U.S. patent application number 14/437534 was filed with the patent office on 2015-10-01 for medicinal treatment of chronic pulmonary inflammatory diseases with norketotifen.
This patent application is currently assigned to BRIDGE PHARMA, INC.. The applicant listed for this patent is BRIDGE PHARMA, INC.. Invention is credited to A. K. Gunnar Aberg, Vincent B. Ciofalo.
Application Number | 20150272941 14/437534 |
Document ID | / |
Family ID | 54188816 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150272941 |
Kind Code |
A1 |
Aberg; A. K. Gunnar ; et
al. |
October 1, 2015 |
MEDICINAL TREATMENT OF CHRONIC PULMONARY INFLAMMATORY DISEASES WITH
NORKETOTIFEN
Abstract
The methods disclosed herein relate to the treatment of chronic
pulmonary disorders, such as for example asthma, COPD, cough,
bronchial hyperactivity and bronchitis, in human patients, by
administering a therapeutically effective amount of
RS-norketotifen.
Inventors: |
Aberg; A. K. Gunnar;
(Sarasota, FL) ; Ciofalo; Vincent B.; (Branford,
CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRIDGE PHARMA, INC. |
Sarasota, |
FL |
US |
|
|
Assignee: |
BRIDGE PHARMA, INC.
Sarasota
FL
|
Family ID: |
54188816 |
Appl. No.: |
14/437534 |
Filed: |
October 29, 2013 |
PCT Filed: |
October 29, 2013 |
PCT NO: |
PCT/US13/67177 |
371 Date: |
April 22, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13744807 |
Jan 18, 2013 |
|
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14437534 |
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61720058 |
Oct 30, 2012 |
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Current U.S.
Class: |
514/171 ;
514/324 |
Current CPC
Class: |
A61K 31/167 20130101;
A61K 9/107 20130101; A61K 31/137 20130101; A61K 9/127 20130101;
A61K 31/4535 20130101; A61K 31/56 20130101; A61K 9/0053 20130101;
A61K 31/4535 20130101; A61K 47/02 20130101; A61K 9/2054 20130101;
A61K 31/573 20130101; A61K 9/0014 20130101; A61K 45/06 20130101;
A61K 31/167 20130101; A61K 9/06 20130101; A61K 31/573 20130101;
A61K 9/10 20130101; A61K 31/137 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/4535 20060101
A61K031/4535; A61K 31/56 20060101 A61K031/56; A61K 45/06 20060101
A61K045/06 |
Claims
1-25. (canceled)
26. A method of treating a chronic, inflammatory pulmonary
condition in a human patient in need of such treatment, the method
comprising orally administering to the human patient in need
thereof a therapeutically effective amount of RS-norketotifen or a
pharmaceutically acceptable salt thereof, wherein the human patient
is susceptible to sedative side effects upon administration of
Generation-1 antihistamines, wherein the therapeutically effective
amount of RS-norketotifen does not produce sedative side effects
upon administration to the human patient, and wherein the amount of
said RS-norketotifen or a pharmaceutically acceptable salt thereof
is 0.5 mg to 20 mg, expressed as free base, and is dosed once or
multiple times daily in said method.
27. The method of claim 26, wherein the pulmonary inflammatory
disorder is selected from the group consisting of asthma, COPD,
cough, bronchial hyperactivity, and bronchitis.
28. The method of claim 26, further comprising pulmonary
administration, sublingual administration, parenteral
administration, dermal administration, transdermal administration,
rectal administration, buccal administration, of a therapeutically
effective dose of RS-norketotifen or a pharmaceutically acceptable
salt thereof.
29. The method of claim 26, the method further comprising
co-administration of RS-norketotifen and a therapeutically
effective amount of a bronchodilating adrenergic beta-receptor
agonist, an insecticidal agent, an antibacterial agent, an
antiviral agent, vitamin D, a vitamin D analog, a corticosteroid, a
cyclooxygenase inhibitor, a leukotriene antagonist, a lipoxygenase
inhibitor, a kinase inhibitor, or an immunosuppressant drug.
30. The method of claim 29, wherein the bronchodilating adrenergic
beta-receptor agonist is salbutamol, terbutaline, fenoterol,
formoterol, salmeterol, or an optically or therapeutically active
isomer thereof.
31. The method of claim 30, wherein the bronchodilating adrenergic
beta-receptor agonist is administered by inhalation, nasal,
parenteral, topical, transdermal, rectal, sublingual or oral
administration.
32. A method of treating an atopic pulmonary inflammatory disorder
in a human patient, comprising determining whether said patient is
susceptible to adverse sedative effects of compounds with
antihistaminic activity, and if said determination is positive,
administering to said patient in need thereof an oral formulation
comprising a therapeutically effective amount of RS-norketotifen or
a pharmaceutically acceptable salt of RS-norketotifen.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a .sctn.371 of PCT/US2013/067177 filed
on Oct. 29, 2013, which claims priority of U.S. application Ser.
No. 13/744,807, filed on Jan. 18, 2013, which claims priority from
U.S. Provisional Application Ser. No. 61/720,058, filed on Oct. 30,
2012, under the provisions of 35 U.S.C. .sctn.119 and the
International Convention for the Protection of Intellectual
Property, the disclosure of which is hereby incorporated by
reference.
TECHNICAL FIELD
[0002] The embodiments disclosed herein relate to methods for the
treatment of chronic inflammatory, infectious, and allergic
pulmonary diseases in humans, while avoiding side effects that are
commonly associated with anti-inflammatory antihistamines.
BACKGROUND
[0003] Ketotifen (Zaditen.RTM., Zaditor.RTM., Sandoz, Novartis) is
a Generation-1 antihistamine that is mainly used for the treatment
of allergic rhinitis. Ketotifen may be the most sedating of all
marketed antihistamines, and the unusually severe sedative side
effects of ketotifen have limited the therapeutic usefulness of the
drug. In the USA, ketotifen is only used as eye drops
(Zaditor.RTM., Novartis) to alleviate the symptoms of allergic
conjunctivitis in humans, and does not cause sedation due to the
extremely low systemic concentrations of the drug after local
administration to the eyes.
[0004] Other anti-inflammatory H-1 antihistamines are, for example,
azatadine (Zadine.RTM., Schering-Plough), chloropheniramine
(Qdall.RTM., Atley Pharmaceuticals), mepyramine (Pyrilamine.RTM.,
Rhone-Poulenc, Tocris) and promethazine (Phenergan.RTM., Baxter).
All have antihistaminic (H-1) activity and all cause sedation and
drowsiness.
[0005] Norketotifen (synonymously called RS-norketotifen), a
hepatic metabolite of ketotifen, is an achiral molecule, but has
two atropisomers, S-norketotifen and R-norketotifen, as has
previously been described in U.S. Pat. Nos. 7,226,934 and
7,557,128. As explained in U.S. Pat. Nos. 7,226,934 and 7,557,128,
norketotifen also had a significant sedation effect when studied in
the art-accepted, and carefully validated mouse model of sedation,
and further, the sedative effects were attributed to the R-isomer.
It was thus proposed that only the S-isomer could be administered
without sedative side effects.
[0006] Atopic dermatitis (AD) is a chronic allergic skin disease
that occurs in 10 to 20 percent of children and 1 to 3 percent of
adults. Of all patients suffering from AD, 40 to 60 percent also
have respiratory allergies. Psoriasis is a chronic autoimmune
dermal disease, caused by overproduction of new skin cells.
Approximately 2.2 percent of the U.S. population suffers from
psoriasis. Like patients with AD, psoriasis patients suffer from
pruritus. Compromised skin barrier function has a role both in AD
and psoriasis.
[0007] Many fungi have been described as normally living on the
skin of various mammal species, including humans. Malassezia
species form a family of lipolytic fungi that currently is believed
to include 14 species. Overgrowth of Malassezia species causes
toxic and/or immunological reactions and contributes to both AD and
psoriasis, and also contributes to various other dermal diseases
and conditions, such as for example, adult seborrheic dermatitis,
dandruff, Malassezia folliculitis, tinea versicolor and rosacea.
These fungal disorders are typically treated with medication for
the underlying condition in combination with an antifungal
mediation that can be administered orally or topically (dermally)
to the skin.
[0008] Dermal bacterial infections are common in patients suffering
from many dermal diseases, such as for example atopic dermatitis
and psoriasis. These infections are often causative, as allergic
reactions with inflammation and pruritus may be triggered by for
example Staphylococcus aureus. As pointed out by Breuer et al.,
Allergy 2001, 56: 1034-1041, (2001), the skin of about 80 to 100
percent of patients with atopic dermatitis is colonized with
Staphylococcus aureus, while Staphylococcus aureus can be found on
the skin of only 5 to 30 percent of normal individuals. Breuer et
al. (2001) and others have noted that the density of Staphylococcus
aureus is increased according to the disease severity and that
Staphylococcus aureus is causative for atopic dermatitis, since
this bacterium promotes inflammation due to the action of
superantigens. It was found by Brockow et al., Dermatology 1999,
199: 231-236 (1991) that topical antibacterial therapy in
combination with an anti-inflammatory steroid not only reduced
Staphylococcus aureus, but also reduced the severity of atopic
dermatitis.
