Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PATENT
ATTORNEY DOCKET NO.: 50164/076W02
THERAPEUTIC REGIMENS FOR ADMINISTERING DRUG
COMBINATIONS
Background of the Invention
The invention relates to dosing regimens for the administration of
combination therapies.
Combination therapy refers to the administration of two or more drugs for
the treatment of a disease or disorder, or two or more comorbid conditions.
While
in some cases each component of the combination is acting independently of the
other(s), in other cases the two drugs may be acting in a combinatorial
manner,
e.g., a synergistically, to produce a result that would not be achieved by the
administration of the two drugs in a non-overlapping manner.
Notwithstanding the foregoing, it may be that combination therapy falling
in the latter category may include drugs having different pharmacokinetic
properties (e.g., different T",~X times). In these cases, the full benefit of
the
combination therapy is not being realized.
Thus, there is a desire to develop better methods for combination therapy.
Summary of the Invention
In a first aspect, the invention features a method of enhancing the efficacy
of a drug combination. The method includes the steps of i) administering a
first
drug in an amount sufficient to produce an effective plasma concentration of
the
first drug for a period of time Tl, and ii) administering a second drug in a
manner
sufficient to produce an effective plasma concentration of the second drug for
at
least 70% of time T1. Desirably, the second drug is administered in a manner
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sufficient to produce an effective plasma concentration of the second drug for
at
least 75%, 80%, 85%, or even 90% of time Tl. Optionally, some or all of the
second drug is formulated for sustained release, andlor the second drug is
administered more than once during time Tl.
The invention also features a method of administering a drug combination.
This method includes the steps of administering simultaneously, or within 30
minutes of one another, a first drug not formulated for sustained release and
a
second drug formulated for sustained release, wherein a) the first drug
produces a
peak plasma concentration at Tr,,aXu b) the second drug produces a peak plasma
concentration at TmaX2, and c) T~X2 is equal to or greater than T",aXl,
provided that
if the second drug were not formulated for sustained release T",~Xl > TmaXa.
The invention further features a pharmaceutical composition including a
unit dosage form including a first drug selected from tricyclic compounds,
SSRIs,
SNRIs, NsIDIs, antihistamines, and tetra-substituted pyrimidopyrimidines; and
a
second drug formulated for sustained release.
The invention features a kit including: (a) a first drug not.formulated for
sustained release, (b) a said second drug formulated for sustained release,
and (c)
instructions for administering simultaneously, or within 30 minutes of one
another,
said first drug and said second drug.
In the above methods, compositions, and kits, the first drug or second drug
is desirably a tricyclic compound, SSRI, SNRI, NsIDI, antihistamine,
corticosteroid, or a tetra-substituted pyrimidopyrimidine.
In any of the above methods, compositions, and kits, the first drug and the
second drug are optionally formulated together in a unit dosage form. Unit
dosage
forms include, for example, a bilayer tablet having a first layer including
the first
drug not formulated for sustained release and a second layer including the
second
drug formulated for sustained release. The unit dosage form may also be a
tablet
having an inner core including the second drug formulated for sustained
release
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and an outer coat including the first drug not formulated for sustained
release.
Furthermore, the unit dosage form may be a capsule having beads including the
second drug formulated for sustained release and beads including the first
drug not
formulated for sustained' release
Any of the unit dosage forms described herein may further include the
second drug not formulated for sustained release.
In any of the above methods, compositions, and kits, the first drug may be a
tricyclic compound and the second drug may be a corticosteroid, such as the
combination of amoxapine and prednisolone or the combination of nortriptyline
and budesonide; the first drug may be an SSRI and the second drug may be a
corticosteroid, such as the combination of paroxetine and prednisolone; the
first
drug may be dipyridamole and the second drug may be a corticosteroid, such as
prednisolone; the fist drug may be an NsIDI and the second drug may be an
antihistamine, such as the combination of cyclosporin A and loratadine; or the
first
drug may be dipyridamole and the second drug may be an antihistamine, such as
loratadine.
The compositions can be formulated for any route of administration. For
example, the combination of nortriptyline and budesonide can be formulated for
inhalation. Desirably, the combination is formulated for oral administration.
Compounds useful in the invention include those described herein in any of
their pharmaceutically acceptable forms, including isomers such as
diastereomers
and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as
racemic
mixtures and pure isomers of the compounds described herein.
The invention features a method of promoting investment in a company
conducting or planning in vivo studies on a composition or kit described
herein, or
a company selling or planning to sell a composition or kit described herein.
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The method includes the step of disseminating information about the identity,
therapeutic use, toxicity, efficacy, or projected date of governmental
approval of
the composition or kit.
The invention also features a method of promoting investment in a
company conducting or planning in vivo studies on a therapeutic method
described herein. The method of promoting investment includes the step of
disseminating information about the dosing regimen, toxicity, efficacy, or
projected date of governmental approval of the therapeutic method.
As used herein "identity" refers to an identifier intended to convey the
identity of a composition, kit, or regimen described herein. The identifier
can
include, for example, a structure, diagram, figure, chemical name, common
name,
tradename, formula, reference label, or any other identifier that conveys the
identity of the composition, kit, or regimen to a person.
By "in vivo studies" is meant any study in which a composition, kit, or
regimen of the invention is administered to a mammal, including, without
limitation, non-clinical studies, e.g., to collect data concerning toxicity
and
efficacy, and clinical studies.
By "projected date of governmental approval" is meant any estimate of the
date on which a company will receive approval from a governmental agency to
sell, e.g., to patients, doctors, or hospitals, a composition, kit, or regimen
of the
invention. A governmental approval includes, for example, the approval of a
drug
application by the Food and Drug Administration, among others.
By "SSRI" is meant any member of the class of compounds that (i) inhibit
the uptake of serotonin by neurons of the central nervous system, (ii) have an
inhibition constant (I~i) of 10 nM or less, and (iii) a selectivity for
serotonin over
norepinephrine (i.e., the ratio of Ki(norepinephrine) over Ki(serotonin)) of
greater
than 100.
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Typically, SSRIs are administered in dosages of greater than 10 mg per day
when
used as antidepressants. Exemplary SSRIs for use in the invention are
described
herein.
By "corticosteroid" is meant any naturally occurring or synthetic compound
characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system
and having inununosuppressive and/or antinflammatory activity. Naturally
occurring corticosteriods are generally produced by the adrenal cortex.
Synthetic
corticosteriods may be halogenated. Examples corticosteroids are provided
herein.
By "non-steroidal immunophilin-dependent immunosuppressant" or
"NsIDI" is meant any non-steroidal agent that decreases proinflammatory
cytokine
production or secretion, binds an immunophilin, or causes a down regulation of
the proinflammatory reaction. NsIDIs include calcineurin inhibitors, such as
cyclosporine, tacrolimus, ascomycin, pimecrolimus, as well as other drugs
(peptides, peptide fragments, chemically modified peptides, or peptide
mimetics)
that inhibit the phosphatase activity of calcineurin. NsIDIs also include
rapamycin
(sirolimus) and everolimus, which bind to an FK506-binding protein, FKBP-12,
and block antigen-induced proliferation of white blood cells and cytokine
secretion.
By "treating" is meant administering or prescribing a pharmaceutical
composition for the treatment or prevention of a disease or disorder.
By "patient" is meant any mammal (e.g., a human).
By "effective plasma concentration" is meant that the concentration of a
drug in the plasma of a patient, in a combination of the invention, is in the
range
required to treat or prevent a disease or disorder in a clinically relevant
manner. A
sufficient amount of an active compound used to practice the present invention
for
therapeutic treatment of conditions caused by or contributing to, for example,
an
immunoinflammatory disease varies depending upon the manner of
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administration, the age, body weight, and general health of the patient.
Ultimately, the prescribers will decide the appropriate amount and dosage
regimen. Additionally, an effective amount may can be that amount of compound
in the combination of the invention that is safe and efficacious in the
treatment of
a patient having a disease or disorder over each drug alone as determined and
approved by a regulatory authority (such as the U.S. Food and Drug
Administration).
By "enhances" or "enhancing" is meant that a treatment exhibits greater
efficacy, or is less toxic, or safer in comparison to a treatment employing
the same
active ingredients, but not using the compositions or methods of the
invention.
Efficacy may be measured by a skilled practitioner using any standard method
that
is appropriate for a given indication.
The term "immunoinflammatory disorder" encompasses a variety of
conditions, including autoimmune diseases, proliferative skin diseases, and
inflammatory dermatoses. Immunoinflammatory disorders result in the
destruction of healthy tissue by an inflammatory process, dysregulation of the
immune system, and unwanted proliferation of cells. Examples of
immunoinflammatory disorders are acne vulgaris; acute respiratory distress
syndrome; Addison's disease; allergic rhinitis; allergic intraocular
inflammatory
diseases, ANCA-associated small-vessel vasculitis; ankylosing spondylitis;
arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic
anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous
pemphigoid; cerebral ischaemia; cirrhosis; chronic obstructive pulmonary
disease;
Cogan's syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's
syndrome; dermatomyositis; diabetes mellitus; discoid lupus erythematosus;
eosinophilic fasciitis; erythema nodosum; exfoliative dermatitis;
fibromyalgia;
focal glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; graft-
versus-host
disease; hand eczema; Henoch-Schonlein purpura; herpes gestationis; hirsutism;
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idiopathic cerato-scleritis; idiopathic pulmonary fibrosis; idiopathic
thrombocytopenic purpura; inflammatory bowel or gastrointestinal disorders,
inflammatory dermatoses; lichen planus; lupus nephritis; lymphomatous
tracheobronchitis; macular edema; multiple sclerosis; myasthenia gravis;
myositis;
osteoarthritis; pancreatitis; pemphigoid gestationis; pemphigus vulgaris;
polyarteritis nodosa; polymyalgia rheumatics; pruritus scroti; pruritis
/inflammation, psoriasis; psoriatic arthritis; rheumatoid arthritis; relapsing
polychondritis; rosacea caused by sarcoidosis; rosacea caused by scleroderma;
rosacea caused by Sweet's syndrome; rosacea caused by systemic lupus
erythematosus; rosacea caused by urticaria; rosacea caused by zoster-
associated
pain; sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock
syndrome; shoulder tendinitis or bursitis; Sj ogren's syndrome; Still's
disease;
stroke-induced brain cell death; Sweet's disease; systemic lupus
erythematosus;
systemic sclerosis; Takayasu's arteritis; temporal arteritis; toxic epidermal
necrolysis; tuberculosis; type-1 diabetes; ulcerative colitis; uveitis;
vasculitis; and
Wegener's granulomatosis.
"Non-dermal inflammatory disorders" include, for example rheumatoid
arthritis, inflammatory bowel disease, asthma, and chronic obstructive
pulmonary
disease.
"Dermal inflammatory disorders" or "inflammatory dermatoses" include,
for example, psoriasis, acute febrile neutrophilic dermatosis, eczema (e.g.,
asteatotic eczema, dyshidrotic eczema, vesicular palmoplantar eczema),
balanitis
circumscripta plasmacellularis, balanoposthitis, Behcet's disease, erythema
annulare centrifugum, erythema dyschromicum perstans, erythema multiforme,
granuloma annulare, lichen nitidus, lichen planus, lichen sclerosus et
atrophicus,
lichen simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma
gangrenosum, sarcoidosis, subcorneal pustular dermatosis, urticaria, and
transient
acantholytic dermatosis.
