U.S. patent application number 16/296876 was filed with the patent office on 2019-07-18 for vitamin b12 nasal spray and method of use.
The applicant listed for this patent is ENDO PHARMACEUTICALS INC.. Invention is credited to Theodore H. FELLER, Thomas E. FLEMING, Angela SUTTERER.
Application Number | 20190216842 16/296876 |
Document ID | / |
Family ID | 37758389 |
Filed Date | 2019-07-18 |
United States Patent
Application |
20190216842 |
Kind Code |
A1 |
FELLER; Theodore H. ; et
al. |
July 18, 2019 |
VITAMIN B12 NASAL SPRAY AND METHOD OF USE
Abstract
The present invention relates generally to vitamin 12 nasal
spray compositions and methods of using the same in the treatment
of vitamin B.sub.12 deficiency and various disorders that are
related to such deficiency. In particular embodiments, the present
invention is directed to treatment methods comprising intranasal
administration of a cobalamin composition according to a particular
dosing and frequency schedule and to a preservative-free nasal
spray composition comprising a cobalamin compound useful in the
practice of such treatment methods.
Inventors: |
FELLER; Theodore H.; (St.
Louis, MO) ; SUTTERER; Angela; (St. Louis, MO)
; FLEMING; Thomas E.; (St. Louis, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ENDO PHARMACEUTICALS INC. |
Malvern |
PA |
US |
|
|
Family ID: |
37758389 |
Appl. No.: |
16/296876 |
Filed: |
March 8, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14738417 |
Jun 12, 2015 |
10251908 |
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16296876 |
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12618099 |
Nov 13, 2009 |
9186374 |
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14738417 |
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11506148 |
Aug 17, 2006 |
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12618099 |
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60709200 |
Aug 17, 2005 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0043 20130101;
A61M 15/08 20130101; A61K 47/12 20130101; A61P 7/06 20180101; A61P
1/02 20180101; A61K 47/10 20130101; A61M 11/006 20140204; A61K
47/02 20130101; A61K 31/714 20130101 |
International
Class: |
A61K 31/714 20060101
A61K031/714; A61K 47/02 20060101 A61K047/02; A61K 47/18 20060101
A61K047/18; A61K 47/12 20060101 A61K047/12; A61K 9/00 20060101
A61K009/00; A61M 15/08 20060101 A61M015/08; A61M 11/00 20060101
A61M011/00; A61K 47/10 20060101 A61K047/10 |
Claims
1. A composition for nasal administration of cyanocobalamin, the
composition comprising an aqueous solution containing about 1% w/w
cyanocobalamin, a pharmaceutically acceptable buffer, a humectant,
and a preservative, wherein: the buffer comprises a citrate buffer;
the humectant comprises glycerin; the preservative comprises
benzalkonium chloride; the composition has a pH of about 4 to about
6.5, and the composition is provided in a container equipped with a
pump adapted to deliver the composition into a patient's
nostril.
2. The composition of claim 1, wherein the composition has a pH of
about 5 to about 6.5.
3. The composition of claim 1, wherein the composition has a pH of
about 6 to about 6.5.
4. The composition of claim 1, wherein the composition comprises
about 0.001% w/w to about 5% w/w of preservative.
5. The composition of claim 1, wherein the composition comprises
about 0.01% w/w to about 1% w/w of preservative.
6. The composition of claim 1, wherein the composition contains
comprises 0.02% w/w to about 0.4% w/w of preservative.
7. The composition of claim 1, wherein the composition comprises
about 0.01% w/w to about 20% w/w of humectant.
8. The composition of claim 1, wherein the composition further
comprises one or more pharmaceutically acceptable excipients
selected from the group consisting of: surfactants, viscosity
modifying agents, osmolarity adjusters, complexing agents,
stabilizers, solubilizers, antioxidants, and any combination
thereof.
9. The composition of claim 8, wherein the composition comprises
about 0.1% w/w to about 50% w/w of surfactant.
10. The composition of claim 1, wherein the composition further
comprises a surfactant selected from the group consisting of:
polyoxyethylene derivatives of fatty acids, partial esters of
sorbitol anhydrides, sodium lauryl sulfate, sodium salicylate,
oleic acid, lecithin, dehydrated alcohol, Tween, Span, polyoxyl 40
stearate, polyoxy ethylene 50 stearate, edetate disodium, propylene
glycol, glycerol monooleate, fusieates, bile salts, octoxynol, and
combinations thereof.
11. The composition of claim 8, wherein the composition comprises
about 0.1% w/w to about 20% w/w of viscosity modifying agent.
12. The composition of claim 1, wherein the composition further
comprises a viscosity modifying agent selected from the group
consisting of: methyl cellulose, xanthan gum, carboxymethyl
cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol,
alginates, acacia, chitosans, and combinations thereof.
13. The composition of claim 8, wherein the composition comprises
about 0.01% w/w to about 5% w/w of antioxidant.
14. The composition of claim 1, wherein the composition further
comprises an antioxidant selected from the group consisting of:
sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate,
and combinations thereof.
15. The composition of claim 1, wherein the aqueous solution is
isotonic.
