U.S. patent application number 12/575356 was filed with the patent office on 2010-01-28 for use of mometasone furoate for treating airway passage and lung disease.
This patent application is currently assigned to Schering Corporation. Invention is credited to Mitchell Cayen, Imtiaz A. Chaudry, Francis M. Cuss, Nagamani Nagabhushan, Keith B. Nolop, James E. Patrick, JOEL A. SEQUEIRA.
Application Number | 20100022493 12/575356 |
Document ID | / |
Family ID | 27539197 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100022493 |
Kind Code |
A1 |
SEQUEIRA; JOEL A. ; et
al. |
January 28, 2010 |
USE OF MOMETASONE FUROATE FOR TREATING AIRWAY PASSAGE AND LUNG
DISEASE
Abstract
The administration of aerosolize particles of mometasone furoate
in the form of dry powders, solutions, or aqueous suspension for
treating corticosteroid-responsive diseases of the surfaces of
upper and/or lower airway passages and/or lungs, e.g., allergic
rhinitis and asthma is disclosed.
Inventors: |
SEQUEIRA; JOEL A.; (Scotch
Plains, NJ) ; Cuss; Francis M.; (Basking Ridge,
NJ) ; Nolop; Keith B.; (Millburn, NJ) ;
Chaudry; Imtiaz A.; (North Caldwell, NJ) ;
Nagabhushan; Nagamani; (Parsippany, NJ) ; Patrick;
James E.; (Belle Meade, NJ) ; Cayen; Mitchell;
(Bedminster, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
27539197 |
Appl. No.: |
12/575356 |
Filed: |
October 7, 2009 |
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Current U.S.
Class: |
514/172 |
Current CPC
Class: |
A61P 11/02 20180101;
A61P 11/06 20180101; A61K 9/0043 20130101; A61P 37/08 20180101;
A61K 9/0075 20130101; A61P 29/00 20180101; A61K 31/58 20130101;
A61P 11/00 20180101; A61K 9/008 20130101; Y10S 514/826 20130101;
Y10S 514/958 20130101; Y10S 514/828 20130101; A61K 31/57
20130101 |
Class at
Publication: |
514/172 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61P 11/00 20060101 A61P011/00 |
Claims
1-29. (canceled)
30. A method of treating allergic, non-allergic and inflammatory
diseases of the upper airway passages comprising administering once
daily to nasal passages about 200 micrograms of mometasone
furoate.
31. The method of claim 30, wherein the corticosteroid responsive
disease is at least one disease selected from the group consisting
of seasonal allergic rhinitis, perennial rhinitis, non-malignant
proliferative disease of the airway passage, inflammatory diseases
of the airway passage and non-allergic rhinitis.
32. The method of claim 30, wherein treating said corticosteroid
responsive disease provides relief of at least one sign or symptom
selected from the group consisting of seasonal or perennial
sneezing, rhinorrhea, nasal congestion, pruritis, eye itching,
redness, and tearing.
33. The method of claim 30, wherein the disease is a non-malignant
proliferative disease of the airway passage.
34. The method of claim 30, wherein the mometasone furoate is
administered as anhydrous mometasone furoate.
35. The method of claim 30, wherein the mometasone furoate is
administered in the form of an aqueous suspension of mometasone
furoate monohydrate.
36. The method of claim 30, wherein the mometasone furoate is
administered in the form of an aqueous suspension of anhydrous
mometasone furoate.
37. The method of claim 30, wherein there are administered 200
micrograms of mometasone furoate by applying two times to each
nostril about 50 micrograms of mometasone furoate.
38. A method of treating allergic, non-allergic and inflammatory
diseases of the upper airway passages comprising administering
twice daily to nasal passages about 200 micrograms of mometasone
furoate.
39. The method of claim 38, wherein the mometasone furoate is
administered in the form of an aqueous suspension.
40. The method of claim 38, wherein the mometasone furoate is
administered in the form of an aqueous suspension of mometasone
furoate monohydrate.
41. The method of claim 38, wherein the mometasone furoate is
administered in the form of an aqueous suspension of anhydrous
mometasone furoate.
42. The method of claim 38, wherein there are administered 200
micrograms of mometasone furoate by applying two times to each
nostril about 50 micrograms of mometasone furoate.
43. The method of claim 38, wherein the corticosteroid responsive
disease is at least one disease selected from the group consisting
of seasonal allergic rhinitis, perennial rhinitis, non-malignant
proliferative disease of the airway passage, inflammatory diseases
of the airway passage and non-allergic rhinitis.
44. The method of claim 38, wherein treating said corticosteroid
responsive disease provides relief of at least one sign or symptom
selected from the group consisting of seasonal or perennial
sneezing, rhinorrhea, nasal congestion, pruritis, eye itching,
redness, and tearing.
45. The method of claim 38, wherein the disease is a non-malignant
proliferative disease of the airway passage.
46. A method of using a mometasone furoate formulation comprising
administering twice daily to nasal passages about 200 micrograms of
mometasone furoate.
47. The method of claim 46, wherein the mometasone furoate is
administered as anhydrous mometasone furoate.
48. The method of claim 46, wherein the mometasone furoate is
administered as mometasone furoate monohydrate.
49. The method of claim 46, wherein there are administered 200
micrograms of mometasone furoate by applying two times to each
nostril about 50 micrograms of mometasone furoate.
Description
INTRODUCTION TO THE INVENTION
[0001] This invention relates to the treating of
corticosteroid-responsive diseases of the upper and lower airway
passages and lungs, such as asthma, by orally or intranasally
administering to said passages and lungs an amount of mometasone
furoate effective for treating such diseases while minimizing
systemic absorption and side effects associated with such systemic
absorption.
[0002] Mometasone furoate is a corticosteroid approved for topical
dermatologic use to treat inflammatory and/or pruritic
manifestations of corticosteroid-responsive dermatoses. The
compound may be prepared in accordance with the procedures
disclosed in U.S. Pat. Nos. 4,472,393, 4,731,447, and 4,873,335,
which U.S. patents are hereby incorporated by reference.