[0009] What is needed are methods of treating inflammatory dermal
disorders without causing sedation or the much feared side effects
of corticosteroids and immunosuppressant drugs. Also needed are
improved topical treatments for combined inflammatory and
infectious dermal disorders. Both topical and oral anti-pruritic
medications are also needed.
SUMMARY
[0010] In one aspect, a method of treating chronic inflammatory
dermal disorders in a human patient in need of such treatment
comprises orally administering to the human patient in need thereof
a therapeutically effective amount of RS-norketotifen or a
pharmaceutically acceptable salt thereof is 0.5 to 20 mg dosed once
or more daily, and wherein the therapeutically effective amount
does not produce sedative side effects upon administration to the
human patient.
[0011] In another aspect, a method of treating a chronic atopic
inflammatory dermal disorder in a human patient comprises
determining whether said patient is susceptible to adverse sedative
effects of compounds with antihistaminic activity, and if said
determination is positive, administering to said patient in need
thereof an oral formulation comprising a therapeutically effective
amount of RS-norketotifen or a pharmaceutically acceptable salt of
RS-norketotifen that is 0.5 to 20 mg, dosed orally once or more
daily.
[0012] A method of treating skin infections in a human patient
suffering from a skin infection comprises topically administering a
topical formulation to an infected skin lesion and areas adjacent
to the skin lesion on the human patient, wherein the topical
formulation comprises a therapeutically effective amount of
RS-norketotifen or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable excipient.
DETAILED DESCRIPTION
[0013] The methods disclosed herein relate to the treatment of
pruritic, inflammatory, and/or infectious dermal disorders, such as
for example eczema, atopic dermatitis, urticaria and psoriasis, in
human patients, by administering the anti-inflammatory,
anti-allergic, and anti-microbial compound, norketotifen and
pharmaceutically acceptable salts thereof. Prior to the present
disclosure, the therapeutically important efficacy of norketotifen
and the two isomers thereof had not been reported. In certain
aspects, administration is oral administration, topical
administration, or a combination thereof.
[0014] It had previously been found and described that both
ketotifen and norketotifen express sedative activity, and were
therefore not considered to be useful as oral medications for the
treatment of chronic diseases, such as for example, atopic
dermatitis. Sedation was determined using a mouse model that has
previously been used successfully in the development of
non-sedating antihistamines, such as loratadine (Claritin.RTM.,
Schering) and desloratadine (Clarinex.RTM., Schering). It was
therefore believed that the mouse model had relevance for
evaluating the clinical use of the current benzocycloheptathiophene
compound that has potent antihistaminic activities. The mouse model
clearly demonstrated the sedative effects of racemic norketotifen
and R-norketotifen.
[0015] It has now surprisingly been found that racemic norketotifen
is completely free from sedative effects when orally administered
to humans, even after repeated administration of high doses of the
compound.
[0016] It has further been unexpectedly discovered that
norketotifen and its isomers have antimicrobial activity and can be
used to inhibit the growth of microorganisms such as fungi and
bacteria including Malassezia sp, Candida albicans, and
Staphylococcus aureus. Thus, in one aspect, disclosed herein is a
method of treating skin infections in a human patient comprising
administering to the skin (e.g., an infected skin lesion and
adjacent areas) of the human patient a topical formulation
comprising a therapeutically effective amount of norketotifen or a
salt or isomer thereof and a pharmaceutically acceptable excipient.
Skin infections can also be treated by oral administration of
norketotifen.
[0017] In one aspect, the active compound is racemic norketotifen,
herein often called RS-norketotifen or just norketotifen.
Norketotifen is an achiral molecule, but has two isomers,
S-norketotifen and R-norketotifen, as has previously been described
in U.S. Pat. Nos. 7,226,934 and 7,557,128. Norketotifen is
particularly useful for both oral and topical administration.
[0018] Chemically, norketotifen is
(RS)-4-(piperidylidene)-9,10-dihydro-4H-benzo-(4,5)-cyclohepta-(1,2-b)
thiophene-10-one. The prefix (RS) can optionally be excluded when
referring to racemic norketotifen.
[0019] Norketotifen is a metabolite of ketotifen
(4-(1-methyl-4-piperidyline)-4H-benzo(4,5)-cyclohepta-(1,2-b)
thiophene-10-one). Ketotifen may be the most sedating of all
marketed antihistamines and the unusually severe sedative side
effects of ketotifen has limited the therapeutic usefulness of the
drug to 1 mg, bid to when administered orally in the treatment of
atopic dermatitis human.
##STR00001##
[0020] The metabolite norketotifen is formed by demethylation of
ketotifen in the liver of humans and it has been calculated that up
to 0.5 mg norketotifen is formed in the liver of human patients
after an oral dose of one milligram ketotifen:
##STR00002##
[0021] Norketotifen can be made from methods known in the art, as
described in U.S. Pat. No. 3,682,930, the disclosure of which is
hereby incorporated by reference for its teaching of the synthesis
of norketotifen.
[0022] Except for U.S. Pat. Nos. 7,226,934 and 7,557,128, no
publications are known that describe the pharmacodynamic activities
of RS-norketotifen. U.S. Pat. No. 6,207,684 and Publications
2010/0105734 and 2010/0130550 describe the effects of
RS-norketotifen when used as eye drops for ocular indications, such
as allergic conjunctivitis and xerophthalmia in humans.
[0023] Certain embodiments disclosed herein provide for the oral
administration of the racemic form of norketotifen or
pharmaceutically acceptable acid addition salts of the compound to
human patients in need thereof. Norketotifen is ideally suited for
the treatment of atopic dermatitis (AD), since this compound, has
potent anti-inflammatory and antipruritic effects, and has now,
surprisingly, been found to be completely free from sedative side
effects and to have antimicrobial effects of significant
importance. In a specific embodiment, the norketotifen is racemic
norketotifen.
[0024] In one embodiment, norketotifen is administered to the
patient orally. In another embodiment, the administration is
topical (dermal or rectal) administration to the skin of the human
patient and in still another embodiment, norketotifen is
administered to the patient by inhalation. In one embodiment,
administration is oral administration. In another embodiment,
administration is by inhalation
[0025] Atopic inflammatory disorders in humans can be caused by
various allergens, such as for example airborne or food allergens,
fleas, bacteria, fungi or contact allergens.
[0026] Atopic inflammatory disorders include dermal disorders such
as for example eczema, atopic dermatitis, urticaria and psoriasis.
Pulmonary disorders include for example asthma, COPD, cough,
bronchial hyperactivity, and bronchitis, and gastrointestinal
disorders including gastric irritation, gastric allergic disorders,
and gastric inflammatory disorders. Examples of gastric
inflammatory disorders are for example various eosinophilic
gastrointestinal disorders, such as for example eosinophilic
esophagitis, eosinophilic gastroenteritis and other forms of
gastrointestinal eosinophilia.
[0027] In one embodiment, a method for reducing sedative side
effects in the treatment of pruritic and/or inflammatory dermal
disorders in a human patient in need of such treatment comprises
orally administering to the patient in need thereof a
therapeutically effective amount of norketotifen or a
pharmaceutically acceptable salt thereof that does not produce
sedative side effects upon administration to the human patient. In
one embodiment, treatment is chronic, subchronic, or acute,
specifically chronic. As used herein chronic administration is
three or more consecutive days of administration. Acute refers to a
single administration. Subchronic refers to less than 3 consecutive
days of administration. In a specific embodiment, the norketotifen
is racemic norketotifen.
[0028] In another aspect, disclosed herein is a method of treating
a human patient in need of treatment for a skin infection
comprising administering to the skin (e.g., to an infected skin
lesion and the infected adjacent non-lesion skin on the patient) a
topical formulation comprising a therapeutically effective amount
of norketotifen or a salt or isomer thereof together with one or
more pharmaceutically acceptable excipient(s). Oral administration
can be used in addition to or as an alternative to topical
administration. Both bacteria and fungi can be found in skin
lesions and in areas of the adjacent to the lesions on humans
suffering from atopic dermatitis. Staphylococcus aureus bacterial
infections are common in human patients with AD and very prevalent
in lesions and in normal skin adjacent to the lesions. S. aureus is
believed to be causative for some of the manifestations of atopic
dermatitis since a toxin that is produced by the bacteria
(staphylococcus enterotoxin B) has been found to induce both
induration and erythema of the skin of healthy human volunteers and
volunteers with atopic dermatitis.
