Note: Descriptions are shown in the official language in which they were submitted.
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HONEY COMPOSITIONS AND USES THEREOF
Technical Field
[0001] The present invention relates to honey compositions and their use to
treat sinusitis
and improve olfactory function.
Background
[0002] Sinusitis is an inflammation of the mucous membrane of any sinus,
especially the
paranasal sinuses, which may be due to infection from a virus, bacteria or
fungus, or the
result of an allergic or autoimmune reaction. Sinusitis is a common condition
with between
24 and 31 million cases occurring in the United States annually.
[0003] One form of sinusitis is chronic rhinosinusitis (CRS). CRS is a common
and often
debilitating form of sinusitis. It affects over 40 million people worldwide,
with more than
200,000 requiring some form of medical intervention (Loehrl T.A., "Autonomic
function and
dysfunction of the nose and sinuses", Otolaryngol Clin North Am, 38(6): 1155-
61, 2005).
CRS typically lasts for a minimum of about 12 weeks and may often persist for
longer
periods of time. CRS may be caused by many different diseases that share
chronic
inflammation of the sinuses as a common symptom, for example cystic fibrosis
("CP'). CRS
is highly prevalent among patients with CF and causes many complications for
these
patients. Potential problems include high risk of lower respiratory tract
infections, sinus pain
and pressure, nasal obstruction, hyposmia or anosmia, and more importantly
increased risk
of pneumonia following lung transplantation. Common treatments for patients
diagnosed
with CRS include functional endoscopic sinus surgery (FESS) and adjunctive
medical
therapies.
[0004] Allergic fungal rhinosinusitis ("AFRS") is another form of sinusitis.
AFRS is a chronic
condition, and often a life debilitating disease. The nature of its etiology
and pathogenesis is
not well understood and a curative treatment for AFRS has not been identified.
Patients with
AFRS often undergo surgery; however, some patients are refractory to post-
operative
medical treatments and continue to suffer from inflammation of the sinuses.
[0005] To date, there has been minimal research in finding alternative
therapeutic agents for
sinusitis with increased efficacy. The effectiveness of a possible alternative
therapeutic
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agent is dependent on its ability to reduce inflammation, and to eradicate the
underlying
pathogens including bacteria and fungus.
[0006] Honey has been used for the treatment of many disorders because of its
anti-
microbial and anti-inflammatory properties. Various forms of honey have been
used to treat
non-healing wounds, such as diabetic foot ulcers, first and second degree
burns, donor
sites, traumatic and surgical wounds, and to treat infections and other
ailments. Honey's
ability to act as an antimicrobial is due to the acidic pH and osmotic effect
of the honey as
well as several key ingredients, including, for example, hydrogen peroxide
produced by
honey glucose oxidase and flavonoid pinocembrin. Moreover, the glucose in
honey
provides energy to vital cells, like phagocytes, which are in need of energy
production in
areas where oxygen supply is often deficient.
[0007] Monofloral honey, such as Manuka honey, is produced from bees who feed
on the
flowers of the Manuka bush, also known as the "Tea Tree". Manuka honey is
known to have
have anti-bacterial properties.
Summary of the Invention
[0008] We have unexpectedly discovered that low concentrations of Manuka
honey, in a
pH-balanced aqueous carrier can be used to significantly decrease the symptoms
associated with sinusitis.
[0009] One exemplary embodiment relates to a composition for treating or
alleviating the
symptoms of sinusitis comprising Manuka honey at a concentration of from about
0.5% v/v
to about 7% v/v in an aqueous pH-balanced solution.
[0010] According to one aspect, there is provided a composition comprising
Manuka honey
at a concentration of from about 3% v/v to about 6% v/v.
[0011] According to another aspect, there is provided a composition comprising
Manuka
honey at a concentration of from about 4% v/v to about 5% v/v.
[0012] Another exemplary embodiment is directed to a method for treating or
alleviating the
symptoms of sinusitis in a patient, where the method comprises the intranasal
administration
of a composition comprising Manuka honey at a concentration of from about 0.5%
v/v to
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about 7% v/v in an aqueous pH-balanced solution to a patient requiring
treatment in order to
treat the sinusitis in the patient.