[0003] Certain corticosteroids, e.g., beclomethasone dipropionate
are commercially available for the treatment of diseases of airway
passages and lungs such as rhinitis and bronchial asthma. However,
the art teaches that not every corticosteroid having topical
anti-inflammatory activity is active in treating rhinitis and/or
asthma. Furthermore, even though a topically active corticosteroid
may exhibit activity in treating bronchial asthma, the long term
use of such steroids has been limited by the occurrence of serious
systemic side-effects, including hypothalamic-pituitary-adrenal
(HPA) axis suppression. The introduction of topically active
steroids administered by metered-dose inhalation has greatly
reduced but not eliminated the detrimental system side-effects of
steroid therapy in the treatment of asthma. Unfortunately, however,
a large portion of an inhaled corticosteriod dose is swallowed by
the patient. Since certain corticosteroids are readily
bioavailable, the swallowed portion of the dose may reach the
systemic circulation through the gastro-intestinal tract and may
cause unwanted systemic side-effects. Some corticosteroids
currently approved for treating asthma have systemic
bioavailability after oral ingestion of greater than 10%
(budesonide) or even 20% (triamcinolone acetonide and flunisolide)
of the inhalation dose. Thus, a topically active steroid which is
not readily bioavailable would provide a therapeutic advantage over
other topically active corticosteroids that are more systematically
bioavailable and it would also be superior to any corticosteroid
orally administered by the oral swallowing of, for example, a
solution, tablet or capsule.
[0004] Discovering an effective corticosteroid for treating
diseases such as asthma with low systemic side-effects is
unpredictable. For example, the corticosteroid tipredane exhibited
not only good initial anti-inflammatory activity against asthma but
also low systemic side effects. However, development of tipredane
for treating asthma has been discontinued because clinical trials
have not demonstrated a level of efficacy in treating asthma which
would be considered therapeutically useful. It has recently been
disclosed that butixocort propionate, another potent topical
anti-inflammatory corticosteroid having reportedly low systemic
side-effects is under development (Phase II) for treating chronic
bronchial asthma. While the clinical results currently available
from the Phase II studies show butixocort propionate has some
efficacy, it remains to be seen if the efficacy in treating asthma
will be sufficient to justify continuing the clinical
development.
[0005] Thus, it would be desirable to find a corticosteroid which
is therapeutically effective in treating disease of the airway
passages and lungs such as asthma and which also exhibits low
bioavailability and low systemic side-effects when it is
administered intra-nasally or by oral inhalation.
SUMMARY OF THE INVENTION
[0006] The present invention provides a method of treating a
corticosteroid-responsive disease of the upper or lower airway
passages and/or of the lungs in patients afflicted with said
disease, which comprises administering once-a-day to said passages
or lungs of said patients a substantially non-systematically
bio-available amount of aerosolized particles of mometasone furoate
effective for treating said disease.
[0007] In a preferred aspect of the present invention, there is
provided a method of treating allergic or non-allergic rhinitis in
patients afflicted with said rhinitis which comprises administering
once-a-day to the surfaces of the upper airway passages of said
patients an amount of aerosolized particles of mometasone furoate
effective to maximize treating said rhinitis in the upper airway
passages while simultaneously substantially minimizing systemic
absorption thereof.
[0008] In another preferred aspect of the present invention, there
is provided a method of treating allergic and/or inflammatory
diseases of the lower airway passages and/or lungs in patients
afflicted with at least one of said diseases which comprises
administering once-a-day via oral inhalation to the surfaces of the
upper and lower airway passages of said patients an amount of
aerosolized particles of mometasone furoate effective to maximize
topically treating said allergic and/or inflammatory disease in the
lower airway passage and/or lungs while simultaneously
substantially minimizing the systemic absorption thereof.
[0009] The present invention also provides a method of producing a
rapid onset of action in treating asthma in a patient afflicted
with asthma which comprises administering via oral inhalation to
the surfaces of the lower airway passages and lungs of the patient
an amount of aerosolized particles of mometasone furoate effective
to produce a rapid onset of action in treating asthma while
simultaneously substantially minimizing systemic absorption
thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 graphically illustrates the variation with time
(measured in hours) of the plasma concentrations of total
radioactivity (measured in ng-eq/mL) following administration of
tritium-labelled mometasone furoate by various formulations and
routes of administration to male volunteers. The curve plotted with
the darkened circles ( ) represents the variations of plasma
concentrations with time after administration of radio-labelled
drug by oral suspension; the curve plotted with open circles
(.smallcircle.) represents the variation of plasma concentrations
with time after administration of drug by nasal spray; the curve
plotted with the darkened squares (.box-solid.) represents the
variation of plasma concentrations with time after administration
by a metered dose inhaler; the curve plotted with the open squares
(.quadrature.) represent the variation of plasma concentrations
with time after administration of drug by Gentlehaler; the curve
plotted with the darkened triangles (.tangle-solidup.) represents
the variation of plasma concentrations with time after
administration of drug by the intravenous route and the curve
plotted with the open triangles (A) represent the variations of
plasma concentration with time after administration of the
radio-labelled drug via oral solution. See Tables in Results
section hereinafter.
DETAILED DESCRIPTION OF THE INVENTION AND OF THE PREFERRED
EMBODIMENTS
[0011] Although corticosteroids have been effective in treating
airway passage diseases such as asthma, such treating with
corticosteroids may often cause systemic side-effects such as
suppression of hypothalamic-pituitary-adrenocortical ("HPA") axis
function by reducing corticotrophin (ACTH) production, which in
turn leads to a reduced cortisol secretion by the adrenal
gland.
[0012] We have surprisingly discovered that mometasone furoate
exhibits superior anti-inflammatory effects in treating airway
passage diseases such as asthma and allergic rhinitis by acting on
surfaces of the upper and lower airways passages and lungs while
having a substantially minimum systemic effect. The substantial
minimization of the systemic effect of mometasone furoate
administered intranasally or by oral inhalation has been measured
by High Performance Liquid Chromatography (HPLC) metabolite
profiling of plasma radioactivity of mometasone furoate, its
substantially complete (>98%) first-pass metabolism in the liver
and by a minimal reduction in cortisol secretion levels.
[0013] When mometasone furoate is administered orally (i.e.,
swallowed as an oral suspension) or by oral or nasal inhalation,
there is a substantial absence of absorption systemically into the
bloodstream of mometasone furoate i.e., there is essentially no
parent drug (substantially less than 1% of mometasone furoate)
which reaches the bloodstream from the gastro-intestinal tract. Any
mometasone furoate found in the bloodstream after it has been
administered by oral or nasal inhalation has already passed through
the lungs and/or airway passage tissue. Therefore, there is no
"wasted" drug (i.e., drug that reaches the relevant tissue in the
lungs and/or airways only via the bloodstream). Thus, mometasone
furoate is an ideal drug for treating diseases of the airway
passages and lungs such as asthma and allergic rhinitis.
[0014] Administering mometasone furoate to the surfaces of the
airways of asthmatic patients will maximize the therapeutic index.
The term "therapeutic index", as used herein, means the ratio of
local efficacy to systemic safety. The local efficacy in asthma of
corticosteroids such as mometasone furoate is assessed by
measurement of lung function and reduction in frequency and
severity of symptoms. Systemic safety of such cortosteroids is
usually measured by HPA-axis function; other measures of systemic
effect include, for example, growth suppression, bone density, and
skin thickness measurements.