[0029] Candida albicans dermal fungal infections are common among
human patients with atopic dermatitis and clinical studies have
linked the presence of anti-Candida albicans antibodies in the
blood with the clinical condition of atopic dermatitis.
[0030] Malassezia sp dermal fungus and in particular Malassezia
globosa is probably the most common microorganism in infected human
skin lesions, and is also known to cause exacerbation of the
disease and to cause intense pruritus. M. globulosa, M. sympodialis
and M. furfur cause Tinea versicolor, which is a chronic
superficial fungal infection in humans with a prevalence of 30-40
percent in tropical areas. M. furfur and possibly other Malassezia
species, can induce the overproduction of molecules (such as
TGF-beta-1) involved in cell migration and hyperpropliferation,
thereby favoring the exacerbation of psoriasis.
[0031] Bacterial skin infections can result from opportunistic
microbes causing infections in patients with an underlying immune
disorder, allergies, hormonal disease, liver disease and kidney
disease, for example Inflammation and scratching break down dermal
barriers leading to the worsening of dermal infections.
[0032] Infected skin lesions can be readily identified by visual
inspection and/or skin cytology of the lesions. Cells from the
lesion are stained and then examined under a microscope. Both fungi
and bacteria can be identified in this manner by different stains
as well as the shape of the cells. In addition, the underlying
causative microorganism can be identified by cell culture
techniques.
[0033] Norketotifen is particularly useful in the treatment of
human patients who are susceptible to sedation upon administration
of drugs with antihistaminic activity. Sedation is a common side
effect of antihistamines such as diphenhydramine, which is a
sedating Generation-1 antihistamine without anti-inflammatory
activity used mainly for the treatment of allergic rhinitis.
Ketotifen is also known to cause sedation. For some patients, the
sedative side effects can outweigh the benefits of such medication,
particularly in the treatment of chronic, non-life-threatening
conditions such as dermal disorders, such as for example atopic
dermatitis, and pulmonary disorders, such as for example asthma.
While allergic rhinitis is a highly seasonal condition, dermal and
pulmonary disorders most often require year-round treatment over
multiple years. Sedation over long periods of time is not
acceptable. Further, while non-sedating antihistamines are
available, these drugs do not have the anti-inflammatory activity
needed for the treatment of inflammatory disorders, such as for
example atopic dermatitis and asthma. Because of the previous
belief that norketotifen has similar sedative side effects as
ketotifen, one would not have used this compound to treat chronic
allergic/inflammatory disorders in patients susceptible to sedative
side effects.
[0034] Those skilled in the art know how to determine if a patient
is susceptible to sedation from sedative (Generation-1) compounds.
For example, the oral administration of a single daily clinical
dose of ketotifen will cause sedation (drowsiness) in individuals
susceptible to sedative side effects, but the dose of ketotifen
will not cause sedation in individuals who are not susceptible to
sedative side effects of Generation-1 antihistaminic drugs.
Likewise, a high clinical dose of diphenhydramine can be used to
differentiate between patients who are susceptible to sedation and
those who are not susceptible to the sedative side effects of
Generation-1 antihistaminic drugs.
[0035] In one embodiment, the doctor may determine if a patient
suffering from an atopic inflammatory disorder is susceptible to
sedative side effects, for example, by using one of the methods
described above. If the patient is susceptible to sedative side
effects, the patient can safely be administered norketotifen for
treatment of chronic atopic inflammatory disorders.
[0036] The embodiments disclosed herein also provide pharmaceutical
compositions, which comprise the compound of the invention,
formulated together with one or more pharmaceutically acceptable
carriers. The pharmaceutical compositions may be formulated for
oral administration, sublingual administration, parenteral
administration, dermal administration (application), transdermal
administration, rectal administration, buccal administration, for
topical administration, or pulmonary administration such as
administration by inhalation, or insufflation of dry powder or
aerosol.
[0037] Pharmaceutical compositions for oral administration of solid
dosage forms include capsules and tablets. In solid dosage forms,
the active compound may be mixed with one or more pharmaceutically
acceptable excipients or carriers (such as for example sodium
citrate, dicalcium phosphate), fillers or extenders (such as for
example starch, lactose, sucrose, glucose, mannitol, silicic acid),
binders (such as for example alginates, carboxymethylcellulose,
gelatin, polyvinylpyrrolidone, sucrose, acacia), humectants (such
as for example glycerol), solution retarding agents (such as for
example paraffin), disintegrating agents (such as for example
agar-agar, calcium carbonate, starch, alginic acid, silicates,
sodium carbonate), absorption accelerators (such as for example
quaternary ammonium compounds), wetting agents (such as for example
cetyl alcohol, glycerol monostearate), absorbents (such as for
example kaolin, bentonite clay), lubricating agents (such as for
example talc, calcium stearate, magnesium stearate, polyethylene
glycols, sodium lauryl sulfate), and/or other excipients, such as
for example buffering agents. Solid forms of capsules, granules,
pills, and tablets can have coatings and/or shells (such as for
example enteric coatings) known in the art. The compositions may
also be designed to release the active ingredient(s) in a certain
part of the gastrointestinal tract or in a controlled release,
slow-release or in a delayed-release manner. The active compound(s)
can also be microencapsulated with one or more of the
above-mentioned excipients or other suitable excipients.
[0038] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. The liquid dosage form may also contain
commonly known diluents (such as for example water, other solvents,
solubilizing agents), emulsifiers (such as for example ethanol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propylene glycol, butylene glycol, dimethyl
formamide, oils, oleic acid, glycerol, polyethylene glycols,
sorbitan fatty esters, and mixtures thereof.)
[0039] The oral compositions may also include other excipients as
known to those skilled in the art.
[0040] Pharmaceutical compositions for parenteral injections
include pharmaceutically acceptable sterile solutions, dispersions,
suspensions, emulsions and sterile powders for reconstitution into
sterile injectable solutions or dispersions prior to use. Various
carriers, diluents, solvents and vehicles may be used.
[0041] Parenteral compositions may also contain excipients such as
for example preservatives, wetting agents, emulsifying agents,
dispersing agents, isotonic agents, and/or absorption-delaying
agents. Absorption-prolonging or absorption-slowing effects may be
achieved by injecting a crystalline or amorphous suspension with
low water solubility. Delayed absorption may also be obtained by
dissolving or suspending the drug in an oil vehicle or by using
injectable depot forms (ex. microencapsulated matrices of the drug
in biodegradable polymers, such as polylactide-polyglycolide,
polyorthoesters, polyanhydrides) or by using various types of
liposomes or microemulsions to hold the drug. Formulations for
injection can be sterilized by various methods.
[0042] Pulmonary administration, such as by inhalation or
insufflation, may be accomplished, for example, using an aerolizer,
a nebulizer, a dry powder inhaler, a metered dose inhaler, and the
like.
[0043] Pharmaceutical compositions for topical application of
norketotifen include, for example, pharmaceutically acceptable
solutions, emulsions, creams and ointments, preferably containing
0.1 percent to 10 of norketotifen or a pharmaceutically acceptable
salt thereof, which may be applied one or more times daily. The
topical formulations will also contain one or more pharmaceutically
acceptable excipients.
[0044] A large number of excipients have now been tested for
compatibility with norketotifen, and excipients have been
identified that are compatible with norketotifen. Examples of
compatible excipients, are antioxidants, such as sulfites or
ascorbates, at concentrations of about 0.05 percent to about 3
percent, specifically about 0.1 percent to about 0.25 percent by
weight; buffering agents, such as for, example, phosphates,
borates, citrates and acetates, at concentrations of about 0.01
percent to about 4 percent by weight; chelating agents, such as,
for example, edetate or chitosan polysaccharides, at concentrations
of about 0.01 percent to about 10 percent, specifically about 0.01
percent to about 2.0 percent by weight; emollients, such as, for
example, glycerin or propylene glycol, at concentrations of about
0.1 percent to about 10 percent, specifically about 0.1 percent to
about 2.0 percent by weight; gelling agents, such as, for example,
alginates or gelling polymers, at concentrations of about 0.05
percent to about 10 percent, specifically about 0.1 percent to
about 2.5 percent by weight; in situ gelling agents, such as
alginate/HPMC (hydroxypropyl methylcellulose) or polyacrylic acid
(Carbopol)/HPMC, at concentrations of about 0.5 percent to about 10
percent, specifically about 0.1 percent to about 2.5 percent by
weight; humectants, such as, for example, polyethylene glycol or
propylene glycol, at concentrations of about 0.05 percent to about
10 percent by weight; stabilizers, such as methylcellulose or
chitosan, at concentrations of about 0.05 percent to about 4
percent, specifically about 0.05 percent to about 2.0 percent by
weight; combined stabilizer/solubilizers, such as for example
.alpha.-, .beta.- or .gamma.-cyclodextrin, at concentrations of
about 0.1 percent to about 20 percent by weight; surfactants, such
as, for example glyceryl stearate or polyethoxylated castor oil, at
concentrations of about 0.05 percent to about 4.0 percent,
specifically about 0.1 percent to about 2.0 percent by weight; and
viscosity-adjusting agents, such as, for example, methylcellulose
or propylene glycol alginate, at concentrations of about 0.1
percent to about 10 percent, specifically about 2.0 percent to
about 5.0 percent by weight.
