U.S. patent application number 14/789771 was filed with the patent office on 2016-01-07 for sterilization of ciprofloxacin composition.
The applicant listed for this patent is Otonomy, Inc.. Invention is credited to Scott H. Coleman, Wei-Cheng Liaw, Robert Savel, Jerry Wroblewski.
Application Number | 20160000948 14/789771 |
Document ID | / |
Family ID | 54932222 |
Filed Date | 2016-01-07 |
United States Patent
Application |
20160000948 |
Kind Code |
A1 |
Coleman; Scott H. ; et
al. |
January 7, 2016 |
STERILIZATION OF CIPROFLOXACIN COMPOSITION
Abstract
Disclosed herein are methods of making sterilized ciprofloxacin
compositions. In some embodiments, the method includes the steps
of: (a) forming an aqueous suspension comprising ciprofloxacin
particles; (b) heating the aqueous suspension comprising
ciprofloxacin particles at a temperature range of from about
100.degree. C. to about 120.degree. C.; and (c) allowing the
aqueous suspension comprising ciprofloxacin particles to cool down.
Also described herein are otic formulations containing
ciprofloxacin formed by the disclosed methods, and therapeutic use
of such otic formulation for providing sustained release of
ciprofloxacin into the ear for treating various otic disorders and
conditions.
Inventors: |
Coleman; Scott H.; (San
Diego, CA) ; Liaw; Wei-Cheng; (San Diego, CA)
; Wroblewski; Jerry; (San Mateo, CA) ; Savel;
Robert; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otonomy, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
54932222 |
Appl. No.: |
14/789771 |
Filed: |
July 1, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62020940 |
Jul 3, 2014 |
|
|
|
Current U.S.
Class: |
514/253.08 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/0046 20130101; A61K 9/06 20130101; A61P 27/16 20180101; A61L
2/0023 20130101; A61L 2/0029 20130101; A61L 2/0017 20130101; A61K
31/496 20130101 |
International
Class: |
A61L 2/00 20060101
A61L002/00; A61K 31/496 20060101 A61K031/496; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of making a sterilized ciprofloxacin composition,
comprising the steps of: (a) forming an aqueous suspension
comprising ciprofloxacin particles; (b) heating the aqueous
suspension comprising ciprofloxacin particles at a temperature
range of from about 100.degree. C. to about 120.degree. C.; (c)
allowing the aqueous suspension comprising ciprofloxacin particles
to cool down; and (d) combining the cooled aqueous suspension
comprising ciprofloxacin particles with a sterilized aqueous
solution comprising a thermoreversible polymer to form an otic
formulation.
2. The method of claim 1, wherein the aqueous suspension in step
(a) is essentially free of organic solvent.
3. The method of claim 1, wherein the ciprofloxacin particles in
step (a) are essentially in the form of ciprofloxacin hydrate
particles.
4. The method of claim 1, wherein the ciprofloxacin particles in
step (a) are present in the aqueous suspension at a concentration
of from about 4 wt % to about 30 wt %.
5. The method of claim 1, wherein the ciprofloxacin particles in
step (a) are present in the aqueous suspension at a concentration
of from about 10 wt % to about 16 wt %.
6. The method of claim 1, wherein the ciprofloxacin particles in
step (a) have a D90 of from about 40 .mu.m to about 80 .mu.m.
7. The method of claim 1, wherein the ciprofloxacin particles in
step (a) have a D90 of from about 50 .mu.m to about 70 .mu.m.
8. The method of claim 1, wherein the aqueous suspension in step
(b) is heated at a temperature of from about 105.degree. C. to
about 115.degree. C.
9. The method of claim 1, wherein the aqueous suspension in step
(b) is heated for a period of from about 30 minutes to about 5
hours.
10. The method of claim 1, wherein the aqueous suspension in step
(b) is heated at a temperature of about 115.degree. C. for a period
of about 1 hour.
11. The method of claim 1, wherein the aqueous suspension in step
(b) is heated at a temperature of about 110.degree. C. for a period
of from about 1 hour to about 2 hours.
12. The method of claim 1, wherein the aqueous suspension in step
(b) is heated at a constant temperature within the temperature
range.
13. The method of claim 1, wherein the aqueous suspension in step
(b) is heated at variable temperatures within the temperature
range.
14. The method of claim 1, wherein the ciprofloxacin particles in
step (b) are homogenized in the aqueous suspension when heated.
15. The method of claim 1, wherein the ciprofloxacin particles in
step (c) are homogenized in the aqueous suspension during
cooling.
16. The method of claim 1, wherein the aqueous suspension in step
(c) is allowed to cool down to from about 2.degree. C. to about
10.degree. C.
17. The method of claim 1, wherein the ciprofloxacin particles in
step (c) have a D90 of from about 5 .mu.m to about 40 .mu.m after
cooling down.
18. The method of claim 1, wherein the thermoreversible polymer in
step (d) is poloxamer 407.
19. The method of claim 1, wherein the aqueous solution in step (d)
further comprises a buffer agent.
20. The method of claim 1, wherein the aqueous solution in step (d)
further comprises an osmolarity modifier.
21. The method of claim 1, wherein the aqueous solution in step (d)
is sterilized through filtration sterilization, heat sterilization,
or radiation sterilization.
22. The method of claim 1, wherein the aqueous solution in step (d)
is sterilized through filtration sterilization.
23. The method of claim 1, wherein the aqueous suspension and the
aqueous solution are combined under aseptic condition.
24. The method of claim 1, wherein the otic formulation comprises
from about 5.5 wt % to about 6.5 wt % of ciprofloxacin.
25. The method of claim 1, wherein the otic formulation comprises
from about 15 wt % to about 17 wt % of the thermoreversible
polymer, and wherein the thermoreversible polymer is poloxamer
407.
26. The method of claim 1, where the otic formulation has a pH of
from about 7.0 to about 8.0.
27. The method of claim 1, where the otic formulation has an
osmolarity of from about 270 mOsm/L to about 320 mOsm/L.
28. A sterilized otic formulation formed by the method of claim 1,
the sterilized otic formulation comprising: from about 5.5 wt % to
about 6.5 wt % multiparticulate ciprofloxacin; from about 15 wt %
to about 17 wt % poloxamer 407; and water, wherein the composition
has a pH of from about 7.0 to about 8.0, an osmolarity of from
about 270 to about 320 mOsm/L, and wherein the sterilized otic
formulation provides sustained release of a therapeutically
effective amount of ciprofloxacin into the ear for a period of at
least 5 days after a single administration.
29. The sterilized otic formulation of claim 28, wherein the
multiparticulate ciprofloxacin has a D90 of from about 5 .mu.m to
about 40 .mu.m.
30. A ready-to-use otic product, comprising an aseptic vial and the
sterilized otic formulation of claim 28.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/020,940, filed Jul. 3, 2014, which application
is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Ciprofloxacin is a quinolone compound with antimicrobial
activities. Some ciprofloxacin-containing pharmaceutical
compositions require sterility for specific medical
applications.
SUMMARY OF THE INVENTION
[0003] Described herein are methods of making sterilized
ciprofloxacin compositions. In some embodiments, the method
includes the steps of: (a) forming an aqueous suspension comprising
ciprofloxacin particles; (b) heating the aqueous suspension
comprising ciprofloxacin particles at a temperature range of from
about 100.degree. C. to about 120.degree. C.; and (c) allowing the
aqueous suspension comprising ciprofloxacin particles to cool
down.
[0004] In some embodiments, the aqueous suspension in step (a) is
formed by mixing ciprofloxacin particles with water. In some
embodiments, the aqueous suspension in step (a) is formed by
homogenizing ciprofloxacin particles in water.
[0005] In some embodiments, the aqueous suspension in step (a) is
essentially free of organic solvent.
[0006] In some embodiments, the ciprofloxacin particles in step (a)
are in the form of ciprofloxacin anhydrous particles, ciprofloxacin
hydrate particles, or a combination thereof. In some embodiments,
the ciprofloxacin particles in step (a) are essentially in the form
of ciprofloxacin hydrate particles.
[0007] In some embodiments, the ciprofloxacin particles in step (a)
are present in the aqueous suspension at a concentration of from
about 4 wt % to about 30 wt %. In some embodiments, the
ciprofloxacin particles in step (a) are present in the aqueous
suspension at a concentration of from about 4 wt % to about 20 wt
%. In some embodiments, the ciprofloxacin particles in step (a) are
present in the aqueous suspension at a concentration of from about
4 wt % to about 16 wt %.
[0008] In some embodiments, the ciprofloxacin particles in step (a)
have a D90 of from about 40 .mu.m to about 80 .mu.m. In some
embodiments, the ciprofloxacin particles in step (a) have a D90 of
from about 45 .mu.m to about 75 .mu.m. In some embodiments, the
ciprofloxacin particles in step (a) have a D90 of from about 50
.mu.m to about 70 .mu.m. In some embodiments, the ciprofloxacin
particles in step (a) have a D90 of from about 40 .mu.m to about 80
.mu.m.
[0009] In some embodiments, the aqueous suspension in step (b) is
heated at a temperature of from about 101.degree. C. to about
119.degree. C. In some embodiments, the aqueous suspension in step
(b) is heated at a temperature of from about 102.degree. C. to
about 118.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 103.degree. C. to
about 117.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 104.degree. C. to
about 116.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 105.degree. C. to
about 115.degree. C.
[0010] In some embodiments, the aqueous suspension in step (b) is
heated for a period of from about 30 minutes to about 5 hours. In
some embodiments, the aqueous suspension in step (b) is heated for
a period of from about 40 minutes to about 4 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 50 minutes to about 3 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 1 hour to about 2 hours.
[0011] In some embodiments, the aqueous suspension in step (b) is
heated at a temperature of about 115.degree. C. for a period of
about 1 hour. In some embodiments, the aqueous suspension in step
(b) is heated at a temperature of about 105.degree. C. for a period
of about 2 hour. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of about 110.degree. C. for a
period of from about 1 hour to about 2 hours.
[0012] In some embodiments, the aqueous suspension in step (b) is
heated at a constant temperature within the temperature range. In
some embodiments, the aqueous suspension in step (b) is heated at
variable temperatures within the temperature range.
[0013] In some embodiments, the ciprofloxacin particles in step (b)
are homogenized in the aqueous suspension when heated.
[0014] In some embodiments, the ciprofloxacin particles in step (c)
are essentially in the form of ciprofloxacin hydrate particles.
[0015] In some embodiments, the ciprofloxacin particles in step (c)
are homogenized in the aqueous suspension during cooling. In some
embodiments, the aqueous suspension in step (c) is allowed to cool
down to from about 2.degree. C. to about 10.degree. C.
[0016] In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 5 .mu.m to about 40 .mu.m after cooling
down. In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 10 .mu.m to about 35 .mu.m after cooling
down. In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 15 .mu.m to about 25 .mu.m after cooling
down.
[0017] In some embodiments, the methods of making sterilized
ciprofloxacin compositions further include the step of: (d)
combining the cooled aqueous suspension comprising ciprofloxacin
particles with a sterilized aqueous solution comprising a
thermoreversible polymer to form an otic formulation.
[0018] In some embodiments, the thermoreversible polymer is a
polyoxyethylene-polyoxypropylene triblock copolymer. In some
embodiments, the thermoreversible polymer is poloxamer 407.
[0019] In some embodiments, the aqueous solution further comprises
a buffer agent. In some embodiments, the buffer agent is
tromethamine.
[0020] In some embodiments, the aqueous solution further comprises
a pH adjusting agent in an amount to adjust the pH of the aqueous
solution to from about 7.0 to about 8.0. In some embodiments, the
pH adjusting agent is hydrochloric acid.
[0021] In some embodiments, the aqueous solution further comprises
an osmolarity modifier. In some embodiments, the osmolarity
modifier is sodium chloride.
[0022] In some embodiments, the aqueous solution is sterilized
through filtration sterilization, heat sterilization, or radiation
sterilization. In some embodiments, the aqueous solution is
sterilized through filtration sterilization. In some embodiments,
the aqueous solution is sterilized by passing through a cold
sterilization filter.
[0023] In some embodiments, the aqueous solution is allowed to cool
down to from about 2.degree. C. to about 10.degree. C.
[0024] In some embodiments, the aqueous suspension and the aqueous
solution are combined under aseptic condition.
[0025] In some embodiments, the otic formulation comprises from
about 5 wt % to about 7 wt % of ciprofloxacin. In some embodiments,
the otic formulation comprises from about 5.5 wt % to about 6.5 wt
% of ciprofloxacin. In some embodiments, the otic formulation
comprises from about 1.5 to about 2.5 wt % of ciprofloxacin.
[0026] In some embodiments, the otic formulation comprises from
about 14 wt % to about 19 wt % of the thermoreversible polymer. In
some embodiments, the otic formulation comprises from about 15 wt %
to about 17 wt % of the thermoreversible polymer. In some
embodiments, the otic formulation comprises from about 15.5 wt % to
about 16.5 wt % of the thermoreversible polymer.
[0027] In some embodiments, the otic formulation has a pH of from
about 7.0 to about 8.0.
[0028] In some embodiments, the otic formulation has an osmolarity
of from about 270 mOsm/L to about 320 mOsm/L.
[0029] In some embodiments, the otic formulation has less than
about 50 colony forming units (cfu) of microbiological agents per
gram of formulation.
[0030] In some embodiments, the otic formulation has less than
about 5 endotoxin units (EU) per kg of body weight of a
subject.
[0031] In some embodiments, the otic formulation has a gelation
temperature between about 19.degree. C. to about 42.degree. C.
[0032] Also described herein are otic formulations containing
ciprofloxacin formed by the disclosed methods, and therapeutic use
of such otic formulation for providing sustained release of
ciprofloxacin into the ear for treating various otic disorders and
conditions.
[0033] In some embodiment, the sterilized otic formulation
comprising: from about from 4.5 wt % to 6 wt % multiparticulate
ciprofloxacin; from 14 wt % to 16 wt % poloxamer; and water,
wherein the composition has a pH of 7.0-7.8, an osmolarity of
270-320 mOsm/L, and a gelation temperature of 20-30.degree. C., and
wherein the composition provides sustained release of a
therapeutically effective amount of ciprofloxacin into the ear for
a period of at least 5 days after a single administration. In some
embodiment, the sterilized otic formulation comprising: from about
from 1.5 wt % to 2.5 wt % multiparticulate ciprofloxacin; from 14
wt % to 16 wt % poloxamer; and water, wherein the composition has a
pH of 7.0-7.8, an osmolarity of 270-320 mOsm/L, and a gelation
temperature of 20-30.degree. C., and wherein the composition
provides sustained release of a therapeutically effective amount of
ciprofloxacin into the ear for a period of at least 5 days after a
single administration.
[0034] In some embodiments, the multiparticulate ciprofloxacin is
micronized ciprofloxacin. In some embodiments, the micronized
ciprofloxacin has a D90 of from about 5 .mu.m to about 40 .mu.m. In
some embodiments, the micronized ciprofloxacin has a D90 of from
about 10 .mu.m to about 35 .mu.m. In some embodiments, the
micronized ciprofloxacin has a D90 of from about 15 .mu.m to about
25 .mu.m.