[0015] In addition to the superb safety profile exhibited by
mometasone furoate administered to patients with asthma and
allergic rhinitis in accordance with the present invention,
mometasone furoate also exhibits an unexpected higher level of
efficacy in treating asthma and allergic rhinitis than the superb
safety profile would suggest.
[0016] The term "rapid onset of action in treating asthma in
patients afflicted with asthma" as used herein means that there is
a significant clinically meaningful improvement in the pulmonary
function of asthma patients within 7, 3 and even 1 day(s) of the
initial administration of mometasone furoate in accordance with the
present invention. These unexpected results were obtained in a
placebo-controlled, parallel group Phase I study of safety and
pilot efficacy wherein mometasone furoate was administered by a
metered dose inhaler twice daily to forty-eight patients with mild
asthma (12 patients in each treatment group). The three groups of
patients treated with mometasone furoate exhibited clinically
meaningful increases in pulmonary function as measured by
improvements in the forced expiratory volume in one second
(FEV.sub.1).
[0017] These increases in FEV.sub.1 are unexpectedly superior even
though mometasone furoate exhibits a superb safety profile.
Furthermore, one would not predict the increases based on the known
clinical data for other corticosteroids available for treating
asthma.
[0018] The term "corticosteroid-responsive disease of the airway
passage ways and lungs" as used herein means those allergic,
non-allergic and/or inflammatory diseases of the upper or lower
airway passages or of the lungs which are treatable by
administering corticosteroids such as mometasone furoate. Typical
corticosteroid-responsive diseases include asthma, allergic and
non-allergic rhinitis as well as non-malignant proliferative and
inflammatory diseases of the airways passages and lungs.
[0019] The term "asthma" as used herein includes any asthmatic
condition marked by recurrent attacks of paroxysmal dyspnea (i.e.,
"reversible obstructive airway passage disease") with wheezing due
to spasmodic contraction of the bronchi (so called "bronchospasm").
Asthmatic conditions which may be treated or even prevented in
accordance with this invention include allergic asthma and
bronchial allergy characterized by manifestations in sensitized
persons provoked by a variety of factors including exercise,
especially vigorous exercise ("exercise-induced bronchospasm"),
irritant particles (pollen, dust, cotton, cat dander) as well as
mild to moderate asthma, chronic asthma, severe chronic asthma,
severe and unstable asthma, nocturnal asthma, and psychologic
stresses. The methods of this invention are particularly useful in
preventing the onset of asthma in mammals e.g., humans afflicted
with reversible obstructive disease of the lower airway passages
and lungs as well as exercise-induced bronchospasm.
[0020] The methods of this invention are also useful in treating
allergic and non-allergic rhinitis as well as non-malignant
proliferative and/or inflammatory disease of the airway passages
and lungs.
[0021] The term "allergic rhinitis" as used herein means any
allergic reaction of the nasal mucosa and includes hay fever
(seasonal allergic rhinitis) and perennial rhinitis (non-seasonal
allergic rhinitis) which are characterized by seasonal or perennial
sneezing, rhinorrhea, nasal congestion, pruritis and eye itching,
redness and tearing.
[0022] The term "non-allergic rhinitis" as used herein means
eosinophilic nonallergic rhinitis which is found in patients with
negative skin tests and those who have numerous eosinophils in
their nasal secretions.
[0023] The term "non-malignant proliferative and/or inflammatory
disease" as used herein in reference to the pulmonary system means
one or more of (1) alveolitis, such as extrinsic allergic
alveolitis, and drug toxicity such as caused by, e.g. cytotoxic
and/or alkylating agents; (2) vasculitis such as Wegener's
granulomatosis, allergic granulomatosis, pulmonary hemangiomatosis
and idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia,
eosinophilic granuloma and sarcoidosis.
[0024] The mometasone furoate administered, for example, by oral
inhalation or intranasally to treat disease of the lower and/or
upper airway passages and/or lungs may be used as monotherapy or as
adjuvant therapy with for example cromolyn sodium or nedocromil
sodium (available from Fisons); immunosuppressive agents such as
methotrexate sodium (available from Astra Pharmaceutical Products,
Inc.), oral gold, or cyclosporine A (available from Sandoz under
the SANDIMMUNE.RTM. tradename); bronchodilators such as albuterol
(available from Schering Corporation under the PROVENTIL.RTM.
tradename) or theophylline (available from Key Pharmaceuticals of
Schering Corporation under the Theo-Dur.RTM. tradename).
[0025] The devices found useful for providing measured
substantially non-systematically bioavailable amounts of
aerosolized mometasone furoate or aerosolized pharmaceutical
compositions thereof for delivery to the oral airway passages and
lungs by oral inhalation or intranasally by inhalation include
pressurized metered-dose inhalers ("MDI") which deliver aerosolized
particles suspended in chlorofluorocarbon propellants such as
CFC-11, CFC-12, or the non-chlorofluorocarbons or alternate
propellants such as the fluorocarbons, HFC-134A or HFC-227 with or
without surfactants and suitable bridging agents; dry-powder
inhalers either breath activated or delivered by air or gas
pressure such as the dry-powder inhaler disclosed in the Schering
Corporation International Patent Application No. PCT/US92/05225,
published 7 Jan. 1993 as well as the TURBUHALER.TM. (available from
Astra Pharmaceutical Products, Inc.) or the ROTAHALER.TM.
(available from Allen & Hanburys) which may be used to deliver
the aerosolized mometasone furoate as a finely milled powder in
large aggregates either alone or in combination with some
pharmaceutically acceptable carrier e.g. lactose; and nebulizers.
The inhalation of aerosolized drugs by use of nebulizers and
metered-dose inhalers such as used to deliver VANCENASE.RTM. (brand
of beclomethasone dipropionate) inhalation aerosol (available from
Schering Corporation, Kenilworth, N.J.) is disclosed in Remington's
Pharmaceutical Sciences, Mack Publishing Co. Easton Pa., 15th Ed.
Chapter 99, pages 1910-1912.
[0026] Mometasone furoate may be also administered in specific,
measured amounts in the form of an aqueous suspension by use of a
pump spray bottle such as the bottles used to deliver VANCENASE
AQ.RTM. Nasal Spray as well as the spray bottle disclosed in the
Schering Corporation Industrial Design Deposit DM/026304,
registered by the Hague Union on Jun. 1, 1993 (each are available
from Schering Corporation). The aqueous suspension compositions of
the present invention may be prepared by admixing mometasone
furoate or mometasone furoate monohydrate (preferably mometasone
furoate monohydrate) with water and other pharmaceutically
acceptable excipients. See International Application No.