16. The composition of claim 15, wherein the solution has an
osmolarity of from about 230 mOsmols to about 340 mOsmols.
17. The composition of claim 15, wherein the solution has an
osmolarity of from about 280 mOsmols to about 290 mOsmols
18. The composition of claim 1, wherein the container is further
equipped with a metering valve for dispensing a predetermined
volume of the composition.
19. A composition for nasal administration of cyanocobalamin, the
composition comprising an aqueous solution containing about 1% w/w
cyanocobalamin, a citrate buffer, glycerin in an amount of about
0.01% w/w to about 20% w/w, and benzalkonium chloride in an amount
of about 0.001% w/w to about 5% w/w, wherein the composition has a
pH of about 4 to about 6.5, and wherein the composition is provided
in a container equipped with a pump adapted to deliver the
composition into a patient's nostril.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application
Ser. No. 14/738,417 filed Jun. 12, 2015, which is a Continuation of
U.S. patent application Ser. No. 12/618,099, now U.S. Pat. No.
9,186,374, filed Nov. 13, 2009, which is a Continuation of U.S.
patent application Ser. No. 11/506,148, filed Aug. 17, 2006, which
claims the benefit of priority to U.S. Provisional Application No.
60/709,200, filed Aug. 17, 2005, the entire content of each of
which is hereby incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to vitamin B.sub.12
nasal spray compositions and methods of using the same in the
treatment of vitamin B.sub.12 deficiency and various disorders that
are related to such deficiency. In particular embodiments, the
present invention is directed to treatment methods comprising
intranasal administration of a cobalamin composition according to a
particular dosing and frequency schedule and to a preservative-free
nasal spray composition comprising a cobalamin compound useful in
the practice of such treatment methods.
BACKGROUND
[0003] Vitamin B.sub.12 is a water soluble vitamin that plays a
role in mammalian growth, hematopoiesis, production of epithelial
cells, and maintenance of the nervous system. It was first isolated
from liver concentrate in 1948 and structurally elucidated in the
late 1950's.
[0004] Cyanocobalamin is a form of vitamin B.sub.12 and is one of
the class of B.sub.12 vitamins or cobalamin compounds that includes
vitamin B.sub.12a (hydroxocobalamin), vitamin B.sub.12b
(aquacobalamin), vitamin B.sub.12c (nitrilocobalamin), methyl
B.sub.12 (methylcobalamin) and coenzyme B.sub.12 (5'deoxyadenosine
cobalamin). Cyanocobalamin and hydroxocobalamin are the principal
members of the class and the most widely employed in compositions
used to treat vitamin B.sub.12 deficiency and disorders that are
related to this deficiency. Such disorders include anemias (most
commonly pernicious anemia) and diphyllobothrium latum (fish
tapeworm) infestation of the intestine, a disorder with
symptomology that mimics pernicious anemia.
[0005] Several routes of administration of vitamin B.sub.12 are
known. Among these are parenterally, including intramuscular and
subcutaneous injection, orally as a component of a tablet or
solution, and nasally, as a component of a nasal spray or gel.
Although the minimum daily dietary requirement of vitamin B.sub.12
is approximately 0.1 .mu.g for a healthy human, therapeutic
administration of vitamin B.sub.12 is typically in significantly
larger doses. For example, the prescribed initial therapeutic dose
is generally from about 100 .mu.g to about 1000 .mu.g, and is most
often administered by intramuscular injection. Subsequent vitamin
B.sub.12 maintenance therapy may be by injection or by oral
administration of a cobalamin composition. Use of vitamin B.sub.12
injections for maintenance therapy has obvious disadvantages,
including the inconvenience and pain associated with the injection
that typically must be administered by medical personnel. Orally
administered cobalamin compositions may fail to be adequately
absorbed in the patient, particularly in those in which secretion
or utilization of intrinsic factor is inadequate.
[0006] Intranasal administration of cobalamin compositions for
vitamin B.sub.12 maintenance therapy offers advantages over these
alternative routes of administration. Typically, such therapy
includes relatively infrequent, high dose nasal administration of a
cobalamin composition. For example, NASCOBAL nasal spray solution
containing 0.5% by weight cyanocobalamin is administered in one
nostril once weekly in a dose of 500 .mu.g (i.e., 500 .mu.g
cyanocobalamin per 0.1 mL actuation of the spray bottle pump).
[0007] Although maintenance therapy with vitamin B.sub.12 nasal
compositions has proven generally effective, those undergoing such
therapy may experience some irritation of the nasal mucosa and
discomfort due, in part, to the high dosage of the cobalamin
compound typically administered as well as preservatives and other
additives often present in these compositions. Moreover, effective
vitamin B.sub.12 maintenance therapy would be enhanced if more
stable or even blood serum levels of vitamin B.sub.12 could be
attained through intranasal administration of a cobalamin
composition. Accordingly, a need persists for improvements in
vitamin B.sub.12 nasal compositions and methods of nasal
administration of such compositions in the treatment of vitamin
B.sub.12 deficiency and various vitamin B.sub.12
deficiency-mediated disorders.
