed a reduced spike to Cmax as compared to
Formulation 5. However, the higher Cmax obtained with Formulation 4
was higher than that for Formulation 3.
[0119] The PK data results in the graph of FIG. 12 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 3, 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 5 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 4
administration produced no significant spike to Cmax and had a Cmax
between those obtained with Formulations 3 and 5, while maintaining
AUC.
Example 7--Formulation of the Invention and a Formulation of the
Closest Prior Art
[0120] A third embodiment of the invention, hereafter referred to
as Formulation 6, 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 3 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.
[0121] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 7, 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.
[0122] A formulation that is not of the invention, hereafter
referred to as Comparative Formulation 8, 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.
[0123] The compositions of these formulations are shown below in
Table 2.
TABLE-US-00005 TABLE 2 Comparative Comparative Formulation 6
Formulation 7 Formulation 8 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 (1-2.5%
w/w) ceteth-10 phosphate (1-2.5% 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 8--14-Day Dose Testing of Formulations of Example 7
[0124] 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 7, 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.
[0125] Two (2) grams of one of the cream formulations of Example 7
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.
13.
[0126] As shown in FIG. 13, pigs dosed with Formulation 7 of the
prior art show a rapid spike to a Cmax value of 6.6 ng/mL at 1 hour
after the 14th consecutive daily dose. In contrast, pigs dosed with
Formulation 6 of the invention containing the phosphate ester
surfactant Crodafos CES show little or no spike to Cmax.
[0127] The results show in the graph of FIG. 13, 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 9--Testing for Multiple Dose Pharmacokinetics Compared to
Prior Art
[0128] A fourth formulation of the invention is shown in Table 3,
hereafter referred to as Formulation 9, 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 9 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-00006 TABLE 3 Formulation 9 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, NF 25.0% w/w 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%
[0129] 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.
[0130] 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. 14 (0.15% roflumilast cream), in FIG. 15 (0.3%
roflumilast), in FIG. 16 (0.5% roflumilast cream), and in FIG. 17
(1.0% roflumilast cream) and in tabular form in Table 4.
[0131] As shown in each of FIGS. 14 to 17, 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. 14 to 17
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-00007 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. 14--Steady State Day 28) 5.0 (males) 5.0 (males)
0.3% Roflumilast Cream 3.7 (females) 4.5 (females) (FIG. 15--Steady
State Day 14) 6.6 (males) 6.6 (males) 0.5% Roflumilast Cream 8.5
(females) 10.7 (females) (FIG. 16--Steady State Day 28) 6.7 (males)
8.2 (males) 1% Roflumilast Cream 16.3 (females) 16.3 (females)
(FIG. 17--Steady State Day 28) 8.4 (males) 10.0 (males)
[0132] 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 10--Clinical Study in Subjects with Plaque Psoriasis
Study Design
[0133] 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).
[0134] 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.
[0135] 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.
[0136] 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 9)
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] 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
[0142] To be eligible for enrollment in Cohort 1, subjects had to
be .gtoreq.18 years of age with .gtoreq.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
[0143] Formulation 9, 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 once daily for 4 weeks. Subjects were
instructed by study staff on proper dosing and administration of
ARQ-151 cream and vehicle.
Study Assessments
[0144] 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.
[0145] Pharmacokinetic profiles for roflumilast and its active
metabolite roflumilast N-oxide 12 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.
[0146] 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 (week 1), 4 (week 2), 5
(week 3), and 6 (week 4) for Cohort 2. Skin irritation was
evaluated using a scale developed by Berger and Bowman 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 .ltoreq.5
represents no depression; 6-10 represents mild depression; 11-15
represents moderate depression; 16-20 represents severe depression;
and .gtoreq.21 represents very severe depression.
Statistical Considerations
[0147] 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.
[0148] 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).
[0149] 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 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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 .gtoreq.1 dose of study drug and had
.gtoreq.1 post-baseline efficacy evaluation.
[0154] 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.