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By "proliferative skin disease" is meant a benign or malignant disease that
is characterized by accelerated cell division in the epidermis or dermis.
Examples
of proliferative skin diseases are psoriasis, atopic dermatitis, non-specific
dermatitis, primary irritant contact dermatitis, allergic contact dermatitis,
basal and
squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic
hyperkeratosis, premalignant keratosis, acne, and seborrheic dermatitis.
As will be appreciated by one skilled in the art, a particular disease,
disorder, or condition may be characterized as being both a proliferative skin
disease and an inflammatory dermatosis. An example of such a disease is
psoriasis.
By "sustained release" is meant a drug formulated for release at a
controlled rate such that upon administration to a human, an effective plasma
concentration of the drug is maintained for a period of time that is greater
than
150%, 200%, 300%, 400%, or even 500% of the of time in which an effective
plasma concentration is maintained upon administration of the same drug not
formulated for sustained release, but otherwise administered under the same
conditions.
By "not formulated for sustained release" is meant any formulation in
which the removal of any one of the excipients present in the formulation
fails to
alter by more than 50% the length of time that an effective plasma
concentration
of the drug is maintained upon administration to a human.
By "Cm$X" is meant the maximum observed plasma concentration for an
administered drug.
By "TmaX" is meant the time at which CmaX occurs following administration
of a drug at time = 0.
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As used herein, "a period of time Tl" refers to the length of time over
which a drug has an effective plasma concentration. Depending upon the amount
administered, the bioavailability, and the elimination half life, for the
particular
drug, time Tl may be as little as 30 minutes or as long as 7 days. Typically,
time
T1 will be between 30 minutes and 24 hours.
As used herein, "administered in a manner sufficient" refers to changes in
either the amounts administered, dosing regimen, or formulation of a drug in
order
to more closely match the pharmacokinetic profile of another drug with which
it is
given.
The compositions and methods of the invention are useful for enhancing
the efficacy of drug combinations in which the drugs of the combination have
poorly overlapping pharmacokinetic profiles. The methods and compositions of
the invention are designed to increase the length of time that each of the
drugs
administered for combination therapy is simultaneously present in the plasma
of
the subject in an amount that renders the two drugs together more
therapeutically
effective.
Other features and advantages of the invention will be apparent from the
following detailed description, and from the claims.
Brief Description of the Drawings
FIGURE 1 is a plot depicting the pharmacokinetic behavior of prednisolone
and amoxapine administered orally to humans. The data show a poor match of
pharmacokinetic curves for the two drugs.
FIGURE 2 is a plot depicting the pharmacokinetic behavior of prednisolone
and paroxetine administered orally to humans. The data show a poor match of
pharmacokinetic curves for the two drugs.
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Detailed Description
The invention provides methods, compositions, and kits for enhancing the
efficacy of drug combinations. Administration of a drug combination in which
one of the drugs is formulated for sustained release or administered
repeatedly is
useful where the pharmacokinetic profile of each drug must be modified to
improve the efficacy of the combination. In the formulations of the invention,
a
pharmacokinetic profile is modified, for example, to increase the length of
time
that each of the drugs is simultaneously present in the plasma of the subject
in an
amount that renders the two drugs together more therapeutically effective than
either drug administered alone. A sustained release formulation may be used to
avoid frequent dosing that may be required in order to sustain the plasma
levels of
both drugs at a therapeutic level.
For example, a bilayer tablet can be formulated for an SSRI/steroid
combination in which different custom granulations are made for each drug of
the
combination and the two drugs are compressed on a bi-layer press to form a
single
tablet. For example, 12.5 mg; 25 mg, 37.5 mg, or 50 mg of paroxetine,
formulated
for a sustained release that results in a paroxetine tii2 of 15 to 20 hours
may be
combined in the same tablet with 3 mg of prednisolone, which is formulated
such
that the tli2 approximates that of paroxetine. Examples of paroxetine extended-
release formulations, including those used in bilayer tablets, can be found in
U.S.
Patent No. 6,548,084. In addition to controlling the rate of predsnisolone
release
ifz vivo, an enteric or delayed release coat may be included that delays the
start of
drug release such that the TmaX of predsnisolone approximates that of
paroxetine
(i.e. 5 to 10 hours).
The invention is described in greater detail below.
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Combination Therapy
SSRI or SNRI in Combination mith a Corticostenoid
A selective serotonin reuptake inhibitor (SSRI) or selective serotonin
norepinephrine reuptake inhibitor (SNRI) can be administered in combination
with
a corticosteroid for the treatment of immunoinflammatory disorders as
described
in U.S.S.N. 10/670,488, entitled "Methods and Reagents for the Treatment of
Diseases and Disorders Associated with Increased Levels of Proinflammatory
Cytokines," filed September 24, 2003. This application is incorporated herein
by
reference in its entirety.
NsII~I in Combination with an Antihistamine
A non-steroidal immunophilin-dependent immunosuppressant (NsIDI) can
be administered in combination with an antihistamine for the treatment of
immunoinflammatory disorders as described in U.S.S.N. 10/777,518, entitled
"Combination Therapy for the Treatment of Immunoinflammatory Disorders,"
filed February 12, 2004. This application is incorporated herein by reference
in its
entirety.
Ti°icyclic Compound in Cornbination with a Contieosteroid
A tricyclic compound can be administered in combination with a
corticosteroid for the treatment of immunoinflammatory disorders as described
in
Provisional Patent Application No. 60/520,446, entitled "Methods and Reagents
for the Treatment of Diseases and Disorders Associated with Increased Levels
of
Proinflammatory Cytokines," filed November 13, 2003. This application is
incorporated herein by reference in its entirety.
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Dipyridarnole in Combination with a Corticoster~oid
Dipyridamole and other tetra-substituted pyrimidopyrimidines can be
administered in combination with a corticosteroid for the treatment of
immunoinflammatory disorders as described in U.S.S.N. 10/264,991, entitled
"Combinations for the Treatment of Immunoinflammatory Disorders," filed
October 4, 2002. This application is incorporated herein by reference in its
entirety.
Dipyridamole in Combination with an Antihistamine
Dipyridamole and tetra-substituted pyrimidopyrimidines can be
administered in combination with an antihistamine for the treatment of
immunoinflammatory disorders as described in d described in Provisional Patent
Application No. 60/512,415, entitled "Methods and Reagents for the Treatment
of
Diseases and Disorders Associated with Increased Levels of Proinflammatory
Cytokines," filed October 15, 2003. This application is incorporated herein by
reference in its entirety.
The TmaX and elimination half life data for a variety of drugs useful in the
methods, compositions, and kits of the invention are provided in Table 1,
below.
With the exception of paroxetine/prednisolone and amoxapine/prednisolone,
these
data reflect the pharmacokinetic parameters for each drug administered as a
monotherapy.
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Table 1
Mean Mean elimination
Dru Combinations Dose half life
Route T ours
ours
Loratadine Claritin~oral10 1.3 8.4
. m
Cyclos orine A (Sandimmune~)oral25 3.5 19
m
Noririp line (Pamelor~)oral25 8 16
m
Budesonide ulmicort inhaled200 0.5 ca. 2
Turbuhaler~
Di ridamole PersantineC~7)oral25 0.75 10
m
Loratadine (Claritin~)oral10 1.3 ~ 8.4
m
Paroxetine (Paxil~)'oral20 7 20.2
m
Prednisolonei oral3 1.9 2.7
m
Di idamole Persantine~oral25 0.75 10
m
Prednisolone oral3 1.9 2.7
m
Amoxa ine (Asendin~)2oral100 2.4 9.7
m
Prednisolone2 oral3 1.9 4.5
m
Di ridamole (Persantine~)oral25 0.75 10
m
Prednisolone oral3 1.9 2.7
m
1. Data from PK study shown in Fig. 1.
2. Data from PK study shown in Fig. 2.
SSRIs and SNRIs
The methods, compositions, and kits of the invention may employ an SSRI,
or a structural or functional analog thereof. Suitable SSRIs include
cericlamine
(e.g., cericlamine hydrochloride); citalopram (e.g., citalopram hydrobromide);
clovoxamine; cyanodothiepin; dapoxetine; escitalopram (escitalopram oxalate);
femoxetine (e.g., femoxetine hydrochloride); fluoxetine (e.g., fluoxetine
hydrochloride); fluvoxamine (e.g., fluvoxamine maleate); ifoxetine; indalpine
(e.g., indalpine hydrochloride); indeloxazine (e.g., indeloxazine
hydrochloride);
litoxetine; milnacipran (e.g., minlacipran hydrochloride); paroxetine (e.g.,
paroxetine hydrochloride hemihydrate; paroxetine maleate; paroxetine
mesylate);
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seriraline (e.g., sertraline hydrochloride); tametraline hydrochloride;
viqualine;
and zimeldine (e.g., zimeldine hydrochloride).
Functional analogs of SSRIs can also be used in the methods, compositions,
and kits of the invention. Exemplary SSRI functional analogs are provided
below.
One class of SSRI analogs are SNRIs (selective serotonin norepinephrine
reuptake
inhibitors), which include venlafaxine, duloxetine, and 4-(2-fluorophenyl)-6-
methyl-2-piperazinothieno [2,3-d] pyrimidine.
Standard recommended dosages for exemplary SSRIs are provided in Table
2, below. Other standard dosages are provided, e.g., in the Merck Manual of
Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians'
Desk Reference 2003 (57th Ed. Medical Economics Staff et al., Medical
Economics Co., 2002).
Table 2
Com ound ~ Standard Dose
Fluoxetine 20 - 80 mg / da
Sertraline 50 - 200 mg / da
Paroxetine 20 - 50 m / day
Fluvoxamine 50-300 mg / day
Citalo ram 10 - 80 m id
Escitalopram 10 mg qid
Generally, when administered orally to a human, the dosage of the SSRI is
normally about 0.001 mg to 200 mg per day, desirably about 1 mg to 100 mg per
day, and more desirably about 5 mg to 50 mg per day. Dosages up to 200 mg per
day may be necessary. For administration of the SSRI by injection, the dosage
is
normally about 1 mg to 250 mg per day, desirably about 5 mg to 200 mg per day,
and more desirably about 10 mg to 150 mg per day. Injections are desirably
given
one to four times daily.
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When systemically administered to a human, the dosage of the corticosteroid
for
use in combination with the SS1ZI is normally about 0.1 mg to 1500 mg per day,
desirably about 0.5 mg to 10 mg per day, and more desirably about 0.5 mg to 5
mg
per day.