[0013] A further embodiment relates to methods for improving olfactory
function in a patient
requiring such improvement. The method comprises the intranasal administration
of a
composition comprising Manuka honey at a concentration of from about 0.5% v/v
to about
7% v/v in an aqueous pH-balanced solution to the patient in order to improve
the olfactory
function of the patient.
Brief description of the drawings
[0014] The following figures set forth embodiments in which like reference
numerals denote
like parts. Embodiments are illustrated by way of example and not by way of
limitation in the
accompanying figures.
[0015] Figure 1 is a photograph of the Sniffin' Sticks used to conduct
olfactory tests;
[0016] Figure 2a is a graph showing the mean overall SNOT-22 scores before and
after 30
days of sinus irrigation with honey;
[0017] Figure 2b is a graph comparing average pre-and post-honey treatment
SNOT-22
scores for nasal obstruction, facial pain and loss of smell or taste;
[0018] Figure 3 is a graph showing a comparison of mean endoscopic staging
scores before
and after 30 days of sinus irrigation with honey;
[0019] Figure 4a is a graph showing a comparison of the mean total olfactory
score (TDI)
assessed by the Sniffin' Sticks test before and after 30 days of sinus
irrigation with honey;
and
[0020] Figure 4b is a graph comparing average pre- and post-honey treatment
olfactory
scores for individual olfactory component: Threshold (T), Discrimination (D)
and
Identification (I).
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Detailed Description
[0021] Definitions:
[0022] For purposes of this description, the following terms as defined in
this section apply,
unless the context of the word indicates a different meaning.
[0023] As used herein the term "sinus" is intended to mean all sinuses, i.e.,
the maxillary,
ethmoid, frontal, and sphenoidal sinuses.
[0024] As used herein, the term "subject' is intended to mean mammalian
subjects, typically
humans. Mammals also include, but are not limited to, primates, farm animals,
sport
animals, cats, dogs, rabbits, mice, and rats. The terms "patient" or "subject"
are used herein
interchangeably with "mammal."
[0025] As used herein, the term "treat", "treating", or "treatment" is
intended to mean the
resolution, reduction, or prevention of sinusitis or the sequelae of
sinusitis.
[0026] As used herein, the term "nasal mucosa" is intended to mean the lining
of the
vestibule of the nose, where vascularized, and extending interiorly to the
boundaries of the
oropharynx and sinuses.
[0027] As used herein, the term "aqueous" is intended to mean a solution
formed in water,
but may contain lesser amounts of other co-solvents, such as salt and baking
soda.
[0028] As used herein, the term "pharmaceutically acceptable" is intended to
mean a
composition which when administered to a human or a mammal by the indicated
route of
administration, provokes no adverse reaction which is disproportionate to the
benefit gained
by administration of the composition.
[0029] As used herein, the term "intranasal administration" or "intranasal
delivery" is
intended to mean delivery of the honey compositions, as described herein,
primarily via the
mucosa of the nasal cavity. This includes the superior, middle and inferior
nasal turbinates
and the nasal pharynx. Note that the olfactory region is concentrated in the
superior (upper
1/3) of the nasal turbinates. Cilial action pushes material back toward the
oropharynx, so
material deposited in the nasal vestibule encounters the nasal mucosa before
entering the
throat.
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[0030] I. Honey compositions
[0031] We have discovered to our surprise that low concentrations of honey in
aqueous
saline solutions, when administered intranasally as a spray to treat
sinusitis, can significantly
alleviate the symptoms of sinusitis in human patients without causing nasal
discomfort
during administration. Moreover, we have discovered that the sprays can be
administered
to achieve beneficial results in human patients who are suffering from post-
operative
sinusitis. In one particular example, patients suffering from sinusitis
secondary to cystic
fibrosis who have undergone functional endoscopic sinus surgery have
demonstrated
unexpected olfactory improvement after nasal administration of the honey
compositions.