PCT/US91/06249 especially Examples 1-5 for preparation of
mometasone furoate monohydrate and aqueous suspensions containing
same. The aqueous suspensions of the invention may contain from
about 0.01 to 10.0 mg, preferably 0.1 to 10.0 mg of mometasone
furoate monohydrate per gram of suspension. The aqueous suspension
compositions according to the present invention may contain, inter
alia, water, auxiliaries and/or one or more of the excipients, such
as: suspending agents, e.g., microcrystalline cellulose, sodium
carboxymethylcellulose, hydroxypropyl-methyl cellulose; humectants,
e.g. glycerin and propylene glycol; acids, bases or buffer
substances for adjusting the pH, e.g., citric acid, sodium citrate,
phosphoric acid, sodium phosphate as well as mixtures of citrate
and phosphate buffers; surfactants, e.g. Polysorbate 80; and
antimicrobial preservatives, e.g., benzalkonium chloride,
phenylethyl alcohol and potassium sorbate.
[0027] Based on the judgment of the attending clinician, the amount
of mometasone furoate administered and the treatment regimen used
will, of course, be dependent on the age, sex and medical history
of the patient being treated, the severity of the specific
asthmatic or non-malignant pulmonary disease condition and the
tolerance of patient to the treatment regimen as evidenced by local
toxicity (e.g., nasal irritation and/or bleeding) and by systemic
side-effects (e.g. cortisol level). Cortisol (also referred to as
hydrocortisone) is the major natural glucocorticosteroid elaborated
by the adrenal cortex.
[0028] For the treatment of allergic, non-allergic rhinitis and/or
inflammatory diseases of the upper or lower airway passages to
treat for example asthma or allergic or non-allergic rhinitis, the
substantially non-systematically bioavailable amount of mometasone
furoate which may be administered as an aqueous suspension or dry
powder is in the range of about 10 to 5000 micrograms ("mcg")/day,
10 to 4000 mcg/day, 10 to 2000 mcg/day, 25-1000 mcg/day, 25 to 400
mcg/day, 25-200 mcg/day, 25-100 mcg/day or 25-50 mcg/day in single
or divided doses.
[0029] In treating allergic and non-allergic rhinitis, the aqueous
suspension of mometasone furoate may be administered intranasally
by inserting an appropriate device (such as the pump spray bottle
used to deliver Vancenase AQ.RTM. Nasal Spray as well as the spray
bottle disclosed in the Schering Corporation Industrial Design
Deposit DM/026304 registered Jun. 1, 1993) into each nostril.
Active drug is then expelled (nasal spray device) or could be
nasally inhaled (sniffed) as a powder. Efficacy is generally
assessed in a double blind fashion by a reduction in nasal symptoms
(e.g., sneezing, itching, congestion, and discharge). Other
objective measurements (e.g., nasal peak flow and resistance) can
be used as supportive indices of efficacy.
[0030] For treatment of allergic and/or inflammatory diseases of
the lower airways and lung parenchyma especially diseases such as
asthma, chronic obstructive pulmonary disease ("COPD"),
granulomatous diseases of the lungs and lower airway passage,
non-malignant proliferative disease of the lungs e.g., idiopathic
pulmonary fibrosis, hypersensitivity pneumonitis and
bronchopulmonary dysplasia the following dosage ranges of
mometasone furoate may be used: (1) for metered dose inhalers with
standard CFC or alternate propellant about 10 to 5000 mcg/day or 10
to 4000 mcg/day or 10 to 2000 mcg/day, or 50 to 1000 mcg/day or 25
to 100 mcg/day, or 25 to 400 mcg/day, or 25 to 200 mcg/day, or
25-50 mcg/day; the preferred dosage range is 50 to 1000 micrograms
a day and the preferred dosages are 25, 100, 200 and 250 mcg,
administered in one to four puffs; preferably one to three puffs,
once-a-day; (2) for the dry powder inhaler--about 10 to 5000
mcg/day or 10-4000 mcg/day or 10-2000 mcg/day or 25-1000 mcg/day or
25-400 mcg/day or 25-200 mcg/day or 50-200 mcg/day or 25-50 mcg/day
of anhydrous mometasone furoate; the preferred dosage range of
anhydrous mometasone furoate in the dry powder inhaler is 50 to 600
micrograms a day more preferably 100 to 600 mcg a day and the
preferred dosages are 50, 100, 200 and 250 mcg, administered in one
to three puffs, once-a-day; typically the metered dose inhaler unit
will contain 120 doses; (3) for aqueous suspension for inhalation,
the preferral dosage ranged from 25 to 800 mcg/100 .mu.L and the
dosages are 25, 50, 100, 125, 150, 175, 200, 225, 250, 300, 400,
500 and 800 mcg/100 .mu.L of mometasone furoate in single or
divided doses. The aqueous suspension of mometasone furoate has
been found to be safe and effective in treating allergic rhinitis
e.g. seasonal allergic rhinitis from 25 micrograms up to 1600
micrograms administered once-a-day; the preferred dosage range is
25-800 micrograms a day, although no improvement in treatment is
typically found above 400 micrograms a day. The most preferred
dosages are 25, 50 and 100 micrograms administered twice to each
nostril, once-a-day for a total once-a-day dose of 100, 200 and 400
mcg. Typically 2-4 mL of the aqueous suspension of mometasone
furoate monohydrate may be placed in a plastic nebulizer container
and the patient would inhale for 2-10 minutes. The total dosage
placed in such a container would be in the range of 300-3000
mcg.
[0031] In a preferred aspect of this invention, the anhydrous
mometasone furoate may be admixed with a dry excipient, for example
dry lactose for use in the dry powder inhaler. The mometasone
furoate:dry lactose ratio varies broadly from 119 to 1:0, and
preferably it is 1:19 to 1:4. Typically, the suitable anhydrous
mometasone furoate dosage range is 25 to 600 micrograms
administered once-a-day. The preferred mometasone furoate dosages
for admixture with dry lactose are 25, 100, 200 and 250 micrograms
which are administered in one to three puffs a day. The preferred
combined mometasone furoate:lactose dose is 500 micrograms for each
dose. For example, for the preferred 1:19 ratio, 25 micrograms of
anhydrous mometasone furoate are admixed with 475 micrograms of
anhydrous lactose and for the preferred 1:4 ratio, 100 micrograms
of anhydrous mometasone furoate are admixed with 400 micrograms of
anhydrous lactose, to produce the 500 microgram dose of the
mometasone furoate:lactose admixture.
[0032] The dosing regimen for lower airway diseases such as asthma
will vary from four times a day to twice a day to once-a-day.
Once-a-day (such as at 8 a.m.) maintenance therapy should be
adequate, once control of asthma is achieved. It is anticipated,
however, that the superior therapeutic index of mometasone furoate
will result in effective treatment of patients by once-a-day dosing
even at the initiation of the methods of this invention.