[0035] In some embodiments, the poloxamer is poloxamer 407.
[0036] In some embodiments, the otic formulation further comprises
tromethamine.
[0037] In some embodiments, the otic formulation further comprises
a sodium salt for osmolarity adjustment.
[0038] In some embodiments, the composition provides sustained
release of a therapeutically effective amount of ciprofloxacin into
the ear for a period of at least 10 days after a single
administration.
[0039] In some embodiments, the composition provides sustained
release of a therapeutically effective amount of ciprofloxacin into
the ear for a period of at least 14 days after a single
administration.
[0040] In some embodiments, the composition has less than 5
endotoxin units (EU) per kg of body weight. In some embodiments,
the ciprofloxacin is moist-heat sterilized.
[0041] In some embodiments, the ciprofloxacin is moist-heat
sterilized and the poloxamer is filtration sterilized.
[0042] Also disclosed herein is a ready-to-use otic product,
comprising an aseptic vial and a sterilized otic formulation as
described herein.
BRIEF DESCRIPTION OF FIGURES
[0043] FIG. 1 shows X-ray characterization of ciprofloxacin
anhydrous, ciprofloxacin hydrate, and an aqueous ciprofloxacin
suspension formed according to the method disclosure herein;
[0044] FIG. 2 shows X-ray characterization of an aqueous
ciprofloxacin suspension after heat sterilization at 135.degree. C.
(without cooling down);
[0045] FIG. 3 is a photograph of the aqueous ciprofloxacin
suspension in FIG. 2 after cooling down, particularly illustrating
the solidification of the suspension;
[0046] FIG. 4 illustrates the anatomy of the ear; and
[0047] FIG. 5 schematically illustrates sustained release of
ciprofloxacin from an otic formulation formed according to the
method disclosure herein.
DETAILED DESCRIPTION OF THE INVENTION
[0048] Provided herein are methods of making sterilized
ciprofloxacin compositions. Also described herein are otic
formulations containing ciprofloxacin formed by the disclosed
methods, and therapeutic use of such otic formulation for providing
sustained release of ciprofloxacin into the ear for treating
various otic disorders and conditions.
Sterilization of Pharmaceutical Products
[0049] Pharmaceutical compositions sometimes need to be sterilized
for specific medical or therapeutic applications. The goal is to
provide a safe pharmaceutical product, relatively free of infection
causing micro-organisms. The U. S. Food and Drug Administration has
provided regulatory guidance in the publication "Guidance for
Industry: Sterile Drug Products Produced by Aseptic Processing"
available at: http://www.fda.gov/cder/guidance/5882fnl.htm, which
is incorporated herein by reference in its entirety.
[0050] As used herein, sterilization means a process used to
destroy or remove microorganisms that are present in a product or
packaging. Any suitable method available for sterilization of
objects and compositions is used. Available methods for the
inactivation of microorganisms include, but are not limited to, the
application of extreme heat, lethal chemicals, or gamma radiation
or E-beam irradiation. In some embodiment, a process for the
preparation of an otic therapeutic formulation comprises subjecting
the formulation to a sterilization method selected from heat
sterilization, chemical sterilization, radiation sterilization or
filtration sterilization. The method used depends largely upon the
nature of the device or composition to be sterilized. Detailed
descriptions of many methods of sterilization are given in Chapter
40 of Remington: The Science and Practice of Pharmacy published by
Lippincott, Williams & Wilkins, and is incorporated by
reference with respect to this subject matter.
[0051] Sterilization by Heat
[0052] Many methods are available for sterilization by the
application of extreme heat. One method is through the use of a
saturated steam autoclave. In some embodiments, saturated steam at
a temperature of at least 121.degree. C. is allowed to contact the
object to be sterilized. The transfer of heat is either directly to
the microorganism, in the case of an object to be sterilized, or
indirectly to the microorganism by heating the bulk of an aqueous
solution to be sterilized. This method is widely practiced as it
allows flexibility, safety and economy in the sterilization
process. For example, a typical moist heat sterilization process,
heating to 121.5 degrees Celsius and holding for a certain duration
is often used to sterilize liquid formulations and this method is
often regarded by regulatory agencies as acceptable for ensuring
sterility.
[0053] Dry heat sterilization is a method which is used to kill
microorganisms and perform depyrogenation at elevated temperatures.
This process takes place in an apparatus suitable for heating
HEPA-filtered microorganism-free air to temperatures of for example
130-180.degree. C. for the sterilization process and to
temperatures of for example 230-250.degree. C. for the
depyrogenation process. Water to reconstitute concentrated or
powdered formulations is also sterilized by autoclave.
[0054] Filtration
[0055] Filtration sterilization is a method used to remove but not
destroy microorganisms from solutions. Membrane filters are used to
filter heat-sensitive solutions. Such filters are thin, strong,
homogenous polymers of mixed cellulosic esters (MCE),
polyvinylidene fluoride (PVF; also known as PVDF), or
polytetrafluoroethylene (PTFE) and have pore sizes ranging from 0.1
to 0.22 .mu.m. Solutions of various characteristics are optionally
filtered using different filter membranes. For example, PVF and
PTFE membranes are well suited to filtering organic solvents while
aqueous solutions are filtered through PVF or MCE membranes. Filter
apparatus are available for use on many scales ranging from the
single point-of-use disposable filter attached to a syringe up to
commercial scale filters for use in manufacturing plants. The
membrane filters are sterilized by autoclave or chemical
sterilization. Validation of membrane filtration systems is
performed following standardized protocols (Microbiological
Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3,
Washington, D.C: Health Industry Manufacturers Association, 1981)
and involve challenging the membrane filter with a known quantity
(ca. 10.sup.7/cm.sup.2) of unusually small microorganisms, such as
Brevundimonas diminuta (ATCC 19146).
[0056] Pharmaceutical compositions are optionally sterilized by
passing through membrane filters. Formulations comprising
nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles
(Richard et al., International Journal of Pharmaceutics (2006), 312
(1-2):144-50) are amenable to sterilization by filtration through
0.22 .mu.m filters without destroying their organized
structure.
[0057] In some embodiments, the methods disclosed herein comprise
sterilizing the formulation (or components thereof) by means of
filtration sterilization. In another embodiment the
auris-acceptable otic therapeutic agent formulation comprises a
particle wherein the particle formulation is suitable for
filtration sterilization. In a further embodiment said particle
formulation comprises particles of less than 300 nm in size, of
less than 200 nm in size, of less than 100 nm in size. In another
embodiment the auris-acceptable formulation comprises a particle
formulation wherein the sterility of the particle is ensured by
sterile filtration of the precursor component solutions. In another
embodiment the auris-acceptable formulation comprises a particle
formulation wherein the sterility of the particle formulation is
ensured by low temperature sterile filtration. In a further
embodiment, low temperature sterile filtration is carried out at a
temperature between 0 and 30.degree. C., between 0 and 20.degree.
C., between 0 and 10.degree. C., between 10 and 30.degree. C., or
between 10 and 20.degree. C.
[0058] In another embodiment is a process for the preparation of an
auris-acceptable particle formulation comprising: filtering the
aqueous solution containing the particle formulation at low
temperature through a sterilization filter; lyophilizing the
sterile solution; and reconstituting the particle formulation with
sterile water prior to administration. In some embodiments, a
formulation described herein is manufactured as a suspension in a
single vial formulation containing the micronized active
pharmaceutical ingredient. A single vial formulation is prepared by
aseptically mixing a sterile poloxamer solution with sterile
micronized active ingredient (e.g., ciprofloxacin) and transferring
the formulation to sterile pharmaceutical containers. In some
embodiments, a single vial containing a formulation described
herein as a suspension is resuspended before dispensing and/or
administration.
[0059] In specific embodiments, filtration and/or filling
procedures are carried out at about 5.degree. C. below the gel
temperature (Tgel) of a formulation described herein and with
viscosity below a theoretical value of 100 cP to allow for
filtration in a reasonable time using a peristaltic pump.
[0060] In another embodiment the auris-acceptable otic therapeutic
agent formulation comprises a nanoparticle formulation wherein the
nanoparticle formulation is suitable for filtration sterilization.
In a further embodiment the nanoparticle formulation comprises
nanoparticles of less than 300 nm in size, of less than 200 nm in
size, or of less than 100 nm in size. In another embodiment the
auris-acceptable formulation comprises a microsphere formulation
wherein the sterility of the microsphere is ensured by sterile
filtration of the precursor organic solution and aqueous solutions.
In another embodiment the auris-acceptable formulation comprises a
thermoreversible gel formulation wherein the sterility of the gel
formulation is ensured by low temperature sterile filtration. In a
further embodiment, the low temperature sterile filtration occurs
at a temperature between 0 and 30.degree. C., or between 0 and
20.degree. C., or between 0 and 10.degree. C., or between 10 and
30.degree. C., or between 10 and 20.degree. C. In another
embodiment is a process for the preparation of an auris-acceptable
thermoreversible gel formulation comprising: filtering the aqueous
solution containing the thermoreversible gel components at low
temperature through a sterilization filter; lyophilizing the
sterile solution; and reconstituting the thermoreversible gel
formulation with sterile water prior to administration.
[0061] In certain embodiments, the active ingredients are dissolved
in a suitable vehicle (e.g. a buffer) and sterilized separately
(e.g. by heat treatment, filtration, gamma or e-beam radiation). In
some instances, the active ingredients are sterilized separately in
a dry state. In some instances, the active ingredients are
sterilized as a suspension or as a colloidal suspension. The
remaining excipients (e.g., fluid gel components present in auris
formulations) are sterilized in a separate step by a suitable
method (e.g. filtration and/or irradiation of a cooled mixture of
excipients); the two solutions that are separately sterilized are
then mixed aseptically to provide a final auris formulation. In
some instances, the final aseptic mixing is performed just prior to
administration of a formulation described herein.
[0062] In some instances, conventionally used methods of
sterilization (e.g., heat treatment (e.g., in an autoclave), gamma
or e-beam irradiation, filtration) lead to irreversible degradation
of polymeric components (e.g., thermosetting, gelling or
mucoadhesive polymer components) and/or the active agent in the
formulation. In some instances, sterilization of an auris
formulation by filtration through membranes (e.g., 0.2 .mu.m
membranes) is not possible if the formulation comprises thixotropic
polymers that gel during the process of filtration.
[0063] Accordingly, provided herein are methods for sterilization
of auris formulations that prevent degradation of polymeric
components (e.g., thermosetting and/or gelling and/or mucoadhesive
polymer components) and/or the active agent during the process of
sterilization. In some embodiments, degradation of the active agent
(e.g., any therapeutic otic agent described herein) is reduced or
eliminated through the use of specific pH ranges for buffer
components and specific proportions of gelling agents in the
formulations. In some embodiments, the choice of an appropriate
gelling agent and/or thermosetting polymer allows for sterilization
of formulations described herein by filtration. In some
embodiments, the use of an appropriate thermosetting polymer and an
appropriate copolymer (e.g., a gelling agent) in combination with a
specific pH range for the formulation allows for high temperature
sterilization of formulations described with substantially no
degradation of the therapeutic agent or the polymeric excipients.
An advantage of the methods of sterilization provided herein is
that, in certain instances, the formulations are subjected to
terminal sterilization via autoclaving without any loss of the
active agent and/or excipients and/or polymeric components during
the sterilization step and are rendered substantially free of
microbes and/or pyrogens.
[0064] Radiation Sterilization
[0065] One advantage of radiation sterilization is the ability to
sterilize many types of products without heat degradation or other
damage. The radiation commonly employed is beta radiation or
alternatively, gamma radiation from a .sup.60Co source. The
penetrating ability of gamma radiation allows its use in the
sterilization of many product types, including solutions,
compositions and heterogeneous mixtures. The germicidal effects of
irradiation arise from the interaction of gamma radiation with
biological macromolecules. This interaction generates charged
species and free radicals. Subsequent chemical reactions, such as
rearrangements and cross-linking processes, result in the loss of
normal function for these biological macromolecules. The
formulations described herein are also optionally sterilized using
beta irradiation. Electron beam (E-beam) irradiation or electron
irradiation is a process which involves using electrons, usually of
high energy, to treat an object for a variety of purposes. This may
take place under elevated temperatures and nitrogen atmosphere.
Possible uses for electron irradiation include sterilization.
Electron beam processing has the ability to break the chains of DNA
in living organisms, such as bacteria, resulting in microbial death
and rendering the space they inhabit sterile. E-beam irradiation
has been used for the sterilization of medical products and aseptic
packaging materials for foods as well as disinfestation, the
elimination of live insects from grain, tobacco, and other
unprocessed bulk crops. In some embodiments, sterilization with
electrons provides quick and reliable sterilization, is compatible
with most materials, and does not require any quarantine following
the processing. For some materials and products that are sensitive
to oxidative effects, radiation tolerance levels for electron beam
irradiation may be higher than for gamma exposure. This is due to
the higher dose rates and shorter exposure times of e-beam
irradiation which have been shown to reduce the degradative effects
of oxygen.
[0066] Chemical Sterilization
[0067] Chemical sterilization methods are an alternative for
products that do not withstand the extremes of heat sterilization.
In this method, a variety of gases and vapors with germicidal
properties, such as ethylene oxide, chlorine dioxide, formaldehyde
or ozone are used as the apoptotic agents. The germicidal activity
of ethylene oxide, for example, arises from its ability to serve as
a reactive alkylating agent. Thus, the sterilization process
requires the ethylene oxide vapors to make direct contact with the
product to be sterilized.
[0068] Microorganisms
[0069] Provided herein are auris-acceptable compositions or devices
that ameliorate or lessen otic disorders described herein. Further
provided herein are methods comprising the administration of said
otic compositions. In some embodiments, the compositions or devices
are substantially free of microorganisms. Acceptable bioburden or
sterility levels are based on applicable standards that define
therapeutically acceptable compositions, including but not limited
to United States Pharmacopeia Chapters <1111> et seq. For
example, acceptable sterility (e.g., bioburden) levels include
about 10 colony forming units (cfu) per gram of formulation, about
50 cfu per gram of formulation, about 100 cfu per gram of
formulation, about 500 cfu per gram of formulation or about 1000
cfu per gram of formulation. In some embodiments, acceptable
bioburden levels or sterility for formulations include less than 10
cfu/mL, less that 50 cfu/mL, less than 500 cfu/mL or less than 1000
cfu/mL microbial agents. In addition, acceptable bioburden levels
or sterility include the exclusion of specified objectionable
microbiological agents. By way of example, specified objectionable
microbiological agents include but are not limited to Escherichia
coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P.
aeruginosa) and/or other specific microbial agents.
[0070] Sterility of the auris-acceptable otic therapeutic agent
formulation is confirmed through a sterility assurance program in
accordance with United States Pharmacopeia Chapters <61>,
<62> and <71>. A key component of the sterility
assurance quality control, quality assurance and validation process
is the method of sterility testing. Sterility testing, by way of
example only, is performed by two methods. The first is direct
inoculation wherein a sample of the composition to be tested is
added to growth medium and incubated for a period of time up to 21
days. Turbidity of the growth medium indicates contamination.