[0045] Numerous compositions using said excipients have been
prepared and tested using an HPLC method for the determination of
concentrations of norketotifen that has been developed for this
purpose.
[0046] The actual dosage levels of active ingredients in the
pharmaceutical compositions disclosed herein may be varied so as to
obtain the desired therapeutic effect. Thus the amount of drug used
varies and will depend on factors such as the administration form,
the severity of the disease, the frequency of dosing, and other
circumstances (such as general health, age, etc.) known to the
patient, the caretaker of the patient and/or the caring
physician.
[0047] The therapeutically effective oral doses of norketotifen
useful for treating human patients with atopic dermatitis (AD) will
be determined by the caring physician and are generally 0.5 mg to
20 mg (calculated as free base), dosed orally as the free base or
as a salt, such as for example the hydrochloride or mesylate salts
or the hydrogen fumarate salt, once, twice or more times daily. In
one embodiment, the treatment is once daily dosing. The
therapeutically effective dose may be administered less than once
daily, such as for example two to six times weekly, as determined
by the patient, the caretaker of the patient and/or the caring
physician. Typically, after therapeutic efficacy has been
established, the dosing of norketotifen may be decreased from daily
dosing to dosing two to six times weekly.
[0048] The actual dosage levels of norketotifen in the topical
compositions disclosed herein may be from 1 percent to 10 percent
by weight, but may be varied so as to obtain the desired
therapeutic effect.
[0049] In general, the therapeutically active pulmonary doses of
norketotifen, useful for treating patients with the previously
defined pulmonary diseases, are 0.5 mg to 20 mg administered with
an aerolizer, a nebulizer, a dry powder inhaler, a metered dose
inhaler, and the like, once or more times daily.
[0050] The embodiments disclosed herein provide methods for
treatment of immunologic, inflammatory and skin disorders in human
patients, while avoiding the sedating side effects of ketotifen.
The embodiments also provide treatment of dermal microbial
disorders in human patients. These methods comprise administering
to the human patient in need of such treatment, effective amounts
of norketotifen free base or a pharmaceutically acceptable salt
thereof, at a dosing frequency to be determined by the individual
human patient, the caretaker of the patient and/or the caring
physician. In one embodiment, dosing frequency is once daily, while
the topical dosing frequency is one or multiple times daily.
[0051] In addition to the use of norketotifen as single-drug
medication in human patients, embodiments disclosed herein also
provide methods for co-administration of norketotifen with at least
one drug of the following classes: adrenergic beta-agonists,
insecticidal agents, antibacterial agents, antiviral agents,
vitamin D or vitamin D analogs, corticosteroids, cyclooxygenase
inhibitors, leukotriene antagonists, lipoxygenase inhibitors,
inhibitors of one or more cytokines, such as for example kinase
inhibitors and immunomodulators, such as for example cyclosporine.
The co-administration may be temporary or may be chronically used
in the patient. The co-administered drug can be administered to the
patient separately or can be co-formulated with norketotifen for
oral, parenteral, pulmonary or dermal administration. Thus, as an
example, norketotifen can be administered orally and/or topically
and the co-administered drug may also be administered orally or
topically. Furthermore, norketotifen and the co-administered drug
may not be administered simultaneously. Thus, as an example,
norketotifen may be administered orally once daily, while a
co-administered corticosteroid may be administered orally or
topically, one or more times daily.
[0052] Of specific importance is co-administration of norketotifen
with an anti-inflammatory corticosteroid, since onset time of the
therapeutic activity of norketotifen in dogs suffering from atopic
dermatitis may be shortened by said co-administration. For this
purpose, norketotifen can be combined with a corticosteroid, for
example for the first one to four weeks of therapy. The full-dose
dose of the corticosteroid depends on the potency of said
corticosteroid. High-potency or mid-potency corticosteroids are
preferred. As an example, if the mid-potency corticosteroid is used
in combination with norketotifen, the regular dose of said
corticosteroid may be 0.1 to 5.0 mg (dosed once or multiple times
daily) and can be combined with a regular oral dose of
norketotifen, which may be from 0.5 mg to 20 mg (dosed once or
multiple times daily and calculated as free base) to the selected
patient. The combination treatment of norketotifen and a
corticosteroid like prednisone or prednisolone can be administered
to patients suffering from atopic dermatitis and other dermal
diseases. The combination of norketotifen and a corticosteroid can
be administered in double dose for the first one to seven days of
therapy. Following the initial treatment of the human patient with
a combination of norketotifen and a corticosteroid, the continued
treatment will consist of norketotifen monotherapy, as described
above.
[0053] In one embodiment, norketotifen is initially orally or
topically co-administered for one to four weeks of therapy with a
corticosteroid in a therapeutically active dose, thereafter
followed by monotherapy, wherein norketotifen or a pharmaceutically
acceptable salt thereof, when orally administered, is administered
in an amount of 0.5 mg to 20 mg, dosed once or multiple times daily
and calculated as free base.
[0054] Those skilled in the art of pharmacology will realize that
corticosteroid-sparing doses will be obtained by co-administration
of norketotifen at normal, oral daily doses of between 0.5 mg and
20 mg dosed once or multiple times daily and calculated as free
base with doses of corticosteroids that are lower than said doses
when the corticosteroids are administered as monotherapy. Thus, in
patients suffering from atopic dermatitis, it will be possible to
reduce the common therapeutic doses of corticosteroids up to 50
percent or more by co-administration of norketotifen at doses
ranging from 0.5 mg to 20 mg dosed once or multiple times daily and
calculated as free base. A regular dose of prednisone to patients
suffering from atopic dermatitis depends on the size and age of the
patient and the severity of the disease and may range from 0.5 mg
to 20 mg once or multiple times daily, or the dose may be higher in
selected patients. During co-administration with norketotifen the
doses of prednisone in the patient may be decreased to between 0.2
mg and 10 mg, or the doses of the steroid may be reduced further in
selected patients, which reductions are herein considered to be
"half the regular dose" of said steroid. As usual, the actual doses
to individual patients may vary due to various factors, such as for
example the severity of the medical conditions, tolerance to acute
drug side effects, age and weight of the patient. Thus the doses of
the corticosteroid to individual patients may be higher or lower
than described herein.
[0055] When used for the treatment of dermal disorders other than
atopic dermatitis in human patients, co-administration of
norketotifen and a corticosteroid, such as for example prednisone,
will result in a corticosteroid-sparing treatment. The same doses
of norketotifen and the corticosteroid as described herein for
corticosteroid-sparing treatment of atopic dermatitis, can be used.
As always, the dose to an individual patient will have to be
modified according to the weight and age of the patient, the
severity of the disease and other circumstances known to the
patient, caretaker of the patient and/or the caring physician.
[0056] Similarly, it will be possible to reduce the doses of an
immunosuppressant drug, such as for example cyclosporine with
co-administration of norketotifen. Thus, in patients suffering from
atopic dermatitis, it will be possible to reduce common therapeutic
doses of an immunosuppressant drug by 50 percent or more by
co-administration of norketotifen at normal oral doses of
norketotifen, which are ranging from 0.5 mg to 20 mg, once or
multiple times daily, thereby reducing the potentially very serious
side effect of the immunosuppressant drug. As an example during
co-administration with a normal dose of norketotifen, the initial
dose of the immunosuppressant drug cyclosporine may be decreased in
a selected patient from about 2 mg/kilogram bodyweight/day to about
1 mg/kilogram bodyweight/day, which is an example of what herein is
called "half the regular dose". The dose of the immunosuppressant
drug can be further reduced by dosing the drug every other day, or
even more seldom. Examples of immunosuppressant drugs are
cyclosporine (Atopica.RTM., Novartis), pimecrolimus (Elidel.RTM.,
Novartis, Meda), tacrolimus (Protopic.RTM., Astellas Pharma) and
oclacitinib (Apoquel.RTM., Zoetis). Some immunosuppressant drugs
can also be called immunomodulating drugs or calcineurin
inhibitors.
[0057] When used for treatment of other dermal disorders than
atopic dermatitis in human patients, co-administration of
norketotifen and an immunomodulating drug, such as for example
cyclosporine, will use the same dose-ranges as described herein for
the treatment of atopic dermatitis. As always, the dose to an
individual dog will have to be modified according to the drug used,
the weight of the patient, the severity of the disease and other
circumstances known to the patient, the caretaker of the patient
and/or the caring physician.