[0033] For other diseases of the lower airway passages and/or
lungs, dosing is likely to be two to four times daily, preferably
two to three times and most preferably once daily, when adequate
control of the disease is achieved.
[0034] For any route of administration, divided or single doses may
be used. For example, when a metered dose inhaler is used to
deliver, for example, 500 mcg of aerosolized mometasone furoate,
once-a-day, two puffs of 250 mcg would normally be used to deliver
the aerosolized drug. When a plastic nebulizer container is used to
deliver for example 200 micrograms a day of an aqueous suspension
of mometasone furoate, two squeezes of 50 micrograms into each
nostril would normally be used to deliver the drug. When the
metered dose inhaler is used to deliver for example 200 mcg of
anhydrous mometasone furoate, two puffs of 500 micrograms of an
admixture of 100 mcg of mometasone furoate and 400 mcg of lactose
once-a-day would normally be used to deliver the aerosolized
drug.
[0035] The effectiveness of the methods of this invention can also
be shown clinically in mammals, e.g. humans being afflicted with or
susceptible to a non-malignant proliferative and/or inflammatory
disease such as idiopathic pulmonary fibrosis or using patients
with inter alia the following entry criteria: 1. an improved
Karnofsky performance status; (2) adequate pulmonary function for
undergoing the required inhalation treatment satisfactorily as
evidenced by (a) an improved forced expiratory volume (FEV) and (b)
an improved forced vital capacity (FVC) and (3) no serious systemic
infections and/or fever.
[0036] Similar results to those achieved in treating asthma are
expected.
Results
[0037] The following is a summary of the clinical results obtained
in treating asthma and asthmatic conditions.
[0038] Prior to enrollment, all patients are thoroughly evaluated
via a medical history, physical examination, chest x-ray, an
electrocardiogram and hematologic and blood chemistry measurements.
Pulmonary function including peak expiatory flow rate (PEF), forced
expiatory volume in one second (FEV.sub.1), and forced vial
capacity (FVC) and cortisol levels may be also measured. Subjective
and objective symptoms including the number and severity of
coughing bouts, shortness of breath, chest tightness and wheezing
are normally assessed.
[0039] Several Phase I studies were conducted using mometasone
furoate formulated for delivery as a suspension in a pressurized
metered dose inhaler (MDI). In a randomized, third-party blinded,
placebo-controlled rising single-dose safety and tolerance study,
aerosolized mometasone furoate was administered by a metered dose
inhaler to eight healthy male volunteers. Doses were administered
at 11 p.m. and plasma cortisol concentrations were measured during
the following 24-hour period. Compared to placebo, mometasone
furoate doses of 1000 mcg, 2000 mcg and 4000 mcg reduced the
24-hour area under the curve plasma cortisol profile (AUC0-24) by
13%, 23% and 36%, respectively. Equivalent doses of beclomethasone
dipropionate (BDP) reduced the AUC0-24 by 30%, 38% and 65%,
respectively.
[0040] In a subsequent placebo-controlled, parallel group Phase I
study of safety and pilot efficacy, mometasone furoate was given by
MDI at dose of 500 mcg twice daily ("BID"), 1 mg BID, and 2 mg BID
for 28 days to 48 patients with mild asthma (12 patients per
treatment group) or placebo also given BID by MDI. Therapy with
mometasone furoate was well tolerated, and all patients completed
the therapy. Patients treated with 1000 mcg of mometasone furoate
daily had values for 8 a.m. plasma cortisol that were similar to
those of patients treated with 2000 mcg of mometasone furoate daily
at all time points; there were small decreases from Baseline on
Days 15 and 21 which were statistically significant compared to
placebo. Patients treated with 4000 mcg of mometasone furoate daily
had greater decreases in plasma cortisol, which were statistically
different from placebo from Day 3 through Day 28. The mean values
of urinary cortisol tended to decrease during the course of the
study for the 2000 mcg and 4000 mcg groups; the mean values of
urinary cortisol for the 1000 mcg group were not different from
placebo. With respect to the responses to ACTH infusions at
post-treatment (Day 30), all of the treatment groups demonstrated
significant increases from Baseline in plasma cortisol both
immediately after the 8 hour infusion and 24 hours after the
beginning of the infusion (i.e., a normal response). The asthma
patients treated with mometasone furoate in this placebo-controlled
Phase I study exhibited unexpected, clinically meaningful increases
in FEV.sub.1 values that were .gtoreq.15% from Baseline at a
majority of time points. The mean increases in FEV.sub.1 values for
the 1 mg/day, 2 mg/day and 4 mg/day treatment groups were
statistically significantly greater than for the placebo group at
every time point from day 3 to day 28. The 1 mg/day treatment group
showed a statistically significant, clinically meaningful
improvement in the FEV.sub.1 value even on day 1 compared to the
FEV.sub.1 value for the placebo group.
[0041] In a recently completed, randomized, double-blinded
multicenter, Phase II study, 395 patients with asthma requiring
treatment with inhaled corticosteroids were randomized to one of
the five treatment groups: mometasone furoate (MDI 112 mcg/day, 400
mcg/day or 1000 mcg/day, beclomethasone dipropionate (BDP) 336
mcg/day, or placebo. All treatment regimens consisted of BID dosing
for 4 weeks. PROVENTIL inhalation aerosol (albuterol, USP) was
supplied as rescue medication.
Evaluation of Efficacy
[0042] Efficacy was evaluated by spirometry and by physician and
patient evaluation of asthma signs and symptoms. The forced
expiratory volume in one second (FEV.sub.1), forced vital capacity
(FVC), and forced expiratory flow between 25% to 75%
(FEF.sub.25%-75%) were measured at each visit by the investigator.
The peak expiratory flow rate (PEFR) was measured twice daily (AM
and PM) by the patient. FEV.sub.1 at endpoint of treatment (last
evaluable visit) was the primary measure of efficacy. The
investigator (at all visits) and the patient (twice daily) rated
wheezing, tightness in chest, shortness of breath, and cough on a
scale from 0 (None) to 6 (Incapacitating). In addition, the
investigator rated the overall condition of asthma on the same
scale at each visit, and the patient kept a diary of the total
number of asthma attacks each day, the number of night awakenings
due to asthma, and the total number of puffs of Proventil
(protocol-permitted rescue medication) used. The actual value and
changes from Baseline were analyzed for each visit.
[0043] All treatments were well tolerated; most frequently reported
adverse events were dysphonia, pharyngitis, cough and headache,
which were generally mild to moderate in severity. All 4 active
treatments were statistically superior to placebo at all visits
with respect to improvement in FEV.sub.1 (p<0.01) compared with
the placebo treatment group which experienced a mean decrease in
this variable. The two higher doses of mometasone furoate were
superior to beclomethasone dipropionate (BDP) at Days 14, 21 and
28. At Day 21 and Day 28, the two higher doses of mometasone
furoate were significantly superior to the low mometasone furoate
dose. Diary a.m. and p.m. PEFR data were similar to FEV.sub.1.