Drawbacks to this method include the small sampling size of bulk
materials which reduces sensitivity, and detection of microorganism
growth based on a visual observation. An alternative method is
membrane filtration sterility testing. In this method, a volume of
product is passed through a small membrane filter paper. The filter
paper is then placed into media to promote the growth of
microorganisms. This method has the advantage of greater
sensitivity as the entire bulk product is sampled. The commercially
available Millipore Steritest sterility testing system is
optionally used for determinations by membrane filtration sterility
testing. For the filtration testing of creams or ointments
Steritest filter system No. TLHVSL210 are used. For the filtration
testing of emulsions or viscous products Steritest filter system
No. TLAREM210 or TDAREM210 are used. For the filtration testing of
pre-filled syringes Steritest filter system No. TTHASY210 are used.
For the filtration testing of material dispensed as an aerosol or
foam Steritest filter system No. TTHVA210 are used. For the
filtration testing of soluble powders in ampoules or vials
Steritest filter system No. TTHADA210 or TTHADV210 are used.
[0071] Testing for E. coli and Salmonella includes the use of
lactose broths incubated at 30-35.degree. C. for 24-72 hours,
incubation in MacConkey and/or EMB agars for 18-24 hours, and/or
the use of Rappaport medium. Testing for the detection of P.
aeruginosa includes the use of NAC agar. United States Pharmacopeia
Chapter <62> further enumerates testing procedures for
specified objectionable microorganisms.
[0072] In certain embodiments, any controlled release formulation
described herein has less than about 60 colony forming units (CFU),
less than about 50 colony forming units, less than about 40 colony
forming units, or less than about 30 colony forming units of
microbial agents per gram of formulation. In certain embodiments,
the otic formulations described herein are formulated to be
isotonic with the endolymph and/or the perilymph.
[0073] Endotoxins
[0074] Provided herein are otic compositions that ameliorate or
lessen otic disorders described herein. Further provided herein are
methods comprising the administration of said otic compositions. In
some embodiments, the compositions or devices are substantially
free of endotoxins. An additional aspect of the sterilization
process is the removal of by-products from the killing of
microorganisms (hereinafter, "Product"). The process of
depyrogenation removes pyrogens from the sample. Pyrogens are
endotoxins or exotoxins which induce an immune response. An example
of an endotoxin is the lipopolysaccharide (LPS) molecule found in
the cell wall of gram-negative bacteria. While sterilization
procedures such as autoclaving or treatment with ethylene oxide
kill the bacteria, the LPS residue induces a proinflammatory immune
response, such as septic shock. Because the molecular size of
endotoxins can vary widely, the presence of endotoxins is expressed
in "endotoxin units" (EU). One EU is equivalent to 100 picograms of
E. coli LPS. Humans can develop a response to as little as 5 EU/kg
of body weight. The bioburden (e.g., microbial limit) and/or
sterility (e.g., absence of microbes) or endotoxin level is
expressed in any units as recognized in the art. In certain
embodiments, otic compositions described herein contain lower
endotoxin levels (e.g. <4 EU/kg of body weight of a subject)
when compared to conventionally acceptable endotoxin levels (e.g.,
5 EU/kg of body weight of a subject). In some embodiments, the
auris-acceptable otic therapeutic agent formulation has less than
about 5 EU/kg of body weight of a subject. In other embodiments,
the auris-acceptable otic therapeutic agent formulation has less
than about 4 EU/kg of body weight of a subject. In additional
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 3 EU/kg of body weight of a
subject. In additional embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 2 EU/kg of body
weight of a subject.
[0075] In some embodiments, the auris-acceptable otic therapeutic
agent formulation or device has less than about 5 EU/kg of
formulation. In other embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 4 EU/kg of
formulation. In additional embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 3 EU/kg of
formulation. In some embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 5 EU/kg Product.
In other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 1 EU/kg Product. In additional
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.2 EU/kg Product. In some
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 5 EU/g of unit or Product. In other
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 4 EU/g of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 3 EU/g of unit or Product. In some
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 5 EU/mg of unit or Product. In
other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 4 EU/mg of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 3 EU/mg of unit or Product. In
certain embodiments, otic compositions described herein contain
from about 1 to about 5 EU/mL of formulation. In certain
embodiments, otic compositions described herein contain from about
2 to about 5 EU/mL of formulation, from about 3 to about 5 EU/mL of
formulation, or from about 4 to about 5 EU/mL of formulation.
[0076] In certain embodiments, otic compositions or devices
described herein contain lower endotoxin levels (e.g. <0.5 EU/mL
of formulation) when compared to conventionally acceptable
endotoxin levels (e.g., 0.5 EU/mL of formulation). In some
embodiments, the auris-acceptable otic therapeutic agent
formulation or device has less than about 0.5 EU/mL of formulation.
In other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.4 EU/mL of formulation. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.2 EU/mL of formulation.
[0077] Pyrogen detection, by way of example only, is performed by
several methods. Suitable tests for sterility include tests
described in United States Pharmacopoeia (USP)<71> Sterility
Tests (23rd edition, 1995). The rabbit pyrogen test and the Limulus
amebocyte lysate test are both specified in the United States
Pharmacopeia Chapters <85> and <151> (USP23/NF 18,
Biological Tests, The United States Pharmacopeial Convention,
Rockville, Md., 1995). Alternative pyrogen assays have been
developed based upon the monocyte activation-cytokine assay.
Uniform cell lines suitable for quality control applications have
been developed and have demonstrated the ability to detect
pyrogenicity in samples that have passed the rabbit pyrogen test
and the Limulus amebocyte lysate test (Taktak et al, J. Pharm.
Pharmacol. (1990, 43:578-82). In an additional embodiment, the
auris-acceptable otic therapeutic agent formulation is subject to
depyrogenation. In a further embodiment, the process for the
manufacture of the auris-acceptable otic therapeutic agent
formulation comprises testing the formulation for pyrogenicity. In
certain embodiments, the formulations described herein are
substantially free of pyrogens.
Sterilization of Ciprofloxacin
[0078] While pharmaceutical formulations can be sterilized by heat,
radiation or filtration, effective sterilization of specific
pharmaceutical compositions often presents unique challenge(s).
Those challenges sometimes depend on for example, physical and
chemical characteristics of the pharmaceutical composition,
physical and chemical characteristics of the active agent, physical
and chemical characteristics of the carrier materials, physical and
chemical characteristics of the auxiliary agents and/or physical
and chemical characteristics of the excipients.
[0079] For some pharmaceutical compositions comprising particulate
active agents, such as micronized active agents, filtration
sterilization of the suspension may lead to physical separation of
at least a portion of the particulate active agent from the rest of
the composition that passes through the sterilization filter.
Moreover, the particulate active agent that fails to pass through
the sterilization filter may not be sufficiently sterilized.
[0080] Radiation or dry heat sterilization of bulk particulate
active agent, on the other hand, may require aseptic powder fill or
formulation as a part of manufacturing process. For example, while
a suspension of micronized ciprofloxacin in an aqueous carrier can
be formulated by radiation or dry heat sterilization of bulk
ciprofloxacin particles and aseptic compounding of sterilized
ciprofloxacin particles and the sterilized aqueous carrier, the
process would require customized equipments and/or process design.
Alternatively, the micronized ciprofloxacin can be radiation or dry
heat sterilized in vials, and subsequently reconstituted with the
aqueous carrier (as a diluent component) before administration.
[0081] The present disclosure recognizes the technical effect of
using a moist heat sterilization process of the ciprofloxacin bulk
suspension to manufacture a ready-to-use sterile ciprofloxacin
suspension. Moreover, the present disclosure also recognizes the
technical effect of particle size and/or particle size distribution
of ciprofloxacin suspension on desirable properties such as release
characteristics of the drug product. Furthermore, the present
disclosure recognizes the technical effect of mixing and/or
homogenization during the sterilization process on the particle
size and/or particle size distribution of ciprofloxacin in
suspension.
[0082] For example, a reactor with a tri-mixer system is used
during heat sterilization of ciprofloxacin suspension to obtain the
desired particle size of ciprofloxacin. It is unexpectedly
discovered that a 13.4% w/w suspension of ciprofloxacin base
(anhydrous) in water, when heated at >121.5.degree. C. for an
extended period of time (e.g. 20 minutes), the liquid suspension
begins to turn into a solid or semi-solid mass during the cool-down
after heat exposure. Eventually, the liquid suspension in some
examples solidifies into a dry, hard solid mixture of ciprofloxacin
and water, as shown in FIG. 3. This solid mixture cannot be further
processed and/or handled, or re-suspended to form the liquid
suspension.
[0083] Furthermore, the present disclosure recognizes that, if the
ciprofloxacin suspension is mixed or homogenized aggressively when
it begins to solidify, the suspension can go through the transition
and remain a liquid. If the suspension can be maintained as a
liquid, a second cycle of heat sterilization at >121.5.degree.
C. can be conducted, in which the ciprofloxacin suspension is less
likely to solidify during the second cool-down. For example, in a
number of large scale manufacturing runs, the mixing tank is opened
up during the first cool-down when the suspension started to
solidify. As the ciprofloxacin suspension is homogenized or mixed
with large Teflon paddles by the operators, it remains a liquid
suspension. On a second heat sterilization cycle, the suspension
sometimes does not solidify.
[0084] Still further, the present disclosure recognizes that that
bulk ciprofloxacin free base (anhydrous) can be dry heat sterilized
or sterilized by Gamma or E-beam irradiation, and that sterile
suspension of ciprofloxacin in water or an aqueous carrier can be
prepared by aseptically adding sterilized bulk ciprofloxacin free
base (anhydrous) to sterile filtered water or aqueous carrier,
followed by extensive mixing. Alternatively, ciprofloxacin free
base (hydrate) can be used in the process. While ciprofloxacin free
based hydrate is not available under an approved Drug Master File
(DMF), it can be produced from either HCl salt or anhydrous free
base of ciprofloxacin.
[0085] In some embodiments, the method of making sterilized
ciprofloxacin compositions disclosed herein includes the steps of:
(a) forming an aqueous suspension comprising ciprofloxacin
particles; (b) heating the aqueous suspension comprising
ciprofloxacin particles at a temperature range of from about
100.degree. C. to about 120.degree. C.; and (c) allowing the
aqueous suspension comprising ciprofloxacin particles to cool
down.
[0086] In some embodiments, the aqueous suspension in step (a) is
formed by mixing ciprofloxacin particles with water. In some
embodiments, the aqueous suspension in step (a) is formed by
homogenizing ciprofloxacin particles in water.
[0087] In some embodiments, the aqueous suspension in step (a) is
essentially free of organic solvent.
[0088] In some embodiments, the ciprofloxacin particles in step (a)
are in the form of ciprofloxacin anhydrous particles, ciprofloxacin
hydrate particles, or a combination thereof. In some embodiments,
the ciprofloxacin particles in step (a) are essentially in the form
of ciprofloxacin hydrate particles.
[0089] In some embodiments, the ciprofloxacin particles in step (a)
are present in the aqueous suspension at a concentration of from
about 4 wt % to about 30 wt %. In some embodiments, the
ciprofloxacin particles in step (a) are present in the aqueous
suspension at a concentration of from about 4 wt % to about 20 wt
%. In some embodiments, the ciprofloxacin particles in step (a) are
present in the aqueous suspension at a concentration of from about
4 wt % to about 16 wt %.
[0090] In some embodiments, the ciprofloxacin particles in step (a)
have a D90 of from about 40 .mu.m to about 80 .mu.m. In some
embodiments, the ciprofloxacin particles in step (a) have a D90 of
from about 45 .mu.m to about 75 .mu.m. In some embodiments, the
ciprofloxacin particles in step (a) have a D90 of from about 50
.mu.m to about 70 .mu.m. In some embodiments, the ciprofloxacin
particles in step (a) have a D90 of from about 40 .mu.m to about 80
.mu.m.
[0091] In some embodiments, the aqueous suspension in step (b) is
heated at a temperature of from about 101.degree. C. to about
119.degree. C. In some embodiments, the aqueous suspension in step
(b) is heated at a temperature of from about 102.degree. C. to
about 118.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 103.degree. C. to
about 117.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 104.degree. C. to
about 116.degree. C. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of from about 105.degree. C. to
about 115.degree. C.
[0092] In some embodiments, the aqueous suspension in step (b) is
heated for a period of from about 5 minutes to about 5 hours. In
some embodiments, the aqueous suspension in step (b) is heated for
a period of from about 10 minutes to about 5 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 20 minutes to about 5 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 30 minutes to about 5 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 40 minutes to about 4 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 50 minutes to about 3 hours. In some
embodiments, the aqueous suspension in step (b) is heated for a
period of from about 1 hour to about 2 hours.
[0093] In some embodiments, the aqueous suspension in step (b) is
heated at a temperature of about 115.degree. C. for a period of
about 1 hour. In some embodiments, the aqueous suspension in step
(b) is heated at a temperature of about 105.degree. C. for a period
of about 2 hour. In some embodiments, the aqueous suspension in
step (b) is heated at a temperature of about 110.degree. C. for a
period of from about 1 hour to about 2 hours.
[0094] In some embodiments, the aqueous suspension in step (b) is
heated at a constant temperature within the temperature range. In
some embodiments, the aqueous suspension in step (b) is heated at
variable temperatures within the temperature range.
[0095] In some embodiments, the ciprofloxacin particles in step (b)
are homogenized in the aqueous suspension when heated.
[0096] In some embodiments, the ciprofloxacin particles in step (c)
are essentially in the form of ciprofloxacin hydrate particles.
[0097] In some embodiments, the ciprofloxacin particles in step (c)
are homogenized in the aqueous suspension during cooling. In some
embodiments, the aqueous suspension in step (c) is allowed to cool
down to from about 2.degree. C. to about 10.degree. C.
[0098] In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 5 .mu.m to about 40 .mu.m after cooling
down. In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 10 .mu.m to about 35 .mu.m after cooling
down. In some embodiments, the ciprofloxacin particles in step (c)
have a D90 of from about 15 .mu.m to about 25 .mu.m after cooling
down.
[0099] It is unexpectedly discovered that if a ciprofloxacin
suspension is heated sterilized at a temperature too high (e.g.
>121.5.degree. C.) or at least initially heated at a temperature
too high (e.g. initially heated at 135.degree. C.), the thick
suspension becomes thinner. Without wishing to be bound by any
particular theory, it is contemplated that ciprofloxacin free base
(anhydrous) is converted into ciprofloxacin free base (hydrate)
upon mixing with water, and the hydrate form ciprofloxacin free
base is reconverted to anhydrous form during the high temperature
exposure.
[0100] It is also unexpectedly discovered that if the initial
ciprofloxacin suspension is heat sterilized at lower sterilization
temperatures (e.g. 100.degree. C. -120.degree. C.), the thickness
of the suspension does not change as much as when the suspension is
heated at the higher temperature. In some embodiments, the
suspension remains thick. Furthermore, the suspension heated at the
lower temperature does not solidify during cool-down as the
suspension heated at the higher temperature. Without wishing to be
bound by any particular theory, it is contemplated that that
ciprofloxacin free base (anhydrous) is converted into ciprofloxacin
free base (hydrate) upon mixing with water, and the hydrate form
ciprofloxacin free base remains in hydrate form during the lower
temperature exposure (e.g. 100.degree. C. -120.degree. C.).