SUMMARY OF THE INVENTION
[0008] Among the various aspects of the present invention is the
provision of a method of frequent, low dose nasal administration of
a vitamin B.sub.12 composition and an improved vitamin B.sub.12
composition suitable for use in such methods of treatment.
[0009] Briefly, therefore, the present invention is directed to a
method for maintaining vitamin B.sub.12 blood serum levels in a
mammals, the method comprising nasally administering to the mammal
at least once every three days an aqueous composition comprising a
cobalamin compound in an amount sufficient to deliver a dose of no
more than about 150 .mu.g of the cobalamin compound to the
mammal.
[0010] The present invention is further directed to a method for
maintaining normal hematologic status in a pernicious anemia
patient following intramuscular vitamin B.sub.12 injection therapy,
the method comprising nasally administering to said patient at
least once every three days an aqueous composition comprising a
cobalamin compound in an amount sufficient to deliver a dose of no
more than about 150 .mu.g of the cobalamin compound to the
patient.
[0011] The present invention is further directed to a composition
for nasal administration of a cobalamin compound, the composition
comprising an aqueous solution containing a cobalamin compound and
a pharmaceutically acceptable buffer, the composition having a pH
of at least about 6.5.
[0012] The present invention is further directed to a composition
for nasal administration of a cobalamin compound, the composition
comprising an aqueous solution containing a cobalamin compound and
a pharmaceutically acceptable buffer and being free of
preservatives.
[0013] Other objects and features will be in part apparent and in
part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 depicts the mean serum vitamin B.sub.12 levels and
95% confidence interval for all six visits in the study conducted
in the Example.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention is based in part on the observation
that conventional intranasal administration of cobalamin
compositions may lead to irritation of the nasal membranes or
mucosa. Irritation may be caused or exacerbated by the relatively
high dose of cobalamin compound typically administered and/or
preservatives and other additives commonly contained in these
compositions. This irritation, compounded by infrequent, high dose
administration of conventional intranasal cobalamin compositions
(e.g., anywhere from once a week to as rarely as once a month), can
lead to patient noncompliance and variable blood serum vitamin B12
levels and ultimately to inconsistent or ineffective treatment of
vitamin B12 deficiency-mediated disorders.
[0016] In order to provide patients with a more consistent and
effective treatment for vitamin B.sub.12 deficiency and related
disorders, the present invention is directed to methods for
maintaining vitamin B.sub.12 blood serum levels in a mammal
comprising more frequent intranasal administration of a cobalamin
composition and at lower dosages than previously recognized as
effective in the treatment of such disorders. The present invention
further provides compositions containing a cobalamin compound
useful in the practice of the treatment methods disclosed herein,
while minimizing the risk of irritation of the nasal mucosa and
patient noncompliance with the prescribed treatment regimen.
[0017] The treatment methods disclosed herein are generally
applicable for maintenance of vitamin B.sub.12 blood serum levels
in a patient in need of vitamin B.sub.12 therapy. Such a patient
may be suffering from a vitamin B.sub.12 deficiency, a disorder
resulting from such a deficiency, or a disorder mimicking the
symptomology of such a deficiency. Examples of disorders resulting
from or mimicking a vitamin B.sub.12 deficiency include, for
example, anemia, including pernicious anemia; nerve degeneration,
typically as a result of degradation or lack of myelin; and
infestation by intestinal parasites or bacteria such as
diphyllobothrium latum (fish tapeworm) that absorb large quantities
of vitamin B.sub.12 in the host. Other indications for application
of the treatment methods disclosed herein include, for example,
maintenance of normal hematologic status in pernicious anemia
patients in remission subsequent to intramuscular vitamin B.sub.12
injection therapy and who have no nervous system involvement;
remedying vitamin B.sub.12 dietary deficiencies (e.g., in
vegetarians); treatment of patients suffering from vitamin B.sub.12
malabsorption phenomena such as that resulting from inadequate
secretion and/or utilization of intrinsic factor (e.g., due to HIV
infection, AIDS, Crohn's disease, tropical and nontropical sprue,
extensive neoplasia, subtotal or total gastrectomy, etc.);
maintenance of vitamin B.sub.12 in excess of normal dietary
requirements due to pregnancy, renal disease, thyrotoxicosis,
hemolytic anemia, hemorrhage, etc; and patients having elevated
serum homocysteine, cystathionine, methylmalonic acid and/or
2-methylcitric acid levels.
[0018] The present invention is directed particularly to the
treatment of humans in need of vitamin B.sub.12 therapy. However,
it should be understood that the methods disclosed herein are
generally applicable to the treatment of mammals including, for
example, domesticated house pets, such as dogs and cats, as well as
farm animals, such as cattle, pigs, horses, sheep and goats.
