F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. –
NASAL COMPOSITIONS COMPRISING ALCAFTADINE
2. Applicant(s)
(a) NAME : ALKEM LABORATORIES LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alkem House, Senapati Bapat Marg, Lower Parel,
Maharashtra, Mumbai 400013, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which
it is to be performed :
2
[1] The present application claims the benefit of Indian Patent Application
No. 202121015680, filed April 1, 2021, which is hereby incorporated by
reference.5
Field of the Invention
[2] The present invention relates to a nasal pharmaceutical composition
comprising alcaftadine or a pharmaceutically acceptable salt and optionally one or
more pharmaceutically acceptable excipients, methods of treating allergic rhinitis,10
allergic rhino-conjunctivitis, or symptoms thereof (such as nasal congestion) with
the nasal pharmaceutical composition, and methods of preparing it.
Background of the Invention
[3] Allergic rhinitis is among the most common disease affecting globally.15
Allergic rhinitis persists throughout the life. It has been reported that allergic
rhinitis self-reported prevalence ranges from 2% to 25% in children and 1% to
greater than 40% in adults. Symptoms of allergic rhinitis include sneezing,
rhinorrhea, nasal itching and nasal congestion. Ocular symptoms are also
common. Allergic rhino-conjunctivitis is associated with itching and redness of20
the eyes and tearing.
[4] Allergic rhinitis is characterized by inflammation of the nasal mucous
membranes because of a complex response to nasal allergen exposure. The levels
of histamine are raised in allergic rhinitis. Allergic rhinitis is characterised by
sensitization-formation and expression of antigen specific IgE, followed by25
inflammation in two phases viz. early and late phase. Mast cells appear to be
activated during the early reaction and basophils during the late reaction. The
early phase develops in 30 minutes and disappears, characterized by sneezing and
rhinorrhea. The early phase response involves cross linking of IgE molecules
leading to degranulation of mast cells and release of mediators such as histamine,30
3
tryptase, prostaglandins, chymase, kinins, heparins and leukotrienes. The late
reaction is inflammatory in nature and shows nasal obstruction approximately six
hours after exposure to allergens and subsides slowly. The late phase response is
characterized by an inflammatory cellular influx of T lymphocytes, basophils and
eosinophils. The late phase response involves mediators released by cells5
including leukotrienes, kinins, histamine, cytokines and chemokines. These
mediators lead to the symptoms of rhinorhhea, nasal congestion, sneezing, itching,
redness of nose, watery eyes, swelling of rhino-pharyngeal region, increase in ear
pressure and postnasal drip.
[5] Nasal congestion is one of the most common symptoms encountered in10
primary care and specialist clinics, and it is the symptom that is most bothersome
to patients. Mucosal inflammation is responsible for many of the distinct and
interrelated factors that contribute to congestion, including increased venous
engorgement, elevated nasal secretions, and tissue swelling or edema.
[6] Research shows that more than 60% of patients with allergic rhinitis are15
not satisfied with their current treatment, particularly due to lack of efficacy
(Bousquet et al., J Allergy Clin Immunol., 2009 September, 124(3):428-33).
[7] US 5468743 discloses alcaftadine and methods of treating allergic
conditions.
[8] US 8664215 discloses an ophthalmic alcaftadine composition and methods20
of treating or preventing ocular allergy.
[9] CN 102283849 discloses a combination of alcaftadine and
pseudoephedrine as well as a combination of alcaftadine, pseudoephedrine and
acetaminophen for the relief of symptoms related to allergic rhinitis and allergic
conjunctivitis.25
[10] US 5164194 discloses a medicament for nasal use or for use in the
eye which contains as an active ingredient azelastine.
[11] US 2009/0324699 discloses a pharmaceutical composition
comprising a corticosteroid and an antihistamine, a polar lipid liposome, and a
4
pharmaceutically acceptable aqueous carrier. However, such compositions
involve use of a complex process for manufacturing such liposomes.
[12] WO 2019/022225 describes a preservative-free aqueous
pharmaceutical composition containing alcaftadine or a salt thereof at a
concentration of more than 0.15% w/v.5
[13] There exists a need for intranasal compositions which provide
improved relief including a faster onset of action compared to the currently
available therapies.
Summary of Invention10
[14] The present invention relates to a nasal pharmaceutical
composition, such as a nasal spray, useful for the treatment of allergic rhinitis,
allergic rhino-conjunctivitis, and nasal congestion comprising alcaftadine or a
pharmaceutically acceptable salt thereof and a mucoadhesive agent. The
composition may be an aqueous composition and optionally includes one or more15
pharmaceutically acceptable excipients. The composition imparts enhanced
mucoadhesion to the nasal mucosa, optimal penetration in the nasal mucosa, and
minimal nasal irritation. The composition also has improved organoleptic
properties that provide better patient compliance and treatment outcomes than
other antihistamine products which provide an unpleasant taste, such as azelastine20
products. In one embodiment, the composition has a faster onset of relief
compared to other nasally administered antihistamines, such as olopatadine. In
one embodiment, the composition, when intranasally administered, has an onset
of action in less than 15 or 10 minutes. In another embodiment, the composition
is devoid of an unpleasant taste.25
[15] In one embodiment, the nasal pharmaceutical composition is an
aqueous pharmaceutical composition comprising (i) about 0.1 to 1.0% w/w
alcaftadine or a pharmaceutically acceptable salt thereof (such as alcaftadine) (for
example, about 0.125 to 0.75% w/w alcaftadine, such as 0.125, 0.25, 0.35, 0.45,
5
0.5, 0.6, and 0.75% w/w), (ii) about 0.01 to 1.0% w/w hydroxypropyl methyl
cellulose (HPMC) (such as an HPMC having a viscosity of 20 cPs or lower (e.g.,
6 cPs)), (iii) about 0.068 to about 6.8% w/w of sodium chloride, (iv) about 0.0019
to about 0.19% w/w monobasic sodium phosphate, (v) about 0.005 to about 0.5%
w/w disodium edetate (e.g., disodium edetate dihydrate), and (vi) about 0.0025 to5
about 0.25% w/w benzalkonium chloride. The composition may include amounts
of sodium hydroxide and/or hydrochloric acid to achieve the desired pH, such as a
pH of 6.5 to 7.0 or 6.3 to 7.3.
[16] In one embodiment, the nasal pharmaceutical composition is an
aqueous pharmaceutical composition comprising (1) about 0.125% w/w10
alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050 %
w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate, (5)
about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl methyl
cellulose, and (7) about 0.25% w/w hydrochloric acid.
[17] In another embodiment, the nasal pharmaceutical composition is an15
aqueous pharmaceutical composition comprising (1) about 0.25% w/w
alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050 %
w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate, (5)
about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl methyl
cellulose, and (7) about 0.25% w/w hydrochloric acid.20
[18] In yet another embodiment, the nasal pharmaceutical composition
is an aqueous pharmaceutical composition comprising (1) about 0.50% w/w
alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050 %
w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate, (5)
about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl methyl25
cellulose, and (7) about 0.25% w/w hydrochloric acid.