[0058] In one aspect, topical drug administration of norketotifen
is combined with oral administration of norketotifen. For example,
a child suffering from atopic dermatitis may have patches of skin
that become infected by the fungus Malassezia, due for example, to
excessive scratching of the skin. By combining systemic (oral
syrup) administration and local (topical cream) administration,
both the skin infection and the underlying dermatitis can be
treated simultaneously. Advantageously, neither the oral nor the
dermal administration of norketotifen will be expected to produce
sedation of the patient.
[0059] When used for pulmonary inflammatory indications, such as
for example asthma, COPD, chronic bronchitis and bronchial
hyperreactivity, norketotifen can be combined with a
therapeutically active dose of a bronchodilating adrenergic
beta-receptor agonist and one or both of the drugs can be
administered by inhalation, nasal, parenteral, topical,
transdermal, rectal, sublingual or oral administration. The
adrenergic beta-receptor agonist can be selected from the group
consisting of albuterol (salbutamol), terbutaline, fenoterol,
formoterol, and salmeterol and the optically and therapeutically
active isomers of the beta-receptor agonists. Since bronchial
inflammation and broncoconstriction are hallmarks of asthma, the
co-administrations of the anti-inflammatory drug norketotifen and a
bronchodilating adrenergic beta-agonist will be advantageous to
patients suffering from asthma and other pulmonary disorders. An
additional advantage is the known inhibition of beta-receptor
downregulation by certain anti-inflammatory drugs. In one
embodiment, the method further comprises co-adminisering a steroid
with norketotifen and an adrenergic beta-agonist.
[0060] In one embodiment, norketotifen and an adrenergic
beta-receptor agonist are co-administered in a formulation suitable
for pulmonary administration.
Examples
Example 1
Antihistaminic Activity In Vitro
[0061] H.sub.1 receptor binding studies were conducted utilizing
human recombinant receptors. In the studies shown herein,
affinities of the test compounds for histamine H.sub.1-receptors
were assessed using a binding assay, where [.sup.3H] pyrilamine was
used as the ligand and the test compounds were used at increasing
concentrations. The specific binding of the radioactive ligand to
the receptor was defined as the difference between total binding
and nonspecific binding, determined in the presence of excess
unlabeled ligand. IC.sub.50 values (the concentration that inhibits
50% of specific binding of the ligand) are determined by non-linear
regression analysis of the competition curves. The results are
shown in Table 1.
TABLE-US-00001 TABLE 1 Antihistaminic activity in vitro
ANTIHISTAMINE H-1/IC50 (nM) KETOTIFEN 2.3 NORKETOTIFEN 11
LORATADINE (Claritin .RTM.) 1,500 DESLORATADINE (Clarinex .RTM.) 16
DIPHENHYDRAMINE (Benadryl .RTM.) 84
[0062] Ketotifen is probably the most potent antihistaminic
compound ever to be approved as a drug for human use. Norketotifen
has less affinity for the histamine H-1 receptors than ketotifen,
but is more potent than the three reference compounds. Loratadine
is a poorly active prodrug and is metabolized in the liver to
desloratadine.
Example 2
Antihistaminic Activity In Vivo
[0063] Male rats (150-200 g) were fasted overnight and twelve hours
after dorsal depilation, the animals were orally pretreated with
the test compound(s). Four dorsal test areas were marked with
permanent ink, carefully avoiding the area closest to the spine.
Sixty minutes after the dosing with the test compound, two
intradermal injections of histamine (50 .mu.L; 1.0 mg/ml of
histamine di-HCl) were performed, one on each side on the back of
the animal Two intradermal injections of the vehicle for the
histamine solution were also performed. Evans blue dye (20 mg/kg)
was injected intravenously one minute prior to the intra-dermal
injections of histamine and the histamine vehicle. Twenty minutes
were allowed for the wheal response to fully develop, whereupon the
animals were euthanized and the dorsal skin with the intradermal
wheals were deflected. The blue spotted areas were measured in
square millimeters and the duplicate wheal areas were averaged. In
vehicle-treated animals, the wheal area, on average, was increased
by histamine by 94 and 82 mm.sup.2 for the vehicles used during the
norketotifen and ketotifen experiments, respectively. The
inhibition was calculated in percent difference from said baseline
values. Results are shown in Table 2. (DPH=diphenhydramine,
Benadryl.RTM.)
TABLE-US-00002 TABLE 2 Antihistaminic activity in vivo Test
compound Histamine Saline Histamine effect Inhibition Dose (mg/kg)
(mm.sup.2) (mm.sup.2) (mm.sup.2) (%) Vehicle* 116 .+-. 5 22 .+-. 1
94 -- Vehicle** 107 .+-. 4 25 .+-. 1 82 -- Ketotifen; 1.0 68 .+-. 6
21 .+-. 2 47 43 Ketotifen; 10 24 .+-. 2 22 .+-. 3 2 98
Norketotifen; 1.0 114 .+-. 8 22 .+-. 1 92 2 Norketotifen; 10 39
.+-. 2 22 .+-. 1 17 82 Norketotifen; 50 10 .+-. 1 12 .+-. 1 0 100
DPH; 10 31 *Vehicle for norketotifen expts **Vehicle for ketotifen
expts
[0064] Results: When plotted, ketotifen was found to be 2 to 3
times more potent than norketotifen as an antihistamine in these in
vivo studies. Norketotifen was significantly more potent than
diphenhydramine.
Example 3
Anti-Inflammatory Effects In Vitro
[0065] In these studies, histamine was the marker compound for
inflammatory mediators that are released from mast cells and other
pro-inflammatory cells in patients with atopic inflammatory
diseases. The inhibition of stimulated histamine release from human
leukocytes (buffy coat) by test articles was studied. Leukocytes
were obtained from healthy volunteers and histamine release was
induced by incubation (20 min/37.degree. C.) with the calcium
ionophore A23187 (5 .mu.M) in the presence or absence of a test
article. Histamine was analyzed by enzyme-immune assays, using
commercially available kits and a microplate reader (MRX,
Dynatech). The test articles were evaluated, in duplicate, at five
concentrations. The study results are shown in Table 3.
TABLE-US-00003 TABLE 3 Inhibition of inflammatory mediator
(histamine) release. Test article IC50 (.mu.M) Ketotifen 91
Norketotifen 9.2
[0066] Norketotifen was approximately 10 times more potent than
ketotifen as an inhibitor of histamine release from
pro-inflammatory cells.
Example 4
Anti-Inflammatory Effects In Vivo: Oral Administration
[0067] In order to investigate the effects of oral administration
of the test compounds in dermal inflammation, a croton oil model
was used as is known in the art. This test consists of topical
application of 20 .mu.l of 1.0% croton oil to each ear of male
mice, weighing 28-32 g. The weight of untreated ears of these
animals is 30-32 mg. Application of the croton oil results in an
inflammatory response. The weight of croton oil-treated ears was
determined and the percent increase in ear weight is calculated.
Test articles were dosed systemically (iP).
[0068] The effects of 10 mg/kg of RS-ketotifen and RS-norketotifen
at 90 and 120 minutes after administration of test articles are
shown in the following table. All results represent mean ear
weights (.+-.S.E.M.) from 10 ears. The results are shown in Table
4.
TABLE-US-00004 TABLE 4 Anti-inflammatory effects in vivo; oral
administration Average Ear weight (mg) .+-. SEM Test Article 90 min
120 min Control 48 .+-. 2 51 .+-. 2 Ketotifen 37 .+-. 1 42 .+-. 1
Norketotifen 34 .+-. 1 40 .+-. 1
[0069] Both test compounds demonstrated dermal anti-inflammatory
effects. All or part of the anti-inflammatory effect of ketotifen
is assumed to be due to norketotifen that is rapidly formed as a
metabolite of ketotifen after oral administration of ketotifen to
rodents
Example 5
Antipruritic Effects In Vivo: Oral Administration
[0070] Antipruritic effects were tested in vivo in CD-1 female mice
aged 10-12 weeks. The hair was clipped over the rostral part of the
back at the interscapular level of the mice one day before dosing.
Before testing, the mice were placed in individual clear plastic
cages for at least one hour for acclimation. After fasting for 1.5
hours, the animals were dosed orally with the test article,
dissolved in a vehicle consisting of 1% methylcellulose/water, 10
mL/kg body-weight. Sixty minutes after oral dosing, an intradermal
injection of histamine (300 nmol in 20 .mu.l phosphate buffered
saline (PBS), pH 7.4) was administered into the clipped area
Immediately after the histamine injection, the bouts of scratches
were counted for 40 minutes. Scratching induced by the histamine
vehicle PBS served as control.
[0071] Norketotifen was tested in escalating doses. In addition, a
supramaximal dose of 100 mg/kg of norketotifen was tested. The
reference compounds JNJ7777120, desloratadine and oclacitinib were
dosed orally at 20 mg/kg. The vehicle for the reference compound
JNJ7777120 was 20% hydroxypropyl-.beta.-cyclodextrin in water. The
vehicle for the reference compound desloratadine was the same as
the vehicle for norketotifen. The reference compound desloratadine
is a selective histamine H-1 inhibitor, oclacitinib is a Jason I/II
kinase inhibitor and JNJ7777120 is a selective histamine H-4
inhibitor.