[0019] Methods for Intranasal Administration of a Cobalamin
Containing Composition
[0020] Generally, the treatment methods of the present invention
comprise more frequent and lower dose intranasal administration of
a composition containing a cobalamin compound. It has been
discovered that more frequent and lower dose intranasal
administration of a cobalamin composition offers several advantages
over conventional intranasal vitamin B.sub.12 maintenance therapy,
including reduced risk of irritation of the nasal mucosa and more
stable or even vitamin B.sub.12 blood serum levels (i.e., smaller
peak to trough variances) by more closely mimicking the typical
mammalian dietary intake of vitamin B.sub.12 Moreover, it is
believed that patient compliance is improved by treatment regimens
including more frequent administration of the cobalamin
composition. As described in greater detail below, the compositions
used in the practice of the methods disclosed herein include, for
example, aqueous solutions of the cobalamin compound along with
various optional components such as isotonicity agents, buffering
agents, humectants, surfactants and preservatives.
[0021] The treatment method for maintaining vitamin B.sub.12 blood
serum levels in a mammal in accordance with the present invention
comprises nasally administering to the mammal an aqueous
composition comprising a cobalamin compound at least once every
three days, preferably at least once every two days. The frequency
of administration may vary during the treatment period. For
example, the composition may be administered every day during an
initial portion (e.g., the first week or first two weeks) of the
treatment period (e.g., daily during an initial "loading" period to
increase vitamin B.sub.12 blood serum levels), and then at less
frequent intervals during the remainder of the treatment period.
However, in order to promote patient compliance, administration
preferably occurs at regular intervals throughout the treatment
period. In accordance with a more preferred embodiment, the
treatment method of the present invention comprises daily
intranasal administration (i.e., one or more administrations per
day), and especially once daily, intranasal administration of the
cobalamin composition during the treatment period.
[0022] The dose of the cobalamin compound delivered to the patient
with each administration will vary generally with the frequency of
administration (a higher dose being utilized with longer intervals
between administrations), as well as with the needs of the patient
and the type of disorder being treated, as would be apparent to
those skilled in the art, but is generally lower than the dosing
conventionally employed. Generally, the dose of the cobalamin
compound delivered to the patient with each administration is no
more than about 150 .mu.g, preferably no more than about 125 .mu.g,
more preferably no more than about 100 .mu.g, and still more
preferably no more than about 75 .mu.g of the cobalamin compound,
and is at least 5 .mu.g, preferably at least about 10 .mu.g of the
cobalamin compound.
[0023] With respect to a preferred treatment regimen comprising
daily intranasal administration of a cobalamin composition, the
daily dose of the cobalamin compound delivered to the patient is
preferably from about 5 .mu.g to about 100 .mu.g, more preferably
from about 20 .mu.g to about 80 .mu.g, still more preferably from
about 30 .mu.g to about 70 .mu.g and even more preferably from
about 40 .mu.g to about 60 .mu.g. In accordance with an especially
preferred embodiment comprising once daily intranasal
administration of the cobalamin composition, the dose of the
cobalamin compound delivered to the patient with each
administration is usually no more than about 80 .mu.g. In such an
embodiment, the dose of the cobalamin compound delivered to the
patient with each administration is preferably from about 5 .mu.g
to about 80 .mu.g, more preferably from about 10 .mu.g to about 60
.mu.g, more preferably from about 15 .mu.g to about 50 .mu.g, more
preferably from about 20 .mu.g to about 50 .mu.g, more preferably
from about 30 .mu.g to about 50 .mu.g, still more preferably from
about 40 .mu.g to about 50 .mu.g and even more preferably from
about 45 .mu.g to about 50 .mu.g. For example, in an embodiment
comprising daily intranasal administration of the cobalamin
composition, the dose of the cobalamin compound delivered to the
patient per administration may be about 10 .mu.g, about 15 .mu.g,
about 20 .mu.g, about 25 .mu.g, about 30 .mu.g, about 35 .mu.g,
about 40 .mu.g, about 45 .mu.g, or about 50 .mu.g.
[0024] In accordance with another embodiment of the treatment
method disclosed herein comprising once daily intranasal
administration of the cobalamin composition, the dose of the
cobalamin compound delivered to the patient with each
administration is from about 5 .mu.g to about 45 .mu.g, preferably
from about 10 .mu.g to about 45 .mu.g, more preferably from about
15 .mu.g to about 45 .mu.g, more preferably from about 20 .mu.g to
about 45 .mu.g, still more preferably from about 30 .mu.g to about
45 .mu.g, and even more preferably from about 40 .mu.g to about 45
.mu.g.
[0025] With respect to the dose of the cobalamin compound delivered
to the patient per administration, it should be understood that
each administration may comprise one or a plurality of applications
or sprays of the cobalamin composition delivered to the nasal
mucosa of the patient through one or both nostrils, the number of
applications or sprays being dependent upon the concentration of
the cobalamin compound in the composition, the quantity of the
composition delivered per spray, and the desired dose per
administration as readily determined by one skilled in the art. As
described in greater detail below, the cobalamin composition is
preferably dispensed from a spray bottle including a pump (e.g., a
manually actuated pump) capable of delivering a metered spray of
the cobalamin composition of predetermined volume (typically about
0.1 mL). Furthermore, and by way of example, a daily dose of 50
.mu.g of a cobalamin compound may be administered in a single
administration comprising one or more applications or metered
sprays containing a total of 50 .mu.g of cobalamin compound (e.g.,
a single administration comprising two applications or metered
sprays, one in each nostril and each containing 25 .mu.g of
cobalamin compound) or in multiple administrations (e.g., four
administrations at six hour intervals, each administration
comprising one or more applications or metered sprays, in one or
both nostrils, each administration containing a total of 12.5 .mu.g
of cobalamin compound).