[19] The nasal pharmaceutical compositions described herein are stable.
In one embodiment, the nasal pharmaceutical composition, after 24 hours, 3 or 6
months storage at 25° C and 60% relative humidity or 40° C and 75% relative
6
humidity has at least 90, 95, or 98% of the initial amount of active ingredient
(here, alcaftadine) present. In another embodiment, the amount of any single
individual impurity (of the active ingredient) is no more than 0.5%, 0.2%, 0.1% or
0.05% by weight, based on the amount of active ingredient (alcaftadine) present.
In yet another embodiment, the amount of total impurities (of the active5
ingredient) is no more than 3%, 2%, 1%, 0.5%, 0.3%, or 0.2% by weight, based
on the amount of active ingredient (alcaftadine) present.
[20] Another embodiment is a method of treating allergic rhinitis,
allergic rhino-conjunctivitis, or symptoms thereof (such as nasal congestion) in a
patient in need thereof by intranasally administering an effective amount of10
alcaftadine or a pharmaceutically acceptable salt thereof. Preferably, the nasal
pharmaceutical composition of the present invention is intranasally administered.
In one embodiment, the patient suffers from allergic rhinitis. In another
embodiment, the patient suffers from seasonal allergic rhinitis. In yet another
embodiment, the patient suffers from perennial allergic rhinitis. In yet another15
embodiment, the patient suffers from moderate to severe seasonal allergic rhinitis.
In yet another embodiment, the patient suffers from moderate to severe perennial
allergic rhinitis.
[21] Yet another embodiment is a method of reducing the use of nasal
decongestants by intranasally administering an effective amount of alcaftadine or20
a pharmaceutically acceptable salt thereof. Preferably, the nasal pharmaceutical
composition of the present invention is intranasally administered.
[22] Yet another embodiment is a method of inhibiting, suppressing, or
preventing nasal polyps in a patient in need thereof by intranasally administering
an effective amount of alcaftadine or a pharmaceutically acceptable salt thereof.25
Preferably, the nasal pharmaceutical composition of the present invention is
intranasally administered.
[23] The methods and nasal compositions described herein can result in
better patient compliance than other treatments for allergic rhinitis as the present
7
inventors discovered that alcaftadine, when intranasally administered does not
result in an unpleasant taste as with the antihistamine azelastine.
[24] Yet another embodiment is a method of preparing a nasal
pharmaceutical composition (such as those described herein) comprising the steps
of (i) dissolving a pH adjusting agent (e.g., hydrochloric acid), a tonicity5
adjustment agent (e.g., sodium chloride), and alcaftadine in water to form an
active phase solution, (ii) mixing a mucoadhesive agent (such as HPMC) with
water and then adding a chelating agent (e.g., disodium edetate such as disodium
edetate dihydrate) and a buffering agent (e.g., monobasic sodium phosphate) to
form a bulk solution, (iii) adding the bulk solution to the active phase solution,10
(iv) adding a preservative (e.g., benzalkonium chloride) to the solution prepared in
step (iii), (v) optionally, adjusting the pH of the solution using sodium hydroxide
(e.g., to a pH of 6.5 to 7.0 or 6.3 to 7.3), and (vi) optionally, adding water (e.g.,
purified water) to the solution to obtain a desired volume and/or concentration for
each component.15
Detailed Description of the Invention
[25] The inventors of the present invention have found that alcaftadine
or a pharmaceutically acceptable salt thereof provides an advantageous
composition for treatment of allergic rhinitis, allergic rhino-conjunctivitis, and20
symptoms thereof (such as nasal congestion). The nasal pharmaceutical
composition provides a rapid onset of action, for instance within 0.15, 0.1, 0.08,
or 0.05 hours. The composition provides improved relief from nasal itching and
nasal decongestion. Furthermore, the composition has fewer side effects. Other
antihistaminic agents have central nervous system adverse effects due to inverse25
agonism at H1-receptors, inhibition of neurotransmission in histaminergic
neurons, and impairment of alertness, cognition, learning, and memory that is not
necessarily associated with sedation, drowsiness, fatigue, or somnolence.
Intranasal administration of alcaftadine provides a local effect without systemic
8
absorption and therefore without CNS side effects. For instance, an intranasal
composition of alcaftadine is associated with fewer adverse reactions such as
headache and epistaxis as compared to olapatadine and azelastine nasal spray.
[26] The inventors have also found that formulating alcaftadine or a
pharmaceutically acceptable salt thereof with a mucoadhesive agent improves the5
residence time of the composition in the nasal cavity, thereby enhancing drug
absorption across nasal mucosa and relief of nasal symptoms, such as nasal
congestion, compared to formulations devoid of mucoadhesive agents.
[27] One embodiment is a nasal pharmaceutical composition of
alcaftadine or a pharmaceutically acceptable salt thereof, characterized in that the10
composition has a faster onset of relief compared to other anti-histaminics (such
as azelstine and olopatadine). In one preferred embodiment, the composition
provides a rapid onset of action with a Tmax for alcaftadine of about 0.25 hours or
less (such as 0.2, 0.15, 0.1, 0.08, or 0.05 hours).
[28] In a further embodiment, the present invention provides a15
pharmaceutical composition of alcaftadine or a pharmaceutically acceptable salt
thereof for the treatment of symptoms associated with allergic rhinitis such as
sneezing, nasal itching, nasal inflammation, nasal irritation, rhinorrhea, nasal
pruritus and nasal congestion. In one embodiment, the composition provides
relief of more than one symptom associated with allergic rhinitis. The20
composition is an effective nasal decongestant. As a result, patients can reduce
their concomitant use of other nasal decongestants.
[29] The nasal pharmaceutical composition of the present invention can
be administered in the nostril(s) or to the eyes once or twice a day.
25
Alcaftadine
[30] Alcaftadine (6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-
imidazo[2,1-b][3]benzazepine-3-carboxaldehyde is an anti-allergic therapeutic
9
agent that has inverse agonist effects on H1, H2, and H4 receptors, as well as mast
cell-stabilizing effects.
[31] H2 receptors play a vital role in nasal congestion. H4 receptors
influence the inflammatory response (eosinophils, T cells, dendritic cells,5
basophils, mast cells, and sensory nerve cells). Alcaftadine has higher binding
affinity to H1 and H2 receptors compared to other antihistamines namely
azelastine and olapatadine, and demonstrates higher efficacy in controlling total
nasal symptoms, including congestion. H1 and H2 receptor signaling contributes
to pruritus, redness of nose, cytokine secretion, fibroblast proliferation, adhesion10
molecule expression, microvascular permeability and production of procollagens.
Estelle et al., J Allergy Clin Immunol, 2011, 128:1139-50. H4 receptor signaling
has been shown to affect cytokine and chemokine release, chemotaxis, and
adhesion molecule expression in allergic rhinitis in experimental allergic rhinitis
model studies. Hanuskova et al., Open Journal of Molecular and Integrative15
Physiology, 2013, 3:6-14.