Corticosteroids
The methods, compositions, and kits of the invention may employ a
corticosteroid. Suitable corticosteroids include 11-alpha,l7-alpha,21-
trihydroxypregn-4-ene-3,20-dione; 11-beta,l6-alpha,17,21-tetrahydroxypregn-4-
ene-3,20-dione; 11-beta,l6-alpha,17,21-tetrahydroxypregn-1,4-dime-3,20-dione;
11-beta,17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-
dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1,4-androstadiene-3,17-
dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-
dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-
methylpregna-1,4,9(11)-triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-3,20-
dione; 17-alpha-hydroxypregneilolone; 17-hydroxy-16-beta-methyl-5-beta-pregn-
9(11)-ene-3,20-dione; 17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione; 17-
hydroxypregna-4,9(11)-dime-3,20-dione; 18-hydroxycorticosterone; 18-
hydroxycortisone; 18-oxocortisol; 21-deoxyaldosterone; 21-deoxycortisone; 2-
deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha,20-
beta, 21-triol-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one; 6-alpha-
hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-
alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-
hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha, 9-alpha-
difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6-
hydroxydexamethasone; 6-hydroxyprednisolone; 9-fluorocortisone;
alclometasone dipropionate; aldosterone; algestone; alphaderm; amadinone;
amcinonide; anagestone; androstenedione; anecortave acetate; beclomethasone;
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beclomethasone dipropionate; beclomethasone dipropionate monohydrate;
betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium
phosphate; betamethasone valerate; bolasterone; budesonide; calusterone;
chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol;
clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone
pivalate;
clogestone; cloprednol; corticosterone; cortisol; cortisol acetate; cortisol
butyrate;
cortisol cypionate; cortisol octanoate; cortisol sodium phosphate; cortisol
sodium
succinate; cortisol valerate; cortisone; cortisone acetate; cortodoxone;
daturaolone;
deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone;
deoxycorticosterone; deprodone; descinolone; desonide; desoximethasone;
dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate;
dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone
diacetate; diflucortolone; dihydroelatericin a; domoprednate; doxibetasol;
ecdysone; ecdysterone; endrysone; enoxolone; flucinolone; fludrocortisone;
fludrocortisone acetate; flugestone; flumethasone; flumethasone pivalate;
flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; fluocinonide;
9-
fluorocortisone; fluocortolone; fluorohydroxyandrostenedione; fluorometholone;
fluorometholone acetate; fluoxymesterone; fluprednidene; fluprednisolone;
flurandrenolide; fluticasone; fluticasone propionate; formebolone; formestane;
formocortal; gestonorone; glyderinine; halcinonide; hyrcanoside; halometasone;
halopredone; haloprogesterone; hydrocortiosone cypionate; hydrocortisone;
hydrocortisone 21-butyrate; hydrocortisone aceponate; hydrocortisone acetate;
hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate;
hydrocortisone hemisuccinate; hydrocortisone probutate; hydrocortisone sodium
phosphate; hydrocortisone sodium succinate; hydrocortisone valerate;
hydroxyprogesterone; inokosterone; isoflupredone; isoflupredone acetate;
isoprednidene; meclorisone; mecortolon; medrogestone; medroxyprogesterone;
medrysone; megestrol; megestrol acetate; melengestrol; meprednisone;
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metr~androstenolone; methylprednisolone; methylprednisolone aceponate;
methylprednisolone acetate; methylprednisolone hemisuccinate;
methylprednisolone sodium succinate; methyltestosterone; metribolone;
mometasone; mometasone furoate; mometasone furoate monohydrate; nisone;
nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone;
paramethasone acetate; ponasterone; prednisolamate; prednisolone; prednisolone
21-hemisuccinate; prednisolone acetate; prednisolone farnesylate; prednisolone
hemisuccinate; prednisolone-21 (beta-D-glucuronide); prednisolone
metasulphobenzoate; prednisolone sodium phosphate; prednisolone steaglate;
prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone;
prednival;
prednylidene; pregnenolone; procinonide; tralonide; progesterone;
promegestone;
rhapontisterone; rimexolone; roxibolone; rubrosterone; stizophyllin;
tixocortol;
topterone; triamcinolone; triamcinolone acetonide; triamcinolone acetonide 21-
palmitate; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone;
turkesterone; and wortmannin.
Standard recommended dosages for various steroid/disease combinations
are provided in Table 3, below.
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Table 3-Standard Recommended Corticosteroid Dosages
IndicationRouteDru Dose Schedule
Psoriasis oralrednisolone 7.5-60 m er da or
divided
b.i.d.
oralrednisone 7.5-60 m er day or
divided
b.i.d.
Asthma inhaledbeclomethasone42 gJ of 4-8 uffs
di ro innate b.i.d.
inhaledbudesonide 200 inhalation1-2 inhalations
b.i.d.
inhaledflunisolide (250 of 2-4 uffs
b.i.d.
inhaledfluticasone (44, 110 2-4 uffs
pro innate or 220 uff) b.i.d.
inhaledtriamcinolone (100 uff) 2-4 uffs
acetonide b.i.d.
COPD oral prednisone 30-40 mg er da
Crohn's oralbudesonide 9 m er da
disease
Ulcerativeoralrednisone 40-60 m er da
colitis
oralhydrocortisone300 mg (N) er day
oralmethyl rednisolone40-60 m er day
Rheumatoid prednisone er day
arthritis 7.5-10 mg
oral
Other standard recommended dosagesfor corticosteroids are provided, e.g.,
in the Merck Manual of Diagnosis ~ Therapy (17th Ed. MH Beers et al., Merck &
Co.) and Physicians' Desk Reference 2003 (57~' Ed. Medical Economics Staff et
al., Medical Economics Co., 2002). In one embodiment, the dosage of
corticosteroid administered is a dosage equivalent to a prednisolone dosage,
as
defined herein. For example, a low dosage of a corticosteroid may be
considered
as the dosage equivalent to a low dosage of prednisolone.
Steroid receptor modulators (e.g., antagonists and agonists) may be used as
a substitute for or in addition to a corticosteroid in the methods,
compositions, and
kits of the invention. Thus, in one embodiment, the invention features the
combination of an SSRI (or analog or metabolite thereof) and a glucocorticoid
receptor modulator or other steroid receptor modulator, and methods of
treating
immunoinflammatory disorders therewith.
l~
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Glucocorticoid receptor modulators that may used in the methods,
compositions, and kits of the invention include compounds described in U.S.
Patent Nos. 6 380 207 6 380 223. 6 448 405 6 506 766 and 6 570 020 U.S.
a > > v ~ > > > > > > s > > >
Patent Application Publication Nos. 20030176478, 20030171585, 20030120081,
20030073703, 2002015631, 20020147336, 20020107235, 20020103217, and
20010041802, and PCT Publication No. WO00/66522, each of which is hereby
incorporated by reference. Other steroid receptor modulators may also be used
in
the methods, compositions, and kits of the invention are described in U.S.
Patent
Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647,
5,693,646, 5,688,810, 5,688,808, and 5,696,130, each of which is hereby
incorporated by reference.
NsIDIs
The methods, compositions, and kits of the invention may employ a non-
steroidal immunophilin-dependent immunosuppressant (NsIDI).
NsIDIs include calcineurin inhibitors (e.g., cyclosporines, tacrolimus,
pimecrolimus), and rapamycin.
Cyclospof°ihes
The cyclosporines are fungal metabolites that include a class of cyclic
oligopeptides that act as immunosuppressants. Cyclosporine A, and its
deuterated
analogue ISAtx247, is a hydrophobic cyclic polypeptide consisting of eleven
amino acids. Cyclosporine A binds and forms a complex with the intracellular
receptor cyclophilin. The cyclosporine/cyclophilin complex binds to and
inhibits
calcineurin, a Ca2+-calmodulin-dependent serine-threonine-specific protein
phosphatase.
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Calcineurin mediates signal transduction events required for T-cell activation
(reviewed in Schreiber et al., Cell 70:365-368, 1991). Cyclosporines and their
functional and structural analogs suppress the T-cell-dependent immune
response
by inhibiting antigen-triggered signal transduction. This inhibition decreases
the
expression of proinflammatory cytokines, such as IL-2.
Many cyclosporines (e.g., cyclosporine A, B, C, D, E, F, G, H, and I) are
produced by fungi. Cyclosporine A is a commercially available under the trade
name NEOR.AL from Novartis. Cyclosporine A structural and functional analogs
include cyclosporines having one or more fluorinated amino acids (described,
e.g.,
in U.S. Patent No. 5,227,467); cyclosporines having modified amino acids
(described, e.g., in U.S. Patent Nos. 5,122,511 and 4,798,823); and deuterated
cyclosporines, such as ISAtx247 (described in U.S. Patent Publication No.
20020132763). Additional cyclosporine analogs are described in U.S. Patent
Nos.
6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include,
but are not limited to, D-Sar (a-SMe)3 Vale-DH-Cs (209-825), Allo-Thr-2-Cs,
Norvaline-2-Cs, D-Ala (3-acetylamino)-8-Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-
Ser (O-CH2CH2-OH)-8-Cs, and D-Ser-8-Cs, which are described in Cruz et al.
(Antirnicrob. Agents Claemother. 44:143-149, 2000).
Cyclosporines are highly hydrophobic and readily precipitate in the
presence of water (e.g., on contact with body fluids). Methods of providing
cyclosporine formulations with improved bioavailability are described in U.S.
Patent Nos. 4,388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066, and
6,022,852. Cyclosporine microemulsion compositions are described in U.S.
PatentNos. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and
6,024,978.
Cyclosporines can be administered either intravenously or orally, but oral
administration is preferred.
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To counteract the hydrophobicity of cyclosporine A, an intravenous
cyclosporine
A is usually provided in an ethanol-polyoxyethylated castor oil vehicle that
must
be diluted prior to administration. Cyclosporine A may be provided, e.g., as a
microemulsion in a 25 mg or 100 mg tablets, or in a 100 mg/ml oral solution
(NEORALTM).
Typically, patient dosage of an oral cyclosporine varies according to the
patient's condition, but some standard recommended dosages in prior art
treatment
regimens are provided herein. Patients undergoing organ transplant typically
receive an initial dose of oral cyclosporine A in amounts between 12 and 15
mg/kg/day. Dosage is then gradually decreased by 5% per week until a 7-12
mg/kg/day maintenance dose is reached. For intravenous administration 2-6
mg/kg/day is preferred for most patients. For patients diagnosed as having
Crohn's disease or ulcerative colitis, dosage amounts from 6-8 mg/kg/day are
generally given. For patients diagnosed as having systemic lupus
erythematosus,
1 S dosage amounts from 2.2-6.0 mg/kg/day are generally given. For psoriasis
or
rheumatoid arthritis, dosage amounts from 0.5-4 mg/kg/day are typical. Other
useful dosages include 0.5-5 mg/kg/day, 5-10 mg/kg/day, 10-15 mg/kg/day, 15-20
mg/kg/day, or 20-25 mg/kg/day. Often cyclosporines are administered in
combination with other immunosuppressive agents, such as glucocorticoids.
Additional information is provided in Table 4.
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Table 4-NsIDIs
Atopic
CompoundDermatitisPsoriasisRA Crohn'sUC TransplantSLE
6_8
6 8
CsA N/A 0.5-4 0.5-4 mg/kg/dayda ~7-12 2.2-6.0
m
y
(NEORAL) mg/kg/daymg/kg/day(oral- ~~) mg/kg/daymg/kg/day
fistulizin
)
.03-0.1
cream/twice.OS-1.151-3 0.1-0.20.1-0.20.1-0.2
Tacrolimusday mg/kg/daymg/daymg/kg/daymg/kg/daymg/kg/dayN/A
(30
and
60 gram(oral) (oral)(oral) (oral) (oral)
tubes)
1%
cream/twice40-60 40-60 80-160 160-24040-120 40-120
Pimecrolimusday mglday mg/daymg/day mg/day mg/day mg/day
(15,
30,
100 (oral) (oral)(oral
gram (oral) (oral) (oral)
tubes)
Legend
CsA=cyclosporine A
RA=rheumatoid arthritis
UC=ulcerative colitis
SLE=systemic lupus erythamatosus
Tacrolimus
Tacrolimus (PROGRAF, Fujisawa), also known as FK506, is an
immunosuppressive drug that targets T-cell intracellular signal transduction
pathways. Tacrolimus binds to an intracellular protein FK506 binding protein
(FKBP-12) that is not structurally related to cyclophilin (Harding et al.