[0026] The weekly dose of the cobalamin compound received by the
patient will generally not be in excess of about 1000 .mu.g, more
preferably about 800 .mu.g, still more preferably about 600 .mu.g,
even more preferably about 500 .mu.g, still more preferably about
450 .mu.g, even more preferably about 400 .mu.g, and most
preferably not in excess of about 350 .mu.g of the cobalamin
compound. Accordingly, in one embodiment, the patient may receive a
weekly dosage of from about 50 .mu.g to about 500 .mu.g of the
cobalamin compound. In another embodiment, the patient may receive
a weekly dosage of from about 100 .mu.g to about 450 .mu.g of the
cobalamin compound. In yet another embodiment, the patient may
receive a weekly dosage of from about 150 .mu.g to about 400 .mu.g
of the cobalamin compound. In still another embodiment, the patient
may receive a weekly dosage of from about 200 .mu.g to about 400
.mu.g of the cobalamin compound. In yet another embodiment, the
patient may receive a weekly dosage of from about 250 .mu.g to
about 350 .mu.g of the cobalamin compound. In still another
embodiment, the patient may receive a weekly dosage of from about
300 .mu.g to about 350 .mu.g of the cobalamin compound. In a
particularly preferred embodiment, the patient may receive a weekly
dosage of about 350 .mu.g of the cobalamin compound, delivered by
once daily nasal administration of 50 .mu.g of a cobalamin
compound.
[0027] Compositions Containing a Cobalamin Compound
[0028] A further aspect of the present invention is a composition
comprising a cobalamin compound that may be used in a regimen to
treat vitamin B.sub.12 deficiency and deficiency related disorders.
The composition may be used in previously known regimens of
treatment for vitamin B.sub.12 deficiency, but preferably is used
in the practice of the treatment regimen of the present invention
described above.
[0029] A composition of the present invention generally comprises
an aqueous solution containing a cobalamin compound. The aqueous
solution is preferably isotonic. The cobalamin may be any of a
number of known cobalamin compounds, including for example,
cyanocobalamin, hydroxocobalamin (vitamin B.sub.12a),
hydroxocobalamin HCl, sulfate, acetate and other hydroxocobalamin
salts, aquacobalamin (vitamin B.sub.12b), nitrilocobalamin (vitamin
B.sub.12c), methylcobalamin (methyl B.sub.12), 5'-deoxyadenosine
cobalamin (coenzyme B.sub.12), pharmaceutically acceptable salts
thereof, chemically modified equivalents thereof, and mixtures
thereof. The selection of the specific form of cobalamin to be used
in the composition depends upon a number of factors known to those
of skill in the art, including, for example, the composition in
which the cobalamin compound is to be mixed or dissolved, the
amount or concentration of cobalamin compound desired in the
composition, the solubility of the cobalamin compound and the pH of
the composition. In one embodiment, the cobalamin compound is
cyanocobalamin USP. In another embodiment, the cobalamin compound
is hydroxocobalamin. The concentration of the cobalamin compound in
the composition can vary depending upon a number of factors known
to those skilled in the art, including, for example, the
composition in which the cobalamin compound is to be mixed or
dissolved, the solubility of the cobalamin compound, the pH of the
composition, the means by which the cobalamin composition is
delivered to the nasal mucosa (e.g., using compressed gas or a
propellant), the volume of the spray dispensed per application and
the desired dosage to be delivered to the patient. Generally, the
cobalamin compound may be present in the composition in a
concentration of no more than about 20 weight percent (% w/w), for
example, from about 0.0001% w/w to about 20% w/w, preferably from
about 0.01% w/w to about 10% w/w, more preferably from about 0.02%
w/w to about 1% w/w, still more preferably from about 0.02% w/w to
about 0.04% w/w and most preferably about 0.025% w/w.
[0030] The isotonicity of the composition may generally be achieved
and maintained using sodium chloride or another pharmaceutically
acceptable isotonicity agent, such as, for example, dextrose, boric
acid, sodium tartrate, other organic or inorganic solutes and
mixtures thereof. The isotonicity agent is typically present in the
composition in a concentration sufficient to cause the osmolarity
of the composition to be from about 280 mOsmols to about 290
mOsmols.+-.50 mOsmols. Sodium chloride is generally preferred,
particularly if a buffer containing sodium ions is used in the
composition, and is typically present in an amount that is
physiologically equivalent to the tonicity of the nasal
membranes.