Dosage Form
[32] The nasal pharmaceutical composition composition may be a nasal
solution, nasal suspension, nasal powder, nasal spray, nasal aerosol, nasal drops,20
nasal ointment, nasal inhalation, or nasal gel.
[33] In one embodiment, the nasal pharmaceutical composition
comprises a therapeutically effective amount of alcaftadine (or a pharmaceutically
acceptable salt thereof) in the range of 0.05% w/w to 5 % w/w. For example, the
topical composition may include 0.1% w/w to 4% w/w, such as 0.1% w/w to 3%25
w/w, 0.1% w/w to 2% w/w, or 0.1 w/w % to 1% w/w (for example, 0.125% w/w,
10
0.25% w/w or 0.50 % w/w) of alcaftadine, based upon 100% total weight of the
composition. In one embodiment, the alcaftadine is present in dissolved form in
the composition.
[34] The nasal pharmaceutical composition may include one or more
pharmaceutically acceptable excipients. Suitable excipients include, but are not5
limited to, mucoadhesive agents, buffering agents, osmotic agents or tonicity
adjustment agents, chelating agents, permeation enhancers, pH adjusting agents,
suspending agents, thickening agents (or viscosity modifiers), preservatives,
solubilizers, and vehicles (such as solvents).
[35] The nasal pharmaceutical composition can include a mucoadhesive10
agent to provide better adherence to nasal mucosa and improve retention of
alcaftadine on the nasal mucosa. Suitable mucoadhesive agents include, but are
not limited to, cellulose derivatives (such as hydroxypropylmethyl cellulose
(HPMC), hydroxyethylcellulose, and carboxymethylcellulose sodium), povidone,
chitosan, poloxamers (Pluronic®) and natural gums (such as guar gum and15
xanthan gum). A preferred mucoadhesive agent is HPMC, such as HPMC having
a viscosity of 20 cPs or lower (e.g., 6 cPs). In one embodiment, the mucoadhesive
agent has a viscosity in the range of 1 to 20 cPs (e.g., 3 to 10 cPs) in order to
irritating sensation of the nose which may occur with higher viscosity
mucoadhesive agents. The mucoadhesive agents may be used in an amount from20
0.01% to 10% by weight of the total composition, preferably 0.01% w/w to 1%
w/w (based on the composition), such as 0.01% w/w to 0.9% w/w, 0.01% w/w to
0.7% w/w, 0.01% w/w to 0.5% w/w, 0.01% w/w to 0.3% w/w, or 0.01% w/w to
0.1% w/w. The mucoadhesive agents may be temperature dependent which upon
applying or spraying in the nasal cavity form a gel on the nasal mucosa. The gel25
provides longer contact and retention time for the alcaftadine on the nasal mucosa
thereby providing extended relief from nasal decongestion.
[36] Suitable buffering agents include, but are not limited to, monobasic
sodium phosphate, disodium hydrogen phosphate, dibasic sodium phosphate,
11
tribasic sodium phosphate, and dibasic potassium phosphate. Buffering agents
may be used in an amount from 0.009 % w/w to 1.9 % w/w of the composition,
such as 0.0009 % w/w to 0.19% w/w, 0.0009 % w/w to 0.1% w/w, 0.009 % w/w
to 0.1% w/w, 0.007 % w/w to 0.1% w/w, or 0.005 % w/w to 0.1% w/w.
[37] Osmotic agents or tonicity adjustment agents refer to agents that5
are specifically added to the composition to increase the solute level in the
composition and contribute to achieving isotonicity of the nasal composition.
Tonicity is the ‘effective osmolality’ and is equal to the sum of the concentrations
of the solutes which have the capacity to exert an osmotic force across the
membrane. Suitable tonicity adjustment agents include, but are not limited to,10
sodium chloride, dextrose (e.g., dextrose USP), glycerine (e.g., glycerin USP),
mannitol (e.g., mannitol USP), and potassium chloride (e.g., potassium chloride
USP). The tonicity adjustment agent may be used in an amount from 0.050% to
7% by weight of the total composition. In one embodiment, the nasal
pharmaceutical composition contains sodium chloride in an amount sufficient to15
cause the composition to have a nasally acceptable osmolality, preferably 50-700
mOsmol/kg. In a preferred embodiment, the nasal pharmaceutical composition
contains 0.068% w/w to 6.8% w/w of sodium chloride, based on the composition,
such as 0.068% w/w to 5.8% w/w, 0.068% w/w to 4.8% w/w, 0.058% w/w to
3.8% w/w, 0.058% w/w to 2.8% w/w, or 0.058% w/w to 1.8% w/w.20
[38] Suitable chelating agents include, but are not limited to, edetate
disodium, diethylene-triamine-pentaacetic acid (DTPA), iminodisuccinic acid,
and ethylenediamine disuccinic acid. The chelating agent may be used in an
amount from 0.005% to 0.5% by weight of the composition. In one embodiment,
the composition includes edetate disodium dihydrate in the range of 0.005% w/w25
to 0.5% w/w, based on the composition, such as 0.005% to 0.4% w/w, 0.005%
w/w to 0.3% w/w, 0.005% w/w to 0.2% w/w, or 0.005% w/w to 0.1% w/w.
[39] The permeation enhancer can enhance the permeation of
alcaftadine through the nasal mucosa. The permeation enhancer can be a
12
hydroxyl group-containing compound. Non-limiting examples of hydroxyl
group-containing compounds that may be used as permeation enhancers include
alcohols (such as ethanol), diols (such as propylene glycol (also known as 1,2-
propanediol), 1,3-propanediol, butylene glycol (including 1,3-butanediol, 1,2-
butanediol, 2,3-butanediol, and 1,4 butanediol), hexylene glycol, dipropylene5
glycol, 1,5-pentanediol, 1,2-pentanediol, 1,8-octanediol, etohexadiol, p-menthane-
3,8 diol, and 2-methyl-2,4-pentanediol), triols (such as glycerin), polyols (such as
suitable polymers containing multiple hydroxyl groups) (including polyethylene
glycols (PEGs), polypropylene glycols, polysorbates, and sorbitan esters, and
suitable sugar alcohols), cyclitols (such as pinitol, insoitol), cyclic diols (such as10
cyclohexane diol), aromatic diols (such as hydroquinone, bisphenol A, resorcinol
and catechol) or any combination thereof. Other permeation enhancer include,
but are not limited to, bile salts, Vitamin E TPGS, Alkyl Maltosides, non-ionic,
anionic or amphoteric surfactants having HLB value 8-14 or combination thereof.
The non-limiting examples of such permeation enhancers are sodium15
glycocholate, sodium taurocholate, dodecyl maltosides, tridecyl maltoside or
tetradecyl maltosides, or any combination thereof. In one embodiment, the
permeation enhancer may be present in the nasal pharmaceutical composition in
an amount from 0.5 % to 50% by weight of the total composition, such as 2%
w/w, 5 % w/w, 7.5% w/w, 10%w/w, 20% w/w, and 40 % w/w.20
[40] Suitable pH adjusting agents include, but are not limited to
hydrochloric acid, sodium hydroxide, ammonium hydroxide, magnesium
hydroxide, sulphuric acid, phosphoric acid, citric acid, malic acid, and tartaric
acid. Preferred pH adjusting agents include hydrochloric acid and sodium
hydroxide. The pH adjusting agent may be used in an amount sufficient to obtain25
a pH of about 3 to about 11, such as about 5 to about 9, about 6 to about 8, about
6.3 to about 7.3, or about 6.7 to about 7.3.