[0072] The test results are shown in Table 5. The numbers of
pruritic bouts for Norketotifen, DES and OCLA are expressed in
percent of the same Vehicle (100% corresponds to 92 pruritic
bouts). Norketotifen inhibited histamine-induced pruritus in a
dose-dependent manner and a supramaximal dose (100 mg/kg)
demonstrated complete inhibition. A test of the vehicle for JNJ
demonstrated 112 bouts of pruritus. Scratches induced by the
histamine-free vehicle PBS (not shown in Table 5) served as control
(6.+-.3 bouts of scratching; N=8)
[0073] This test used histamine to induce pruritus. Histamine H-1
and H-4 receptors express constitutive activity and the H-1 and H-4
receptor signaling does not require the availability of free
histamine. The histamine inhibitors are "inverse agonists" at both
receptor types. The constitutive histamine receptors are known to
be up-regulated during inflammation. The results from this study
are shown in Table 5.
TABLE-US-00005 TABLE 5 Antipruritic activity in mice; oral
administration. Bouts/40 min Bouts as % Test Article N Mean .+-.
SEM of Vehicle Controls Vehicle for NORK, 9 92.0 .+-. 15.3 100 DES
and OCLA Norketotifen 1 mg/kg 7 84.7 .+-. 11.6 92 Norketotifen 3
mg/kg 7 34.1 .+-. 9.6 37 ** Norketotifen 10 mg/kg 6 17.8 .+-. 3.1
19 ** Norketotifen 100 mg/kg 8 8.3 .+-. 2.8 9 *** Desloratadine 20
mg/kg 7 112.0 .+-. 14.5 122 Oclacitinib 20 mg/kg 8 50.9 .+-. 18.7
55 * J&J7777120 20 mg/kg 8 63.6 .+-. 11.7 57 * Vehicle for
JNJ7777120 8 112.0 .+-. 14.3 (100) * means P .ltoreq. 0.05 ** means
P .ltoreq. 0.01 *** means P .ltoreq. 0.001 NORK = norketotifen DES
= desloratadine OCLA = oclacitinib
Example 6
Sedative Effects in Mice
[0074] The sedation study in mice has previously been used by
Schering in the loratadine project (U.S. Pat. No. 4,659,716, 1987)
and by Sepracor in the desloratadine project (U.S. Pat. No.
5,595,997), which patents are hereby included by reference for
their disclosure of sedation studies. In short, physostigmine (1.0
mg/kg to 2.0 mg/kg, s.c.) generally results in 100% lethality when
given to groups of mice (10 mice/group) transferred into a small
volume of space. Mice administered a sedating drug prior to the
physostigmine injection are protected from the stress and survive.
In the present study, test compounds were given orally 60 minutes
prior to physostigmine injection. The number of surviving (sedated)
mice was counted 30 minutes after injection of the physostigmine
dose. Results are shown from tests that were performed between the
years 1997 and 2009 in Table 6.
TABLE-US-00006 TABLE 6 Sedative effects in mice Oral dose Sedated
(mg/kg) animals VEHICLE -- 0/10 NORKETOTIFEN 83 3/10 NORKETOTIFEN
100 3/10 NORKETOTIFEN 150 3/10 NORKETOTIFEN 180 6/10 S-NORKETOTIFEN
100 0/10 S-NORKETOTIFEN 150 0/10 R-NORKETOTIFEN 100 3/10
R-NORKETOTIFEN 150 3/10 KETOTIFEN (Zaditen .RTM.; Gen-1) 25 5/10
KETOTIFEN (Zaditen .RTM.; Gen-1) 50 8/10 KETOTIFEN (Zaditen .RTM.;
Gen-1) 100 10/10 CYPROHEPTADINE (Periactin .RTM.; Gen-1) 100 9/10
PYRILAMINE (Mepyramine .RTM.; Gen-1) 100 8/10 HYDROXYZINE (Atarax
.RTM.; Gen-1) 100 9/10 DIPHENHYDRAMINE (Benadryl .RTM.; Gen-1) 50
5/10 DIPHENHYDRAMINE (Benadryl .RTM.; Gen-1) 100 8/10 ASTEMIZOLE
(Hismanal .RTM.; Gen-2) 100 1/10 NORASTEMIZOLE (Soltara .TM.;
Gen-2) 100 0/10 LORATADINE (Claritin .RTM.; Gen-2) 150 1/10
DESLORATADINE (Clarinex .RTM.; Gen-2) 150 0/10 TERFENADINE (Seldane
.RTM.; Gen-2) 150 0/10 FEXOFENADINE (Allegra .RTM.; Gen-2) 150 0/10
Gen-1 = Generation-1 (sedating antihistamines) Gen-2 = Generation-2
(non-sedating antihistamines)
[0075] Results: All registered Generation-1 antihistamines were
sedating in mice and all registered Generation-2 antihistamines
were free from sedation, using the physostigmine lethality test.
This test system has therefore been considered to be highly
reliable in differentiation between sedative and non-sedative
antihistaminic compounds. Racemic norketotifen expressed sedative
activity in this test system.
Example 7
Sedative Effects in Humans
[0076] Sedation studies were performed in human volunteers, where
the volunteers were administered norketotifen orally at doses of 5
mg or 10 mg (o.d. and b.i.d. for one to four days), which is
believed to be about a 10-fold and 20-fold, respectively, higher
dose than the amount of norketotifen formed as a metabolite after a
clinical dose of ketotifen 1.0 mg. The test articles were
administered in gelatin capsules and vehicle-capsules were empty.
The volunteers were dosed at 8-10 AM and had been fasted overnight
before dosing. All observations regarding sedation/sleepiness were
made by the individual volunteers and by a scientist with previous
experience in human CNS-studies. As a positive control, ketotifen
was administered as a single oral dose of 2 mg to the volunteers
(two tablets Zaditen.RTM., Paladin, each tablet containing 1 mg
ketotifen). All test articles were in the form of hydrogen fumarate
salts.
[0077] The test results demonstrated complete lack of sedation in
all volunteers who had been administered racemic norketotifen at
oral doses of 5 mg or 10 mg (o.d. or bid for up to four days. The
test results also demonstrated that ketotifen caused sedation in
the human volunteers, which is not surprising, since
sedation/drowsiness is a dose-dependent and dose-limiting side
effect of ketotifen. As understood by those skilled in medical
sciences, lack of sedation of RS-norketotifen in humans implies
lack of sedation of both S- and R-norketotifen in humans.
[0078] Humans are known to express sedation within one hour after a
single oral dose of Generation-1 antihistamines, such as for
example diphenhydramine (Benadryl.RTM., McNeill) or ketotifen
(Zaditen.RTM., Novartis). The test article was therefore usually
administered for one day only, although some experiments were
performed with the test article being administered for three
consecutive days.
[0079] Surprisingly, norketotifen did not cause sedation in the
human volunteers, which is contrary to the results from earlier
animal studies using the mouse physostigmine model (Example 6),
which had been considered to be of high predictive value. To our
knowledge, this is the first study that has been performed to
specifically study sedative side effects of RS-norketotifen in
humans and it has now surprisingly been found that racemic
norketotifen is completely free from sedative effects in humans,
even after administration of high oral doses.
Example 8
Toxicological Effects
[0080] Acute toxicological studies were performed in rats
(Sprague-Dawley; M and F; 200-250 grams). The animal-sparing
Up-and-Down Procedure, recommended by FDA and OECD, was used. Both
oral and intravenous toxicity tests were performed.
[0081] The acute toxicity, expressed as estimated LD50 and
calculated in mg/kg body weight of norketotifen and ketotifen are
shown in Table 7. Both compounds were administered as hydrogen
fumarate salts.
[0082] Results: Norketotifen is significantly less toxic than
ketotifen after intravenous administration and after oral
administration.
TABLE-US-00007 TABLE 7 Toxicological effects Acute toxicity
(estimated LD50) mg/kg TEST SYSTEM NORKETOTIFEN KETOTIFEN RAT;
intravenous 10-15 5-10 RAT; oral 1500-2000 <300
Example 9
Anti-Inflammatory Effects In Vivo. Topical Drug Administration
[0083] In order to investigate the effects of topical
administration of the test compounds in dermal inflammation, a
modified croton oil model was used. About 10 mg of a cream
containing 1.0% norketotifen or a vehicle cream was applied to both
ears of mice for 30 minutes. The cream was then removed and a
solution of 1% croton oil in 20 n1 acetone was applied to both
ears. After the acetone had dried (10 seconds), the cream
containing the test article (or vehicle) was reapplied and the
animals were returned to their cages. At 0, 30, 60 and 90 minutes
following the croton oil administration, groups of four animals
were anesthetized with halothane and euthanized. Cream was wiped
from the ears and ears were removed and weighed.