Nature
341:758-7601, 1989; Siekienka et al. Nature 341:755-757, 1989; and Soltoff et
al.,
J. Biol. Chem. 267:17472-17477, 1992). The FKBP/FI~506 complex binds to
calcineurin and inhibits calcineurin's phosphatase activity. This inhibition
prevents the dephosphorylation and nuclear translocation of NFAT, a nuclear
component that initiates gene transcription required for lymphokine (e.g., IL-
2,
gamma interferon) production and T-cell activation. Thus, tacrolimus inhibits
T-
cell activation.
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Tacrolimus is a macrolide antibiotic that is produced by St~eptomyces
tsukubaehsis. It suppresses the immune system and prolongs the survival of
transplanted organs. It is currently available in oral and injectable
formulations.
Tacrolimus capsules contain 0.5 mg, 1 mg, or S mg of anhydrous tacrolimus
within a gelatin capsule shell. The injectable formulation contains 5 mg
anhydrous tacrolimus in castor oil and alcohol that is diluted with 9% sodium
chloride or 5% dextrose prior to injection. While oral administration is
preferred,
patients unable to take oral capsules may receive injectable tacrolimus. The
initial
dose should be administered no sooner than six hours after transplant by
continuous intravenous infusion.
Tacrolimus and tacrolimus analogs are described by Tanaka et al., (J. Am.
Chem. ,Soc., 109:5031, 1987), and in U.S. Patent Nos. 4,894,366, 4,929,611,
and
4,956,352. FK506-related compounds, including FR-900520, FR-900523, and
FR-900525, are described in U.S. Patent No. 5,254,562; O-aryl, O-alkyl, O-
alkenyl, and O-alkynylmacrolides are described in U.S. Patent Nos. 5,250,678,
532,248, 5,693,648; amino O-aryl macrolides are described in U.S. Patent No.
5,262,533; alkylidene macrolides are described in U.S. Patent No. 5,284,840; N-
heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl
macrolides are described in U.S. Patent No. 5,208,241; aminomacrolides and
/ derivatives thereof are described in U.S. Patent No. 5,208,228;
fluoromacrolides
are described in U.S. Patent No. 5,189,042; amino O-alkyl, O-alkenyl, and O-
alkynylmacrolides are described in U.S. Patent No. 5,162,334; and
halomacrolides
are described in U.S. Patent No. 5,143,918.
While suggested dosages will vary with a patient's condition, standard
recommended dosages and regimens are provided below. Patients diagnosed as
having Crohn's disease or ulcerative colitis are administered 0.1-0.2
mg/kg/day
oral tacrolimus. Patients having a transplanted organ typically receive doses
of
0.1-0.2 mg/kg/day of oral tacrolimus. Patients being treated for rheumatoid
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arthritis typically receive 1-3 mg/day oral tacrolimus. For the treatment of
psoriasis, 0.01-0.15 mg/kg/day of oral tacrolimus is administered to a
patient.
Atopic dermatitis can be treated twice a day by applying a cream having 0.03-
0.1 % tacrolimus to the affected area. Patients receiving oral tacrolimus
capsules
typically receive the first dose no sooner than six hours after transplant, or
eight to
twelve hours after intravenous tacrolimus infusion was discontinued. Other
suggested tacrolimus dosages include 0.005-0.01 mg/kg/day, 0.01-0.03
mg/kg/day, 0.03-0.05 mg/kg/day, 0.05-0.07 mg/kg/day, 0.07-0.10 mg/kg/day,
0.10-0.25 mg/kg/day, or 0.25-0.5 mg/kg/day.
Tacrolimus is extensively metabolized by the mixed-function oxidase
system, in particular, by the cytochrome P-450 system. The primary mechanism
of metabolism is demethylation and hydroxylation. While various tacrolimus
metabolites are likely to exhibit immunosuppressive biological activity, the
13-
demethyl metabolite is reported to have the same activity as tacrolimus.
Pimecrolimus ahd Ascomyeira Derivatives
Ascomycin is a close structural analog of FK506 and is a potent
immunosuppressant. It binds to FKBP-12 and suppresses its proline rotamase
activity. The ascomycin-FKBP complex inhibits calcineurin, a type 2B
phosphatase.
Pimecrolimus (also known as SDZ ASM-981) is an 33-epi-chloro
derivative of the ascomycin. It is produced by the strain Streptomyees
hygroscopicus var. ascomyeeitus. Like tacrolimus, pimecrolimus (ELIDELTM,
Novartis) binds FKBP-12, inhibits calcineurin phosphatase activity, and
inhibits
T-cell activation by blocking the transcription of early cytokines. In
particular,
pimecrolimus inhibits IL-2 production and the release of other proinflammatory
cytokines.
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Pimecrolimus structural and functional analogs are described in U.S. Patent
No. 6,384,073. Pimecrolimus is particularly useful for the treatment of atopic
dermatitis. Pimecrolimus is currently available as a 1 % cream. While
individual
dosing will vary with the patient's condition, some standard recommended
dosages are provided below. Oral pimecrolimus can be given for the treatment
of
psoriasis or rheumatoid arthritis in amounts of 40-60 mg/day. For the
treatment of
Crohn's disease or ulcerative colitis amounts of 80-160 mg/day pimecrolimus
can
be given. Patients having an organ transplant can be administered 160-240
mg/day of pimecrolimus. Patients diagnosed as having systemic lupus
erythamatosus can be administered 40-120 mg/day of pimecrolimus. Other useful
dosages of pimecrolimus include 0.5-5 mg/day, 5-10 mg/day, 10-30 mg/day, 40-
80 mg/day, 80-120 mg/day, or even 120-200 mg/day.
Raparnycin
Rapamycin (Rapamune~ sirolimus, Wyeth) is a cyclic lactone produced by
Steptomyees hygroscopicus. Rapamycin is an immunosuppressive drug that
inhibits T-lymphocyte activation and proliferation. Like cyclosporines,
tacrolimus, and pimecrolimus, rapamycin forms a complex with the immunophilin
FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit calcineurin
phosphatase activity. The rapamycin-immunophilin complex binds to and inhibits
the mammalian target of rapamycin (mTOR), a kinase that is required for cell
cycle progression. Inhibition of mTOR kinase activity blocks T-lymphocyte
proliferation and lymphokine secretion.
Rapamycin structural and functional analogs include mono- and diacylated
rapamycin derivatives (U.S. Patent No. 4,316,885); rapamycin water-soluble
prodrugs (U.S. Patent No. 4,650,803); carboxylic acid esters (PCT Publication
No.
WO 92/05179); carbamates (U.S. Patent No. 5,118,678); amide esters (U.S.
Patent
No. 5,118,678); biotin esters (U.S. Patent No. 5,504,091); fluorinated esters
(U.S.
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Patent No. 5,100,883); acetals (U.S. Patent No. 5,151,413); silyl ethers (U.S.
Patent No. 5,120,842); bicyclic derivatives (U. S. Patent No. 5,120,725);
rapamycin dimers (U.S. Patent No. 5,120,727); O-aryl, O-alkyl, O-alkyenyl and
O-alkynyl derivatives (U.S. Patent No. 5,258,389); and deuterated rapamycin
(U.S. Patent No. 6,503,921). Additional rapamycin analogs are described in
U.S.
Patent Nos. 5,202,332 and 5,169,851.
Everolimus (40-O-(2-hydroxyethyl)rapamycin; CERTICANTM; Novartis) is
an immunosuppressive macrolide that is structurally related to rapamycin, and
has
been found to be particularly effective at preventing acute rejection of organ
transplant when give in combination with cyclosporiri A.
Rapamycin is currently available for oral administration in liquid and tablet
formulations. RAPAMUNETM liquid contains 1 mg/mL rapamycin that is diluted
in water or orange juice prior to administration. Tablets containing 1 or 2 mg
of
rapamycin are also available. Rapamycin is preferably given once daily as soon
as
possible after transplantation. It is absorbed rapidly and completely after
oral
administration. Typically, patient dosage of rapamycin varies according to the
patient's condition, but some standard recommended dosages are provided below.
The initial loading dose for rapamycin is 6 mg. Subsequent maintenance doses
of
2 mg/day are typical. Alternatively, a loading dose of 3 mg, 5 mg, 10 mg, 15
mg,
20 mg, or 25 mg can be used with a 1 mg, 3 mg, 5 mg, 7 mg, or 10 mg per day
maintenance dose. In patients weighing less than 40 kg, rapamycin dosages are
typically adjusted based on body surface area; generally a 3 mg/m2/day loading
dose and a 1-mg/ma/day maintenance dose is used.
Tricyclic Compounds
The methods, compositions, and kits of the invention may employ a
tricyclic compound. Tricyclic compounds include amitriptyline, amoxapine,
clomipramine, desipramine, dothiepin, doxepin, imipramine, lofepramine,
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maprotiline, mianserin, mirtazapine, nortriptyline, octriptyline,
oxaprotiline,
protriptyline, trimipramine, 10-(4-methylpiperazin-1-yl)pyrido(4,3-
b)(1,4)benzothiazepine; 11-(4-methyl-1-piperazinyl)-SH-
dibenzo(b,e)(1,4)diazepine; 5,10-dihydro-7-chloro-10-(2-(morpholino)ethyl)-
11H-dibenzo(b,e)(1,4)diazepin-11-one; 2-(2-(7-hydroxy-4-
dibenzo(b,f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol; 2-chloro-11-(4-
methyl-1-piperazinyl)-SH-dibenzo(b,e)(1,4)diazepine; 4-(11H-dibenz(b,e)azepin-
6-yl)piperazine; 8-chloro-11-(4-methyl-1-piperazinyl)- SH-
dibenzo(b,e)(1,4)diazepin-2-ol; 8-chloro-11-(4-methyl-1-piperazinyl)- SH-
dibenzo(b,e)(1,4)diazepine monohydrochloride; (Z)-2-butenedioate SH-
dibenzo(b,e)(1,4)diazepine; adinazolam; amineptine; amitriptylinoxide;
butriptyline; clothiapine; clozapine; demexiptiline; 11-(4-methyl-1-
piperazinyl)-
dibenz(b,f)(1,4)oxazepine; 11-(4-methyl-1-piperazinyl)-2-nitro-
dibenz(b,f)(1,4)oxazepine; 2-chloro-11-(4-methyl-1-piperazinyl)-
dibenz(b,f)(1,4)oxazepine monohydrochloride; dibenzepin; 11-(4-methyl-1-
piperazinyl)-dibenzo(b,f)(1,4)thiazepine; dimetacrine; fluacizine;
fluperlapine;
imipramine N-oxide; iprindole; lofepramine; melitracen; metapramine;
metiapine;
metralindole; mianserin; mirtazapine; 8-chloro-6-(4-methyl-1-piperazinyl)-
morphanthridine; N-acetylamoxapine; nomifensine; norclomipramine;
norclozapine; noxiptilin; opipramol; oxaprotiline; perlapine; pizotyline;
propizepine; quetiapine; quinupramine; tianeptine; tomoxetine; flupenthixol;
clopenthixol; piflutixol; chlorprothixene; and thiothixene. Other tricyclic
compounds are described, for example, in U.S. Patent Nos. 2,554,736;
3,046,283;
3,310,553; 3,177,209; 3,205,264; 3,244,748; 3,271,451; 3,272,826; 3,282,942;
3,299,139; 3,312,689; 3,389,139; 3,399,201; 3,409,640; 3,419,547; 3,438,981;
3,454,554; 3,467,650; 3,505,321; 3,527,766; 3,534,041; 3,539,573; 3,574,852;
3,622,565; 3,637,660; 3,663,696; 3,758,528; 3,922,305; 3,963,778; 3,978,121;
3,981,917; 4,017,542; 4,017,621; 4,020,096; 4,045,560; 4,045,580; 4,048,223;
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4,062,848; 4,088,647; 4,128,641; 4,148,919; 4,153,629; 4,224,321; 4,224,344;
4,250,094; 4,284,559; 4,333,935; 4,358,620; 4,548,933; 4,691,040; 4,879,288;
5,238,959; 5,266,570; 5,399,568; 5,464,840; 5,455,246; 5,512,575; 5,550,136;
5,574,173; 5,681,840; 5,688,805; 5,916,889; 6,545,057; and 6,600,065, and
phenothiazine compounds that fit Formula (I) of U.S. Patent Application Nos.