Such improvement includes the ability to discriminate and identify different
odours.
[0032] Honey compositions include types of honey having strong antibacterial
and
antifungal properties. For example, the nectar from the flowers of the
Leptospermum plant
genus (also known as Manuka or the Tea Tree) is used in the making of
Leptospermum
honey also known as Manuka honey.
[0033] Thus, there is provided a composition for treating or alleviating the
symptoms of
sinusitis, the composition comprising: Manuka honey at a concentration of from
about 0.5%
v/v to about 7% v/v in an aqueous, pH-balanced solution.
[0034] The concentration of the Manuka honey is typically in the range of from
about 1 % v/v
to about 7% v/v. In one embodiment, the Manuka honey is present at a
concentration from
about 3% v/v to about 6% v/v. In another embodiment, the concentration of the
Manuka
honey is from about 4% v/v to about 5% v/v.
[0035] In a further alternative embodiment, the composition consists of 0.5%
v/v Manuka
honey and 99.5% v/v of the aqueous pH-balanced solution. In another specific
example, the
composition consists of 5% v/v Manuka honey and 95% of the aqueous pH-balanced
solution. In another specific example, the composition consists of 7% v/v
Manuka honey
and 93% of the aqueous pH-balanced solution.
[0036] In another alternative embodiment, the composition consists essentially
of 0.5% v/v
Manuka honey and 99.5% of the aqueous pH-balanced solution. In yet another
specific
example, the composition consists essentially of 5% v/v Manuka honey and 95%
of the
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aqueous pH-balanced solution. In still another specific example, the
composition consists
essentially of 7% v/v Manuka honey and 93% of the aqueous pH-balanced
solution.
[0037] The compositions described herein are aqueous pH-balanced solutions,
which are
compatible for human use. In the examples described herein, the aqueous pH-
balanced
solution includes a mixture of sodium chloride and sodium bicarbonate. The
solution has
the required osmolality for human use and is pharmaceutically acceptable for
use as a nasal
spray and has a final pH that is about pH 7Ø
[0038] Additional excipients may be used in the composition. These may include
but are
not limited to benzalkonium chloride, benzyl alcohol, phenylethyl alcohol,
polyethylene
glycol, glycerin, water, sodium hydroxide, aloe vera, camphor, boric acid,
ascorbic acid, and
citric acid.
[0039] II. Utilities
[0040] The compositions of this discovery are useful to treat, or alleviate
the symptoms of
sinusitis in human patients or affect olfactory function and comprise
intranasally
administering the composition to the patient in need thereof to treat the
sinusitis.
Specifically, the compositions are useful to treat chronic rhinosinusitis or
the sinusitis is after
functional endoscopic sinus surgery. Also, allergic fungal rhinosinusitis is
also contemplated
as being treatable using the honey compositions described herein. Further, the
compositions are useful to improve general olfactory function.
[0041] Typically, the composition is administered every 24 hours. In one
example, the
composition is administered every 24 hours for 30 days.
[0042] Typically, the patient irrigates each of their nostrils with about
120mL of the prepared
honey solution, every 24 hours for 30 days
[0043] Several delivery mechanisms are known to those skilled in the art and
include, for
example, actuator dispensers commonly used for nasal solutions and gels. It is
possible to
use such dispensers to administer multiple, single-dose, and metered doses.
Such
dispensers may be child resistant, and disposable, and may be sold in kit
format.
[0044] The above-described honey compositions can be administered to the nasal
mucosa
in flush form, liquid stream form, drop form or in spray form. However, the
typical mode of
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administration is in flush form or liquid stream form. An example of suitable
sinus rinse
delivery mechanisms include the NeilMed Sinus Rinse Bottle produced by
NeilMed
Pharmaceuticals, Inc., California, a medical syringe of about 20 to 60 ml in
size, and other
squeeze bottle irrigation devices. A person skilled in the art would
understand that other
delivery mechanisms may also be used for delivery of the honey compositions.