[0084] The effects of 10 mg of a cream containing 1.0 percent
RS-norketotifen at 30, 60 and 90 minutes after administration of
test articles are shown in the following table 8. All results
represent mean ear weights (.+-.S.E.M.) from 8 ears.
TABLE-US-00008 TABLE 8 Anti-inflammatory effects of norketotifen in
vivo after dermal application Time after Croton Oil Average Ear
Weight (mg) .+-. S.E.M Application (min) Vehicle RS-Norketotifen 0
(predose) 35 .+-. 1 36 .+-. 1 30 41 .+-. 1 36 .+-. 1 60 41 .+-. 1
37 .+-. 2 90 46 .+-. 2 36 .+-. 2
[0085] In this study, the test article (racemic norketotifen) was
applied topically to the ears of mice in the concentration 1.0
percent. A cream containing 1.0 percent (w/w) of norketotifen
completely inhibited the pro-inflammatory of topically applied
croton oil.
[0086] Since a cream containing 1.0 percent norketotifen completely
inhibited the inflammation, it was concluded that the concentration
of norketotifen in topical formulations could be further decreased
to 0.1 percent.
Example 10
Antipruritic Effects In Vivo. Topical Drug Administration
[0087] Antipruritic effects were tested in vivo in CD-1 female mice
aged 10-12 weeks, according to methods known in the art. The hair
was clipped over the rostral part of the back at the interscapular
level of the mice one day before dosing. Before testing, the mice
were placed in individual clear plastic cages for at least one hour
for acclimation. The animals were dosed topically by applying to
the skin, the formulated cream, containing 1.0%
RS-norketotifen.
[0088] In preparing 1% creams, the free base of RS-norketotifen was
dissolved in ethanol, resulting in a 2.5% solution. Lanolin was
weighed and liquified by submerging the vessel containing lanolin
in hot water. While the lanolin was liquid, it was rapidly nixed
(by vortexing) with the 2.5% norketotifen solution in ethanol,
resulting in a 1.0 percent solution. The ethanol/lanolin solution
was allowed to solidify, resulting in a cream which consisted of
1.0% RS-norketotifen in 60% lanolin/40% ethanol. A cream containing
60% lanolin/40% ethanol served as control. Sixty minutes after the
topical application of the cream, an intradermal injection of
histamine (300 nmol in 20 .mu.l phosphate buffered saline (PBS), pH
7.4) was administered into the clipped area Immediately after the
histamine injection, the bouts of scratches by the mice were
counted for 40 minutes. Test results are shown in Table 9.
TABLE-US-00009 TABLE 9 Effects of norketotifen cream on histamine-
induced pruritus in mice. Bouts as % Test Article N Bouts/40 min of
Vehicle Controls Cream (vehicle) 8 144 .+-. 16 100 Cream w. NORK 8
61 .+-. 9 42 ** 10 mg/ml ** means P .ltoreq. 0.01 NORK =
norketotifen
[0089] From these results, it can be concluded that a single
topical application of a cream containing 1.0 percent
RS-norketotifen reduced the histamine-induced pruritus in mice by
58% when compared with the Vehicle Control. It was concluded that
since a concentration of 1.0 percent of norketotifen offered 58
percent inhibition within a short time of dermal application, the
concentration of norketotifen in topical formulations for clinical
use can be further decreased to 0.1 percent.
Example 11
Antimicrobial Tests of Norketotifen
[0090] Several studies have been performed to evaluate possible
antimicrobial activities of norketotifen. Shown here are the
results from a standard microbiological test, where the results are
expressed as MIC (Minimal Inhibitory Concentration) of the test
article against selected exemplary dermal bacteria (such as for
example Streptococcus aureus) and dermal fungi (such as for example
Malassezia sp) that are commonly found in human with dermal
diseases. Tests of the antimicrobial activities of norketotifen
against other fungi and other bacteria, such as for example the
fungi Candida albicans and Malassezia pachydermatis and the
bacterium Helicobacter pylori have demonstrated potent
antimicrobial activities of norketotifen. All the MIC-tests shown
in Table 10 were performed in duplicates, using 10 concentrations
of the test articles. The Initial Numbers Controls had to
demonstrate .gtoreq.1.times.10 4 CFU/ml (CFU=Colony Forming Units)
for each test microorganism. The test culture tubes/plates were
incubated in temperatures and durations appropriate for each
microorganism (S. aureus: 36.degree. C. and 24 hours; M. globosa:
30.degree. C. and 24 hours). Results from tests with the bacterium
Staphylococcus aureus and the fungus Malassezia globosa are shown
in Table 10.
TABLE-US-00010 TABLE 10 Antimicrobial activities of norketotifen S.
aureus * M. globosa Test Article MIC (mg/ml) MIC (mg/ml)
RS-norketotifen HF 0.5 0.25 R-norketotifen HF 1.0 0.5
S-norketotifen HF 0.5 0.25 * Methicillin-resistant S. aureus (MRSA)
or non-resistant S. aureus.
[0091] The results indicate that topical (dermal) compositions
containing 1.0% (10 mg/ml) of norketotifen (or an isomer thereof)
express significant antimicrobial efficacy, particularly when
applied to the skin of patients suffering from atopic dermatitis,
psoriasis and other dermal diseases, where the epidermal barriers
are severely malfunctioning.
Example 12
Exemplary Oral Dosage Formulation
[0092] The active ingredient is blended with the lactose and
cellulose until a uniform blend is formed. The blue lake is added
and further blended. Finally, the calcium stearate is blended in,
and the resulting mixture is compressed into tablets using for
example a 9/32-inch (7 mm) shallow concave punch. Tablets of other
strengths may be prepared by altering the ratio of active
ingredient to the excipients or to the final weight of the tablet.
Those skilled in the art realize that oral formulations can also be
in the form of for example a capsule or a liquid formulation.
TABLE-US-00011 TABLE 11 Tablet formulations Ingredient Amount per
tablet Amount per batch Norketotifen 40 mg 400 g Microcrystalline
cellulose 30 mg 300 g Lactose 70 mg 700 g Calcium stearate 2 mg 20
g FD&C Blue #1 Lake 0.03 mg.sup. 300
Example 13
Exemplary Topical (Dermal) Formulations
[0093] Examples of topical (dermal) solutions, ointments, emulsions
and creams are shown in Tables 12-18.
TABLE-US-00012 TABLE 12 Examples of topical solutions formulations
containing norketotifen Excipients in percent 1008 1009 S1010
Norketotifen HF (%) 0.2 0.2 0.2 Sodium phosphate dibasic 0.473 --
0.160 Sodium phosphate 0.460 -- -- monobasic, monohydrate NaCl
0.480 -- -- Sodium citrate -- 0.300 -- Propylene glycol -- 1.750 --
Methylcellulose -- -- 0.500 Glycerin -- -- 2.400 Water q.s. q.s.
q.s. pH 4.6-6.2 4.6-6.2 4.6-6.2 Norketotifen HF = norketotifen
hydrogen fumarate
[0094] If needed, the viscosity can be adjusted by a
viscosity-modifying agent to obtain the preferred viscosity. The
final acidity can be adjusted by adjusting the concentrations of
the buffering agents or by adding an acid or a base.
[0095] The solution formulations were prepared by adding the
excipients, one at a time to an appropriate amount of water,
followed by mixing until dissolved. Once all excipients had been
added and dissolved, norketotifen was added to the solution of
excipients and mixed continuously until dissolved. The acidity of
the solutions was measured and adjusted by modifying the buffer
system or by adding an acid or a base solution to the desired pH.
If needed, viscosity and tonicity were adjusted as indicated.
TABLE-US-00013 TABLE 13 An example of hydrophilic ointments/gels
containing norketotifen Batch G1009 Norketotifen HF (%) 1.0 PEG 300
(%) 69.0 PEG 3350 (%) 30.0
[0096] The solubility of norketotifen was significantly increased
in certain formulations, such as gels and ointments where the
solvents were not water. Thus, the solubility of norketotifen was
about 1.0 percent in formulation G1009 (Table 13), where the
solvent was a mixture of two polyethylene glycols.
[0097] The composition of Table 13 was prepared by mixing the two
polyethylene glycols in a suitable container and heating to
60-65.degree. C. This heating step melts the high molecular weight
polyethylene glycol. Next, norketotifen was added and the
composition was mixed until the active ingredient was dissolved.
Finally, the composition was cooled with mixing to allow the
ointment/gel to thicken. The viscosity was 30,000 cP or greater.
The pH range for these compositions was not measured since the
formulations were non-aqueous. If needed, the tonicity can be
adjusted by adding a tonicity-adjusting agent to obtain the
preferred tonicity.