During the final week of treatment, all mometasone furoate doses
were significantly better than 336 mg dose of BDP in improving a.m.
PEFR. Total asthma scores, assessment of overall condition, and
therapeutic response to treatment confirmed superiority of all
mometasone furoate doses relative to placebo, as well as
relationships among the active treatment groups.
[0044] Mometasone furoate (intranasally in the form of an aqueous
suspension of mometasone furoate monohydrate) has been used for
treating patients with seasonal allergic rhinitis. The term
"seasonal allergic rhinitis" as used herein means a
hypersensitivity response to seasonal pollens characterized by
inflammation of the nasal mucous membranes, nasal discharge,
sneezing and congestion.
[0045] Several Phase I studies have been completed using the
aqueous nasal spray suspension formulation of mometasone furoate
monohydrate. In a randomized, third party-blinded,
placebo-controlled rising single-dose safety and tolerance study,
the aqueous nasal spray suspension formulation was administered to
eight healthy male volunteers. Doses were administered at 11 pm,
and plasma cortisol concentrations were measured during the
following 24-hour period. Compared to placebo, mometasone furoate
at doses of 1000 mcg, 2000 mcg, and 4000 mcg did not significantly
affect the 24-hour area under the curve plasma cortisol profile
(AUC0-24).
[0046] In a follow-up multiple dose study, 48 normal male
volunteers were empanelled in a randomized, third party-blinded,
placebo and active-controlled parallel group study. Twelve
volunteers in each of four groups received one of the following
treatments for 28 days: A) Intranasal aqueous nasal spray
suspension formulation of mometasone furoate monohydrate, 400
mcg/day; B) Intranasal aqueous nasal spray suspension formulation
of mometasone furoate monohydrate, 1600 mcg/day; C) Intranasal
placebo; D) Oral prednisone, 10 mg/day. All treatments were
administered as once daily dosing in the morning. The mometasone
furoate aqueous nasal spray formulation was well tolerated, and all
patients completed the study. Neither of the 2 doses of the
mometasone furoate aqueous nasal spray formulation were associated
with any changes in cortisol secretion compared to placebo.
[0047] In addition, a single-dose absorption, excretion and
metabolism study using 200 mcg of .sup.3H-mometasone furoate as the
nasal spray formulation was conducted in 6 normal male volunteers.
When systemic absorption (based on urinary excretion) was compared
to an intravenously administered dose of .sup.3H-mometasone
furoate, it was 8%. The plasma concentrations of parent drug could
not be determined by metabolite profiling because the levels of
plasma radioactivity were below the limit of quantification. These
data are consistent with substantially less than 1% of
bioavailability of mometasone furoate. See Tables 1 to 2 herein
below.
[0048] In a dose ranging safety and efficacy study, the mometasone
furoate aqueous nasal spray formulation at doses of 50 mcg/day, 100
mcg/day, 200 mcg/day, 800 mcg/day or placebo was administered to
480 patients with seasonal allergic rhinitis for 4 weeks. All
treatments were well tolerated; results of statistical analysis
indicated that all doses of mometasone furoate were effective
relative to placebo. These results showed that administration of an
aqueous suspension of mometasone furoate as a nasal spray to
patients with seasonal allergic rhinitis was effacious, well
tolerated with little potential for systemic side effects and are
consistent with the low oral bioavailability of mometasone
furoate.
[0049] The term "rapid onset of action in treating allergic or
seasonal allergic rhinitis" as used herein means that there is a
clinically and statistically significant reduction in the total
nasal symptom score from baseline for seasonal allergic rhinitis
patients treated with mometasone furoate nasal spray with medium
onset to moderate or complete relief at 3 days (35.9 hours)
compared to 72 hours for the patients treated with a placebo nasal
spray. These results were obtained in a randomized, double-blind,
multicenter, placebo-controlled, parallel group study to
characterize the period between initiation of dosing with
mometasone furoate nasal spray and onset of clinical efficacy as
measured by the total nasal symptom score in symptomatic patients
with seasonal allergic rhinitis. The study lasted 14 days in
length. Data from 201 patients were used for analysis.
[0050] A. Clinical Evaluations
[0051] 1. Seasonal Allergy Rhinitis
[0052] a. Signs and symptoms were individually scored by the
patient on the diary card, and by the investigator or designee at
Screening and Baseline (Day 1), Day 4, Day 8, and Day 15 after
treatment.
TABLE-US-00001 Signs and Symptoms of Rhinitis Nasal Non-Nasal Nasal
stuffiness/congestion Itching/buring eyes Rhinorrhea (nasal
discharge/ Tearing/watering eyes runny nose) Redness of eyes Nasal
itching, Itching of ears or palate Sneezing
[0053] All symptoms (nasal and non-nasal) were rated by the
investigator or designee according to the following scale: [0054]
0=None: No signs/symptoms are evident [0055] 1=Mild: Signs/symptoms
are clearly present but minimal awareness; easily tolerated [0056]
2=Moderate: Definite awareness of signs/symptoms which are
bothersome but tolerable [0057] 3=Severe: Signs/symptoms are hard
to tolerate; may cause interference with activities of daily living
and/or sleeping
[0058] 2. Overall Condition of Seasonal Allergic Rhinitis
[0059] The overall condition of rhinitis was evaluated by the
investigator or designee and patient at the same time as symptoms,
and scored according to the following criteria: [0060] 0=None: No
signs/symptoms are evident [0061] 1=Mild: Signs/symptoms are
clearly present but minimal awareness; easily tolerated [0062]
2=Moderate: Definite awareness of signs/symptoms which are
bothersome but tolerable [0063] 3=Severe: Signs/symptoms are hard
to tolerate; may cause interference with activities of daily living
and/or sleeping.
[0064] In order to qualify for randomization, a patient must have
had: [0065] 1. Nasal congestion .gtoreq.2 (moderate) at both
Screening and Basline. [0066] 2. Total score of the four nasal
symptoms .gtoreq.7 at both Screening and Baseline. [0067] 3.
Overall condition .gtoreq.2 (moderate) at both Screening and
Basline.
[0068] At visits after Basline, evaluations included the entire
time period since the last visit, up to and including the time of
the current observations.
[0069] 3. Drug--Each patient was given a metered nasal pump spray
bottle containing either an aqueous suspension of mometasone
furoate or placebo. Dosing instructions on the bottle informed
patient to deliver 2 sprays of drug (mometasone furoate 50
mcg/spray) or placebo into each nostril once-a-day, each
morning.