[41] Suitable preservatives include, but are not limited to, benzalkonium
chloride, potassium sorbate, methyl paraben, propyl paraben, chlorbutol,
13
chlorocresol, chlorhexidine, sodium benzoate, benzyl alcohol, and propylene
glycol. In one embodiment, preservatives may be used in an amount from
0.0025% to 2.5% by weight of the total composition. In another embodiment, the
composition contains 0.0025% w/w to 0.25% w/w of a preservative, based on the
weight of the composition, such as 0.0025% w/w to 0.15% w/w, 0.0025% w/w to5
0.1% w/w, or 0.0025% w/w to 0.05% w/w. In one preferred embodiment, the
composition includes benzalkonium chloride. In one embodiment, the
composition includes from 0.0025% w/w to 2.5% w/w benzalkonium chloride,
based on the weight of the composition.
[42] In another embodiment, the nasal pharmaceutical composition is10
preservative-free.
[43] Suitable vehicles and solubilizers include, but are not limited to,
purified water, glycols such as propylene glycol, polyethylene glycol,
polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and
polyoxyethylene fatty acid esters. The vehicle or solubilizer may be present in the15
composition in an amount from 5% w/w to 20% w/w, based on the weight of the
composition, such as 5% w/w to 15% w/w, 5% w/w to 10% w/w, or 5% w/w to
7% w/w. Propylene glycol and polyethylene glycol may be used in an amount
from 5% w/w to 20 % w/w of the total composition. Purified water may be used
in an amount to make the formulation 100% by weight of the total composition.20
[44] In one embodiment, the nasal pharmaceutical composition has an
osmolality of 50 to 700 mOsmol/kg, such as 100 to 600 mOsmol/kg or 100 to 500
mOsmol/kg.
[45] In one embodiment, the nasal pharmaceutical composition (e.g., a
nasal solution) has a viscosity of about 1.5 to about 4 cPs, preferably about 2 cPs.25
The viscosity can be measured with a Brookfiled (DV II+ Pro) AD-VS-02, with a
ULA spindle and a 10 mL sample at a 100 rpm, ambient temperature, and a 60
second measurement time. The viscosity measurement can be the average of
three measurements.
14
[46] In one embodiment, the pH of the nasal pharmaceutical
composition ranges from about 3.5 to about 11. In a preferred embodiment, the
pH is in the range of about 3 to about 11, preferably in the range of about 5 to
about 9, more preferably in the range of about 6 to about 8, more preferably in
the range of about 6.3 to about 7.3. In another embodiment, the pH of the nasal5
pharmaceutical composition ranges from about 6 to about 8, such as at about 6.7
to 7.3 (such as 6.8, 6.9, 7.0, 7.1, or 7.2). The nasal pharmaceutical composition
may include a buffering agent in an effective amount to maintain the pH at about
3 to about 11, about 6 to about 8, or about 6.7 to 7.3 (such as 6.8, 6.9, 7.0, 7.1, or
7.2).10
[47] Yet another embodiment is an aqeuous pharmaceutical
composition for nasal administration to a patient comprising (1) about 0.125%
w/w alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050
% w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate,
(5) about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl15
methyl cellulose, and (7) about 0.25% w/w hydrochloric acid.
[48] Yet another embodiment is an aqeuous pharmaceutical
composition for nasal administration to a patient comprising (1) about 0.25% w/w
alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050 %
w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate, (5)20
about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl methyl
cellulose, and (7) about 0.25% w/w hydrochloric acid.
[49] Yet another embodiment is an aqeuous pharmaceutical
composition for nasal administration to a patient comprising (1) about 0.50% w/w
alcaftadine, (2) about 0.0125% w/w benzalkonium chloride, (3) about 0.050 %25
w/w disodium edetate, (4) about 0.019 % w/w monobasic sodium phosphate, (5)
about 0.68 % w/w sodium chloride, (6) about 0.1% w/w hydroxypropyl methyl
cellulose, and (7) about 0.25% w/w hydrochloric acid.
15
[50] In one embodiment, the nasal pharmaceutical compositions
described herein has a droplet size distribution at 3 cm with a D10 of no more
than 40 μm (e.g., from about 5 to about 30 μm), D50 of no more than 80 μm (e.g.,
from about 10 to about 50 μm), a D90 of no more than 180 μm (e.g., from about
40 to about 100 μm), and/or a SPAN of no more than 3 (e.g., from about 1.0 to5
about 3.0). In one embodiment, the spray content uniformity is from about 85 to
about 115%.
[51] In another embodiment, the nasal pharmaceutical composition of
the present invention has a spray pattern at 3 cm with a Dmax of no more than 75
mm (e.g., about 20 to about 75 mm), a Dmin of no more than 50 mm (e.g., about 1510
to about 50 mm), an ovality of no more than 2.0 (e.g., about 0.5 to about 2.0), and
an area of no more than 2000 mm2. In yet another embodiment, the nasal
pharmaceutical composition of the present invention has a spray pattern at 6 cm
with a Dmax of no more than 100 mm (e.g., about 50 to about 100 mm), a Dmin of
no more than 75 mm (e.g., about 40 to about 75 mm), an ovality of no more than15
2.0 (e.g., about 0.5 to about 2.0), and an area of no more than 5000 mm2.
Preparation Method
[52] One embodiment is a method of preparing a nasal pharmcaceutical
composition (such as those described herein) comprising the steps of (i)20
dissolving a pH adjusting agent (e.g., hydrochloric acid), a tonicity adjustment
agent (e.g., sodium chloride), and alcaftadine in water to form an active phase
solution, (ii) mixing a mucoadhesive agent (such as HPMC) with water and then
adding a chelating agent (e.g., disodium edetate such as disodium edetate
dihydrate) and a buffering agent (e.g., monobasic sodium phosphate) to form a25
bulk solution, (iii) adding the bulk solution to the active phase solution, (iv)
adding a preservative (e.g., benzalkonium chloride) to the solution prepared in
step (iii), (v) optionally, adjusting the pH of the solution using sodium hydroxide
(e.g., to a pH of 6.5 to 7.0 or 6.3 to 7.3), and (vi) optionally, adding water (e.g.,
16
purified water) to the solution to obtain a desired volume and/or concentration for
each component.
[53] In a further embodiment of the present invention, the nasal
pharmaceutical composition is in the form of an aerosol or a solution which
includes a delivery system, such as a bottle or a pump delivery or a high-density5
polyethylene container equipped with a nasal spray pump, metered-dose spray
pump, inhaler, with dropper and other forms for intra-nasal usage. The
composition can be delivered in a mist of spray droplets or minor droplets to coat
the nasal mucosa upon administration. Preferred pumps for use in such products
of the invention are metered multi-dose pumps. The selection of the pump is10
based on the desired dose per spray volume and spray pattern appropriate for
topical delivery to the nasal mucosa. The dosage per spray may range from 1 ml
to 100 ml, where each spray may deliver 100 μl to 400 μl per spray.