[0101] Furthermore, ciprofloxacin solubility significantly
increases between room temperature to the higher sterilization
temperature (e.g. 121.degree. C. and above). For example, it is
measured to increase from 30-60 .mu.g/mL to 10-15 mg/mL. Without
wishing to be bound by any particular theory, it is contemplated
that the solubility increase can contribute to the solidification
of ciprofloxacin suspension when heated at higher temperatures
(e.g. 121.degree. C. and above). For example, at higher
temperature, more ciprofloxacin dissolves into the water and then
when cooled back down, the ciprofloxacin precipitates/crystallizes
back out of solution. It can grow onto existing crystals and lead
to long needles of solid ciprofloxacin, making the solidifying mass
difficult to break down. The present disclosure recognizes the
technical effects of solubility change and crystallization process
on heat sterilization of ciprofloxacin suspensions.
Otic Ciprofloxacin Formulations
CERTAIN DEFINITIONS
[0102] The term "auris-acceptable" with respect to a formulation,
composition or ingredient, as used herein, includes having no
persistent detrimental effect on the auris structure of the subject
being treated. By "auris-pharmaceutically acceptable," as used
herein, refers to a material, such as a carrier or diluent, which
does not abrogate the biological activity or properties of the
compound in reference to the auris structure, and is relatively or
is reduced in toxicity to the auris structure, i.e., the material
is administered to an individual without causing undesirable
biological effects or interacting in a deleterious manner with any
of the components of the composition in which it is contained.
[0103] As used herein, amelioration or lessening of the symptoms of
a particular otic disease, disorder or condition by administration
of a particular compound or pharmaceutical composition refers to
any decrease of severity, delay in onset, slowing of progression,
or shortening of duration, whether permanent or temporary, lasting
or transient that is attributed to or associated with
administration of the compound or composition.
[0104] "Auris interna" refers to the inner ear, including the
cochlea and the vestibular labyrinth, and the round window that
connects the cochlea with the middle ear.
[0105] "Auris media" refers to the middle ear, including the
tympanic cavity, auditory ossicles and oval window, which connects
the middle ear with the inner ear.
[0106] "Balance disorder" refers to a disorder, illness, or
condition which causes a subject to feel unsteady, or to have a
sensation of movement. Included in this definition are dizziness,
vertigo, disequilibrium, and pre-syncope. Diseases which are
classified as balance disorders include, but are not limited to,
Ramsay Hunt's Syndrome, Meniere's Disease, mal de debarquement,
benign paroxysmal positional vertigo, and labyrinthitis.
[0107] "Blood plasma concentration" refers to the concentration of
compounds provided herein in the plasma component of blood of a
subject.
[0108] "Carrier materials" are excipients that are compatible with
moist-heat, the auris structure target site and the release profile
properties of the auris-acceptable pharmaceutical formulations.
Such carrier materials include, e.g., binders, suspending agents,
disintegration agents, filling agents, surfactants, solubilizers,
stabilizers, lubricants, wetting agents, diluents, and the like.
"Auris-pharmaceutically compatible carrier materials" include, but
are not limited to, acacia, gelatin, colloidal silicon dioxide,
calcium glycerophosphate, calcium lactate, maltodextrin, glycerine,
magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol,
cholesterol esters, sodium caseinate, soy lecithin, taurocholic
acid, phosphatidylcholine, sodium chloride, tricalcium phosphate,
dipotassium phosphate, cellulose and cellulose conjugates, sugars
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and the like.
[0109] The term "diluent" refers to chemical compounds that are
used to dilute the antimicrobial agent prior to delivery and which
are compatible with the auris structure target site.
[0110] "Dispersing agents," and/or "viscosity modulating agents"
are materials that control the diffusion and homogeneity of the
antimicrobial agent through liquid media. Examples of diffusion
facilitators/dispersing agents include but are not limited to
hydrophilic polymers, electrolytes, Tween.RTM. 60 or 80, PEG,
polyvinylpyrrolidone (PVP; commercially known as Plasdone.RTM.),
and the carbohydrate-based dispersing agents such as, for example,
hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),
hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC
K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl
acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers; and poloxamines (e.g., Tetronic 908.RTM.,
also known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,
polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene
glycol, e.g., the polyethylene glycol has a molecular weight of
about 300 to about 6000, or about 3350 to about 4000, or about 7000
to about 5400, sodium carboxymethylcellulose, methylcellulose,
polysorbate-80, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, sodium carboxymethylcellulose,
methylcellulose, sodium carboxymethylcellulose, polysorbate-80,
sodium alginate, polyethoxylated sorbitan monolaurate,
polyethoxylated sorbitan monolaurate, povidone, carbomers,
polyvinyl alcohol (PVA), alginates, chitosans and combinations
thereof. Plasticizers such as cellulose or triethyl cellulose are
also be used as dispersing agents. Dispersing agents useful in
liposomal dispersions and self-emulsifying dispersions of the
antimicrobial agents disclosed herein are dimyristoyl phosphatidyl
choline, natural phosphatidyl choline from eggs, natural
phosphatidyl glycerol from eggs, cholesterol and isopropyl
myristate.
[0111] "Drug absorption" or "absorption" refers to the process of
movement of the ciprofloxacin from the localized site of
administration into the ear. The terms "co-administration" or the
like, as used herein, are meant to encompass administration of the
ciprofloxacin to a single patient, and are intended to include
treatment regimens in which the ciprofloxacin are administered by
the same or different route of administration or at the same or
different time.
[0112] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of the
ciprofloxacin being administered that would be expected to relieve
to some extent one or more of the symptoms of the disease or
condition being treated. For example, the result of administration
of ciprofloxacin disclosed herein is reduction and/or alleviation
of the signs, symptoms, or causes of tinnitus or balance disorders.
For example, an "effective amount" for therapeutic uses is the
amount of ciprofloxacin, including a formulation as disclosed
herein required to provide a decrease or amelioration in disease
symptoms without undue adverse side effects. The term
"therapeutically effective amount" includes, for example, a
prophylactically effective amount. An "effective amount" of
ciprofloxacin disclosed herein is an amount effective to achieve a
desired pharmacologic effect or therapeutic improvement without
undue adverse side effects. It is understood that "an effective
amount" or "a therapeutically effective amount" varies, in some
embodiments, from subject to subject, due to variation in
metabolism of the compound administered, age, weight, general
condition of the subject, the condition being treated, the severity
of the condition being treated, and the judgment of the prescribing
physician. It is also understood that "an effective amount" in an
extended-release dosing format may differ from "an effective
amount" in an immediate release dosing format based upon
pharmacokinetic and pharmacodynamic considerations.
[0113] The terms "enhance" or "enhancing" refers to an increase or
prolongation of either the potency or duration of a desired effect
of ciprofloxacin, or a diminution of any adverse symptomatology
that is consequent upon the administration of the therapeutic
agent. Thus, in regard to enhancing the effect of ciprofloxacin
disclosed herein, the term "enhancing" refers to the ability to
increase or prolong, either in potency or duration, the effect of
other therapeutic agents that are used in combination with
ciprofloxacin disclosed herein. An "enhancing-effective amount," as
used herein, refers to an amount of ciprofloxacin or other
therapeutic agent which is adequate to enhance the effect of
another therapeutic agent or ciprofloxacin of the target auris
structure in a desired system. When used in a patient, amounts
effective for this use will depend on the severity and course of
the disease, disorder or condition, previous therapy, the patient's
health status and response to the drugs, and the judgment of the
treating physician.
[0114] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
the desired site within the auris media and/or auris interna.
[0115] "Pharmacokinetics" refers to the factors which determine the
attainment and maintenance of the appropriate concentration of drug
at the desired site within the auris media and/or auris
interna.
[0116] The term "otic intervention" means an external insult or
trauma to one or more auris structures and includes implants, otic
surgery, injections, cannulations, or the like. Implants include
auris-interna or auris-media medical devices, examples of which
include cochlear implants, hearing sparing devices,
hearing-improvement devices, tympanostomy tubes, short electrodes,
micro-prostheses or piston-like prostheses; needles; stem cell
transplants; drug delivery devices; any cell-based therapeutic; or
the like. Otic surgery includes middle ear surgery, inner ear
surgery, tympanostomy, cochleostomy, labyrinthotomy, mastoidectomy,
stapedectomy, stapedotomy, endolymphatic sacculotomy or the like.
Injections include intratympanic injections, intracochlear
injections, injections across the round window membrane or the
like. Cannulations include intratympanic, intracochlear,
endolymphatic, perilymphatic or vestibular cannulations or the
like.
[0117] In prophylactic applications, compositions comprising
ciprofloxacin described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. For example, such conditions include and are
not limited to otitis externa, otitis media, Ramsay Hunt syndrome,
otosyphilis, AIED, Meniere's disease, and vestibular neuronitis.
Such an amount is defined to be a "prophylactically effective
amount or dose." In this use, the precise amounts also depend on
the patient's state of health, weight, and the like.
[0118] The term "essentially free of organic solvent" means less
than 5% by weight of the active agent are degradation products of
the active agent. In further embodiments, the term means less than
3% by weight of the active agent are degradation products of the
active agent. In yet further embodiments, the term means less than
2% by weight of the active agent are degradation products of the
active agent. In further embodiments, the term means less than 1%
by weight of the active agent are degradation products of the
active agent.
[0119] As used herein "essentially in the form of micronized
powder" includes, by way of example only, greater than 70% by
weight of the active agent is in the form of micronized particles
of the active agent. In further embodiments, the term means greater
than 80% by weight of the active agent is in the form of micronized
particles of the active agent. In yet further embodiments, the term
means greater than 90% by weight of the active agent is in the form
of micronized particles of the active agent.
[0120] "Ready-to-use" refers to pharmaceutical compositions or
medical products that can be used without the needs of further
changing, modifying, or optimizing the composition or the product
prior to administration, for example through dilution,
reconstitution, further sterilization, etc.
[0121] "Stabilizers" refers to compounds such as any antioxidation
agents, buffers, acids, preservatives and the like that are
compatible with the environment of the middle or inner ear.
Stabilizers include but are not limited to agents that will do any
of (1) improve the compatibility of excipients with a container, or
a delivery system, including a syringe or a glass bottle, (2)
improve the stability of a component of the composition, or (3)
improve formulation stability.
[0122] As used herein, the term "subject" is used to mean an
animal, preferably a mammal, including a human or non-human. The
terms patient and subject may be used interchangeably.
[0123] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating a disease or
condition, for example tinnitus, symptoms, preventing additional
symptoms, ameliorating or preventing the underlying metabolic
causes of symptoms, inhibiting the disease or condition, e.g.,
arresting the development of the disease or condition, relieving
the disease or condition, causing regression of the disease or
condition, relieving a condition caused by the disease or
condition, or stopping the symptoms of the disease or condition
either prophylactically and/or therapeutically.
[0124] Other objects, features, and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only.
[0125] Method of Formulation
[0126] In some embodiments, the methods of making sterilized
ciprofloxacin compositions further include the step of: (d)
combining the cooled aqueous suspension comprising ciprofloxacin
particles with a sterilized aqueous solution comprising a
thermoreversible polymer to form an otic formulation.
[0127] In some embodiments, the thermoreversible polymer is a
polyoxyethylene-polyoxypropylene triblock copolymer. In some
embodiments, the thermoreversible polymer is poloxamer 407.
[0128] In some embodiments, the aqueous solution further comprises
a buffer agent. In some embodiments, the buffer agent is
tromethamine.
[0129] In some embodiments, the aqueous solution further comprises
a pH adjusting agent in an amount to adjust the pH of the aqueous
solution to from about 7.0 to about 8.0. In some embodiments, the
pH adjusting agent is hydrochloric acid.
[0130] In some embodiments, the aqueous solution further comprises
an osmolarity modifier. In some embodiments, the osmolarity
modifier is sodium chloride.
[0131] In some embodiments, the aqueous solution is sterilized
through filtration sterilization, heat sterilization, or radiation
sterilization. In some embodiments, the aqueous solution is
sterilized through filtration sterilization. In some embodiments,
the aqueous solution is sterilized by passing through a cold
sterilization filter.
[0132] In some embodiments, the aqueous solution is allowed to cool
down to from about 2.degree. C. to about 10.degree. C.
[0133] In some embodiments, the aqueous suspension and the aqueous
solution are combined under aseptic condition.
[0134] In some embodiments, the otic formulation comprises from
about 5 wt % to about 7 wt % of ciprofloxacin. In some embodiments,
the otic formulation comprises from about 5.5 wt % to about 6.5 wt
% of ciprofloxacin.
[0135] In some embodiments, the otic formulation comprises from
about 14 wt % to about 19 wt % of the thermoreversible polymer. In
some embodiments, the otic formulation comprises from about 15 wt %
to about 17 wt % of the thermoreversible polymer. In some
embodiments, the otic formulation comprises from about 15.5 wt % to
about 16.5 wt % of the thermoreversible polymer.
[0136] In some embodiments, the otic formulation has a pH of from
about 7.0 to about 8.0.
[0137] In some embodiments, the otic formulation has an osmolarity
of from about 270 mOsm/L to about 320 mOsm/L.
[0138] In some embodiments, the otic formulation has less than
about 50 colony forming units (cfu) of microbiological agents per
gram of formulation.
[0139] In some embodiments, the otic formulation has less than
about 5 endotoxin units (EU) per kg of body weight of a
subject.
[0140] In some embodiments, the otic formulation has a gelation
temperature between about 19.degree. C. to about 42.degree. C.
[0141] Otic Gel Formulations
[0142] Gels have been defined in various ways. For example, the
United States Pharmacopoeia defines gels as semisolid systems
consisting of either suspensions made up of small inorganic
particles or large organic molecules interpenetrated by a liquid.
Gels include a single-phase or a two-phase system. A single-phase
gel consists of organic macromolecules distributed uniformly
throughout a liquid in such a manner that no apparent boundaries
exist between the dispersed macromolecules and the liquid. Some
single-phase gels are prepared from synthetic macromolecules (e.g.,
carbomer) or from natural gums, (e.g., tragacanth). In some
embodiments, single-phase gels are generally aqueous, but will also
be made using alcohols and oils. Two-phase gels consist of a
network of small discrete particles.
[0143] Gels can also be classified as being hydrophobic or
hydrophilic. In certain embodiments, the base of a hydrophobic gel
consists of a liquid paraffin with polyethylene or fatty oils
gelled with colloidal silica, or aluminum or zinc soaps. In
contrast, the base of hydrophilic gels usually consists of water,
glycerol, or propylene glycol gelled with a suitable gelling agent
(e.g., tragacanth, starch, cellulose derivatives,
carboxyvinylpolymers, and magnesium-aluminum silicates). In certain
embodiments, the rheology of the compositions or devices disclosed
herein is pseudo plastic, plastic, thixotropic, or dilatant.
[0144] In one embodiment the enhanced viscosity auris-acceptable
formulation described herein is not a liquid at room temperature.
In certain embodiments, the enhanced viscosity formulation is
characterized by a phase transition between room temperature and
body temperature (including an individual with a serious fever,
e.g., up to about 42.degree. C.). In some embodiments, the phase
transition occurs at 1.degree. C. below body temperature, at
2.degree. C. below body temperature, at 3.degree. C. below body
temperature, at 4.degree. C. below body temperature, at 6.degree.