[0070] 4. Clinical Efficacy
[0071] 1. Parameters
[0072] After the Baseline visit, each patient was instructed to
enter into his/her diary the information about the time of onset of
nasal relief and level of nasal symptom relief as no relief,
slight, moderate, marked, or complete.
[0073] At Baseline and each follow-up visit, the physician
evaluated the following signs and symptoms of allergic rhinitis,
scored as 0=none, 1=mild, 2=moderate, 3=severe. [0074] a. NASAL
SYMPTOMS [0075] nasal discharge [0076] congestion/stuffiness [0077]
sneezing [0078] itching [0079] b. TOTAL NASAL SCORE: sum of the 4
individual nasal scores [0080] c. COMPOSITE TOTAL SCORE: sum of the
8 nasal and non-nasal scores
[0081] The overall condition of rhinitis was also evaluated by both
the physician and patient using the same scoring system.
[0082] At each follow-up visit post Baseline, the physician and
patient evaluated the therapeutic response as 5=no relief, 4=slight
relief, 3=moderate relief, 2=marked relief, 1=complete relief.
[0083] After the Basline visit, each morning and evening the
patient completed a diary to assess the 8 signs and symptoms of
allergic rhinitis as described above.
[0084] Results
[0085] The primary efficacy results are based on a survival
analysis of the onset times of relief (defined as the first time
patient experienced at least moderate relief of nasal symptoms) for
the mometasone furoate nasal spray and placebo groups. In this
analysis, patients reporting slight or no relief for the first 3
days after treatment were censored at Day 3. Also, results from the
patient regular diary (by 15-day average) data were evaluated.
[0086] Data from 201 patients were used in the survival analysis.
There were 101 patients in the mometasone furoate nasal spray group
and 100 patients in the placebo group. From the individual patient
onset diary data, it was found that there were a total of 24
patients who recorded slight or no relief (i.e. censored) at Day 3
in the mometasone furoate nasal spray group as compared to 50
patients in the placebo group similarly recording slight or no
relief (i.e. censored).
[0087] Survival analysis results suggest that mometasone furoate
nasal spray group had a median onset time to relief of 35.9 hours
as compared to placebo group's 72 hours (due to more censored
observations in this group). From a plot of the survival
distribution for the two groups, it was seen that proportion
reporting slight or no relief with increasing duration (in total
hours) in the placebo group was higher compared to the mometasone
furoate nasal spray group. Using a log-rank data showed a
statistically significant difference between the two treatment
groups (p-value <0.001).
[0088] Analysis of morning & evening averaged diary data showed
that (for the 15-days average) reduction in the total nasal symptom
score from baseline for mometasone furoate nasal spray group was
statistically significantly higher than that for the placebo
group.
[0089] In a first Phase I trial of the mometasone furoate dry
powder inhaler (DPI), mometasone furoate-DPI was once-a-day given
to eight normal volunteers in single doses of 400, 800, 1600, 3200
mcg and placebo. Parallel groups of volunteers received either
budesonide dry powder (400, 800, 1600, 3200 mcg and placebo) or
prednisone (5 mg, 10 mg, 20 mg, 40 mg, or placebo). All doses were
administered at 11 p.m., and plasma cortisol levels over the next
24 hours were monitored.
[0090] Drug Metabolism/Clinical Pharmacology Study
[0091] A drug metabolism and clinical pharmacology study was
conducted by administering (by various routes) tritium-labeled
mometasone furoate (".sup.3H-MF") to 6 groups of 6 normal male
volunteers in each group. Blood and urine samples were collected
for measurement of total drug (including metabolites).
[0092] The objectives of these studies in male volunteers were to
determine the absorption, metabolism and excretion of
.sup.3H-labeled mometasone furoate (".sup.3H-MF") following
administration by oral swallow as a solution and as an aqueous
suspension of the monohydrate, by oral inhalation as a suspension
from a standard metered dose inhaler (MDI) and from a metered dose
inhaler containing a spacer device (Gentlehaler), by nasal
inhalation as an aqueous suspension of the mometasone furoate
monohydrate from a nasal spray unit and by intravenous injection as
a solution.
[0093] Population
[0094] Thirty-six (n=6 per treatment group) normal healthy male
volunteers between the ages of 19 and 40 yr. (average 29 yr.)
having weights in accordance with current actuarial tables (+10%)
were enrolled in these single dose studies. All subjects were
determined to be in good health by their medical history, physical
examinations, clinical and laboratory tests.
[0095] Study Design
[0096] Six volunteers in each of the six treatment groups received
one of the following .sup.3H-MF dosage forms listed in Table 1:
TABLE-US-00002 TABLE 1 Dose* Dosage Form mg/Subject .mu.Ci/Subject
Mode of Administration Oral Solution 1.03 209 33.3 ml (0.031 mg/ml)
by oral swallow MDI (metered- 0.86 163 4 puffs from a MDI dose
inhaler) canister (215 .mu.g/actuation) Nasal Spray 0.19 197 4
sprays from a nasal spray bottle (47 .mu.g/spray) Gentlehaler 0.40
79 4 bursts from a MDI canister containing a spacer (referred to as
Gentlehaler) (101 .mu.g/burst) Intravenous 1.03 204 1.03 mg/ml
administered Solution at a rate of 1 ml/min. Oral Suspension 0.99
195 1.6 ml (0.62 mg/ml by (hydrated) oral swallow *Doses based on
analysis of dosage forms prior to start of study
[0097] Plasma, urine, expired air filters, Respirgard and fecal
samples were collected and assayed for radioactivity content. The
limit of quantitation (LOQ) for plasma radioactivity ranged from
0.103 to 0.138 ng eq/ml., except for the nasal spray treatment
where the LOQ was 0.025 ng eq/ml. Selected plasma, urine and fecal
samples were analyzed for metabolite profiles.
Results
[0098] Clinical Summary--Mometasone furoate was found to be safe
and well tolerated by all volunteers after administration of all
dosage forms.
[0099] Pharmacokinetics--The mean (n=6) plasma concentrations of
total radioactivity are illustrated in Summary FIG. 1 and the mean
(n=6) pharmacokinetic parameters derived from total plasma
radioactivity are presented in Table 2.