EXAMPLES
Example 1: Preparation of a Honey- Saline Solution
[0045] A honey-saline solution was prepared by dissolving Wedderspoon Manuka
honey
(from Wedderspoon Organic ) in a pH-balanced sodium chloride and sodium
bicarbonate
mixture. The sodium chloride and sodium bicarbonate mixture was made by
dissolving 1
Sinus RinseTM packet in 240 mL of distilled water. The Manuka honey and the
sodium
chloride and sodium bicarbonate mixture were combined in the various volume to
volume
ratios as shown in Table 1 to prepare honey-saline solutions with different
concentrations of
honey:
[0046] Table 1:
Solution Honey (cc) Saline Mixture
(ml)
1 2.5 240
2 5 240
3 7.5 240
4 10 240
12.5 240
6 15 240
7 18 240
Example 2: Improving sinusitis symptoms in cystic fibrosis patients who
continue to
suffer from CRS following surgery
[0047] Ten patients with cystic fibrosis ("CF") who were diagnosed with
chronic
rhinosinusitis and had undergone functional endoscopic sinus surgery ("FESS")
at least
three months prior to the study were enrolled in a prospective study. The ten
patients were a
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mean age of 31.9 years (range 21-48 years) and six of the patients were males
(60%) and
four of the patients were females (40%). All study subjects provided informed
consents.
[0048] STEP 1: Olfactory Test & Health-Related Questionnaire. On the first day
of the
study, patients completed a Sniffin' Sticks olfactory test (see Figure 1), and
the 22 item
sinonasal outcome test (SNOT-22). The Sniff in' Sticks olfactory test is a
well validated test
with a good test-rest reliability (r=0.72) which examines a subject's
olfactory threshold (1-
butanol), odor discrimination and odor identification (TDI). SNOT-22 is a
rhinosinusitis-
specific, health-related questionnaire that effectively combines symptoms
related to
rhinosinusitis and general health.
[0049] STEP 2: Endoscopic Staging. After completing step 1 above, subjects
were
examined endoscopically and staged using the newly developed Philpott-Javer
Scoring
system (see Figure 2a) which gives a maximum endoscopic score (ES) out of 10
for each
sinus cavity bilaterally (possible maximum score of 80).
[0050] STEP 3: Treatment with Honey. The honey saline solution used for this
study was
made by dissolving 10cc of Wedderspoon Manuka honey (donated by Wedderspoon
Organic ) in 240mL of pH-balanced sodium chloride and sodium bicarbonate
mixture
(made by dissolving 1 Sinus RinseTM mixture packet in 240mL of distilled
water). Patients
were given 1 custom 240mL nasal irrigator, purchased from NeilMed
Pharmaceuticals,
Inc., and were instructed to irrigate each of their nostrils with 120mL of the
prepared honey
solution, every 24 hours for 30 days. On day 30, last day of the study, step 1
and 2 were
repeated for all 10 patients and the three scores (TDI, SNOT-22, ES) were
compared to
those obtained on Day 1.
[0051] Statistical Analysis. For comparing mean scores before and after honey
treatment,
we calculated the 95% Confidence interval and obtained appropriate error bars.
[0052] The following results were obtained from the study:
[0053] SNOT-22 Scores. The mean total SNOT-22 score (all 22 items) was 35.6
and 26.1
before and after honey treatment, respectively (see Figure. 2a). This
represents a reduction
of 26% in symptom scores. More specific results can be obtained by analyzing
individual
symptoms. In order to compare our results to other published data we selected:
(1) nasal
obstruction; (2) facial pain; and (3) loss of smell or taste (see Figure. 2b).
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[0054] Nasal Obstruction. Mean pre-honey treatment score for nasal obstruction
was 4.2,
which equates to a 'severe problem' compared with a post-honey treatment score
of 2.8, or
a 'very mild problem'. Seven out of ten patients (70%) reported an improvement
of at least 1
point in nasal obstruction.
[0055] Facial Pain. Mean pre-honey treatment score was 3.1, mean post-honey
treatment
score was 2.92. This difference was not statistically significant.