[0031] The cobalamin composition of the present invention may
further include a pharmaceutically acceptable buffer in order to
maintain the desired pH. Non-limiting examples of suitable buffers
used to adjust and maintain the pH of the composition include
acetate, citrate, prolamine, phosphate, carbonate, phthalate,
borate, or other pharmaceutically acceptable buffers and mixtures
thereof. In a particular embodiment, the buffer comprises sodium
phosphate. The pH of the composition is maintained generally to be
compatible with the fluids of the nasal membrane in order to
minimize irritation. For example, the composition may be maintained
at a pH from about 3 to about 11. In one embodiment, the
composition may be maintained at a pH from about 3 to about 6.5,
preferably from about 4 to about 6.5, more preferably from about 5
to about 6.5, still more preferably from about 6 to about 6.5, and
most preferably about 6.5. Alternatively, the composition may be
maintained at a pH greater than 6.5, preferably from about 6.5 to
about 11, more preferably from about 7 to about 10, still more
preferably from about 7 to about 9, even more preferably from about
7 to about 7.7, even more preferably about 7.2, and most preferably
about 7.7. The concentration of the buffer in the composition will
depend upon the selection of the buffer and the desired pH.
[0032] The present composition may also contain various
pharmaceutically acceptable additives such as tolerance enhancers
(sometimes more specifically referred to as humectants), absorption
enhancers (sometimes also referred to as surfactants),
preservatives, viscosity modifying agents (e.g., thickening
agents), osmolarity adjusters, complexing agents, stabilizers,
solubilizers, or any combination thereof.
[0033] A tolerance enhancer may be used in order to inhibit drying
of the nasal membrane or mucosa. A tolerance enhancer may also
serve the purpose of inhibiting or relieving irritation of the
nasal membranes. Examples of suitable tolerance enhancers include,
for example, humectants such as sorbitol, propylene glycol,
glycerol, glycerin, hyaluronan, aloe, mineral oil, vegetable oil,
soothing agents, membrane conditioners, sweeteners, and mixtures
thereof. The selection and concentration of a tolerance enhancer
may depend on a number of factors, including, for example, the type
and concentration of cobalamin compound being used in the
composition. When used, the concentration of the tolerance enhancer
in the composition will typically be in amounts from about 0.01%
w/w to about 20% w/w.
[0034] A surfactant or absorption enhancer may also be used in the
composition in order to enhance the absorption of the cobalamin
compound across the nasal membrane. Suitable absorption enhancers
include non-ionic, anionic and cationic surfactants. Any of a
number of well-known surfactants may be used, including, for
example, polyoxyethylene derivatives of fatty acids, partial esters
of sorbitol anhydrides, sodium lauryl sulfate, sodium salicylate,
oleic acid, lecithin, dehydrated alcohol, Tween (e.g., Tween 20,
Tween 40, Tween 60, Tween 80 and the like), Span (e.g., Span 20,
Span 40, Span 80 and the like), polyoxyl 40 stearate, polyoxy
ethylene 50 stearate, edetate disodium, propylene glycol, glycerol
monooleate, fusieates, bile salts, octoxynol and combinations
thereof. When used, the concentration of the surfactant in the
composition will typically be from about 0.1% w/w to about 50% w/w.
By way of example, concentrations of sodium salicylate, sodium
lauryl sulfate and edetate disodium may be from about 0.01% to
about 5% w/w of the composition. Concentrations of polyoxyl 40
stearate, lecithin, dehydrated alcohol, can be from about 0.1% to
about 10% w/w of the composition. Concentrations of oleic acid can
be from about 0.01% to about 5% w/w of the composition.
Concentrations of propylene glycol and Tween 20 can be from about
0.1% to about 25% w/w of the composition.
[0035] A pharmaceutically acceptable thickening agent may also be
used in the composition in order to modify the viscosity of the
composition. Numerous pharmaceutically acceptable thickening agents
are well-known and include, for example, methyl cellulose, xanthan
gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer,
polyvinyl alcohol, alginates, acacia, chitosans and combinations
thereof. The concentration of the thickening agent will depend upon
the agent selected and the viscosity desired. Such agent may be
present in the composition at a concentration of from about 0.1%
w/w to about 20% w/w.
[0036] A preservative may also be employed to increase the
shelf-life of the composition. A number of well-known and
pharmaceutically acceptable preservatives may be used in the
present composition, including, for example, parabens, thimerosal,
chlorobutanol, benzalkonium chloride, or benzyl alcohol and
combinations thereof. Other ingredients which extend shelf life can
be added such as for example, antioxidants. Examples of
antioxidants include sodium metabisulfite, potassium metabisulfite,
ascorbyl palmitate and other pharmaceutically acceptable
antioxidants. Typically, the antioxidant will be present in the
composition in a concentration of from about 0.01% w/w to about 5%
w/w.
[0037] Benzyl alcohol and benzalkonium chloride are preferred
preservatives. A suitable concentration of preservative will depend
on a number of factors, including, for example, the particular
preservative selected, the intended shelf-life of the composition,
and the results of preservative effectiveness and minimum
preservative studies. When used, the concentration of the
preservative in the composition will typically be from about 0.001%
w/w to about 5% w/w, preferably from about 0.01% w/w to about 1%
w/w and more preferably from about 0.02% w/w to about 0.4% w/w.