10/617,424 or 60/504,310.
Typically, patient dosages of maprotiline vary according to the patient's
condition, but some standard recormnended dosages are provided herein.
Maprotiline, which is currently available in 25, 50, and 100 mg tablets, is
most
often administered in doses of 100-150 mg/day, although standard recommended
dosages of 1-25 mg/day, 25-100 mg/day, 100-150 mg/day, 150-225 mg/day, or
225-350 mg/day can be administered. Most antidepressants are well absorbed
when administered orally, although intramuscular administration of some TCAs
(e.g., amitriptyline, clomipramine) is also possible.
Dipyridamole and Related Tetrasubstituted Pyrimidopyrimidines
The methods, compositions, and kits of the ,invention may employ
dipyridamole or tetra-substituted pyrimidopyrimidines. Dipyridamole (2,6-
bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine) is a tetra-
substituted pyrimidopyrimidine that is used as a platelet inhibitor, e.g., to
prevent
blood clot formation following heart valve surgery and to reduced the
moribundity
associated with clotting disorders, including myocardial and cerebral
infarction.
Typically, anticoagulation therapy (prophylaxis or treatment) is effected by
administering dipyridamole at about 75-200 mg b.i.d, t.i.d., or q.i.d. either
alone or
in combination with aspirin. In the invention, lower doses generally can be
used,
e.g., 20-80 mg, administered by any of the prior art routes.
Tetra-substituted pyrimidopyrimidines are structural analogs that can
replace dipyridamole in the methods and compositions of this invention. Tetra-
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substituted pyrimidopyrimidines generally are of formula (I), described in
U.S.S.N. 10/264,991 entitled "Combinations for the Treatment of
Immunoinflammatory Disorders," filed October 4, 2002, and incorporated herein
by reference in its entirety.
Exemplary tetra-substituted pyrimidopyrimidines that are useful in the
methods and compositions of this invention include 2,6-disubstituted 4,8-
dibenzylaminopyrimido[5,4-d]pyrimidines. Particularly useful tetra-substituted
pyrimidopyrimidines include dipyridamole (also l~nown as 2,6-
bis(diethanolamino)-4,8-dipiperidinopyrimido(5,4-d)pyrimidine), mopidamole,
dipyridamole monoacetate, NU3026 (2,6-di-(2,2-dimethyl-1,3-dioxolan-4-yl)-
methoxy-4,8-di-piperidinopyrimidopyrimidine), NU3059 (2,6-bis-(2,3-
dimethyoxypropoxy)-4,8-di-piperidinopyrimidopyrimidine), NU3060 (2,6-
bis[N,N-di(2-methoxy)ethyl]-4,6-di-piperidinopyrimidopyrimidine), and NU3076
(2,6-bis(diethanolamino)-4,8-di-4-methoxybenzylaminopyrimidopyrimidine).
For oral, intramuscular, subcutaneous, topical, inhalation, rectal, vaginal
and ophthalmic administration of the tetra-substituted pyrimidopyrimidine, the
dosage used according to the invention is about 0.5-800 mg/day, preferably
about
5-600 mg/day, 10-100 mg/day, and more preferably 0.5-50 mg/day.
Administration can be one to four times daily for one day to one year, and may
even be for the life of the patient. Chronic, long-term administration will be
indicated in many cases. In some cases of serious illness, up to 1600 mg/day
may
be necessary. For intravenous administration of the tetra-substituted
pyrimidopyrimidine, the dosage used is about 0.1-200 mg/day, preferably about
0.5-150 mg/day, 1-100 mg/day, and more preferably about 0.5-50 mg/day.
Administration can be one to four times daily. Systemic dosing will result in
steady-state plasma concentrations preferably of 0.1-7.0 ~,M, more preferably,
0.5-
5.0 ~,M, and most preferably, 1.0-2.0 ~M.
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Antihistamines
The methods, compositions, and kits of'the invention may employ an
antihistamine. Antihistamines are compounds that block the action of
histamine.
Classes of antihistamines include:
(1) Ethanolamines (e.g., bromodiphenhydramine, carbinoxamine,
clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and
doxylamine);
(2) Ethylenediamines (e.g., pheniramine, pyrilamine, tripelennamine, and
triprolidine);
(3) Phenothiazines (e.g., diethazine, ethopropazine, methdilazine,
promethazine, thiethylperazine, and trimeprazine);
(4) Alkylamines (e.g., acrivastine, brompheniramine, chlorpheniramine,
desbrompheniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine);
(5) Piperazines (e.g., buclizine, cetirizine, chlorcyclizine, cyclizine,
meclizine, hydroxyzine);
(6) Piperidines (e.g., astemizole, azatadine, cyproheptadine, desloratadine,
fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and
terfenadine);
(7) Atypical antihistamines (e.g., azelastine, levocabastine, methapyrilene,
and phenyltoxamine).
In the methods, compositions, and kits of the invention, both non-sedating
and sedating'antihistamines may be employed. Particularly desirable
antihistamines for use in the methods, compositions, and kits of the invention
are
non-sedating antihistamines such as loratadine and desloratadine. Sedating
antihistamines can also be used in the methods, compositions, and kits of the
invention. Preferred sedating antihistamines for use in the methods,
compositions,
and kits of the invention are azatadine, bromodiphenhydramine;
chlorpheniramine;
clemizole; cyproheptadine; dimenhydrinate; diphenhydramine; doxylamine;
meclizine; promethazine; pyrilamine; thiethylperazine; and tripelennamine.
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Other antihistamines suitable for use in the methods and compositions of
the invention are acrivastine; ahistan; antazoline; astemizole; azelastine
(e.g.,
azelsatine hydrochloride); bamipine; bepotastine; bietanautine;
brompheniramine
(e.g., brompheniramine maleate); carbinoxamine (e.g., carbinoxamine maleate);
cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine;
chloropyramine; chlorothen; chlorphenoxamine; cinnarizine; clemastine (e.g.,
t
clemashne fumarate); clobenzepam; clobenztropine; clocinizine; cyclizine
(e.g.,
cyclizine hydrochloride; cyclizine lactate); deptropine; dexchlorpheniramine;
dexchlorpheniramine maleate; diphenylpyraline; doxepin; ebastine; embramine;
emedastine (e.g., emedastine difumarate); epinastine; etymemazine
hydrochloride;
fexofenadine (e.g., fexofenadine hydrochloride); histapyrrodine; hydroxyzine
(e.g., hydroxyzine hydrochloride; hydroxyzine pamoate); isopromethazine;
isothipendyl; levocabastine (e.g., levocabastine hydrochloride); mebhydroline;
mequitazine; methafurylene; methapyrilene; metron; mizolastine; olapatadine
(e.g., olopatadine hydrochloride); orphenadrine; phenindamine (e.g.,
phenindamine tartrate); pheniramine; phenyltoloxamine; p-
methyldiphenhydramine; pyrrobutamine; setastine; talastine; terfenadine;
thenyldiamine; thiazinamium (e.g., thiazinamium methylsulfate); thonzylamine
hydrochloride; tolpropamine; triprolidine; and tritoqualine.
Structural analogs of antihistamines may also be used in according to the
invention. Antihistamine analogs include, without limitation; 10-
piperazinylpropylphenothiazine; 4-(3-(2-chlorophenothiazin-10-yl)propyl)-1-
piperazineethanol dihydrochloride; 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-
10H-
phenothiazin-2-yl)-(9CI) 1-propanone; 3-methoxycyproheptadine; 4-(3-(2,-Chloro-
lOH-phenothiazin-10-yl)propyl)piperazine-1-ethanol hydrochloride; 10,11-
dihydro-5-(3-(4-ethoxycarbonyl-4-phenylpiperidino)propylidene)-SH-
dibenzo(a,d)cycloheptene; aceprometazine; acetophenazine; alimemazin (e.g.,
alimemazin hydrochloride); aminopromazine; benzimidazole; butaperazine;
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carfenazine; chlorfenethazine; chlormidazole; cinprazole; desmethylastemizole;
desmethylcyproheptadine; diethazine (e.g., diethazine hydrochloride);
ethopropazine (e.g., ethopropazine hydrochloride); 2-(p-bromophenyl-(p'-
tolyl)methoxy)-N,N-dimethyl-ethylamine hydrochloride; N,N-dimethyl-2-
(diphenylmethoxy)-ethylamine methylbromide; EX-10-542A; fenethazine;
fuprazole; methyl 10-(3-(4-methyl-1-piperazinyl)propyl)phenothiazin-2-yl
ketone;
lerisetron; medrylamine; mesoridazine; methylpromazine; N-
desmethylpromethazine; nilprazole; northioridazine; perphenazine (e.g.,
perphenazine enanthate); 10-(3-dimethylaminopropyl)-2-methylthio-
phenothiazine; 4-(dibenzo(b,e)thiepin-6(11H)-ylidene)-1-methyl-piperidine
hydrochloride; prochlorperazine; promazine; propiomazine (e.g., propiomazine
hydrochloride); rotoxamine; rupatadine; Sch 37370; Sch 434; tecastemizole;
thiazinamium; thiopropazate; thioridazine (e.g., thioridazine hydrochloride);
and
3-( 10,11-dihydro-SH-dibenzo(a,d)cyclohepten-5-ylidene)-tropane. Other
compounds that are suitable for use in the invention are AD-0261; AHR-5333;
alinastine; arpromidine; ATI-19000; bermastine; bilastin; Bron-12;
carebastine;
chlorphenamine; clofurenadine; corsym; DF-1105501; DF-11062; DF-1111301;
EL-301; elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609;
icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine;
levoprotiline; metoclopramide; NIP-531; noberastine; oxatomide; PR-881-884A;
quisultazine; rocastine; selenotifen; SK&F-94461; SODAS-HC; tagorizine; TAK-
427; temelastine; UCB-34742; UCB-35440; VLJF-K-8707; Wy-49051; and ZCR-
2060. Still other compounds that are suitable for use in the invention are
described in U.S. Patent Nos. 3,956,296; 4,254,129; 4,254,130; 4,282,833;
4,283,408; 4,362,736; 4,394,508; 4,285,957; 4,285,958; 4,440,933; 4,510,309;
4,550,116; 4,692,456; 4,742,175; 4,833,138; 4,908,372; 5,204,249; 5,375,693;
5,578,610; 5,581,011; 5,589,487; 5,663,412; 5,994,549; 6,201,124; and
6,458,958.