[0100] Comparison of plasma radioactivity illustrated in FIG. 1
and/or urinary excretion data and presented in Table 2 after the
various formulations with those after intravenous treatment
demonstrated that drug-derived radioactivity was completely
absorbed when .sup.3H-MF was administered orally as a solution. In
contrast, systemic absorption of drug-derived radioactivity
following administration of .sup.3H-MF as an oral suspension or as
a nasal spray suspension was approximately 8% of the dose. Systemic
absorption of drug-derived radioactivity following administration
of .sup.3H-MF via the MDI (30%) and Gentlehaler.TM. (67%) was
higher than that following nasal spray or oral suspension. Although
the peak plasma concentration of radioactivity was less than 1 ng
eq/ml for both MDI and Gentlehaler, comparative dose normalized AUC
radioactivity data and urinary excretion data suggested that
absorption of drug-derived radioactivity from the MDI and
Gentlehaler was approximately 23-30% and 67-69%, respectively. The
drug derived radioactivity data suggested that systemic
bioavailability was greater following administration with the
Gentlehaler.TM. compared to MDI administration. This may have been
the result of enhanced lung deposition of drug due to the use of a
spacer device in the Gentlehaler.TM.. The Gentlehaler.TM. device is
a MDI actuator described in U.S. Pat. No. 4,972,830.
[0101] Radioactivity was predominantly excreted in the feces
regardless of dosage form and route of administration. Excretion of
radioactivity in the urine was approximately 25% for the
intravenous and oral solution formulations, 7% for the MDI and 16%
for the Gentlehaler and 2% or less for both the nasal spray and
oral suspension formulations, respectively. These data thus
demonstrate that the drug was well absorbed when orally
administered as a solution formulation but poorly absorbed
following oral or intranasal administration as a suspension
formulation.
TABLE-US-00003 TABLE 2 PHARMACOKINETIC PARAMETERS OF TOTAL
RADIOACTIVITY FOLLOWING ADMINISTRATION OF .sup.3H-MF IN MALE
VOLUNTEERS Dosage Form Oral Nasal Oral Parameter Intravenous
Solution MDI Gentlehaler Spray Suspension Cmax 23.7 4.8 0.80
(0.93*) 0.69 (1.71*) BQL** BQL AUC(1) 401 488 81 (94*) 110 (275*)
BQL BQL Urine 24 25 7 16 2 2 (% dose) Feces 54 62 86 89 78 73 (%
dose) U + F 78 87 94 105 80 75 (% dose) % Absorbed AUC -- 122 23*
69* -- -- Urine -- 104 30 67 8 8 *Based on dose normalized data
**BQL = Below Quantifiable Limit Parameter Units Definition Cmax ng
eq/ml Maximum plasma concentration, except for the intravenous
treatment, which is C.sub.5 min. AUC(1) ng eq hr/ml Area under the
plasma concentration- time curve to infinity. Urine % Percent of
administered radioactivity excreted in the (% dose) urine through
168 hr. Feces % Percent of administered radioactivity excreted in
(% dose) feces through 168 hr. U + F % Total percent dose recovered
in the urine and (% dose) feces through 168 hr. % Absorbed %
Percent of administered radioactivity absorbed (AUC) based on dose
normalized treatment data versus intravenous data. % Absorbed %
Percent of administered radioactivity absorbed (Urine) (based on
urinary excretion data) compared to the intravenous dose.
[0102] Selected plasma, urine and fecal extracts were analyzed by
high performance liquid chromatography (HPLC) with radio-flow
monitoring to determine metabolite profiles. The results of these
analyses demonstrated that, following administration of the oral
solution, most of the plasma radioactivity was associated with
metabolites more polar than the available standards. Approximately
1.5% of the 3 hr. plasma radioactivity was associated with parent
drug indicating extensive first past metabolism and rapid
inactivation by the liver. In contrast, following intravenous
administration, approximately 39% of the 3 hr. plasma radioactivity
was associated with parent drug. Approximately 12% and 33% of the 3
hr. plasma radioactivity was associated with parent drug following
administration of the MDI and Gentlehaler, respectively. In
general, the plasma concentrations of radioactivity following the
nasal and oral suspension routes of administration were too low for
metabolite profiling.
[0103] HPLC/radio-flow analysis of both urinary and fecal extracts
following both intravenous and oral solution administration
demonstrated that all of the radioactivity was associated with
metabolites more polar than parent drug. Analysis of urine
specimens obtained from subjects who received .sup.3H-MF by the
Gentlehaler also demonstrated that all of the radioactivity was
associated with metabolites more polar than parent drug. However,
analyses of fecal extracts following administration of the nasal
spray, oral suspension and inhalation (MDI and Gentlehaler)
formulations, demonstrated the presence primarily of mometasone
furoate, presumably due to unabsorbed drug which was swallowed.
Hydrolysis of plasma and urine was performed with an enzyme
preparation containing both .beta.-glucuronidase and aryl sulfates.
These experiments yielded modest changes in the HPLC metabolite
profiles that were consistent with the hydrolytic release of
conjugated metabolites.
[0104] The percent of dose as tritiated water in the body was
estimated from urinary distillation experiments to be approximately
3.7% after intravenous and 2.9% after oral solution dosing.
[0105] These findings suggested that less than 4% of the tritium
label had exchanged with body water following administration of
.sup.3H-MF to male volunteers.
[0106] The results of these drug metabolism/clinical pharmacology
studies demonstrate that:
[0107] 1. Drug-derived radioactivity was completely absorbed when
.sup.3H-MF was given orally as a solution to male volunteers.
However, the absolute bioavailability of unchanged mometasone
furoate was extremely low (less than approximately 1%) due to
extensive first pass metabolism.
[0108] 2. Drug-derived radioactivity was moderately absorbed
following oral inhalation of .sup.3H-MF by the metered dose inhaler
(23-30%) and Gentlehaler.TM. (67-69%).
[0109] 3. The absorption of drug-derived radioactivity following
administration of .sup.3H-MF nasal spray and oral suspension
formulations was approximately 8%.
[0110] 4. The plasma concentrations of unchanged mometasone furoate
could not be determined after administration by oral inhalation as
a suspension from a MDI or a Gentlehaler, or by nasal inhalation of
an aqueous suspension of mometasone furoate monohydrate from a
nasal spray unit or by oral swallow of an aqueous suspension of the
monohydrate because the plasma concentrations of total
radioactivity were too low for metabolite profiling.
[0111] 5. Mometasone furoate was extensively metabolized following
all routes of administration.
[0112] As shown in Table 2, .sup.3H-MF-derived radioactivity
suggests that systemic absorption was greater from an orally
swallowed solution (about 100%) than from an orally swallowed
suspension or an intranasally inhaled suspension (8%). Mometasone
furoate was detectable in plasma by metabolite profiling after
administration of the drug by intravenous injection or oral
administration as solution dosage forms, but not after
administration of the oral or nasal suspensions. Similarly, the
excretion of radioactivity in urine after dosing with the solution
formulation was greater (25%) than after dosing with the nasal
spray or oral suspension (2%). The total recovery or radioactivity
in urine and feces was 87% and 75% respectively, with most of the
radioactivity being excreted in the feces. After intravenous
dosing, the total radioactivity excreted was 78% with 24% being
excreted in the urine and 54% being excreted in the feces.
* * * * *