[54] Compositions prepared by the process as described herein can
withstand the accelerated stability conditions of temperature and relative humidity15
and maintain their physical and chemical integrity at accelerated conditions of
stability.
Methods of Treatment
[55] Another embodiment is a method of treating allergic rhinitis,20
allergic rhino-conjunctivitis, or symptoms thereof (such as nasal congestion) in a
patient in need thereof by intranasally administering an effective amount of
alcaftadine or a pharmaceutically acceptable salt thereof (such as a nasal
pharmaceutical composition comprising alcaftadine or a pharmaceutically
acceptable salt thereof). Preferably, the nasal pharmaceutical composition of the25
present invention is intranasally administered. In one embodiment, the patient
suffers from allergic rhinitis. In another embodiment, the patient suffers from
seasonal allergic rhinitis. In yet another embodiment, the patient suffers from
perennial allergic rhinitis. In yet another embodiment, the patient suffers from
17
moderate to severe seasonal allergic rhinitis. In yet another embodiment, the
patient suffers from moderate to severe perennial allergic rhinitis. In one
embodiment, the nasal pharmaceutical composition is intranasally administered as
1 or 2 sprays per nostril of the patient once daily. In another embodiment, the
nasal pharmaceutical composition is intranasally administered as 1 or 2 sprays per5
nostril of the patient twice daily. Each spray of the nasal pharmaceutical
composition may comprise about 171.25 mcg, about 342.5 mcg, about 685 mcg of
alcaftadine.
[56] The nasal pharmaceutical composition of the present invention can
be administered in the nostril(s) or to the eyes once or twice a day. In one10
embodiment, from about 340 to about 5500 mcg of alcaftadine is administered
daily (such as in one dose once daily, or in two equally divided doses twice daily).
For instance, from about 170 to about 2740 mcg of alcaftadine can be
administered to each nostril daily.
[57] In one embodiment, one spray of a nasal pharmaceutical15
composition containing alcaftadine (such as described herein) is administered per
nostril once per day.
[58] In another embodiment, two sprays of a nasal pharmaceutical
composition containing alcaftadine (such as described herein) are administered
per nostril once per day.20
[59] In yet another embodiment, one spray of a nasal pharmaceutical
composition containing alcaftadine (such as described herein) is administered per
nostril twice per day.
[60] In yet another embodiment, two sprays of the nasal pharmaceutical
composition described herein are administered per nostril twice per day.25
[61] Each spray of the nasal pharmaceutical composition may provide
from about 170 to about 685 mcg of alcaftadine (on a free base basis), such as
about 171.25, 342.5, or 685 mcg of alcaftadine.
18
[62] In one embodiment, from about 170 to about 1370 mcg alcaftadine
are administered once or twice daily to each nostril. In another embodiment,
about 171.25, 342.5, 685, or 1370 mcg of alcaftadine is administered to each
nostril once daily. In yet another embodiment, about 171.25, 342.5, 685, or 1370
mcg of alcaftadine is administered to each nostril twice daily.5
[63] In one embodiment of the methods described herein, from about
340 to about 5480 mcg of alcaftadine are administered daily to a patient in need
thereof. In another embodiment, from about 340 to about 1370 mcg of alcaftadine
are administered daily to a patient in need thereof. In yet another embodiment,
from about 340 to about 690 mcg of alcaftadine are administered daily to a patient10
in need thereof.
[64] In one embodiment, the patient is 6 to 17 years of age. In another
embodiment, the patient is 17 or 18 years of age or older.
Definitions15
[65] By "pharmaceutically acceptable excipients", it is meant any of the
components of a pharmaceutical composition other than the active ingredients and
which are approved by regulatory authorities or are generally regarded as safe for
human or animal use.
[66] As used herein, the term "mucoadhesion" refers to adhesion or20
adherence of a substance to a mucous membrane within the nasal mucosa. In the
context of the present invention, the mucoadhesion is intended to convey a
material that is capable of adhering to the nasal mucosa when placed in contact
with that surface in order to enable compositions of the invention to adhere to that
surface. Such materials are hereinafter referred to together as “mucoadhesives” or25
“mucoadhesive agents.”
[67] The term “allergic rhinitis” includes allergic reactions of the nasal
mucosa and includes hay fever, seasonal allergic rhinitis, and perennial rhinitis
(non-seasonal allergic rhinitis) which are characterized by seasonal or perennial
19
sneezing, rhinorrhea, nasal congestion, pruritus and eye itching, redness and
tearing.
[68] The term “patient” or “subject” refers to a human patient unless
indicated otherwise. The patient can be 12 years of age or older or 18 years of age
or older. The patient can also be 6 to 17 years of age.5
[69] The terms "treat," "treatment," and "treating" in the context of the
administration of a therapy to a patient refers to the reduction or inhibition of the
progression and/or duration of a disease or condition, the reduction or
amelioration of the severity of a disease or condition, and/or the amelioration of
one or more symptoms thereof resulting from the administration of one or more10
therapies.
[70] An “effective amount” is an amount sufficient for a compound to
accomplish a stated purpose relative to the absence of the compound (e.g. reduce
one or more symptoms of a disease or condition). An example of an “effective
amount” is an amount sufficient to contribute to the treatment, prevention, delay,15
inhibition, suppression, or reduction of a symptom or symptoms of a disease or
disorder, which could also be referred to as a “therapeutically effective amount.”
A “reduction” of a symptom or symptoms (and grammatical equivalents of this
phrase) means decreasing of the severity or frequency of the symptom(s), or
elimination of the symptom(s). An “effective amount” of a drug can be an amount20
of a drug that, when administered to a subject, will have the intended prophylactic
effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury,
disease, pathology or condition, or reducing the likelihood of the onset (or
reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
The exact amounts will depend on the purpose of the treatment, and will be25
ascertainable by one skilled in the art using known techniques (see, e.g.,
Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art,
Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage
Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th
20
Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages may be
varied depending upon the requirements of the patient and the compound being
employed. The dose administered to a patient, in the context of the present
disclosure, should be sufficient to effect a beneficial therapeutic response in the
patient over time. The size of the dose may also be determined by the existence,5
nature, and extent of any adverse side-effects. Determination of the proper dosage
for a particular situation is within the skill of the practitioner.
[71] As used herein, unless indicated otherwise, the term “stable” refers
to a pharmaceutical composition of the present invention, which after 3 or 6
months storage at 25° C and 60% relative humidity or 40° C and 75% relative10
humidity has at least 90, 95, or 98% of the initial amount of active ingredient
(here, alcaftadine) present.