TABLE-US-00014 TABLE 14 An example of hydrophobic ointments/gels
containing norketotifen Batch G1012 Norketotifen HF (%) 1.0
Propylene glycol (%) 10.0 Glyceryl stearate (%) 0.5 Cetyl alcohol
(%) 0.5 White petrolatum q.s.
[0098] Batch G1012 contained propylene glycol as a solvent for
norketotifen, glycerol stearate and cetyl alcohol as surfactants
and white petrolatum as base.
[0099] The hydrophobic ointment was prepared by dissolving
norketotifen in propylene glycol. The solubility of norketotifen
was about 1.0 percent in propylene glycol. Next, glyceryl stearate,
cetyl alcohol, and white petrolatum were added to a suitable
container and heated to 65-70.degree. C. This heating step melts
the surfactants and the petrolatum. Next, norketotifen solution was
slowly added and the composition mixed until the solvent was
dispersed. Finally, the composition was cooled with mixing to allow
the ointment to thicken. If needed, acidity can be adjusted by
adding an acid solution or a base solution to obtain the preferred
acidity. If needed, viscosity can be adjusted with a
viscosity-modifying agent to obtain the preferred viscosity.
TABLE-US-00015 TABLE 15 Examples of topical emulsions containing
norketotifen ED1012b ED1015b Norketotifen HF (%) 1.0 1.0 Sodium
phosphate dibasic (%) 0.160 0.160 Propylene glycol (%) 1.850 1.850
Castor oil (%) 1.250 1.250 Polyoxyl 35 castor oil (%) 1.000 1.000
Methylcellulose (%) 0.200 -- 1.0N HCl or q.s. to q.s. to 1.0N NaOH
(%) target pH target pH Water q.s. (2) q.s. (2) pH 5 to 7 5 to
7
[0100] The batches ED1012b and ED1015b contained a phosphate
buffer, propylene glycol as solvent/moisturizer/tonicity modifier,
parabens as preservatives, castor oil and polyoxyl castor oil as
surfactants and methylcellulose (if used) as a stabilizer/viscosity
modifier. Emulsions containing norketotifen can be used at pH of
about 5.0 to about 7.0.
[0101] The selected emulsions in Table 15 were prepared by adding
propylene glycol, castor oil, ethoxylated castor oil, and water to
a suitable container. The contents of the container were sonicated
with a 1/2'' ultrasonic probe (Sonics Inc. Vibra Cell) for 20
minutes. The resulting emulsion droplets were mostly less than 0.5
microns. The emulsion was filtered through a 0.22-micron cellulose
acetate filter. After filtration, norketotifen and buffer salts
were added. The viscosity of norketotifen emulsions can be adjusted
by a compatible viscosity-modifying agent.
TABLE-US-00016 TABLE 16 An example of topical liposome compositions
containing norketotifen LIP1011 Norketotifen HF (%) 1.0 Sodium
phosphate dibasic (%) 0.16 Glycerin (%) 2.40 Soy lecithin (%) 1.00
Cholesterol (%) 0.05 Water q.s.
[0102] Topical liposome compositions were made, comprising
norketotifen at concentrations preferably between 1.0 percent and
10.0 percent. The liposome compositions were having a preferred
viscosity that ranged from 1.000 to 200,000 cP. Topical liposome
compositions have pH of 4 to 7, preferably pH 5.2 to 6.2. The
liposome compositions are approximately iso-osmotic. Said emulsions
also contained excipients, such as humectants, viscosity modifying
agents, tonicity agents, chelating agents, buffers, surfactants,
mucoadhesives and antioxidants. Said liposome emulsions were
designed for once-daily dermal administration or for repeated
dermal administrations from two to five times daily to a mammal in
need thereof.
[0103] Incorporating norketotifen in a selected liposome
composition will enhance residence time in the skin and improve
drug delivery to the tissues. An exemplary liposome composition
containing norketotifen is shown in Table 16. The acidity can be
changed by adjustment of the buffer or by adding an acid or a base
as known to those skilled in the art.
TABLE-US-00017 TABLE 17 An example of a dermal suspension
containing norketotifen SUS1011 Norketotifen FB (%) 5.0 Poloxamer
407 0.6 Boric acid 0.2 Sodium chloride 0.2 Water q.s. pH 5.0 to 7.0
Norketotifen FB = norketotifen free base
[0104] Both norketotifen salts and norketotifen FB can be
formulated as suspensions. Several experiments were done and
acidity was adjusted over a wide range. It was determined that
emulsions can be used at pH of about 5.0 to about 7.0. An example
of a preferred suspension containing norketotifen free base is
shown in Table 17, where all percent are w/w. Viscosity will be
adjusted by addition of one or more viscosity-modifying agents,
which will offer stability to the suspensions.
TABLE-US-00018 TABLE 18 An example of a dermal cream containing
norketotifen PT 112706 Norketotifen FB (%) 1.0 Ethanol (%) 39.0
Lanolin (%) 60.0 Surfactant(s) (%) (0.2) Antioxidant(s) (%)
(0.2)
[0105] Both norketotifen salts and norketotifen free base can be
formulated as creams. An example of a cream containing norketotifen
free base is shown in Table 18, where all percent are w/w.
[0106] In preparing creams containing 1 percent of the free base of
norketotifen, the active ingredient was dissolved in ethanol,
resulting in a 2.5 percent solution. Lanolin was weighed and
liquefied by submerging the vessel containing lanolin in hot water.
While the lanolin was a liquid, it was rapidly mixed (by vortexing)
with the 2.5% norketotifen solution in ethanol to result in a 1.0
solution. The ethanol/lanolin solution was allowed to cool off and
solidify, resulting in a cream which consisted of 1 percent
norketotifen in the lanolin/ethanol cream, which will be kept in a
closed tube to avoid evaporation. To improve shelf-life, a
surfactant (such as for example glyceryl stearate, 0.1 to 0.3
percent) and an antioxidant (such as for example ascorbic acid, 0.1
to 0.3 percent) can optionally be added, as shown in Table 18.
[0107] Dosage forms for topical (dermal) application may be
prepared for example as solutions (Table 12), as hydrophilic
ointments (Table 13), as hydrophobic ointments (Table 14), as
emulsions (Table 15), as liposome compositions (Table 16), as
suspensions (Table 17), and as creams (Table 18). The dermal
compositions may also contain additional excipients, and a large
number of excipients have been tested for compatibility with
norketotifen. Dermal composition may contain one or more active
compounds and the compounds may be prepared as bases or salts.
Dermal composition may be applied to the skin under occlusive
dressing or as a constituent of a dermal delivery system ("patch,"
etc.)
[0108] As used herein, the terms "pharmaceutically acceptable
salts" or "a pharmaceutically acceptable salt thereof" refer to
norketotifen salts, which have been prepared from pharmaceutically
acceptable non-toxic acids. Exemplary pharmaceutically acceptable
acid as for the compound of the present invention include acetic,
benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,
ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric,
p-toluenesulfonic, succinic, sulfuric, tartaric, and the like. The
hydrochloride salt and the hydrogen fumarate salt are particularly
preferred.
[0109] The term "topical" (as for example "topical treatment") as
used herein is synonymous to the term "dermal" (as for example
"dermal treatment".) The term "dermal" (as for example "dermal
infection") as used herein is synonymous to the term "skin" (as for
example "skin infection".) The term "antimicrobial" as used herein
refers to antibacterial, antifungal and antiviral activities or
effects. The term "formulation" (as for example "dermal
formulation") as used herein is synonymous to the term
"composition" (as for example "dermal composition").
[0110] The use of the terms "a" and "an" and "the" and similar
referents (especially in the context of the following claims) are
to be construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. The
terms first, second etc. as used herein are not meant to denote any
particular ordering, but simply for convenience to denote a
plurality of, for example, layers. The terms "comprising",
"having", "including", and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to")
unless otherwise noted.
[0111] Recitation of ranges of values are merely intended to serve
as a shorthand method of referring individually to each separate
value falling within the range, unless otherwise indicated herein,
and each separate value is incorporated into the specification as
if it were individually recited herein. The endpoints of all ranges
are included within the range and independently combinable. All
methods described herein can be performed in a suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as"), is intended merely to better illustrate the
invention and does not pose a limitation on the scope of the
invention unless otherwise claimed. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the invention as used
herein.
[0112] While the invention has been described with reference to a
preferred embodiment, it will be understood by those skilled in the
art that various changes may be made and equivalents may be
substituted for elements thereof without departing from the scope
of the invention. In addition, many modifications may be made to
adapt a particular situation or material to the teachings of the
invention without departing from essential scope thereof.
Therefore, it is intended that the invention not be limited to the
particular embodiment disclosed as the best mode contemplated for
carrying out this invention, but that the invention will include
all embodiments falling within the scope of the appended
claims.
* * * * *