[0056] Loss of Smell or Taste. Mean pre-honey treatment score was 3.4 which
equates to a
'moderate problem', compared to mean a post-honey treatment score of 2.4, or a
'slight
problem'. Six out of ten patients (60%) reported an improvement of at least 1
point in loss of
smell or taste.
[0057] Endoscopic Scores. The mean endoscopic scores using the Philpott-Javer
Scoring
system were 15.8 and 12 before and after honey treatment, respectively. This
difference
was not statistically significant (see Figure 3).
[0058] Olfactory Scores. The olfactory score consists of three measures: (1)
threshold (T),
(2) discrimination (D), and (3) identification (I). The mean total TDI scores
were 19.80 and
25.45 before and after honey treatment, respectively (see Figure 4a). The mean
score for T
was the only olfactory measure that did not significantly change following
honey treatment
(5.30 to 5.55) (see Figure 4b). The mean scores for D and I improved
significantly following
honey treatment. The greatest improvement was observed for D at 3.1 points
followed by
2.3 points for I (see Figure 4b).
[0059] Results. After 30 days of sinus irrigation with honey the overall mean
scores for
olfactory function and SNOT-22 improved significantly, where as endoscopic
staging scores
remained relatively unchanged. The only olfactory component that did not
significantly
improve, following treatment with honey, was odor threshold (5.3 to 5.55),
which could be
due to the use of only a single odorant. Therefore, in spite of no apparent
improvement in
the sinus cavities, treatment with honey improved the self-reported quality of
life scores and
the overall olfactory performance scores. Just after 30 days of sinus
irrigation with honey,
the CF patients' ability to discriminate and identify different odors improved
significantly.
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Example 3: Sinusitis symptoms in patients who continue to suffer from symptoms
of
sinusitis after maximal topical medical and surgical treatment for AFRS
[0060] Materials and Methods. A randomized, single-blinded, prospective study
was carried
out. Patients included in the study had undergone bilateral functional
endoscopic sinus
surgery (FESS) and had a definitive diagnosis of allergic fungal sinusitis
prior to
consideration for the study. Those accepted into the study had to have failed
standard
medical treatment for at least twelve weeks post-FESS. All patients were 19
years of age or
older. Patients allergic to pollen, honey or bees were prohibited from
partaking in the study.
[0061] The rigid endoscope was used to assess the mucosal inflammation. The
mucosa
was graded by the staging system used in the clinic where the study was
performed, which
is based on the old Kupferberg staging. Each sinus cavity (frontal, ethmoid,
maxillary and
sphenoid) was given a score between zero and nine, with an extra point for the
presence of
fungal mucin, giving a total potential maximum score of forty out of forty per
side of the nose
and a total of 80 for both sides of the nose, as set out in Table 2.
[0062] Table 2:
Frontal 0-9 1 0-9 1
Ethmoid 0-9 1 0-9 1
Maxillary 0-9 1 0-9 1
Sphenoid 0-9 1 0-9 1
Total 40 40
Bilateral total 80
Grading, State of mucos
0 No oedema
1-3 Mucosal oedema (mild/moderate/severe)
4-6 Polypoid oedema (mild/moderate/severe)
7-9 Frank polyps (mild/moderate/severe)
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[0063] For patients who fitted the inclusion criteria for the study, the
senior investigator
stepped out of the room and a closed envelope system was use to randomly pick
which
nostril would receive the honey treatment. Patients acted as their own
control. In other
words, the patient continued with their current medical management in both
nostrils but only
one nasal cavity was selected to undergo honey treatment. At this time,
microbiology
samples were taken from both ethmoid cavities and sent to the laboratory for
cultures and
sensitivity.
[0064] Patients were instructed to spray 2mL of a 50/50 honey-saline solution
using a
mucosal atomisation device in their selected nostril once a day at night for
thirty days.
Patients were seen after thirty days and the senior investigator who was
blinded assessed
both nostrils and determined which nasal mucosa looked healthier using the
endoscopic
mucosal grading system. Each patient filled out a validated survey (the SNOT-
22
questionnaire) regarding their nasal symptoms during their initial visit and
after 4 weeks of
treatment.