[0038] In one embodiment of the present invention, the cobalamin
composition comprises sodium chloride, 0.649% w/w (0.11M); sodium
phosphate, monobasic, anhydrous, 0.19% w/w (0.016M); benzyl
alcohol, NF, 0.366% w/w (0.034M); sodium hydroxide, NF, 0.04% w/w
(0.010M); benzalkonium chloride, 50%, NF, 0.02% w/w;
cyanocobalamin, USP, 0.025% w/w (0.00018M); in purified water, USP,
98.71% w/w.
[0039] Alternatively, and in accordance with a preferred embodiment
of the present invention, the cobalamin composition may be
formulated to be a sterile, preservative-free composition. While
preservatives may extend the shelf life of a composition, they may
also cause or exacerbate irritation to the nasal membranes.
Furthermore, because of the frequency with which the composition of
the present invention is preferably administered, a bottle of
typical volume for storing and dispensing the composition will
likely be emptied by the patient before the occurrence of the
degradation, spoilage, or bacterial growth that a preservative is
meant to prevent.
[0040] Thus in another embodiment, the cobalamin composition is
preservative-free and comprises sodium chloride, 0.649% w/w
(0.11M); sodium phosphate, monobasic, anhydrous, 0.19% w/w
(0.016M); sodium hydroxide, NF, 0.04% w/w (0.010M); cyanocobalamin,
USP, 0.025% w/w (0.00018M); in purified water, USP, 99.096%
w/w.
[0041] The composition may be prepared by methods known to those of
skill in the art, including by combining or mixing the components
according to generally accepted procedures. By way of example, the
selected components may be simply mixed in a blender or other
standard mixing machine to produce a concentrated composition which
is then adjusted to the final concentration by the addition of
water.
[0042] Typically, the cobalamin composition will be stored in and
dispensed from a sealed container equipped with a metering valve
and pump capable of being actuated to deliver or emit an aerosol
(e.g., mist or spray) of the composition of predetermined volume
into the patient's nostril and having a suitable droplet size
distribution as known to those skilled in the art. Generally, the
size of the droplets are large enough to prevent them from passing
directly through the nasal passages and into the lungs, but small
enough that they do not coalesce into large drops which either run
out of the nose or down into the throat.
[0043] Suitable containers and metering valves for dispensing the
cobalamin composition according to the methods of the invention are
available commercially and are known to those of skill in the art.
The container and valve system used to deliver the cobalamin
composition may incorporate any of the conventional aerosol
formation techniques. These include, for example, mechanical pumps;
compressed air mechanisms in which delivery is made by hand pumping
air into the container; compressed gas techniques in which delivery
is made by the controlled release of a compressed gas (such as, for
example, carbon dioxide, nitrogen, and dinitrogen oxide) into the
cobalamin containing composition; and liquid propellant techniques
in which a low boiling liquid hydrocarbon (such as, for example,
butane, isobutane, propane, and other low boiling hydrocarbons in
either pure or mixed forms), halohydrocarbon, fluorocarbons (such
as, for example, FC-152A), chlorofluorocarbons (such as Freon or
Freon like fluorocarbons, such as, for example, CFC-11, CFC-12 and
CFC-114), and hydrofluorocarbons, also referred to as
hydrofluoroalkanes (such as, for example, HFA-134a and HFA-227) are
vaporized to exert a pressure and force the composition through the
metering valve.
[0044] In accordance with a preferred embodiment, and especially
when a preservative-free composition is formulated, the cobalamin
composition is stored for administration in a container or bottle
including a pump and metering valve adapted for delivery of a
metered spray of the composition and designed to inhibit or prevent
degradation or spoilage of and bacterial growth in the composition
contained therein. Examples of such a container are the spray pump
bottles produced by and available from Pfeiffer (Advanced
Preservative Free System) and from Valois (VPY).
[0045] The following non-limiting example is provided to further
illustrate the present invention. It should be appreciated by those
skilled in the art that the techniques disclosed in the example
that follows represent approaches the inventors have found function
well in the practice of the invention, and thus can be considered
to constitute examples of modes for its practice. However, those
skilled in the art should, in light of the present disclosure,
appreciate that many changes can be made in the specific
embodiments that are disclosed and still obtain a like or similar
result without departing from the spirit and scope of the
invention.
EXAMPLE
[0046] The study comprised twenty-five subjects, ages 18 85, with a
history of documented vitamin B.sub.12 deficiency who had
previously been receiving maintenance intramuscular (IM) injections
of B.sub.12 The purpose of this study was to determine whether as
an alternative to IM injections, one daily administration of a
0.025% by weight cobalamin composition is sufficient to sustain an
efficacious level of B.sub.12 in place of IM therapy and, thereby,
maintain a serum B.sub.12 level within the therapeutic range of
greater than about 200 ng/L.
[0047] As an alternative to an IM injection, an aqueous isotonic
composition containing a cobalamin compound was provided to the
subjects to allow them to dose themselves at home with one daily
intranasal (IN) administration comprising two puffs or sprays of
B.sub.12 (cobalamin). The intranasal cobalamin composition used in
this study is listed in Table 1.