[0155] Results
Patients
[0156] 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.
[0157] 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-00008 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
[0158] 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 ARQ-151 cream 0.5% and 0.15% showed similar
efficacy in this primary endpoint throughout the study
duration.
[0159] 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.
[0160] Patients receiving ARQ-151 cream 0.5%, 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.
[0161] 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 (6.4%) 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
(3.2%) in the vehicle group.
Pharmacokinetic Results
[0162] 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.
[0163] As shown in FIGS. 19A and 19B, 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.
19A and 19B, 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 9 (ARQ-151 cream) in
human subjects. The pharmacokinetic profile of roflumilast after
dosing the skin with Formulation 9 has the same low rise to Cmax
shape when applied to humans or pigs.
TABLE-US-00009 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 (SD) [n] 4.37 (5.84) [10] 2.34
(2.56) [7] C.sub.max, mean ng/mL (SD) [n] 1.38 (2.26) [10] 0.578
(0.468) [7] T.sub.max, mean h {minimum, maximum} [n] 3.20 {1.00,
6.00} [10] .sup. 3.71 {1.00, 6.00} [7] .sup. Roflumilast N-oxide
AUC.sub.0-last, mean h .times. ng/mL (SD) [n] 2.61 (2.13) [4] 3.18
(2.54) [2] C.sub.max, mean ng/mL (SD) [n] 0.965 (0.858) [4] 1.07
(0.950) [2] T.sub.max, mean h [minimum, maximum] [n] 6.00 {6.00,
6.00} [4] .sup. 6.00 {6.00, 6.00} [2] .sup. Day 28 Roflumilast
AUC.sub.0-last, mean h .times. ng/mL (SD) [n] 29.2 (19.9) [20] 24.4
(22.8) [21] C.sub.max, mean ng/mL (SD) [n] 1.48 (0.978) [20] 1.30
(1.06) [21] T.sub.max, mean h [minimum, maximum] [n] 3.70 {0.00,
24.0} [20] .sup. 4.95 {0.00, 24.0} [21] .sup. Roflumilast N-oxide
AUC.sub.0-last, mean h .times. ng/mL (SD) [n] 172 (116) [20] 127
(119) [22] C.sub.max, mean ng/mL (SD) [n] 8.41 (5.54) [20] 6.11
(5.53) [22] T.sub.max, mean h [minimum, maximum] [n] 8.25 {0.00,
24.0} [20] .sup. 8.59 {0.00, 24.0} [22] .sup. 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
[0164] In Cohort 1, only 1 subject reported a TEAE, which was
considered unrelated to treatment (Table 7). 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 7); 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-00010 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.
[0165] Discussion
[0166] In this phase 1/2a clinical trial, Formulation 9 (ARQ-151
cream) 0.5% and 0.15% was well tolerated, safe, and effective for
the treatment of chronic plaque psoriasis. Formulation 9 (ARQ-151
cream) at both doses tested demonstrated strong efficacy as shown
by statistically significant reductions in plaque severity and size
compared to vehicle.
[0167] Statistically significant efficacy of ARQ-151 (Formulation 9
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. 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..
[0168] The safety profile of Formulation 9 (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, vomiting), psychiatric disturbances
(insomnia, anxiety, depression, suicidal thoughts or other mood
changes), weight loss in a minority of patients, and headache.
Typically, clinical development of PDE-4 inhibitors for oral use
has been limited by gastrointestinal effects such as nausea and
vomiting. Indeed, nausea, vomiting, psychiatric disturbances, 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` Cmax variation; lower Cmax
values than observed following oral administration; or bypassing of
the gastrointestinal tract with topical administration. The absence
of psychiatric disturbances and weight loss seen in our studies may
also be explained by the markedly different PK of topical vs oral
administration. PDE-4 inhibition represents a validated mechanism
of action for oral psoriasis therapy (Otezla), 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 roflumilast is an effective modality for the treatment of
psoriasis. 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.
[0169] 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.