C. below body temperature, at 8.degree. C. below body temperature,
or at 10.degree. C. below body temperature. In some embodiments,
the phase transition occurs at about 15.degree. C. below body
temperature, at about 20.degree. C. below body temperature or at
about 25.degree. C. below body temperature. In specific
embodiments, the gelation temperature (Tgel) of a formulation
described herein is about 20.degree. C., about 25.degree. C., or
about 30.degree. C. In certain embodiments, the gelation
temperature (Tgel) of a formulation described herein is about
35.degree. C., or about 40.degree. C. In one embodiment,
administration of any formulation described herein at about body
temperature reduces or inhibits vertigo associated with
intratympanic administration of otic formulations. Included within
the definition of body temperature is the body temperature of a
healthy individual, or an unhealthy individual, including an
individual with a fever (up to .about.42.degree. C.). In some
embodiments, the pharmaceutical compositions or devices described
herein are liquids at about room temperature and are administered
at or about room temperature, reducing or ameliorating side effects
such as, for example, vertigo.
[0145] Polymers composed of polyoxypropylene and polyoxyethylene
form thermoreversible gels when incorporated into aqueous
solutions. These polymers have the ability to change from the
liquid state to the gel state at temperatures close to body
temperature, therefore allowing useful formulations that are
applied to the targeted auris structure(s). The liquid state-to-gel
state phase transition is dependent on the polymer concentration
and the ingredients in the solution.
[0146] Poloxamer 407 is a thermoreversible polymer composed of
polyoxyethylene-polyoxypropylene copolymers. Other
polyoxyethylene-polyoxypropylene copolymers (i.e. poloxamers)
include 188 (F-68 grade), 237 (F-87 grade), 338 (F-108 grade).
Aqueous solutions of poloxamers are stable in the presence of
acids, alkalis, and metal ions. Poloxamer 407 is a commercially
available and can be further purified by suitable methods that will
enhance gelation properties of the polymer. It contains
approximately 70% ethylene oxide, which accounts for its
hydrophilicity. It is one of the series of poloxamer ABA block
copolymers, whose members share the chemical formula shown
below.
##STR00001##
[0147] Some aqueous poloxamer solutions (e.g. poloxamer 407)
transform from low viscosity solutions to solid gels on heating to
body temperature (e.g. after administration into the ear).
Furthermore, poloxamer 407 has good solubilizing capacity, low
toxicity and is, therefore, considered a good medium for drug
delivery systems.
[0148] In an alternative embodiment, the thermogel is a
PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature (1997),
388:860-2; Jeong et al, J. Control. Release (2000), 63:155-63;
Jeong et al, Adv. Drug Delivery Rev. (2002), 54:37-51). The polymer
exhibits sol-gel behavior over a concentration of about 5% w/w to
about 40% w/w. Depending on the properties desired, the
lactide/glycolide molar ratio in the PLGA copolymer ranges from
about 1:1 to about 20:1. The resulting copolymers are soluble in
water and form a free-flowing liquid at room temperature, but form
a hydrogel at body temperature. A commercially available
PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured
by Boehringer Ingelheim. This material is composed of a PGLA
copolymer of 50:50 poly (DL-lactide-co-glycolide) and is 10% w/w of
PEG and has a molecular weight of about 6000.
[0149] ReGel.RTM. is a trade name of MacroMed Incorporated for a
class of low molecular weight, biodegradable block copolymers
having reverse thermal gelation properties as described in U.S.
Pat. Nos. 6,004,573, 6,117,949, 6,201,072, and 6,287,588. It also
includes biodegradable polymeric drug carriers disclosed in pending
U.S. patent application Ser. Nos. 09/906,041, 09/559,799 and
10/919,603. The biodegradable drug carrier comprises ABA-type or
BAB-type triblock copolymers or mixtures thereof, wherein the
A-blocks are relatively hydrophobic and comprise biodegradable
polyesters or poly(orthoester)s, and the B-blocks are relatively
hydrophilic and comprise polyethylene glycol (PEG), said copolymers
having a hydrophobic content of between 50.1 to 83% by weight and a
hydrophilic content of between 17 to 49.9% by weight, and an
overall block copolymer molecular weight of between 2000 and 8000
Daltons. The drug carriers exhibit water solubility at temperatures
below normal mammalian body temperatures and undergo reversible
thermal gelation to then exist as a gel at temperatures equal to
physiological mammalian body temperatures. The biodegradable,
hydrophobic A polymer block comprises a polyester or
poly(orthoester), in which the polyester is synthesized from
monomers selected from the group consisting of D,L-lactide,
D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic
acid, glycolide, glycolic acid, .epsilon.-caprolactone,
.epsilon.-hydroxyhexanoic acid, .gamma.-butyrolactone,
.gamma.-hydroxybutyric acid, .delta.-valerolactone,
.delta.-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and
copolymers thereof and having an average molecular weight of
between about 600 and 3000 Daltons. The hydrophilic B-block segment
is preferably polyethylene glycol (PEG) having an average molecular
weight of between about 500 and 2200 Daltons.
[0150] Additional biodegradable thermoplastic polyesters include
AtriGel.RTM. (provided by Atrix Laboratories, Inc.) and/or those
disclosed, e.g., in U.S. Pat. Nos. 5,324,519; 4,938,763; 5,702,716;
5,744,153; and 5,990,194; wherein the suitable biodegradable
thermoplastic polyester is disclosed as a thermoplastic polymer.
Examples of suitable biodegradable thermoplastic polyesters include
polylactides, polyglycolides, polycaprolactones, copolymers
thereof, terpolymers thereof, and any combinations thereof. In some
such embodiments, the suitable biodegradable thermoplastic
polyester is a polylactide, a polyglycolide, a copolymer thereof, a
terpolymer thereof, or a combination thereof. In one embodiment,
the biodegradable thermoplastic polyester is 50/50
poly(DL-lactide-co-glycolide) having a carboxy terminal group; is
present in about 30 wt. % to about 40 wt. % of the composition; and
has an average molecular weight of about 23,000 to about 45,000.
Alternatively, in another embodiment, the biodegradable
thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide)
without a carboxy terminal group; is present in about 40 wt. % to
about 50 wt. % of the composition; and has an average molecular
weight of about 15,000 to about 24,000. In further or alternative
embodiments, the terminal groups of the
poly(DL-lactide-co-glycolide) are either hydroxyl, carboxyl, or
ester depending upon the method of polymerization. Polycondensation
of lactic or glycolic acid provides a polymer with terminal
hydroxyl and carboxyl groups. Ring-opening polymerization of the
cyclic lactide or glycolide monomers with water, lactic acid, or
glycolic acid provides polymers with the same terminal groups.
However, ring-opening of the cyclic monomers with a monofunctional
alcohol such as methanol, ethanol, or 1-dodecanol provides a
polymer with one hydroxyl group and one ester terminal groups.
Ring-opening polymerization of the cyclic monomers with a diol such
as 1,6-hexanediol or polyethylene glycol provides a polymer with
only hydroxyl terminal groups.
[0151] Since the polymer systems of thermoreversible gels dissolve
more completely at reduced temperatures, methods of solubilization
include adding the required amount of polymer to the amount of
water to be used at reduced temperatures. Generally after wetting
the polymer by shaking, the mixture is capped and placed in a cold
chamber or in a thermostatic container at about 0-10.degree. C. in
order to dissolve the polymer. The mixture is stirred or shaken to
bring about a more rapid dissolution of the thermoreversible gel
polymer.
[0152] In one embodiment are auris-acceptable pharmaceutical gel
formulations which do not require the use of an added viscosity
enhancing agent. Such gel formulations incorporate at least one
pharmaceutically acceptable buffer. In one aspect is a gel
formulation comprising ciprofloxacin and a pharmaceutically
acceptable buffer. In another embodiment, the pharmaceutically
acceptable excipient or carrier is a gelling agent.
[0153] Also described herein are controlled release formulations or
devices comprising ciprofloxacin and a viscosity enhancing agent.
Suitable viscosity-enhancing agents include by way of example only,
gelling agents and suspending agents. In one embodiment, the
enhanced viscosity formulation does not include a buffer. In other
embodiments, the enhanced viscosity formulation includes a
pharmaceutically acceptable buffer. Sodium chloride or other
tonicity agents are optionally used to adjust tonicity, if
necessary.
[0154] By way of example only, the auris-acceptable viscosity
agents include hydroxypropyl methylcellulose, hydroxyethyl
cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl
alcohol, sodium chondroitin sulfate, sodium hyaluronate. Other
viscosity enhancing agents compatible with the targeted auris
structure include, but are not limited to, acacia (gum arabic),
agar, aluminum magnesium silicate, sodium alginate, sodium
stearate, bladderwrack, bentonite, carbomer, carrageenan, Carbopol,
xanthan, cellulose, microcrystalline cellulose (MCC), ceratonia,
chitin, carboxymethylated chitosan, chondrus, dextrose,
furcellaran, gelatin, Ghatti gum, guar gum, hectorite, lactose,
sucrose, maltodextrin, mannitol, sorbitol, honey, maize starch,
wheat starch, rice starch, potato starch, gelatin, sterculia gum,
xanthum gum, gum tragacanth, ethyl cellulose, ethylhydroxyethyl
cellulose, ethylmethyl cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethylcellulose (HPMC), sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (dextrose,
maltodextrin and sucralose) or combinations thereof. In specific
embodiments, the viscosity-enhancing excipient is a combination of
MCC and CMC. In another embodiment, the viscosity-enhancing agent
is a combination of carboxymethylated chitosan, or chitin, and
alginate. The combination of chitin and alginate with ciprofloxacin
disclosed herein acts as a controlled release formulation,
restricting the diffusion of ciprofloxacin from the formulation.
Moreover, the combination of carboxymethylated chitosan and
alginate is optionally used to assist in increasing the
permeability of ciprofloxacin into the ear.
[0155] In some embodiments is an enhanced viscosity formulation,
comprising from about 0.1 mM and about 100 mM of ciprofloxacin, a
pharmaceutically acceptable viscosity agent, and water for
injection, the concentration of the viscosity agent in the water
being sufficient to provide an enhanced viscosity formulation with
a final viscosity from about 100 to about 100,000 cP. In certain
embodiments, the viscosity of the gel is in the range from about
100 to about 50,000 cP, about 100 cP to about 1,000 cP, about 500
cP to about 1500 cP, about 1000 cP to about 3000 cP, about 2000 cP
to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000
cP to about 500,000 cP, about 15,000 cP to about 1,000,000 cP. In
other embodiments, when an even more viscous medium is desired, the
biocompatible gel comprises at least about 35%, at least about 45%,
at least about 55%, at least about 65%, at least about 70%, at
least about 75%, or even at least about 80% or so by weight of
ciprofloxacin. In highly concentrated samples, the biocompatible
enhanced viscosity formulation comprises at least about 25%, at
least about 35%, at least about 45%, at least about 55%, at least
about 65%, at least about 75%, at least about 85%, at least about
90% or at least about 95% or more by weight of ciprofloxacin.
[0156] In some embodiments, the viscosity of the gel formulations
presented herein is measured by any means described. For example,
in some embodiments, an LVDV-II+CP Cone Plate Viscometer and a Cone
Spindle CPE-40 is used to calculate the viscosity of the gel
formulation described herein. In other embodiments, a Brookfield
(spindle and cup) viscometer is used to calculate the viscosity of
the gel formulation described herein. In some embodiments, the
viscosity ranges referred to herein are measured at room
temperature. In other embodiments, the viscosity ranges referred to
herein are measured at body temperature (e.g., at the average body
temperature of a healthy human).
[0157] In one embodiment, the pharmaceutically acceptable enhanced
viscosity auris-acceptable formulation comprises ciprofloxacin and
at least one gelling agent. Suitable gelling agents for use in
preparation of the gel formulation include, but are not limited to,
celluloses, cellulose derivatives, cellulose ethers (e.g.,
carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum,
locust bean gum, alginates (e.g., alginic acid), silicates, starch,
tragacanth, carboxyvinyl polymers, carrageenan, paraffin,
petrolatum and any combinations or mixtures thereof. In some other
embodiments, hydroxypropylmethylcellulose (Methocel.RTM.) is
utilized as the gelling agent. In certain embodiments, the
viscosity enhancing agents described herein are also utilized as
the gelling agent for the gel formulations presented herein.
[0158] In some embodiments, the otic therapeutic agents disclosed
herein are dispensed as an auris-acceptable paint. As used herein,
paints (also known as film formers) are solutions comprised of a
solvent, a monomer or polymer, an active agent, and optionally one
or more pharmaceutically-acceptable excipients. After application
to a tissue, the solvent evaporates leaving behind a thin coating
comprised of the monomers or polymers, and the active agent. The
coating protects active agents and maintains them in an immobilized
state at the site of application. This decreases the amount of
active agent which may be lost and correspondingly increases the
amount delivered to the subject. By way of non-limiting example,
paints include collodions (e.g. Flexible Collodion, USP), and
solutions comprising saccharide siloxane copolymers and a
cross-linking agent. Collodions are ethyl ether/ethanol solutions
containing pyroxylin (a nitrocellulose). After application, the
ethyl ether/ethanol solution evaporates leaving behind a thin film
of pyroxylin. In solutions comprising saccharide siloxane
copolymers, the saccharide siloxane copolymers form the coating
after evaporation of the solvent initiates the cross-linking of the
saccharide siloxane copolymers. For additional disclosures
regarding paints, see Remington: The Science and Practice of
Pharmacy which is hereby incorporated with respect to this subject
matter. The paints contemplated for use herein, are flexible such
that they do not interfere with the propagation of pressure waves
through the ear. Further, the paints may be applied as a liquid
(i.e. solution, suspension, or emulsion), a semisolid (i.e. a gel,
foam, paste, or jelly) or an aerosol.
[0159] In some embodiments, the otic therapeutic agents disclosed
herein are dispensed as a controlled-release foam. Examples of
suitable foamable carriers for use in the compositions disclosed
herein include, but are not limited to, alginate and derivatives
thereof, carboxymethylcellulose and derivatives thereof, collagen,
polysaccharides, including, for example, dextran, dextran
derivatives, pectin, starch, modified starches such as starches
having additional carboxyl and/or carboxamide groups and/or having
hydrophilic side-chains, cellulose and derivatives thereof, agar
and derivatives thereof, such as agar stabilized with
polyacrylamide, polyethylene oxides, glycol methacrylates, gelatin,
gums such as xanthum, guar, karaya, gellan, arabic, tragacanth and
locust bean gum, or combinations thereof. Also suitable are the
salts of the aforementioned carriers, for example, sodium alginate.
The formulation optionally further comprises a foaming agent, which
promotes the formation of the foam, including a surfactant or
external propellant. Examples of suitable foaming agents include
cetrimide, lecithin, soaps, silicones and the like. Commercially
available surfactants such as Tween.RTM. are also suitable.