[72] As used herein, the term “salts” or “pharmaceutically acceptable
salt”, it is meant those salts, solvate and esters which are, within the scope of
sound medical judgment, suitable for use in contact with the tissues of humans15
and lower animals without undue toxicity, irritation, and allergic response,
commensurate with a reasonable benefit to risk ratio, and effective for their
intended use. Representative acid additions salts include hydrochloride, furoate,
hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate,
stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate,20
maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and
lauryl sulphate salts. Representative alkali or alkaline earth metal salts include
sodium, calcium, potassium and magnesium salts.
[73] The transitional term “comprising,” which is synonymous with
“including,” “containing,” or “characterized by,” is inclusive or open-ended and25
does not exclude additional, unrecited elements or method steps. The specification
will be understood to also include embodiments which have the transitional
phrase “consisting of” or “consisting essentially of” in place of the transitional
phrase “comprising.” The transitional phrase “consisting of” excludes any
21
element, step, or ingredient not specified in the claim, except for impurities
associated therewith. The transitional phrase “consisting essentially of” limits the
scope of a claim to the specified materials or steps “and those that do not
materially affect the basic and novel characteristic(s)” of the claimed invention.
[74] The present invention is further illustrated by reference to the5
following examples which is for illustrative purpose only and does not limit the
scope of the invention in any way.
[75] Examples 1A-1I
[76] The aqueous compositions shown in Tables 1A and 1B below were
prepared.10
22
Table 1A
Ingredient 1A
(%w/w)
1B
(%w/w)
1C
(%w/w)
1D
(%w/w)
1E
(%w/w)
Alcaftadine 0.125 0.25 0.50 0.5 0.5
Benzalkonium
chloride (50%)*
0.025 0.025 0.025 0.025 0.025
Disodium Edetate 0.050 0.050 0.050 0.050 0.050
Monobasic sodium
Phosphate
0.019 0.019 0.019 0.019 0.019
Sodium Chloride 0.68 0.68 0.68 0.68 0.68
Hydroxypropyl
methylcellulose
2910
0.1 0.1 0.1 --
Sodium
Carboxymethylcellu
lose
-- -- -- 0.1 --
Povidone -- -- -- -- 0.1
Hydroxypropylcellu
lose-L
-- -- -- -- --
Hydrochloric acid 0.25 0.25 0.25 0.25 0.25
Sodium Hydroxide q.s. q.s. q.s. q.s. q.s.
Purified water q.s. q.s. q.s. q.s. q.s.
Table 1B
Ingredient 1F
(%w/w)
1G
(%w/w)
1H
(%w/w)
1I
(%w/w)
Alcaftadine 0.25 0.25 0.25 0.5
Benzalkonium chloride
(50%)
0.025 0.025 0.025 0.025
Disodium Edetate 0.050 0.050 0.050 0.050
Monobasic sodium
Phosphate
0.019 0.019 0.019 0.019
Sodium Chloride 0.68 0.68 0.68 0.68
Hydroxypropyl
methylcellulose 2910
-- -- -- --
Sodium
Carboxymethylcellulose
0.1 -- -- --
Povidone - 0.1 -- --
Hydroxypropylcellulose-L -- -- 0.1 0.1
Hydrochloric acid 0.25 0.25 0.25 0.25
Sodium Hydroxide q.s. q.s. q.s. q.s.
Purified water q.s. q.s. q.s. q.s.
23
[77] Examples 1A through 1I include 0.0125% w/w of benzalkonium
chloride since it is incorporated into the composition in the form of a 50%
benzalkonium chloride solution.
[78] Examples 1A-1I were prepared as follows:5
a) Preparation of Active Phase Solution: Hydrochloric acid, sodium
chloride, and alcaftadine were added to a suitable quantity of purified
water and stirred to obtain a clear Active Phase Solution.
b) For aqueous compositions containing them, hypromellose 2910, sodium
carboxymethylcellulose, povidone, or hydroxypropylcellulose-L (low-10
substituted hydroxypropyl cellulose) was added to a suitable quantity of
purified water and stirred to obtain a clear solution.
c) Disodium edetate and monobasic sodium phosphate were added to the
solution prepared in step (b), and stirred to obtain a clear Second Solution.
d) The Second Solution from step (c) was added to the Active Phase Solution15
of step (a) under stirring to obtain a clear solution. The container of the
Second Solution was rinsed with purified water and stirred to obtain a
clear solution, and then also added to the Active Phase Solution.
e) Benzalkonium chloride was added to the solution prepared in step (d) and
stirred to obtain a uniform solution.20
f) The pH of the solution prepared in step (e) was adjusted to 6.3 to 7.3 using
sodium hydroxide (1M).
g) Purified water was added to the solution of step (f) to obtain the desired
concentrations and volume.
[79] Each spray of Examples 1A-1I can provide 137 μL of the25
composition, which would provide 171.25, 342.5, or 685 mcg of alcaftadine for
the compositions containing 0.125, 0.25, and 0.5% w/w alcaftadine, respectively.
[80] The stability of Examples 1A-1I was assessed by measuring the
amount of impurities, pH, viscosity, and osmolality initially and after 3 and 6
24
months (3M and 6M) storage at 25° C and 60% relative humidity (RH) or 40° C
and 75% RH. The results are shown in Table 1C below.