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Standard recommended dosages for several exemplary antihistamines are
shown in Table 5. Other standard dosages are provided, e.g., in the Merck
Manual
of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians'
Desk Reference 2003 (57th Ed. Medical Economics Staff et al., Medical
Economics Co., 2002).
Table 5
Com ound Standard Dose
Desloratadine 5 m / once daily
Thiethylperazine 10 mg / 1-3 times daily
Bromodiphenhydramine12.5-25 mg l every 4-6
hours
Promethazine 25 m / twice dail
Cyproheptadine 12-16 mg/day
Loratadine 10 m / once Bail
Clemizole 100 m 'ven as IV or
IM
Azatadine 1-2 mg / twice daily
Cetirizine 5-10 mg / once daily
Chlorpheniramine 2 mg / every 6 hours
or
4 m / ever 6 hours
Dimenhydramine 50-100 mg / every 4-6
hours
Diphenydramine 25 mg / every 4 -6 hours
or
38 mg / every 4-6 hours
Doxylamine 25 mg / once daily or
12.5
m / ever four hours
Fexofenadine 60 mg/ twice daily or
180
mg/ once daily
Meclizine 25 - 100 m / da
Pyrilamine 30 m / every 6 hours
Tripelennamine 25 - 50 mg / every 4
to 6
hours or 100 mg / twice
daily (extended release)
Loratadine (CLARITIN~) is a tricyclic piperidine that acts as a selective
peripheral histamine H1-receptor antagonist. We report herein that loratadine
and
structural and functional analogs thereof, such as piperidines, tricyclic
piperidines,
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histamine Hl-receptor antagonists, are useful in the anti-immunoinflammatory
combination of the invention for the treatment of immunoinflammatory
disorders,
transplanted organ rejection, and graft versus host disease.
Loratadine functional and/or structural analogs include other H1-receptor
antagonists, such as AHR-11325, acrivastine, antazoline, astemizole,
azatadine,
azelastine, bromopheniramine, carebastine, cetirizine, chlorpheniramine,
chlorcyclizine, clemastine, cyproheptadine, descarboethoxyloratadine,
dexchlorpheniramine, dimenhydrinate, diphenylpyraline, diphenhydramine,
ebastine, fexofenadine, hydroxyzine ketotifen, lodoxamide, levocabastine,
, methdilazine, mequitazine, oxatomide, pheniramine pyrilamine, promethazine,
pyrilamine, setastine, tazifylline, temelastine, terfenadine, trimeprazine,
tripelennamine, triprolidine, utrizine, and similar compounds (described,
e.g., in
U.S. PatentNos. 3,956,296, 4,254,129, 4,254,130, 4,283,408, 4,362,736,
4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, 4,550,116, 4,692,456,
4,742,175, 4,908,372, 5,204,249, 5,375,693, 5,578,610, 5,581,011, 5,589,487,
5,663,412, 5,994,549, 6,201,124, and 6,458,958).
Loratadine, cetirizine, and fexofenadine are second-generation H1-receptor
antagonists that lack the sedating effects of many first generation H1-
receptor
antagonists. Piperidine H1-receptor antagonists include loratadine,
cyproheptadine hydrochloride (PERIACTIN), and phenindiamine tartrate
(NOLAHIST). Piperazine H1-receptor antagonists include hydroxyzine
hydrochloride (ATAR.AX), hydroxyzine pamoate (VISTARIL), cyclizine
hydrochloride (MAREZINE), cyclizine lactate, and meclizine hydrochloride.
Loratadine oral formulations include tablets, redi-tabs, and syrup:
Loratadine tablets contain 10 mg micronized loratadine. Loratadine syrup
contains 1 mg/ml micronized loratadine, and reditabs (rapidly-disintegrating
tablets) contain 10 mg micronized loratadine in tablets that disintegrate
quickly in
the mouth. While suggested dosages will vary with a patient's condition,
standard
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recommended dosages are provided below. Loratadine is typically administered
once daily in a 10 mg dose, although other daily dosages useful in the anti-
immunoinflammatory combination of the invention include 0.01-0.05 mg, 0.05-1
mg, 1-3 mg, 3-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, and 30-40 mg.
Loratadine is rapidly absorbed following oral administration. It is
metabolized in the liver to descarboethoxyloratadine by cytochrome P450 3A4
and
cytochrome P450 2D6. Loratadine metabolites are also useful in the anti-
immunoinflammatory combination of the invention.
Administration
Using the methods of the invention, the drugs are administered within 30
minutes of each other, or simultaneously. The drugs may be formulated together
as a single composition, or may be formulated and administered separately. It
may be desirable to administer to the patient other compounds, such as an
NSAID
(e.g., naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin,
sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline
magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen,
flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin,
sulindac,
and tolmetin), COX-2 inhibitor (e.g., rofecoxib, celecoxib, valdecoxib, and
lumiracoxib), glucocorticoid receptor modulator, or DMARD. Combination
therapies of the invention are especially useful for the treatment of
immunoinflammatory disorders in combination with other anti-cytokine agents or
agents that modulate the immune response to positively effect disease, such as
agents that influence cell adhesion, or biologics (i.e., agents that block the
action
of IL-6, IL-l, IL-2, IL-12, IL-15 or TNFa (e.g., etanercept, adelimumab,
infliximab, or CDP-870).
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In this example (that of agents blocking the effect of TNFa), the combination
therapy reduces the production of cytokines, etanercept or infliximab act on
the
remaining fraction of inflammatory cytokines, providing enhanced treatment.
Therapy according to the invention may be performed alone or in
conjunction with another therapy and may be provided at home, the doctor's
office, a clinic, a hospital's outpatient department, or a hospital. Treatment
optionally begins at a hospital so that the doctor can observe the therapy's
effects
closely and make any adjustments that are needed, or it may begin on an
outpatient basis. The duration of the therapy depends on the type of disease
or
disorder being treated, the age and condition of the patient, the stage and
type of
the patient's disease, and how the patient responds to the treatment.
Additionally,
a person having a greater risk of developing an inflammatory disease (e.g., a
person who is undergoing age-related hormonal changes) may receive treatment
to
inhibit or delay the onset of symptoms.
Routes of administration for the various embodiments include, but are not
limited to, topical, transdermal, and systemic administration (such as,
intravenous,
intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal,
intraperitoneal,
intraarticular, ophthalmic or oral administration). As used herein, "systemic
administration" refers to all nondermal routes of administration, and
specifically
excludes topical and transdermal routes of administration.
In combination therapy, the dosage and frequency of administration of each
component of the combination can be controlled independently. For example, one
compound may be administered three times per day, while the second compound
may be administered once per day. Combination therapy may be given in on-and-
off cycles that include rest periods so that the patient's body has a chance
to
recover from any as yet unforeseen side effects. The compounds may also be
formulated together such that one administration delivers both compounds.
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Formulation of Pharmaceutical Compositions
The administration of a combination of the invention may be by any
suitable means that results in the desired therapeutic outcome. A component,
or
the entire combination, may be contained in any appropriate amount in any
suitable carrier substance, and is generally present in an amount of 1-95% by
weight of the total weight of the composition. The composition may be provided
in a dosage form that is suitable for the oral, parenteral (e.g.,
intravenously,
intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch),
or ocular
administration route. Thus, the composition may be in the form of, e.g.,
tablets,
capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels
including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic
delivery devices, suppositories, enemas, injectables, implants, sprays, or
aerosols.
The pharmaceutical compositions may be formulated according to conventional
pharmaceutical practice (see, e.g., Remington:~ The Science and Practice of
Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins,
Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick
and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
Each compound of the combination may be formulated in a variety of ways
that are known in the art. For example, the first and second drugs may be
formulated together or separately. Desirably, the first and second drugs are
formulated together for the simultaneous or near simultaneous administration
of
the drugs. Such co-formulated compositions can include, for example, the SS1ZI
and the steroid formulated together in the same pill, capsule, liquid, etc. By
using
different formulation strategies for different drugs, the pharmacokinetic
profiles
for each drug can be suitably matched.
The individually or separately formulated drugs can be packaged together
as a kit. Non-limiting examples include kits that contain, e.g., two pills, a
pill and
a powder, a suppository and a liquid in a vial, two topical creams, etc.
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The kit can include optional components that aid in the administration of the
unit
dose to patients, such as vials for reconstituting powder forms, syringes for
inj ection, customized IV delivery systems, inhalers, etc. Additionally, the
unit
dose kit can contain instructions for preparation and administration of the
compositions. The kit may be manufactured as a single use unit dose for one
patient, multiple uses for a particular patient (at a constant dose or in
which the
individual compounds may vary in potency as therapy progresses); or the kit
may
contain multiple doses suitable for administration to multiple patients ("bulk
packaging"). The kit components may be assembled in cartons, blister packs,
bottles, tubes, and the like.
Sustained Release Formulations
Administration of any combination of the invention in which one of the
active agents is formulated for sustained release is useful where one of the
agents
has (i) a narrow therapeutic index (e.g., the difference between the plasma
concentration leading to harmful side effects or toxic reactions and the
plasma
concentration leading to a therapeutic effect is small; generally, the
therapeutic
index, TI, is defined as the ratio of median lethal dose (LDso) to median
effective
dose (EDso)); (ii) a narrow absorption window in the gastro-intestinal tract;
(iii) a
short biological half life; or (iv) the pharmacokinetic profile of each
component
must be modified to improve the efficacy of the combination. In the
formulations
of the invention, a pharmacokinetic profile can be modified, for example, to
increase the length of time that each of the agents is simultaneously present
in the
plasma of the subj ect in an amount that renders the two agents together more
therapeutically effective than either agent administered alone. Accordingly, a
sustained release formulation of one of the agents may be used to avoid
frequent
dosing that may be required in order to sustain the plasma levels of both
agents at
a therapeutic level.
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For example, in preferable oral pharmaceutical compositions of the invention
half life and mean residency times from 10 to 20 hours for one or both agents
of
the combination of the invention are observed.
Many strategies can be pursued to obtain sustained release in which the rate
of release outweighs the rate of metabolism of the therapeutic compound. For
example, sustained release can be obtained by the appropriate selection of
formulation parameters and ingredients (e.g., appropriate sustained release
compositions and coatings). Examples include single or multiple unit tablet or
capsule compositions, oil solutions, suspensions, emulsions, microcapsules,
microspheres, nanoparticles, patches, and liposomes. The release mechanism can
be controlled such that the a drug of the combination is released at period
intervals, the release could be simultaneous, or a delayed release of one of
the
agents of the combination can be affected, when the early release of one
particular
agent is preferred over the other.