[0160] Other useful gel formulations are considered to fall within
the scope of the present disclosure. For example, other
commercially-available glycerin-based gels, glycerin-derived
compounds, conjugated, or crosslinked gels, matrices, hydrogels,
and polymers, as well as gelatins and their derivatives, alginates,
and alginate-based gels, and even various native and synthetic
hydrogel and hydrogel-derived compounds are all expected to be
useful in the ciprofloxacin formulations described herein. In some
embodiments, auris-acceptable gels include, but are not limited to,
alginate hydrogels SAF.RTM.-Gel (ConvaTec, Princeton, N.J.),
Duoderm.RTM. Hydroactive Gel (ConvaTec), Nu-gel.RTM.(Johnson &
Johnson Medical, Arlington, Tex.); Carrasyn.RTM.(V) Acemannan
Hydrogel (Carrington Laboratories, Inc., Irving, Tex.); glycerin
gels Elta.RTM. Hydrogel (Swiss-American Products, Inc., Dallas,
Tex.) and K-Y.RTM. Sterile (Johnson & Johnson). In further
embodiments, biodegradable biocompatible gels also represent
compounds present in auris-acceptable formulations disclosed and
described herein.
[0161] In some embodiments, the amount of thermoreversible polymer
in any formulation described herein is about 10%, about 15%, about
20%, about 25%, about 30%, about 35% or about 40% of the total
weight of the formulation. In some embodiments, the amount of
thermoreversible polymer in any formulation described herein is
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,
about 16%, about 17%, about 18%, about 19%, about 20%, about 21%,
about 22%, about 23%, about 24% or about 25% of the total weight of
the formulation. In some embodiments, the amount of
thermoreversible polymer (e.g., poloxamer 407) in any formulation
described herein is about 7.5% of the total weight of the
formulation. In some embodiments, the amount of thermoreversible
polymer (e.g., poloxamer 407) in any formulation described herein
is about 10% of the total weight of the formulation. In some
embodiments, the amount of thermoreversible polymer (e.g.,
poloxamer 407) in any formulation described herein is about 11% of
the total weight of the formulation. In some embodiments, the
amount of thermoreversible polymer (e.g., poloxamer 407) in any
formulation described herein is about 12% of the total weight of
the formulation. In some embodiments, the amount of
thermoreversible polymer (e.g., poloxamer 407) in any formulation
described herein is about 13% of the total weight of the
formulation. In some embodiments, the amount of thermoreversible
polymer (e.g., poloxamer 407) in any formulation described herein
is about 14% of the total weight of the formulation. In some
embodiments, the amount of thermoreversible polymer (e.g.,
poloxamer 407) in any formulation described herein is about 15% of
the total weight of the formulation. In some embodiments, the
amount of thermoreversible polymer (e.g., poloxamer 407) in any
formulation described herein is about 16% of the total weight of
the formulation. In some embodiments, the amount of
thermoreversible polymer (e.g., poloxamer 407) in any formulation
described herein is about 17% of the total weight of the
formulation. In some embodiments, the amount of thermoreversible
polymer (e.g., poloxamer 407) in any formulation described herein
is about 18% of the total weight of the formulation. In some
embodiments, the amount of thermoreversible polymer (e.g.,
poloxamer 407) in any formulation described herein is about 19% of
the total weight of the formulation. In some embodiments, the
amount of thermoreversible polymer (e.g., poloxamer 407) in any
formulation described herein is about 20% of the total weight of
the formulation. In some embodiments, the amount of
thermoreversible polymer (e.g., poloxamer 407) in any formulation
described herein is about 21% of the total weight of the
formulation. In some embodiments, the amount of thermoreversible
polymer (e.g., poloxamer 407) in any formulation described herein
is about 23% of the total weight of the formulation. In some
embodiments, the amount of thermoreversible polymer (e.g.,
poloxamer 407) in any formulation described herein is about 25% of
the total weight of the formulation. In some embodiments, the
amount of thickening agent (e.g., a gelling agent) in any
formulation described herein is about 1%, about 5%, about 10%, or
about 15% of the total weight of the formulation. In some
embodiments, the amount of thickening agent (e.g., a gelling agent)
in any formulation described herein is about 0.5%, about 1%, about
1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about
4.5%, or about 5% of the total weight of the formulation.
[0162] In some formulations developed for administration to a
mammal, and for compositions formulated for human administration,
the auris-acceptable gel comprises substantially all of the weight
of the composition. In other embodiments, the auris-acceptable gel
comprises as much as about 98% or about 99% of the composition by
weight. This is desirous when a substantially non-fluid, or
substantially viscous formulation is needed. In a further
embodiment, when slightly less viscous, or slightly more fluid
auris-acceptable pharmaceutical gel formulations are desired, the
biocompatible gel portion of the formulation comprises at least
about 50% by weight, at least about 60% by weight, at least about
70% by weight, or even at least about 80% or 90% by weight of the
compound. All intermediate integers within these ranges are
contemplated to fall within the scope of this disclosure, and in
some alternative embodiments, even more fluid (and consequently
less viscous) auris-acceptable gel compositions are formulated,
such as for example, those in which the gel or matrix component of
the mixture comprises not more than about 50% by weight, not more
than about 40% by weight, not more than about 30% by weight, or
even those than comprise not more than about 15% or about 20% by
weight of the composition.
[0163] Concentration of Ciprofloxacin
[0164] In some embodiments, the compositions described herein have
a concentration of active pharmaceutical ingredient between about
0.01% to about 90%, between about 0.01% to about 50%, between about
0.1% to about 70%, between about 0.1% to about 50%, between about
0.1% to about 40%, between about 0.1% to about 30%, between about
0.1% to about 20%, between about 0.1% to about 10%, or between
about 0.1% to about 5%, of the active ingredient, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition. In some embodiments, the compositions described
herein have a concentration of active pharmaceutical agent, or
pharmaceutically acceptable prodrug or salt thereof, between about
1% to about 50%, between about 5% to about 50%, between about 10%
to about 40%, or between about 10% to about 30%, of the active
ingredient, or pharmaceutically acceptable prodrug or salt thereof,
by weight of the composition. In some embodiments, formulations
described herein comprise about 70% by weight of ciprofloxacin, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the formulation. In some embodiments, formulations described herein
comprise about 60% by weight of ciprofloxacin, or pharmaceutically
acceptable prodrug or salt thereof, by weight of the formulation.
In some embodiments, formulations described herein comprise about
50% by weight of ciprofloxacin, or pharmaceutically acceptable
prodrug or salt thereof, by weight of the formulation. In some
embodiments, formulations described herein comprise about 40% by
weight of ciprofloxacin, or pharmaceutically acceptable prodrug or
salt thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 30% by weight, or
pharmaceutically acceptable prodrug or salt thereof, of
ciprofloxacin by weight of the formulation. In some embodiments,
formulations described herein comprise about 20% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 15% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 10% by weight of
ciprofloxacin by weight of the formulation. In some embodiments,
formulations described herein comprise about 5% by weight
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 2.5% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 1% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.5% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.1% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.01% by weight of
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments, the
formulations described herein have a concentration of active
pharmaceutical ingredient, or pharmaceutically acceptable prodrug
or salt thereof, between about 0.1 to about 70 mg/mL, between about
0.5 mg/mL to about 70 mg/mL, between about 0.5 mg/mL to about 50
mg/mL, between about 0.5 mg/mL to about 20 mg/mL, between about 1
mg to about 70 mg/mL, between about 1 mg to about 50 mg/mL, between
about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL to about 10
mg/mL, or between about 1 mg/mL to about 5 mg/mL, of the
ciprofloxacin, or pharmaceutically acceptable prodrug or salt
thereof, by volume of the formulation.
[0165] Osmolarity
[0166] In some embodiments, an otic composition or device disclosed
herein is formulated to provide an ionic balance that is compatible
with inner ear fluids (e.g., endolymph and/or perilymph).
[0167] In certain instances, the ionic composition of the endolymph
and perilymph regulate the electrochemical impulses of hair cells
and thus hearing. In certain instances, changes in the conduction
of electrochemical impulses along otic hair cells results in
hearing loss. In certain instances, changes in the ionic balance of
the endolymph or perilymph results in complete hearing loss. In
certain instances, changes in the ionic balance of the endolymph or
perilymph results in partial hearing loss. In certain instances,
changes in the ionic balance of the endolymph or perilymph results
in permanent hearing loss. In certain instances, changes in the
ionic balance of the endolymph or perilymph results in temporary
hearing loss.
[0168] In some embodiments, a composition or device disclosed
herein is formulated in order to not disrupt the ionic balance of
the endolymph. In some embodiments, a composition or device
disclosed herein has an ionic balance that is the same as or
substantially the same as the endolymph. In some embodiments, a
composition or device disclosed herein does not does not disrupt
the ionic balance of the endolymph so as to result in partial or
complete hearing loss. In some embodiments, a composition or device
disclosed herein does not does not disrupt the ionic balance of the
endolymph so as to result in temporary or permanent hearing
loss.
[0169] In some embodiments, a composition or device disclosed
herein does not substantially disrupt the ionic balance of the
perilymph. In some embodiments, a composition or device disclosed
herein has an ionic balance that is the same as or substantially
the same as the perilymph. In some embodiments, a composition or
device disclosed herein does not result in partial or complete
hearing loss as the composition or device does not disrupt the
ionic balance of the perilymph. In some embodiments, a composition
or device disclosed herein does not result in temporary or
permanent hearing loss as the composition or device does not
disrupt the ionic balance of the perilymph.
[0170] As used herein, "practical osmolarity/osmolarity" or
"deliverable osmolarity/osmolarity" means the osmolarity/osmolarity
of a composition or device as determined by measuring the
osmolarity/osmolarity of the active agent and all excipients except
the gelling and/or the thickening agent (e.g.,
polyoxyethylene-polyoxypropylene copolymers, carboxymethylcellulose
or the like). The practical osmolarity of a composition or device
disclosed herein is measured by a suitable method, e.g., a freezing
point depression method as described in Viegas et. al., Int. J.
Pharm., 1998, 160, 157-162. In some instances, the practical
osmolarity of a composition or device disclosed herein is measured
by vapor pressure osmometry (e.g., vapor pressure depression
method) that allows for determination of the osmolarity of a
composition or device at higher temperatures. In some instances,
vapor pressure depression method allows for determination of the
osmolarity of a composition or device comprising a gelling agent
(e.g., a thermoreversible polymer) at a higher temperature wherein
the gelling agent is in the form of a gel.
[0171] In some embodiments, the osmolarity at a target site of
action is about the same as the delivered osmolarity (i.e.,
osmolarity of materials that cross or penetrate to the target site)
of a composition or device described herein. In some embodiments, a
composition or device described herein has a deliverable osmolarity
of about 150 mOsm/L to about 500 mOsm/L, about 250 mOsm/L to about
500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 280 mOsm/L
to about 370 mOsm/L or about 250 mOsm/L to about 320 mOsm/L.
[0172] The practical osmolality of an otic composition or device
disclosed herein is from about 100 mOsm/kg to about 1000 mOsm/kg,
from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg
to about 500 mOsm/kg, or from about 250 mOsm/kg to about 320
mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg or from
about 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, a
composition or device described herein has a practical osmolarity
of about 100 mOsm/L to about 1000 mOsm/L, about 200 mOsm/L to about
800 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L
to about 350 mOsm/L, about 250 mOsm/L to about 320 mOsm/L, or about
280 mOsm/L to about 320 mOsm/L.
[0173] The main cation present in the endolymph is potassium. In
addition the endolymph has a high concentration of positively
charged amino acids. The main cation present in the perilymph is
sodium. In certain instances, the ionic composition of the
endolymph and perilymph regulate the electrochemical impulses of
hair cells. In certain instances, any change in the ionic balance
of the endolymph or perilymph results in a loss of hearing due to
changes in the conduction of electrochemical impulses along otic
hair cells. In some embodiments, a composition disclosed herein
does not disrupt the ionic balance of the perilymph. In some
embodiments, a composition disclosed herein has an ionic balance
that is the same as or substantially the same as the perilymph. In
some embodiments, a composition disclosed herein does not disrupt
the ionic balance of the endolymph. In some embodiments, a
composition disclosed herein has an ionic balance that is the same
as or substantially the same as the endolymph. In some embodiments,
an otic formulation described herein is formulated to provide an
ionic balance that is compatible with inner ear fluids (e.g.,
endolymph and/or perilymph).
[0174] In some embodiments, the deliverable osmolarity of any
formulation described herein is designed to be isotonic with the
targeted otic structure (e.g., endolymph, perilymph or the like).
In specific embodiments, auris compositions described herein are
formulated to provide a delivered perilymph-suitable osmolarity at
the target site of action of about 250 to about 320 mOsm/L; and
preferably about 270 to about 320 mOsm/L. In specific embodiments,
auris compositions described herein are formulated to provide a
delivered perilymph-suitable osmolality at the target site of
action of about 250 to about 320 mOsm/kg H.sub.2O; or an osmolality
of about 270 to about 320 mOsm/kg H.sub.2O. In specific
embodiments, the deliverable osmolarity/osmolarity of the
formulations (i.e., the osmolarity/osmolarity of the formulation in
the absence of gelling or thickening agents (e.g., thermoreversible
gel polymers) is adjusted, for example, by the use of appropriate
salt concentrations (e.g., concentration of potassium or sodium
salts) or the use of tonicity agents which renders the formulations
endolymph-compatible and/or perilymph-compatible (i.e. isotonic
with the endolymph and/or perilymph) upon delivery at the target
site. The osmolarity of a formulation comprising a thermoreversible
gel polymer is an unreliable measure due to the association of
varying amounts of water with the monomeric units of the polymer.
The practical osmolarity of a formulation (i.e., osmolarity in the
absence of a gelling or thickening agent (e.g. a thermoreversible
gel polymer) is a reliable measure and is measured by any suitable
method (e.g., freezing point depression method, vapor depression
method). In some instances, the formulations described herein
provide a deliverable osmolarity (e.g., at a target site (e.g.,
perilymph) that causes minimal disturbance to the environment of
the ear and causes minimum discomfort (e.g., vertigo and/or nausea)
to a mammal upon administration.
[0175] In some embodiments, any formulation described herein is
isotonic with the perilymph and/or endolymph. Isotonic formulations
are provided by the addition of a tonicity agent. Suitable tonicity
agents include, but are not limited to any pharmaceutically
acceptable sugar, salt or any combinations or mixtures thereof,
such as, but not limited to dextrose, glycerin, mannitol, sorbitol,
sodium chloride, and other electrolytes. In some embodiments,
tonicity agents are non-ototoxic.
[0176] Useful auris compositions include one or more salts in an
amount required to bring osmolarity of the composition into an
acceptable range. Such salts include those having sodium, potassium
or ammonium cations and chloride, citrate, ascorbate, borate,
phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions;
suitable salts include sodium chloride, potassium chloride, sodium
thiosulfate, sodium bisulfite and ammonium sulfate.
[0177] pH
[0178] The endolymph and the perilymph have a pH that is close to
the physiological pH of blood. The endolymph has a pH range of
about 7.2-7.9; the perilymph has a pH range of about 7.2-7.4. The
in situ pH of the proximal endolymph is about 7.4 while the pH of
distal endolymph is about 7.9.