Example 11--Preparing a Foam Formulation
[0170] A fifth formulation of the invention is shown in Table 8,
hereinafter referred to as Formulation 10. Formulation 10 is a foam
concentrate which can be mixed with a propellant to produce a foam.
Sixty four grams of the foam concentrate was blended with 8-10
grams of AP-70 propellant to make a foam.
TABLE-US-00011 TABLE 8 Formulation 10 Roflumilast 0.15, 0.3, 0.5 or
1.0% w/w Petrolatum, USP 5.0% w/w Isopropyl Palmitate, NF 2.5% w/w
Crodafos CES 2% w/w cetostearyl alcohol (1.2-1.6% w/w) dicetyl
phosphate (0.2-0.5% w/w) ceteth-10 phosphate (0.2-0.5% w/w)
Diethylene Glycol Monoethyl Ether, NF 25.0% w/w 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%
Example 12--Comparison of Adverse Event Profiles of Daliresp and
Topical Formulations
[0171] Treatment of 4,438 patients with once daily DALIRESP.RTM.
500 mcg tablets was associated with an increase in psychiatric
adverse reactions and weight loss. In 8 controlled clinical trials
5.9% (263) of patients treated with DALIRESP.RTM. 500 mcg daily
reported psychiatric adverse reactions compared to 3.3% (137)
treated with placebo. The most commonly reported psychiatric
adverse reactions were insomnia, anxiety, and depression which were
reported at higher rates in those treated with DALIRESP.RTM. 500
mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP.RTM. versus 1.0%,
0.9%, and 0.9% for placebo, respectively). Instances of suicidal
ideation and behavior, including completed suicide, have been
observed in clinical trials. Three patients experienced
suicide-related adverse reactions (one completed suicide and two
suicide attempts) while receiving DALIRESP.RTM. compared to one
patient (suicidal ideation) who received placebo. Cases of suicidal
ideation and behavior, including completed suicide, have been
observed in the post-marketing setting in patients with or without
a history of depression. Weight loss was a common adverse reaction
in DALIRESP.RTM. clinical trials and was reported in 7.5% (331) of
patients treated with DALIRESP.RTM. 500 mcg once daily compared to
2.1% (89) treated with placebo [see DALIRESP.RTM. 500 mcg package
insert Adverse Reactions (6.1)]. In addition to being reported as
adverse reactions, weight was prospectively assessed in two
placebo-controlled clinical trials of one-year duration. In these
studies, 20% of patients receiving roflumilast experienced moderate
weight loss (defined as between 5-10% of body weight) compared to
7% of patients who received placebo. In addition, 7% of patients
who received roflumilast compared to 2% of patients receiving
placebo experienced severe (>10% body weight) weight loss.
During follow-up after treatment discontinuation, the majority of
patients with weight loss regained some of the weight they had lost
while receiving DALIRESP.RTM.. (Section 5.2 and 5.3 of the Daliresp
package insert)
[0172] In contrast to the psychiatric adverse reactions and weight
loss associated with orally administered roflumilast (Daliresp.RTM.
500 .mu.g tablets), no significant safety concerns or signals have
been identified during the completed or ongoing clinical studies of
roflumilast cream or roflumilast foam. It is estimated that about
2,412 clinical trial subjects have been exposed to at least one
dose of topical roflumilast cream or roflumilast foam. While
adverse events associated with marketed oral roflumilast
(Daliresp.RTM. 500 .mu.g tablets), such as depression, weight loss
and gastrointestinal adverse events, were assessed with regard to
topical roflumilast cream and roflumilast foam studies, the side
effects associated with oral administration of roflumilast have not
been observed in roflumilast cream and roflumilast foam clinical
studies. The pharmacokinetic profile of topical roflumilast appears
to be distinct from that of oral roflumilast likely due to the lack
of `peak to trough` Cmax variation, lower Cmax values than observed
following oral administration, and/or bypassing of the
gastrointestinal tract with topical administration.
* * * * *