Table 1C
Examples Condition
Related Substances
( % w/w)
pH Viscosity
(cP)
Osmolality
(Osmol/Kg)
Any
Individual
Impurity
Total
Impurities
1A
Initial 0.042 0.171 7.17 1.83 0.275
25°C/60% RH (3M) 0.043 0.105 7.14 1.98 0.303
25°C/60% RH (6M) 0.029 0.086 7.15 1.95 ND
40°C/75% RH (3M) 0.042 0.112 7.15 1.94 0.289
40°C/75% RH (6M) 0.029 0.125 7.16 1.93 ND
1B
Initial 0.033 0.085 7.24 1.88 0.276
25°C/60% RH (3M) 0.041 0.138 6.96 1.95 0.266
25°C/60% RH (6M) 0.030 0.046 7.02 1.996 0.287
40°C/75% RH (3M) 0.040 0.161 6.99 1.97 0.260
40°C/75% RH (6M) 0.044 0.089 7.02 1.94 0.305
1C
Initial 0.050 0.091 7.17 1.84 0.271
25°C/60% RH (3M) 0.042 0.123 7.06 1.95 0.272
25°C/60% RH (6M) 0.042 0.058 7.10 1.81 0.283
40°C/75% RH (3M) 0.044 0.134 7.05 1.95 0.276
40°C/75% RH (6M) 0.037 0.079 7.15 1.83 0.310
1D
Initial 0.053 0.082 6.96 3.34 0.268
25°C/60% RH (3M) 0.042 0.085 6.93 3.07 0.318
25°C/60% RH (6M) 0.042 0.181 6.97 3.16 0.3
40°C/75% RH (3M) 0.039 0.073 6.93 3.08 0.306
40°C/75% RH (6M) 0.070 0.232 6.95 3.07 0.299
25
Examples Condition
Related Substances
( % w/w)
pH Viscosity
(cP)
Osmolality
(Osmol/Kg)
Any
Individual
Impurity
Total
Impurities
1E
Initial 0.056 0.069 7 1.76 0.266
25°C/60% RH (3M) 0.043 0.086 6.95 1.82 0.302
25°C/60% RH (6M) 0.043 0.185 6.96 1.82 0.301
40°C/75% RH (3M) 0.044 0.092 7.00 1.83 0.307
40°C/75% RH (6M) 0.042 0.242 6.96 1.79 0.292
1F
Initial 0.056 0.083 7.11 3.54 0.273
25°C/60% RH (3M) 0.041 0.073 7.16 3.52 0.305
25°C/60% RH (6M) 0.043 0.175 7.12 3.46 0.292
40°C/75% RH (3M) 0.041 0.072 7.18 3.43 0.307
40°C/75% RH (6M) 0.040 0.224 7.16 3.15 0.332
1G
Initial 0.051 0.084 7.27 1.70 0.272
25°C/60% RH (3M) 0.036 0.098 7.15 1.79 0.309
25°C/60% RH (6M) 0.043 0.183 7.12 1.80 0.295
40°C/75% RH (3M) 0.041 0.134 7.19 1.78 0.309
40°C/75% RH (6M) 0.042 0.204 7.14 1.83 0.304
1H
Initial 0.040 0.040 7.09 1.8 0.261
25°C/60% RH (3M) 0.034 0.099 7.14 1.86 0.272
25°C/60% RH (6M) 0.041 0.136 7.04 1.92 0.273
40°C/75% RH (3M) 0.043 0.163 7.15 1.87 0.272
40°C/75% RH (6M) 0.042 0.162 7.01 1.93 0.249
1I
Initial 0.044 0.085 7.00 1.79 0.268
25°C/60% RH (3M) 0.043 0.135 7.18 1.84 0.267
25°C/60% RH (6M) 0.042 0.145 7 1.94 0.263
26
Examples Condition
Related Substances
( % w/w)
pH Viscosity
(cP)
Osmolality
(Osmol/Kg)
Any
Individual
Impurity
Total
Impurities
40°C/75% RH (3M) 0.042 0.158 7.15 1.87 0.267
40°C/75% RH (6M) 0.042 0.193 6.99 1.95 0.254
[81] ND = Not determined
[82] The spray patterns for the aqueous compositions in Examples 1A-
1C were tested and the results are report in Table 1D below. In particular, the
spray content uniformity (SCU), pump delivery, and droplet size distribution5
(DSD) were measured.
Table 1D
Examples Condition
SCU Pump
delivery DSD (3cm)
Beginning
Life %
Shot
weight
Avg. (mg)
D10
(μm)
D50
(μm)
D90
(μm) SPAN
1A
Initial 99.12 137.78 15.7 34.3 73.9 1.7
25°C/60% RH (3M) 96.78 138.56 12.21 29.71 70.36 1.950
25°C/60% RH (6M) 101.6 139.2 13.41 32.13 75.85 1.940
40°C/75% RH (3M) 98.20 139.12 12.73 30.94 75.21 2.000
40°C/75% RH (6M) 94.50 137.13 15.8 35.2 75.7 1.7
1B
Initial 96.97 137.81 15.5 33.08 70.75 1.67
25°C/60% RH (3M) ND 137.36 12.64 30.67 72.03 1.930
25°C/60% RH (6M) 97.44 137.42 12.63 31.04 73.69 1.960
40°C/75% RH (3M) ND 138.32 12.38 30.16 71.88 1.970
27
Examples Condition
SCU Pump
delivery DSD (3cm)
Beginning
Life %
Shot
weight
Avg. (mg)
D10
(μm)
D50
(μm)
D90
(μm) SPAN
40°C/75% RH(6M) 97.71 138.19 12.26 30.93 75.37 2.04
1C
Initial 95.33 137.23 15.7 34.3 73.95 1.7
25°C/60% RH (3M) ND 137.32 12.63 30.46 72.47 1.960
25°C/60% RH (6M) 96.50 137.07 12.04 29.64 72.00 2.020
40°C/75% RH (3M) ND 139.64 12.53 30.64 73.80 2.000
40°C/75% RH (6M) 96.20 138.44 11.75 28.85 68.09 1.95
28
[83] Example 2: Mucoadhesive Property Measurement
[84] The possible role of surface energy thermodynamics in
mucoadhesion was investigated by measuring the contact angle of Examples 1C,
1D, 1E, and 1I, each of which contained one of hydroxypropylmethylcellulose
(HPMC), sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and5
hydroxypropylcellulose. The contact angle of each composition was measured
with an instrument Kruss Model-DSA100, CN membrane (0.45 micron 47mm;
Make: MDI). For the analysis, 17 microlitres of each sample was passed through
the instrument syringe to form a liquid drop on the CN membrane to measure the
contact angle. The results are provided in Table 2 below.10
Table 2
Sample Contact Angle (in degrees)
Example 1C 102.88
Example 1D 104.62
Example 1E 108.41
Example 1I 109.92
[85] A lower contact indicates better adherence to the membrane and
therefore better mucoadhesion. HPMC resulted in superior mucoadhesion
compared to the other polymers.15
[86] Example 3: Bitterness Evaluation
[87] The aqueous composition of Example 1A was evaluated for
bitterness and compared to a similar formulation without alcaftadine (placebo
formulation) and three commercial intransal products (Astelin®, Patanase®, and20
Azep®). The compositions were evaluated in 20 volunteers according to the
evaluation criteria shown in Table 3 below.
29
Table 3
Evaluation Criteria Score
Very much bitter 4
Bitter 3
Moderate bitter 2
No bitterness 1
[88] The results are shown in Table 4 below.
Table 45
Test No. Product name Active Taste
score Evaluation
1 Alcaftadine Alcaftadine 1 No bitterness
2 Placebo composition of the
Alcaftadine formulation
None 1 No bitterness
3 Astelin® Azelastine
hydrochloride
4 Very much
bitter
4 Patanase® Olopatadine
hydrochloride
2 Moderately
bitter
5 Azep® Azelastine
hydrochloride
4 Very much
bitter
[89] Alcaftadine was found to have a more acceptable taste compared to
azelastine hydrochloride and olopatadine hydrochloride.
30
[90] Example 4: Pharmacokinetics of Intranasal Alcaftadine
[91] The nasal formulations of Example 1A, 1B and 1C
[92] The pharmacokinetic profiles for Example 1A, 1B and 1C as well
as an olapatdine nasal formulation were each determined on 6 male New Zealand5
white rabbits. The olopatadine nasal formulation (0.6% w/v) was prepared from
Olopat Max® 0.7 % w/v, where Olopat Max® was diluted to 0.6% w/v by using
purified water.
[93] The study was carried out on total 24 male New Zealand white
rabbits, which were segregated into four groups (G1 to G4, 6 rabbits/group). Mild10
anaesthesia was induced in all rabbits by inhalation of 2% isoflurane. Three
groups (G1-G3) of anaesthetized rabbits were intranasally administered 250 μL of
alcaftadine once daily using the formulations of Examples 1A, 1B, and 1C. A
comparator, 250 μL of olopatadine at a concentration of 0.6 % w/v, was
intranasally administered once-daily to a fourth group G4 of anaesthetized rabbits.15
[94] Sampling details for the test and reference formulations:
Approximately 0.5 mL of blood sample from each rabbit was withdrawn via
marginal ear vein into pre-labelled Eppendorf tubes containing 10% EDTA as an
anticoagulant. Blood samples were withdrawn at 0 min, 5 min, 10 min, 15 min,
30 min, 60 min, 120 min, 240 min, 480 min and 1440 min after administration of20
test and reference formulations.