[0179] In other embodiments, useful auris-acceptable ciprofloxacin
formulations also include one or more pH adjusting agents or
buffering agents to provide an endolymph or perilymph suitable pH.
Suitable pH adjusting agents or buffers include, but are not
limited to acetate, bicarbonate, ammonium chloride, citrate,
phosphate, pharmaceutically acceptable salts thereof and
combinations or mixtures thereof. Such pH adjusting agents and
buffers are included in an amount required to maintain pH of the
composition between a pH of about 5 and about 9, in one embodiment
a pH between about 6.5 to about 7.5, and in yet another embodiment
at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4,
7.5. In one embodiment, when one or more buffers are utilized in
the formulations of the present disclosure, they are combined,
e.g., with a pharmaceutically acceptable vehicle and are present in
the final formulation, e.g., in an amount ranging from about 0.1%
to about 20%, from about 0.5% to about 10%. In certain embodiments
of the present disclosure, the amount of buffer included in the gel
formulations are an amount such that the pH of the gel formulation
does not interfere with the auris media or auris interna's natural
buffering system, or does not interfere with the natural pH of the
endolymph or perilymph. In some embodiments, from about 10 .mu.M to
about 200 mM concentration of a buffer is present in the gel
formulation. In certain embodiments, from about a 5 mM to about a
200 mM concentration of a buffer is present. In certain
embodiments, from about a 20 mM to about a 100 mM concentration of
a buffer is present. In one embodiment is a buffer such as acetate
or citrate at slightly acidic pH. In one embodiment the buffer is a
sodium acetate buffer having a pH of about 4.5 to about 6.5. In one
embodiment the buffer is a sodium citrate buffer having a pH of
about 5.0 to about 8.0, or about 5.5 to about 7.0.
[0180] In an alternative embodiment, the buffer used is
tris(hydroxymethyl)aminomethane, bicarbonate, carbonate or
phosphate at slightly basic pH. In one embodiment, the buffer is a
sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or
about 7.0 to about 8.0. In another embodiment the buffer is a
sodium phosphate dibasic buffer having a pH of about 6.0 to about
9.0.
[0181] In one embodiment, when one or more buffers are utilized in
the formulations of the present disclosure, they are combined,
e.g., with a pharmaceutically acceptable vehicle and are present in
the final formulation, e.g., in an amount ranging from about 0.1%
to about 20%, from about 0.5% to about 10%. In certain embodiments
of the present disclosure, the amount of buffer included in the gel
formulations are an amount such that the pH of the gel formulation
does not interfere with the body's natural buffering system.
[0182] In one embodiment, diluents are also used to stabilize
compounds because they can provide a more stable environment. Salts
dissolved in buffered solutions (which also can provide pH control
or maintenance) are utilized as diluents in the art, including, but
not limited to a phosphate buffered saline solution.
[0183] In some embodiments, any gel formulation described herein
has a pH that allows for sterilization (e.g., by filtration or
aseptic mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization) of a gel formulation without degradation of the
ciprofloxacin or the polymers comprising the gel. In order to
reduce hydrolysis and/or degradation of the otic agent and/or the
gel polymer during sterilization, the buffer pH is designed to
maintain pH of the formulation in the 7-8 range during the process
of sterilization (e.g., high temperature autoclaving).
[0184] In specific embodiments, any gel formulation described
herein has a pH that allows for terminal sterilization (e.g., by
heat treatment and/or autoclaving) of a gel formulation without
degradation of the ciprofloxacin or the polymers comprising the
gel. For example, in order to reduce hydrolysis and/or degradation
of the otic agent and/or the gel polymer during autoclaving, the
buffer pH is designed to maintain pH of the formulation in the 7-8
range at elevated temperatures. Any appropriate buffer is used
depending on the otic agent used in the formulation. In some
instances, since pK.sub.a of TRIS decreases as temperature
increases at approximately -0.03/.degree. C. and pK.sub.a of PBS
increases as temperature increases at approximately 0.003/.degree.
C., autoclaving at 250.degree. F. (121.degree. C.) results in a
significant downward pH shift (i.e. more acidic) in the TRIS buffer
whereas a relatively much less upward pH shift in the PBS buffer
and therefore much increased hydrolysis and/or degradation of an
otic agent in TRIS than in PBS. Degradation of an otic agent is
reduced by the use of an appropriate combination of a buffer and
polymeric additives (e.g. CMC) as described herein.
In some embodiments, a formulation pH of between about 5.0 and
about 9.0, between about 5.5 and about 8.5, between about 6.0 and
about 7.6, between about 7 and about 7.8, between about 7.0 and
about 7.6, between about 7.2 and 7.6, or between about 7.2 and
about 7.4 is suitable for sterilization (e.g., by filtration or
aseptic mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization)) of auris formulations described herein. In specific
embodiments a formulation pH of about 6.0, about 6.5, about 7.0,
about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6
is suitable for sterilization (e.g., by filtration or aseptic
mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization)) of any composition described herein. In some
embodiments, the pharmaceutical formulations described herein are
stable with respect to pH over a period of any of at least about 1
day, at least about 2 days, at least about 3 days, at least about 4
days, at least about 5 days, at least about 6 days, at least about
1 week, at least about 2 weeks, at least about 3 weeks, at least
about 4 weeks, at least about 5 weeks, at least about 6 weeks, at
least about 7 weeks, at least about 8 weeks, at least about 1
month, at least about 2 months, at least about 3 months, at least
about 4 months, at least about 5 months, or at least about 6
months. In other embodiments, the formulations described herein are
stable with respect to pH over a period of at least about 1 week.
Also described herein are formulations that are stable with respect
to pH over a period of at least about 1 month.
[0185] Particle Size
[0186] Size reduction is used to increase surface area and/or
modulate formulation dissolution properties. It is also used to
maintain a consistent average particle size distribution (PSD)
(e.g., micrometer-sized particles, nanometer-sized particles or the
like) for any formulation described herein. In some embodiments,
any formulation described herein comprises multiparticulates, i.e.,
a plurality of particle sizes (e.g., micronized particles,
nano-sized particles, non-sized particles, colloidal particles);
i.e., the formulation is a multiparticulate formulation. In some
embodiments, any formulation described herein comprises one or more
multiparticulate (e.g., micronized) therapeutic agents.
Micronization is a process of reducing the average diameter of
particles of a solid material. Micronized particles are from about
micrometer-sized in diameter to about nanometer-sized in diameter.
In some embodiments, the average diameter of particles in a
micronized solid is from about 0.5 .mu.m to about 500 .mu.m. In
some embodiments, the average diameter of particles in a micronized
solid is from about 1 .mu.m to about 200 .mu.m. In some
embodiments, the average diameter of particles in a micronized
solid is from about 2 .mu.m to about 100 .mu.m. In some
embodiments, the average diameter of particles in a micronized
solid is from about 3 .mu.m to about 50 .mu.m. In some embodiments,
a particulate micronized solid comprises particle sizes of less
than about 5 microns, less than about 20 microns and/or less than
about 100 microns. In some embodiments, the use of particulates
(e.g., micronized particles) of ciprofloxacin allows for extended
and/or sustained release of ciprofloxacin from any formulation
described herein compared to a formulation comprising
non-multiparticulate ciprofloxacin. In some instances, formulations
containing multiparticulate (e.g. micronized) ciprofloxacin are
ejected from a 1 mL syringe adapted with a 27 G needle without any
plugging or clogging.
[0187] In some instances, any particle in any formulation described
herein is a coated particle (e.g., a coated micronized particle,
nano-particle) and/or a microsphere and/or a liposomal particle.
Particle size reduction techniques include, by way of example,
grinding, milling (e.g., air-attrition milling (jet milling), ball
milling), coacervation, complex coacervation, high pressure
homogenization, spray drying and/or supercritical fluid
crystallization. In some instances, particles are sized by
mechanical impact (e.g., by hammer mills, ball mill and/or pin
mills). In some instances, particles are sized via fluid energy
(e.g., by spiral jet mills, loop jet mills, and/or fluidized bed
jet mills). In some embodiments formulations described herein
comprise crystalline particles and/or isotropic particles. In some
embodiments, formulations described herein comprise amorphous
particles and/or anisotropic particles. In some embodiments,
formulations described herein comprise therapeutic agent particles
wherein the therapeutic agent is a free base, or a salt, or a
prodrug of a therapeutic agent, or any combination thereof.
[0188] The multiparticulates and/or micronized ciprofloxacin
formulations described herein are delivered to an auris structure
(e.g., middle ear) by means of any type of matrix including solid,
liquid or gel matrices. In some embodiments, the multiparticulates
and/or micronized ciprofloxacin described herein are delivered to
an auris structure (e.g., middle ear) by means of any type of
matrix including solid, liquid or gel matrices via intratympanic
injection.
Therapeutic Use of Otic Ciprofloxacin Formulations
[0189] Anatomy of the Ear
[0190] As shown in FIG. 4, the outer ear is the external portion of
the organ and is composed of the pinna (auricle), the auditory
canal (external auditory meatus) and the outward facing portion of
the tympanic membrane, also known as the ear drum. The pinna, which
is the fleshy part of the external ear that is visible on the side
of the head, collects sound waves and directs them toward the
auditory canal. Thus, the function of the outer ear, in part, is to
collect and direct sound waves towards the tympanic membrane and
the middle ear.
[0191] The middle ear is an air-filled cavity, called the tympanic
cavity, behind the tympanic membrane. The tympanic membrane, also
known as the ear drum, is a thin membrane that separates the
external ear from the middle ear. The middle ear lies within the
temporal bone, and includes within this space the three ear bones
(auditory ossicles): the malleus, the incus and the stapes. The
auditory ossicles are linked together via tiny ligaments, which
form a bridge across the space of the tympanic cavity. The malleus,
which is attached to the tympanic membrane at one end, is linked to
the incus at its anterior end, which in turn is linked to the
stapes. The stapes is attached to the oval window, one of two
windows located within the tympanic cavity. A fibrous tissue layer,
known as the annular ligament connects the stapes to the oval
window. Sound waves from the outer ear first cause the tympanic
membrane to vibrate. The vibration is transmitted across to the
cochlea through the auditory ossicles and oval window, which
transfers the motion to the fluids in the auris interna. Thus, the
auditory ossicles are arranged to provide a mechanical linkage
between the tympanic membrane and the oval window of the
fluid-filled auris interna, where sound is transformed and
transduced to the auris interna for further processing. Stiffness,
rigidity or loss of movement of the auditory ossicles, tympanic
membrane or oval window leads to hearing loss, e.g. otosclerosis,
or rigidity of the stapes bone.
[0192] The tympanic cavity also connects to the throat via the
eustachian tube. The eustachian tube provides the ability to
equalize the pressure between the outside air and the middle ear
cavity. The round window, a component of the auris interna but
which is also accessible within the tympanic cavity, opens into the
cochlea of the auris interna. The round window is covered by round
window membrane, which consists of three layers: an external or
mucous layer, an intermediate or fibrous layer, and an internal
membrane, which communicates directly with the cochlear fluid. The
round window, therefore, has direct communication with the auris
interna via the internal membrane.
[0193] Movements in the oval and round window are interconnected,
i.e. as the stapes bone transmits movement from the tympanic
membrane to the oval window to move inward against the auris
interna fluid, the round window (round window membrane) is
correspondingly pushed out and away from the cochlear fluid. This
movement of the round window allows movement of fluid within the
cochlea, which leads in turn to movement of the cochlear inner hair
cells, allowing hearing signals to be transduced. Stiffness and
rigidity in round window membrane leads to hearing loss because of
the lack of ability of movement in the cochlear fluid. Recent
studies have focused on implanting mechanical transducers onto the
round window, which bypasses the normal conductive pathway through
the oval window and provides amplified input into the cochlear
chamber.
[0194] Auditory signal transduction takes place in the auris
interna. The fluid-filled auris interna, or inner ear, consists of
two major components: the cochlear and the vestibular apparatus.
The auris interna is located in part within the osseous or bony
labyrinth, an intricate series of passages in the temporal bone of
the skull. The vestibular apparatus is the organ of balance and
consists of the three semi-circular canals and the vestibule. The
three semi-circular canals are arranged relative to each other such
that movement of the head along the three orthogonal planes in
space can be detected by the movement of the fluid and subsequent
signal processing by the sensory organs of the semi-circular
canals, called the crista ampullaris. The crista ampullaris
contains hair cells and supporting cells, and is covered by a
dome-shaped gelatinous mass called the cupula. The hairs of the
hair cells are embedded in the cupula. The semi-circular canals
detect dynamic equilibrium, the equilibrium of rotational or
angular movements.
[0195] When the head turns rapidly, the semicircular canals move
with the head, but endolymph fluid located in the membranous
semi-circular canals tends to remain stationary. The endolymph
fluid pushes against the cupula, which tilts to one side. As the
cupula tilts, it bends some of the hairs on the hair cells of the
crista ampullaris, which triggers a sensory impulse. Because each
semicircular canal is located in a different plane, the
corresponding crista ampullaris of each semi-circular canal
responds differently to the same movement of the head. This creates
a mosaic of impulses that are transmitted to the central nervous
system on the vestibular branch of the vestibulocochlear nerve. The
central nervous system interprets this information and initiates
the appropriate responses to maintain balance. Of importance in the
central nervous system is the cerebellum, which mediates the sense
of balance and equilibrium.
[0196] The vestibule is the central portion of the auris interna
and contains mechanoreceptors bearing hair cells that ascertain
static equilibrium, or the position of the head relative to
gravity. Static equilibrium plays a role when the head is
motionless or moving in a straight line. The membranous labyrinth
in the vestibule is divided into two sac-like structures, the
utricle and the saccule. Each structure in turn contains a small
structure called a macula, which is responsible for maintenance of
static equilibrium. The macula consists of sensory hair cells,
which are embedded in a gelatinous mass (similar to the cupula)
that covers the macula. Grains of calcium carbonate, called
otoliths, are embedded on the surface of the gelatinous layer.
[0197] When the head is in an upright position, the hairs are
straight along the macula. When the head tilts, the gelatinous mass
and otoliths tilts correspondingly, bending some of the hairs on
the hair cells of the macula. This bending action initiates a
signal impulse to the central nervous system, which travels via the
vestibular branch of the vestibulocochlear nerve, which in turn
relays motor impulses to the appropriate muscles to maintain
balance.
[0198] The cochlea is the portion of the auris interna related to
hearing. The cochlea is a tapered tube-like structure which is
coiled into a shape resembling a snail. The inside of the cochlea
is divided into three regions, which is further defined by the
position of the vestibular membrane and the basilar membrane. The
portion above the vestibular membrane is the scala vestibuli, which
extends from the oval window to the apex of the cochlea and
contains perilymph fluid, an aqueous liquid low in potassium and
high in sodium content. The basilar membrane defines the scala
tympani region, which extends from the apex of the cochlea to the
round window and also contains perilymph. The basilar membrane
contains thousands of stiff fibers, which gradually increase in
length from the round window to the apex of the cochlea. The fibers
of the basement membrane vibrate when activated by sound. In
between the scala vestibuli and the scala tympani is the cochlear
duct, which ends as a closed sac at the apex of the cochlea. The
cochlear duct contains endolymph fluid, which is similar to
cerebrospinal fluid and is high in potassium.