Sustained release formulations may include a degradable or nondegradable
polymer, hydrogel, organogel, or other physical construct that modifies the
bioabsorption, half life or biodegradation of the agent. The sustained release
formulation can be a material that is painted or otherwise applied onto the
afflicted
site, either internally or externally. In one example, the invention provides
a
biodegradable bolus or implant that is surgically inserted at or near a site
of
interest (for example, proximal to an arthritic joint). In another example,
the
sustained release formulation implant can be inserted into an organ, such as
in the
lower intestine for the treatment inflammatory bowel disease.
Hydrogels can be used in sustained release formulations for the
combinations of the present invention. Such polymers include those described
in
U.S. Patent No. 5,626,863. For example, hydrogels be gelled into a
biodegradable
network that can be used to entrap and homogeneously disperse combinations of
the invention for delivery at a controlled rate.
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Chitosan and mixtures of chitosan with carboxymethylcellulose sodium
(CMC-Na) have been used as vehicles for the sustained release of drugs, as
described by Inouye et al., Drug Design afad Delivery 1: 297-305, 1987.
Mixtures
of these compounds and agents of the combinations of the invention, when
compressed under 200 kg/cm2, form a tablet from which the active agent is
slowly
released upon administration to a subject. The release profile can be changed
by
varying the ratios of chitosan, CMC-Na, and active agent(s). The tablets can
also
contain other additives, including lactose, CaHP04 dihydrate, sucrose,
crystalline
cellulose, or croscarmellose sodium. Several examples are given in Table 6.
Table 6
Materials Tablet
components
(mg)
Active agent20 20 20 20 20 20 20 20 20 20 20 20
~ Chitosan 10 10 10 10 10 20 3.3 20 3.3 70 40 28
I
Lactose 110 220 36.7
CMC-Na 60 60 60 60 60 120 20 120 20 30 42
CaHP04*2Hz0 110 220 36.7110 110 110
Sucrose 110
Crystalline
Cellulose 110
Croscarmellose 110
Na
Baichwal, in U.S. Patent No. 6,245,356, describes a sustained release oral
solid dosage forms that includes agglomerated particles of a therapeutically
active
medicament (e.g., a combination or component thereof of the present invention)
in
amorphous form, a gelling agent, an ionizable gel strength enhancing agent and
an
inert diluent.
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The gelling agent can be a mixture of a xanthan gum and a locust bean gum
capable of cross-linking with the xanthan gum when the gums are exposed to an
environmental fluid. Preferably, the ionizable gel enhancing agent acts to
enhance
the strength of cross-linking between the xanthan gum and the locust bean gum
and thereby prolonging the release of the medicament component of the
formulation. In addition to xanthan gum and locust bean gum, acceptable
gelling
agents that may also be used include those gelling agents well-known in the
art.
Examples include naturally occurring or modified naturally occurring gums such
as alginates, carrageenan, pectin, guar gum, modified starch,
hydroxypropylmethylcellulose, methylcellulose, and other cellulosic materials
or
polymers, such as, for example, sodium carboxymethylcellulose and
hydroxypropyl cellulose, and mixtures of the foregoing.
In another formulation useful for the combinations of the invention,
Baichwal and Staniforth in U.S. Patent No. 5,135,757 describe a free-flowing
slow
release granulation for use as a pharmaceutical excipient that includes from
about
to about 70 percent or more by weight of a hydrophilic material that includes
a
heteropolysaccharide (such as, for example, xanthan gum or a derivative
thereof)
and a polysaccharide material capable of cross-linking the
heteropolysaccharide
(such as, for example, galactomannans, and most preferably locust bean gum) in
20 the presence of aqueous solutions, and from about 30 to about 80 percent by
weight of an inert pharmaceutical filler (such as, for example, lactose,
dextrose,
sucrose, sorbitol, xylitol, fructose or mixtures thereof). After mixing the
excipient
with a combination, or combination agent, of the invention, the mixture is
directly
compressed into solid dosage forms such as tablets. The tablets thus formed
slowly release the medicament when ingested and exposed to gastric fluids. By
varying the amount of excipient relative to the medicament, a slow release
profile
can be attained.
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Combinations of the invention can be formulated as provided in U.S. Patent
No. 5,007,790, which describes sustained release oral drug-dosage forms that
release a drug in solution at a rate controlled by the solubility of the drug.
The
dosage form includes a tablet or capsule that includes a plurality of
particles of a
dispersion of a limited solubility drug in a hydrophilic, water-swellable,
crosslinked polymer that maintains its physical integrity over the dosing
lifetime
but thereafter rapidly dissolves. Once ingested, the particles swell to
promote
gastric retention and permit the gastric fluid to penetrate the particles,
dissolve
drug and leach it from the particles, assuring that drug reaches the stomach
in the
solution state which is less injurious to the stomach than solid-state drug.
The
programmed eventual dissolution of the polymer depends upon the nature of the
polymer and the degree of crosslinking. The polymer is nonfibrillar and
substantially water soluble in its uncrosslinked state, and the degree of
crosslinking is sufficient to enable the polymer to remain insoluble for the
desired
time period, normally at least from about 4 hours to 8 hours up to 12 hours,
with
the choice depending upon the drug incorporated and the medical treatment
involved. Examples of suitable crosslinked polymers that may be used in the
invention are gelatin, albumin, sodium alginate, carboxymethyl cellulose,
polyvinyl alcohol, and chitin. Depending upon the polymer, crosslinking may be
achieved by thermal or radiation treatment or through the use of crosslinking
agents such as aldehydes, polyamino acids, metal ions and the like.
Silicone microspheres for pH-controlled gastrointestinal drug delivery that
are useful in the formulation of the combinations of the invention have been
described by Carelli et al., Int. J. Pharmaceutics 179: 73-83, 1999. The
microspheres so described are pH-sensitive semi-interpenetrating polymer
hydrogels made of varying proportions of poly(methacrylic acid-co-
methylmethacrylate) (Eudragit L 100 or Eudragit S 100) and crosslinked
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polyethylene glycol 8000 that are encapsulated into silicone microspheres in
the
500 to 1000 ~,m size range.
Slow-release formulations can include a coating which is not readily water-
soluble but which is slowly attacked and removed by water, or through which
water can slowly permeate. Thus, combinations of the invention can be spray-
coated with a solution of a binder under continuously fluidizing conditions,
such
as describe by Kitamori et al., U.S. Patent No. 4,036,948. Examples of water-
soluble binders include pregelatinized starch (e.g., pregelatinized corn
starch,
pregelatinized white potato starch), pregelatinized modified starch, water-
soluble
celluloses (e.g. hydroxypropyl-cellulose, hydroxymethyl-cellulose,
hydroxypropylmethyl-cellulose, carboxymethyl-cellulose), polyvinylpyrrolidone,
polyvinyl alcohol, dextrin, gum arabicum and gelatin, organic solvent-soluble
binders, such as cellulose derivatives (e.g., cellulose acetate phthalate,
hydroxypropylmethyl-cellulose phthalate, ethylcellulose).
Combinations of the invention, or a component thereof, with sustained
release properties can also be formulated by spray drying techniques. In one
example, as described by Espositio et al., Pharm. Dev. Technol. 5: 267-78,
2000,
prednisolone was encapsulated in methyacrylate microparticles (Eudragit RS)
using a Mini Spray Dryer, model 190 (Buchi, Laboratorium Technik AG, Flawil,
Germany). Optimal conditions for microparticle formation were.found to be a
feed (pump) rate of 0.5 mL/min of a solution containing 50 mg prednisolone in
10
mL of acetonitrile, a flow rate of nebulized air of 600 L/hr, dry air
temperature
heating at 80°C, and a flow rate of aspirated drying air of 28 m~/hr.
Yet another form of sustained release combinations can be prepared by
microencapsulation of combination agent particles in membranes which act as
microdialysis cells. In such a formulation, gastric fluid permeates the
microcapsule walls and swells the microcapsule, allowing the active agents) to
dialyze out (see, for example, Tsuei et al., U.S. Patent No. 5,589,194).
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One commercially available sustained release system of this kind consists of
microcapsules having membranes of acacia gum/gelatine/ethyl alcohol. This
product is available from Eurand Limited (France) under the trade name
DiffucapsTM. Microcapsules so formulated might be carried in a conventional
gelatine capsule or tabletted.
Extended- and/or sustained release formulations of both SSRIs and
corticosteroids are known. For example, Paxil CR~, commercially available from
GlaxoSmithKline, is an extended release form of paroxetine hydrochloride in a
degradable polymeric matrix (GEOMATRIXTM, see also U.S. Patent Nos.
4,839,177, 5,102,666, and 5,422,123), which also has an enteric coat to delay
the
start of drug release until after the tablets have passed through the stomach.
For
example, U.S. Pat. No. 5,102,666 describes a polymeric sustained release
composition including a reaction complex formed by the interaction of (1) a
calcium polycarbophil component which is a water-swellable, but water
insoluble,
fibrous cross-linked carboxy-functional polymer, the polymer containing (a) a
plurality of repeating units of which at least about 80% contain at least one
carboxyl functionality, and (b) about 0.05 to about 1.5% cross-linking agent
substantially free from polyalkenyl polyether, the percentages being based
upon
the weights of unpolymerised repeating unit and cross-linking agent,
respectively,
with (2) water, in the presence of an active agent selected from the group
consisting of SSRIs such as paroxetine. The amount of calcium polycarbophil
present is from about 0.1 to about 99% by weight; for example about 10%. The
amount of active agent present is from about 0.0001 to about 65% by weight,
for
example between about 5 and 20%. The amount of water present is from about 5
to about 200% by weight, for example between about 5 and 10%. The interaction
is carried out at a pH of between about 3 and about 10, for example about 6 to
7.
The calcium polycarbophil is originally present in the form of a calcium salt
containing from about 5 to about 25% calcium.
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Other extended-release formulation examples are described in U.S. Patent
No. 5,422,123. This formulation includes (a) a deposit-core having an
effective
amount of the active substance and having defined geometric form, and (b) a
support-plafform applied to the deposit-core, wherein the deposit-core
contains at
least the active substance, and at least one member selected from the group
consisting of ( 1 ) a polymeric material which swells on contact with water or
aqueous liquids and a gellable polymeric material wherein the ratio of the
swellable polymeric material to the gellable polymeric material is in the
range 1:9
to 9:1, and (2) a single polymeric material having both swelling and gelling
properties, and wherein the support-platform is an elastic support, applied to
the
deposit-core so that it partially covers the surface of the deposit-core and
follows
changes due to hydration of the deposit-core and is slowly soluble and/or
slowly
gellable in aqueous fluids. The support-platform may include polymers such as
hydroxypropylmethylcellulose, plasticizers such as a glyceride, binders such
as
polyvinylpyrrolidone, hydrophilic agents such as lactose and silica, and/or
hydrophobic agents such as magnesium stearate and glycerides. The polymers)
typically make up 30 to 90% by weight of the support-platform, for example
about
35 to 40%. Plasticizer may make up at least 2% by weight of the support-
platform, for example about 15 to 20%. Binder(s), hydrophilic agents) and
hydrophobic agents) typically total up to about 50% by weight of the support-
platform, for example about 40 to 50%.
In another example, an extended-release formulation for venlafaxine
(Effexor XR~~ is commercially available from Wyeth Pharmaceuticals. This
formulation includes venlafaxine hydrochloride, microcrystalline cellulose and
hydroxypropylmethylcellulose, coated with a mixture of ethyl cellulose and
hydroxypropylmethylcellulose (see U.S. Patent Nos. 6,403,120 and 6,419,958).