[0065] The honey used in the study is formally known as Medihoney with active
leptospermum honey. The honey was obtained from Derma Sciences, Inc.
[0066] To obtain a significant result with a power of 80% (p<0.05), at least
31 patients with
AFRS were require to detect a benefit from the treatment. An improvement in
the
endoscopic mucosal score of five or more points was considered significant.
Paired t-tests
were used to compare the mucosal and SNOT-22 scores using Stata software.
[0067] Results. It was not evident from the results that the 50% solution
showed anti-
inflammatory and antimicrobial activity. The treatment group had a mean
endoscopic
mucosal score that was -1.74 units different from the control group (95% Cl: -
5.02,1.55),
which was not statistically significant (p=0.2901). Further, qualitative
analysis of the
microbiology results did not reveal consistent trends. Patients grew varying
ranges of
bacterial flora with no obvious response to the honey treatment, as shown in
Table 3 below.
[0068] Table 3:
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Control Treatment
Mean (sd) Mean (sd) Difference p-value
(95% CI)
Mucosal score 18.94 (8.92) 17.21 (9.90) -1.74 0.2901
(-5.02,1.55)
Change in Mucosal score -0.74 (9.48) -2.62 (7.27) -1.88 0.2334
(-5.04,1.27)
*based on a paired t-test.
[0069] As for any stated side effects from honey administration, four patients
complained of
a burning sensation within the sinus cavity. Nonetheless, all four patients
were compliant
with their honey treatment and were able to continue with the study. On the
other hand, one
patient documented nausea after spraying the honey and consequently became non-
compliant with the study.
Example 4: Use of honey-saline solutions in patients who continue to suffer
from
symptoms of sinusitis after maximal topical medical and surgical treatment for
AFRS
[0070] Materials and Methods. The materials and methods used in Example 3 were
used in
a prospective study of ten patients, except that the honey-saline solution
used by the
patients in this study differed. Five patients were instructed to spray 2mL of
a honey-saline
solution with 25% v/v of honey: 75% v/v of saline solution, and the other five
patients were
instructed to spray 2mL of a honey-saline solution with 15% v/v of honey: 85%
v/v of saline
solution, in accordance with the instructions set out Example 3. The patients
were
examined after twelve weeks of treatment.
[0071] Results. Both groups of patients were able to tolerate the honey-saline
solutions;
however, the patients did complain of a burning sensation when using the honey-
saline
solutions. Endoscopic examination of mucosal inflammation in the treatment
groups did not
show a statistically significant difference in endoscopic mucosal score over a
twelve week
period. It was not evident from the results that the 25% solution showed anti-
inflammatory
and antimicrobial activity.
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Example 5: Sinusitis symptoms in patients who continue to suffer from symptoms
of
sinusitis after maximal topical medical and surgical treatment for AFRS
[0072] Materials and Methods. The materials and methods used in Example 3 were
used in
a prospective study of five patients, except that the honey-saline solution
used by the
patients in this study differed. The patients were instructed to spray 2mL of
a honey-saline
solution with 5% v/v of honey: 95% v/v of saline solution, in accordance with
the instructions
set out Example 3. The patients were examined after twelve weeks of treatment.
[0073] Results. The patients were able to tolerate the honey-saline solutions.
The
endoscopic mucosal scores for the patients improved significantly and the
overall mean
scores for olfactory function and SNOT-22 improved significantly. The results
demonstrate
that the 5% solution showed anti-inflammatory and antimicrobial activity.
[0074] While preferred embodiments of the present discovery have been shown
and
described herein, it will be obvious to those skilled in the art that such
embodiments are
provided by way of example only. Numerous variations, changes, and
substitutions will be
obvious to those skilled in the art without departing from the discovery. It
should be
understood that various alternatives to the embodiments of the discovery
described herein
may be employed in practicing the invention. It is intended that the following
claims define
the scope of the discovery and that methods and structures within the scope of
these claims
and their equivalents be covered thereby.
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