[95] Procedure for sample preparation: Collected blood samples were
mixed gently and kept on crushed ice. Plasma samples were separated after
centrifugation at 3500 rpm for 10 min at 4ºC. Plasma separation was carried out
within 30 min of sample collection and stored at -70 ± 10ºC. The animals were25
euthanized by intravenous administration of sodium thiopental injection overdose
and nasal epithelium was collected. Half of the tissues of nasal epithelium were
homogenized using phosphate buffered solution (20% homogenation) for
quantification of alcaftadine and olopatidine. The remaining half of the tissues
31
were stored in 10% neutral buffered formalin for detailed gross histopathological
examination such as necrosis, inflammation or any changes during necropsy.
[96] Rabbit plasma and nasal epithelial tissue concentrations of
alcaftadine or olopatidine were determined using a fit-for-purpose LC-MS/MS
method with LLOQ of 0.500 ng/mL or 0.250 ng/mL, respectively. The5
pharmacokinetic parameters were evaluated using Phoenix WinNonlin® Ent-
Version 8.0 by non-compartmental analysis.
[97] Results: The time to reach peak concentration following
administration of 1.5 mg of olopatadine to New Zealand rabbits was 0.38 hours
after a single administration. After a single intranasal instillation of alcaftadine at10
a doses of 0.312 mg, 0.625 mg and 1.25 mg, the time to achieve maximum
concentration (Tmax) was found to be 0.08 hours in all three groups. Tmax was
achieved much earlier than olopatdine at a dose of 1.5 mg. Thus, intranasal
alcaftadine exhibited a faster onset of action than intranasal olopatadine.
[98] After a single administration of alcaftadine at a doses of 0.625 to15
1.25 mg, the area under the curve (AUC0-24h) and peak plasma concentrations
(Cmax) were dose proportional.
[99] Following intranasal administration of alcaftadine at doses of 0.312
mg, 0.625 mg and 1.25 mg to rabbits, no signs or symptoms of inflammation or
irritation were observed in any of the three groups. On histopathological20
examination, minimum to mild inflammatory cell (lymphocytes/heterophils)
infiltration and increased mucous secretion in nasal epithelium was observed in a
few animals across the groups administered the test and reference formulations.
[100] The plasma concentration of alcaftadine was found to be dose
proportional with overall low systemic exposure.25
32
[101] Example 5
[102] The aqueous alcaftadine composition shown in Table 5 below can
be prepared as described for Examples 1A-1I. The pH of the composition can be
6.3-7.3.
Table 55
Ingredient % w/w
Alcaftadine 0.1 to 1.0
(such as 0.125 to 0.75, for example, 0.125,
0.25, 0.35, 0.45, 0.5, 0.6, and 0.75)
Hydroxypropylmethyl cellulose 0.01 to 1
Sodium chloride 0.068 to 6.8
Monobasic sodium phosphate 0.0019 to 0.19
Edetate Disodium, Dihydrate 0.005 to 0.5
Sodium hydroxide q.s.to pH
Hydrochloric acid 0.025 to 2.5
Benzalkonium chloride 0.0025 to 0.25
Purified water q.s.
[103] Although the inventions herein have been described with reference
to particular embodiments, it is to be understood that these embodiments are
merely illustrative of the principles and application of the present invention. It is
therefore to be understood that numerous modifications may be made to the10
illustrative embodiments and that other arrangements may be devised without
departing from the spirit and scope of the present invention as described.
33
[104] All publications, patents, and patent applications cited in this
application are herein incorporated by reference to the same extent as if each
individual publication, patent, or patent application was specifically and
individually indicated to be incorporated herein by reference.
5
10
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WE CLAIM :
1. A nasal pharmaceutical composition comprising alcaftadine or a5
pharmaceutically acceptable salt thereof and a mucoadhesive agent.
2. The composition of claim 1, wherein the alcaftadine is in free
form.
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3. The composition of claim 1 or 2, wherein the mucoadhesive agent
is selected from hydroxypropylmethyl cellulose, hydroxyethylcellulose,
carboxymethylcellulose sodium, povidone, chitosan, guar gum, xanthan gum, and
any combination of any of the foregoing.
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4. The composition of any one of the preceding claims, wherein the
mucoadhesive agent is hydroxypropylmethyl cellulose.
5. The composition of any one of the preceding claims, wherein the
mucoadhesive agent has a viscosity of 1 to 20 cPs.20
6. The composition of any of the preceding claims, further
comprising a preservative.
7. The composition of any of the preceding claims, further25
comprising at least 0.0125% w/w benzalkonium chloride, based upon the total
weight of the composition.
8. The composition of any of the preceding claims, further
comprising a buffering agent, a tonicity adjustment agent, a chelating agent, or30
any combination of any of the foregoing.
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9. The composition of claim 8, wherein the buffering agent is
monobasic sodium phosphate.
10. The composition of claim 8 or 9, wherein the tonicity adjustment
agent is sodium chloride.5
11. The composition of any one of claims 8-10, wherein the chelating
agent is disodium edetate.
12. The composition of any one of the preceding claims, wherein the10
viscosity of the composition is from about 1.5 to about 4.0 cPs.
13. The composition of any one of the preceding claims, wherein the
pH of the composition is from about 6.3 to about 7.3.
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14. An aqueous nasal pharmaceutical composition comprising (i) about
0.1 to 1.0% w/w alcaftadine or a pharmaceutically acceptable salt thereof, (ii)
about 0.01 to 1.0% w/w hydroxypropyl methyl cellulose, (iii) about 0.068 to about
6.8% w/w of sodium chloride, (iv) about 0.0019 to about 0.19% w/w monobasic
sodium phosphate, (v) about 0.005 to about 0.5% w/w disodium edetate, and (vi)20
about 0.0025 to about 0.25% w/w benzalkonium chloride, wherein the
composition has a pH of 6.3 to 7.3.
15. The composition of claim 14, wherein the hydroxypropylmethyl
cellulose has a viscosity of 1 to 20 cPs.25
16. The composition of claim 14 or 15, wherein the viscosity of the
composition is from about 1.5 to about 4.0 cPs.
17. The composition of any of the preceding claims for use in the30
treatment of allergic rhinitis or one or more symptoms thereof.
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18. The composition of any of the preceding claims for use in the
treatment of nasal congestion.
19. A method of treating allergic rhinitis or one or more symptoms
thereof in a patient in need thereof comprising nasally administering to the patient5
an effective amount of the composition of any one of claims 1-16.
20. A method of treating nasal congestion in a patient in need thereof
comprising nasally administering to the patient an effective amount of the
composition of any one of claims 1-16.10