TABLE-US-00001 TABLE 1 Cobalamin Containing Composition Used in
Study % Quantity Required per Description w/w Batch Molarity Sodium
Chloride 0.649 248.1 gm 0.11 Sodium Phosphate, 0.19 72.6 gm 0.016
Monobasic, anhydrous Benzyl Alcohol, NF 0.366 139.9 gm 0.034 Sodium
Hydroxide, 0.04 15.3 gm 0.010 NF Benzalkonium 0.02 7.65 gm NA
(isomeric Chloride, 50%, NF (3.83 g BAC + mix) 3.83 g water)
Cyanocobalamin, USP 0.025 9.56 gm 0.00018 Purified Water, USP 98.71
37.7 kg NA Total 100 38.2 kg NA
[0048] Study Design
[0049] This study was an open label, non-randomized, single-arm,
active treatment study. All subjects were instructed to complete
daily diaries to record the date and time of administration and any
adverse events.
[0050] Subjects with chronic B.sub.12 deficiencies were treated
with intramuscular (IM) injections every 4-8 weeks. At the midpoint
of the usual IM therapy interval (between 2 and 4 weeks post
injection) subjects presented at the clinic for screening and
provided blood samples for the measurement of levels of vitamin
B.sub.12. At the end of the IM therapy interval (4 to 8 weeks post
injection) the subjects returned to the clinic to provide a blood
sample for a low level of B.sub.12 measurement and began the
intranasal 0.025% cyanocobalamin therapy. Each morning during the 8
week administration of nasal cyanocobalamin, subjects sprayed 1
spray (0.1 mL) of the saline solution containing 0.025% by weight
cyanocobalamin from an upright metered dose bottle directly into
each nostril for a 50 .mu.g daily dose of cyanocobalamin.
[0051] Subjects returned to the clinic every two weeks (post dosing
initiation) for eight weeks to provide blood samples for the
evaluation of B.sub.12 levels.
[0052] Primary Efficacy Analysis
[0053] The primary efficacy endpoint is the average of the vitamin
B.sub.12 levels from Visits 3, 4, 5 and 6 relative to the B.sub.12
levels at Visit 1. The ratio of each post baseline value to
baseline was calculated, and the repeated measures model was used
to calculate the means of the ratios at each visit. The estimate
statement (statement 1) provided an estimate of the average of the
ratios across visits 3, 4, 5 and 6 and the confidence interval
around that average.
[0054] Statistical Analysis
[0055] Because the study subjects are on different IM therapy
intervals, Visit 1 and Visit 2 will not correspond to the same
relative week. The following schedule describes the actual
times:
[0056] Visit #1 (V1)--Midpoint between IM injections (anywhere from
2 to 4 weeks post IM therapy).
[0057] Visit #2 (V2)--Termination of IM therapy (anywhere from 4 to
8 weeks post IM therapy). This is the point at which the next IM
injection would have been given, but for the fact that the study
participants began intranasal therapy instead.
[0058] Visit #3 (V3)--2 weeks post IN therapy initiation.
[0059] Visit #4 (V4)--4 week post IN therapy initiation.
[0060] Visit #5 (V5)--6 weeks post IN therapy initiation.
[0061] Visit #6 (V6)--8 weeks post IN therapy initiation.
[0062] Analysis Results
[0063] Descriptive Statistics
[0064] The average (standard deviation) age of the 25 subjects was
59.8 (15.5) years, ranging from 28.0 to 82.6 years. Seventeen
(68.0%) of the subjects were female. Twenty-one (84.0%) were
Caucasian and four (16.0%) were African American. The general
pattern was an initial decline from Visit #1 to Visit #2 and a
steady increase in the last four visits (Visits #3-#6), although
there were exceptions. The mean 12 value, range, and standard
deviation at each visit are summarized in Table 2, and the means
and their 95% confidence intervals are also shown in FIG. 1.
TABLE-US-00002 TABLE 2 SUMMARY OF B.sub.12 LEVEL AT EACH VISIT
DURING THE STUDY FOR THE 25 SUBJECTS Mean Standard Deviation Range
(low-high) Visit N (.mu.g/mL) (.mu.g/mL) (.mu.g/mL) #1 25 484.28
157.93 (419.09, 549.47) #2 25 402.96 149.51 (341.24, 464.68) #3 25
505.76 136.73 (449.32, 562.20) #4 25 519.76 132.96 (464.88, 574.64)
#5 25 510.60 162.41 (443.56, 577.64) #6 25 568.28 194.39 (488.04,
648.52)
[0065] The above description of the preferred embodiments is
intended only to acquaint others skilled in the art with the
invention, its principles, and its practical application, so that
others skilled in the art may adapt and apply the invention in its
numerous forms, as may be best suited to the requirements of a
particular use. The present invention, therefore, is not limited to
the above embodiments, and may be variously modified.
[0066] With reference to the use of the word(s) "comprise" or
"comprises" or "comprising" in this specification, including the
appended claims, unless the context requires otherwise, those words
are used on the basis and clear understanding that they are to be
interpreted inclusively, rather than exclusively, and that it is
intended each of those words to be so interpreted in construing
this specification.
* * * * *