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A sustained release formulation of budesonide (3 mg capsules) for the
treatment of inflammatory bowel disease is available from AstraZeneca (sold as
"EntocortTM"). A sustained release formulation useful for corticosteroids is
also
described in U.S. Patent No. 5,792,476, where the formulation includes 2.5-7
mg
of a glucocorticoid as active substance with a regulated sustained release
such that
at least 90% by weight of the glucocorticoid is released during a period of
about
40-80 min, starting about 1-3 h after the entry of the glucocorticoid into the
small
intestine of the patient. To make these low dose levels of active substance
possible, the active substance, i.e., the glucocorticoid, such as prednisolone
or
prednisone, is micronised, suitably mixed with known diluents, such as starch
and
lactose, and granulated with PVP (polyvinylpyrrolidone). Further, the
granulate is
laminated with a sustained release inner layer resistant to a pH of 6.8 and a
sustained release outer layer resistant to a pH of 1Ø The inner layer is
made of
Eudragit~RL (copolymer of acrylic and methacrylic esters with a low content of
quaternary ammonium groups) and the outer layer is made of Eudragit~L (anionic
polymer synthesized from methacrylic acid and methacrylic acid methyl ester).
A bilayer tablet can be formulated for any combination of the invention in
which different custom granulations are made for each agent of the combination
and the two agents are compressed on a bi-layer press to form a single tablet.
For
example, 12.5 mg, 25 mg, 37.5 mg, or 50 mg of paroxetine, formulated for a
sustained release that results in a paroxetine tliz of 15 to 20 hours may be
combined in the same tablet with 3 mg of prednisolone, which is formulated
such
that the tli2 approximates that of paroxetine. Examples of paroxetine extended-
release formulations, including those used in bilayer tablets, can be found in
U.S.
Patent No. 6,548,084. In addition to controlling the rate of predsnisolone
release
in vivo, an enteric or delayed release coat may be included that delays the
start of
drug release such that the TmaX of predsnisolone approximate that of
paroxetine
(i.e. 5 to 10 hours).
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Cyclodextrins are cyclic polysaccharides containing naturally occurring
D(+)-glucopyranose units in an a-(1,4) linkage. Alpha-, beta- and gamma-
cyclodextrins, which contain, respectively, six, seven or eight glucopyranose
units, .
are most commonly used and suitable examples are described in W091111172,
W094/02518 and WO98/55148. Structurally, the cyclic nature of a cyclodextrin
forms a torus or donut-like shape having an inner apolar or hydrophobic
cavity,
the secondary hydroxyl groups situated on one side of the cyclodextrin torus
and
the primary hydroxyl groups situated on the other. The side on which the
secondary hydroxyl groups are located has a wider diameter than the side on
which the primary hydroxyl groups are located. The hydrophobic nature of the
cyclodextrin inner cavity allows for the inclusion of a variety of compounds.
(Comprehensive Supramolecular Chemistry, Volume 3, J. L. Atwood et al., eds.,
Pergamon Press (1996); Cserhati, A~alytieal Biochemistry 225: 328-32, 1995;
Husain et al., Applied Spectroscopy 46: 652-8, 1992. Cyclodextrins have been
used as a delivery vehicle of various therapeutic compounds by forming
inclusion
complexes with various drugs that can fit into the hydrophobic cavity of the
cyclodextrin or by forming non-covalent association complexes with other
biologically active molecules. U.S. Patent No. 4,727,064 describes
pharmaceutical preparations consisting of a drug with substantially low water
solubility and an amorphous, water-soluble cyclodextrin-based mixture in which
the drug forms an inclusion complex with the cyclodextrins of the mixture.
Formation of a drug-cyclodextrin complex can modify the drug's solubility,
dissolution rate, bioavailability, and/or stability properties. For example,
cyclodextrins have been described for improving the bioavailability of
prednisolone, as described by Uekama et al., J. Pharm l9yn. 6: 124-7, 1983. A
~3-
cyclodextrin/prednisolone complex can be prepared by adding both components to
water and stirring at 25°C for 7 days. The resultant precipitate
recovered is a 1:2
prednisolone/cyclodextrin complex.
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Sulfobutylether-(3-cyclodextrin (SBE-(3-CD, commercially available from
CyDex, Inc, Overland Park, KA, USA and sold as CAPTISOL~) can also be used
as an aid in the preparation of sustained release formulations of agents of
the
combinations of the present invention. For example, a sustained release tablet
has
been prepared that includes prednisolone and SBE-(3-CD compressed in a
hydroxypropyl methylcellulose matrix (see Rao et al., J. Pha~rra. Sci. 90: X07-
16,
2001). In another example of the use of various cyclodextrins, EP 110906 B1
describes cyclodextrin complexes of paroxetine, where a-, y-, or (3-
cyclodextrins
[including eptakis(2-6-di-O-methyl)-~-cyclodextrin, (2,3,6-tri-O-methyl)-~-
cyclodextrin, monosuccinyl eptakis(2,6-di-O-methyl)-(3-cyclodextrin, or 2-
hydroxypropyl-~3-cyclodextrin] in anhydrous or hydrated form formed complex
ratios of agent to cyclodextrin of from 1:0.25 to 1:20 can be obtained.
Polymeric cyclodextrins have also been prepared, as described in U.S.
Patent Application Serial Nos. 10/021,294 and 10/021,312. The cyclodextrin
1 S polymers so formed can be useful for formulating agents of the
combinations of
the present invention. These multifunctional polymeric cyclodextrins are
commercially available from Insert Therapeutics, Inc., Pasadena, CA, USA.
As an alternative to direct complexation with agents, cyclodextrins may be
used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
Formulations
that include cyclodextrins and other agents of the combinations of the present
invention (e.g., tricyclic compounds, SSRIs, SNRIs, NsIDIs, antihistamines,
corticosteroids, and/or a tetra-substituted pyrimidopyrimidines) can be
prepared by
methods similar to the preparations of the cyclodextrin formulations described
herein.
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Liposomal Formulations
One or both components of the combinations of the invention, or mixtures
of the two components together, can be incorporated into liposomal carriers
for
administration. The liposomal carriers are composed of three general types of
-vesicle-forming lipid components. The first includes vesicle-forming lipids
which
will form the bulls of the vesicle structure in the liposome. Generally, these
vesicle-forming lipids include any amphipathic lipids having hydrophobic and
polar head group moieties, and which (a) can form spontaneously into bilayer
vesicles in water, as exemplified by phospholipids, or (b) are stably
incorporated
into lipid bilayers, with its hydrophobic moiety in contact with the interior,
hydrophobic region of the bilayer membrane, and its polar head group moiety
oriented toward the exterior, polar surface of the membrane.
The vesicle-forming lipids of this type are preferably ones having two
hydrocarbon chains, typically acyl chains, and a polar head group. Included in
this
15~ class are the phospholipids, such as phosphatidylcholine (PC), PE,
phosphatidic
acid (PA), phosphatidylinositol (PI), and sphingomyelin (SM), where the two
hydrocarbon chains are typically between about 14-22 carbon atoms in length,
and
have varying degrees of unsaturation. The above-described lipids and
phospholipids whose acyl chains have a variety of degrees of saturation can be
obtained commercially, or prepared according to published methods. Other
lipids
that can be included in the invention are glycolipids and sterols, such as
cholesterol.
The second general component includes a vesicle-forming lipid which is
derivatized with a polymer chain which will form the polymer layer in the
composition. The vesicle-forming lipids which can be used as the second
general
vesicle-forming lipid component are any of those described for the first
general
vesicle-forming lipid component.
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Vesicle forming lipids with diacyl chains, such as phospholipids, are
preferred:
One exemplary phospholipid is phosphatidylethanolamine (PE), which provides a
reactive amino group which is convenient for coupling to the activated
polymers.
An exemplary PE is distearyl PE (DSPE).
The preferred polymer in the derivatized lipid, is polyethyleneglycol (PEG),
preferably a PEG chain having a molecular weight between 1,000-15,000 daltons,
more preferably between 2,000 and 10,000 daltons, most preferably between
2,000
and 5,000 daltons. Other hydrophilic polymers which may be suitable include
polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline,
polyhydroxypropyl methacrylamide, polymethacrylamide and
polydimethylacrylamide, polylactic acid, polyglycolic acid, and derivatized
celluloses, such as hydroxymethylcellulose or hydroxyethylcellulose.
Additionally, block copolymers or random copolymers of these polymers,
particularly including PEG segments, may be suitable. Methods for preparing
lipids derivatized with hydrophilic polymers, such as PEG, are well known
e.g., as
described in U.S. Patent No. 5,013,556.
A third general vesicle-forming lipid component, which is optional, is a
lipid anchor by which a targeting moiety is anchored to the liposome, through
a
polymer chain in the anchor. Additionally, the targeting group is positioned
at the
distal end of the polymer chain in such a way so that the biological activity
of the
targeting moiety is not lost. The lipid anchor has a hydrophobic moiety which
serves to anchor the lipid in the outer layer of the liposome bilayer surface,
a polar
head group to which the interior end of the polymer is covalently attached,
and a
free (exterior) polymer end which is or can be activated for covalent coupling
to
the targeting moiety. Methods for preparing lipid anchor molecules of this
types
are described below.
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The lipids components used in forming the liposomes are preferably present
in a molar ratio of about 70-90 percent vesicle forming lipids, 1-25 percent
polymer derivatized lipid, and 0.1-5 percent lipid anchor. One exemplary
formulation includes 50-70 mole percent underivatized PE, 20-40 mole percent
cholesterol, 0.1-1 mole percent of a PE-PEG (3500) polymer with a chemically
reactive group at its free end for coupling to a targeting moiety, 5-10 mole
percent
PE derivatized with PEG 3500 polymer chains, and 1 mole percent alpha-
tocopherol.
The liposomes are preferably prepared to have substantially homogeneous
sizes in a selected size range, typically between about 0.03 to 0.5 microns.
One
effective sizing method for REVS and MLVs involves extruding an aqueous
suspension of the liposomes through a series of polycarbonate membranes having
a selected uniform pore size in the range of 0.03 to 0.2 micron, typically
0.05,
0.08, 0.1, or 0.2 microns. The pore size of the membrane corresponds roughly
to
the largest sizes of liposomes produced by extrusion through that membrane,
particularly where the preparation is extruded two or more times through the
same
membrane. Homogenization methods are also useful for down-sizing liposomes
to sizes of 100 nm or less.
Other established liposomal formulation techniques can be applied as
needed. For example, the use of liposomes to facilitate cellular uptake is
described in U.S. PatentNos. 4,897,355 and 4,394,448.
Administration of each drug in any of the combinations described herein
can, independently, be one to four times daily for one day to one year, and
may
even be for the life of the patient. Chronic, long-term administration will be
indicated in many cases.
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Other Embodiments
All publications, patent applications, and patents mentioned in this
specification are herein incorporated by reference.
While the invention has been described in connection with specific
embodiments, it will be understood that it is capable of further
modifications.
Therefore, this application is intended to cover any variations, uses, or
adaptations
of the invention that follow, in general, the principles of the invention,
including
departures from the present disclosure that come within known or customary
practice within the art.
Other embodiments are within the claims. What is claimed is:
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