[0199] The organ of Corti, the sensory organ for hearing, is
located on the basilar membrane and extends upward into the
cochlear duct. The organ of Corti contains hair cells, which have
hairlike projections that extend from their free surface, and
contacts a gelatinous surface called the tectorial membrane.
Although hair cells have no axons, they are surrounded by sensory
nerve fibers that form the cochlear branch of the vestibulocochlear
nerve (cranial nerve VIII).
[0200] As discussed, the oval window, also known as the elliptical
window communicates with the stapes to relay sound waves that
vibrate from the tympanic membrane. Vibrations transferred to the
oval window increases pressure inside the fluid-filled cochlea via
the perilymph and scala vestibuli/scala tympani, which in turn
causes the round window membrane to expand in response. The
concerted inward pressing of the oval window/outward expansion of
the round window allows for the movement of fluid within the
cochlea without a change of intra-cochlear pressure. However, as
vibrations travel through the perilymph in the scala vestibuli,
they create corresponding oscillations in the vestibular membrane.
These corresponding oscillations travel through the endolymph of
the cochlear duct, and transfer to the basilar membrane. When the
basilar membrane oscillates, or moves up and down, the organ of
Corti moves along with it. The hair cell receptors in the Organ of
Corti then move against the tectorial membrane, causing a
mechanical deformation in the tectorial membrane. This mechanical
deformation initiates the nerve impulse which travels via the
vestibulocochlear nerve to the central nervous system, mechanically
transmitting the sound wave received into signals that are
subsequently processed by the central nervous system.
[0201] Otic Disorders or Conditions
[0202] Otitis externa (OE), also referred to as swimmer's ear, is
an inflammation of the external ear and/or ear canal. OE is
primarily caused by bacteria (e.g., Pseudomonas aeruginosa and
Staphylococcus aureus) or fungi (e.g., Candida albicans and
Aspergillus) in the outer ear, which establish infection following
damage to the skin of the ear canal. Symptoms of OE include
otalgia, swelling, and otorrhea. If the condition progresses
significantly, OE may cause temporary conductive hearing loss as a
result of the swelling and discharge. Treatment of OE involves
eliminating the aggravating pathogen from the ear canal and
reducing inflammation, which is usually accomplished by
administering combinations of antimicrobial agents, e.g.,
ciprofloxacin, with anti-inflammatory agents, e.g., steroids.
[0203] Otitis media (OM) is an inflammation of the middle ear.
Bacterial infection accounts for a large percentage of OM cases,
with more than 40% of cases attributed to Streptococcus pneumoniae
infection. However, viruses, as well as other microbes, may account
for OM conditions. Because OM can be caused by a virus, bacteria or
both, ciprofloxacin is used to eliminate the underlying
pathogen.
[0204] Syphilis is a venereal disease, caused by the spirochete
Treponema pallidum, which may result in otic disorders,
particularly cochleovestibular disorders, due to membranous
labyrinthitis, and secondarily meningitis. Both acquired and
congenital syphilis can cause otic disorders. Symptoms of
cochleovestibular disorders resulting from syphilis are often
similar to those of other otic disorders, such as AIED and
Meniere's disease, and include tinnitus, deafness, vertigo,
malaise, sore throat, headaches, and skin rashes.
[0205] Treatment of otosyphilis (syphilis presenting otic symptoms)
typically includes a combination of steroids and antibacterial
agents. Such treatments may be effective in eradicating the
spirochete organism while reducing inflammation. However,
Treponemas may remain in the cochlear and vestibular endolymph even
after eradication from other sites in the body. Accordingly, long
term treatment with penicillins may be required to achieve complete
eradication of the spirochete organism from the endolymph
fluid.
[0206] Systemic antimicrobial administration for the treatment of
otic disorders, e.g., OE, OM and otosyphilis, may create a
potential inequality in drug concentration with higher circulating
levels in the serum, and lower levels in the target auris organ
structures. As a result, fairly large amounts of drug are required
to overcome this inequality in order to deliver sufficient,
therapeutically effective quantities to the ear. Further,
bioavailability is often decreased due to metabolism of the drug by
the liver. In addition, systemic drug administration may increase
the likelihood of systemic toxicities and adverse side effects as a
result of the high serum amounts required to effectuate sufficient
local delivery to the target site. Systemic toxicities may also
occur as a result of liver breakdown and processing of the
therapeutic agents, forming toxic metabolites that effectively
erase any benefit attained from the administered therapeutic.
[0207] To overcome the toxic and attendant undesired side effects
of systemic delivery of ciprofloxacin (which are generally
understood to be toxic to cells), disclosed herein are methods and
compositions for local delivery of ciprofloxacin to auris media
and/or auris interna structures. In further or alternative
embodiments, the auris controlled-release formulations are capable
of being administered via intratympanic injection. In some
embodiments, the auris controlled release formulation is applied
via syringe and needle, wherein the needle is inserted through the
tympanic membrane and guided to the area of target site in the
middle ear.
[0208] Because of the localized targeting of the ciprofloxacin
formulations and compositions, as well as the biological blood
barrier present in the auris structure, the risk of adverse effects
will be reduced as a result of treatment with previously
characterized toxic or ineffective ciprofloxacin. Localized
administration of antimicrobial agent compositions reduces the risk
of development of resistance to antibiotics compared to the risk
for development of antibiotic resistance when an antibiotic is
administered systemically. The compositions described herein are
effective for recurring otic diseases or conditions including, for
example, recurring ear infections in children without the need for
changing treatment regimens (e.g., in response to development of
antibiotic resistance). Accordingly, also contemplated within the
scope of the embodiments herein is the use of ciprofloxacin in the
treatment of otic diseases or conditions including otitis externa,
otitis media, Ramsay Hunt syndrome, otosyphilis, AIED, Meniere's
disease, and vestibular neuronitis, including therapeutic agents
that have been previously rejected by practitioners because of
adverse effects or ineffectiveness of the ciprofloxacin.
[0209] Also included within the embodiments disclosed herein is the
use of additional auris media and/or auris interna-acceptable
agents in combination with the ciprofloxacin formulations and
compositions disclosed herein. When used, such agents assist in the
treatment of hearing or equilibrium loss or dysfunction resulting
from an autoimmune disorder, including vertigo, tinnitus, hearing
loss, balance disorders, infections, inflammatory response or
combinations thereof. Accordingly, agents that ameliorate or reduce
the effects of vertigo, tinnitus, hearing loss, balance disorders,
infections, inflammatory response or combinations thereof are also
contemplated to be used in combination with the ciprofloxacin
formulations described herein.
[0210] In some embodiments, the composition further comprises
ciprofloxacin as an immediate release agent wherein the immediate
release ciprofloxacin is the same agent as the controlled-release
agent, a different antimicrobial agent, an additional therapeutic
agent, or a combination thereof. In some embodiments, the
composition further comprises an additional therapeutic agent,
including an additional antimicrobial agent, an anti-inflammatory
agent, a corticosteroid, a cytotoxic agent, an anti-TNF agent, a
collagen, a gamma-globulin, an interferon, a platelet activator
factor antagonist, a nitric oxide synthase inhibitor, or
combinations thereof. In another aspect, the additional therapeutic
agent is an immediate release or a controlled release agent.
[0211] In some embodiments, the additional therapeutic agent is an
immediate release agent. In some embodiments, the additional
therapeutic agent is a controlled release agent.
[0212] Accordingly, provided herein are controlled release
ciprofloxacin formulations and compositions to locally treat auris
media and/or auris interna structures, thereby avoiding side
effects as a result of systemic administration of ciprofloxacin.
The locally applied ciprofloxacin formulations and compositions are
compatible with auris media and/or auris interna structures, and
are administered either directly to the desired auris media and/or
auris interna structure, e.g. the tympanic cavity. By specifically
targeting the auris media or auris interna structures, adverse side
effects as a result of systemic treatment are avoided. Moreover, by
providing a controlled release ciprofloxacin formulation or
composition to treat otic disorders, a constant and/or extended
source of ciprofloxacin is provided to the individual or patient
suffering from an otic disorder, reducing or eliminating the
variability of treatment.
[0213] Intratympanic injection of therapeutic agents also includes
the technique of injecting a therapeutic agent behind the tympanic
membrane into the auris media and/or auris interna.
[0214] However, intra-tympanic injections create several
unrecognized problems not addressed by currently available
treatment regimens, such as changing the osmolarity and pH of the
perilymph and endolymph, and introducing pathogens and endotoxins
that directly or indirectly damage ear structures. One of the
reasons the art may not have recognized these problems is that
there are no approved intra-tympanic compositions: the middle and
inner ear provides sui generis formulation challenges. Thus,
compositions developed for other parts of the body have little to
no relevance for an intra-tympanic composition.
[0215] There is no guidance in the prior art regarding requirements
(e.g., level of sterility, pH, osmolarity) for otic formulations
that are suitable for administration to humans. There is wide
anatomical disparity between the ears of animals across species. A
consequence of the inter-species differences in auditory structures
is that animal models of ear disease are often unreliable as a tool
for testing therapeutics that are being developed for clinical
approval.
[0216] Provided herein are otic formulations that meet stringent
criteria for pH, osmolarity, ionic balance, sterility, endotoxin
and/or pyrogen levels. The auris compositions described herein are
compatible with the microenvironment of the ear (e.g., the middle
ear) and are suitable for administration to humans. In some
embodiments, the formulations described herein comprise dyes and
aid visualization of the administered compositions obviating the
need for invasive procedures (e.g., removal of perilymph) during
preclinical and/or clinical development of intratympanic
therapeutics.
[0217] Provided herein are controlled release ciprofloxacin
formulations and compositions to locally treat targeted auris
structures, thereby avoiding side effects as a result of systemic
administration of the ciprofloxacin formulations and compositions.
The locally applied ciprofloxacin formulations and compositions and
devices are compatible with the targeted auris structures, and
administered either directly to the desired targeted auris
structure, e.g. the cochlear region, the tympanic cavity or the
external ear. By specifically targeting an auris structure, adverse
side effects as a result of systemic treatment are avoided.
Moreover, clinical studies have shown the benefit of having long
term exposure of drug to the perilymph of the cochlea, for example
with improved clinical efficacy of sudden hearing loss when the
therapeutic agent is given on multiple occasions. Thus, by
providing a controlled release ciprofloxacin formulation or
composition to treat otic disorders, a constant, and/or extended
source of ciprofloxacin is provided to the individual or patient
suffering from an otic disorder, reducing or eliminating
variabilities in treatment. Accordingly, one embodiment disclosed
herein is to provide a composition that enables ciprofloxacin to be
released in therapeutically effective doses either at variable or
constant rates such as to ensure a continuous release of the at
least one agent. In some embodiments, the ciprofloxacin disclosed
herein are administered as an immediate release formulation or
composition. In other embodiments, the ciprofloxacin are
administered as a sustained release formulation, released either
continuously, variably or in a pulsatile manner, or variants
thereof. In still other embodiments, ciprofloxacin formulation is
administered as both an immediate release and sustained release
formulation, released either continuously, variably or in a
pulsatile manner, or variants thereof. The release is optionally
dependent on environmental or physiological conditions, for
example, the external ionic environment (see, e.g. Oros.RTM.
release system, Johnson & Johnson).
[0218] In addition, the ciprofloxacin compositions or formulations
or devices included herein also include carriers, adjuvants, such
as preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure, and/or
buffers. Such carriers, adjuvants, and other excipients will be
compatible with the environment in the targeted auris structure(s).
Accordingly, specifically contemplated for the compositions and
devices described herein are carriers, adjuvants and excipients
that lack ototoxicity or are minimally ototoxic in order to allow
effective treatment of the otic disorders contemplated herein with
minimal side effects in the targeted regions or areas.
[0219] Intratympanic injection of compositions or devices creates
several additional problems that must also be addressed before the
composition or device can be administered. For example, there are
many excipients that are ototoxic. While these excipients can be
used when formulating an active agent for delivery by another
method (e.g., topical), their use should be limited, reduced or
eliminated when formulating a delivery device to be administered to
the ear due to their ototoxic effects.
[0220] By way of non-limiting example, the use of the following
commonly used solvents should be limited, reduced or eliminated
when formulating agents for administration to the ear: alcohols,
propylene glycol, and cyclohexane. Thus, in some embodiments, a
device disclosed herein is free or substantially free of alcohols,
propylene glycol, and cyclohexane. In some embodiments, a device
disclosed herein comprises less than about 50 ppm of each of
alcohols, propylene glycol, and cyclohexane. In some embodiments, a
device disclosed herein comprises less than about 25 ppm of each of
alcohols, propylene glycol, and cyclohexane. In some embodiments, a
device disclosed herein comprises less than about 20 ppm of each of
alcohols, propylene glycol, and cyclohexane. In some embodiments, a
device disclosed herein comprises less than about 10 ppm of each of
alcohols, propylene glycol, and cyclohexane. In some embodiments, a
device disclosed herein comprises less than about 5 ppm of each of
alcohols, propylene glycol, and cyclohexane. In some embodiments, a
device disclosed herein comprises less than about 1 ppm of each of
alcohols, propylene glycol, and cyclohexane.
[0221] Further, by way of non-limiting example, the use of the
following commonly utilized preservatives should be limited,
reduced or eliminated when formulating agents for administration to
the ear: Benzethonium chloride, Benzalkonium chloride, and
Thiomersal. Thus, in some embodiments, a device disclosed herein is
free or substantially free of benzethonium chloride, benzalkonium
chloride, and thiomersal. In some embodiments, a device disclosed
herein comprises less than about 50 ppm of each of benzethonium
chloride, benzalkonium chloride, and thiomersal. In some
embodiments, a device disclosed herein comprises less than about 25
ppm of each of benzethonium chloride, benzalkonium chloride, and
thiomersal. In some embodiments, a device disclosed herein
comprises less than about 20 ppm of each of benzethonium chloride,
benzalkonium chloride, and thiomersal. In some embodiments, a
device disclosed herein comprises less than about 10 ppm of each of
benzethonium chloride, benzalkonium chloride, and thiomersal. In
some embodiments, a device disclosed herein comprises less than
about 5 ppm of each of benzethonium chloride, benzalkonium
chloride, and thiomersal. In some embodiments, a device disclosed
herein comprises less than about 1 ppm of each of benzethonium
chloride, benzalkonium chloride, and thiomersal.
[0222] Certain antiseptics used to disinfect components of
therapeutic preparations (or the devices utilized to administer the
preparations) should be limited, reduced, or eliminated in otic
preparations. For example, acetic acid, iodine, and merbromin are
all known to be ototoxic. Additionally, chlorhexidene, a commonly
used antiseptic, should be limited, reduced or eliminated to
disinfect any component of an otic preparation (including devices
used to administer the preparation) as it is highly ototoxic in
minute concentrations (e.g., 0.05%). Thus, in some embodiments, a
device disclosed herein is free or substantially free of acetic
acid, iodine, merbromin, and chlorhexidene. In some embodiments, a
device disclosed herein comprises less than about 50 ppm of each of
acetic acid, iodine, merbromin, and chlorhexidene. In some
embodiments, a device disclosed herein comprises less than about 25
ppm of each of acetic acid, iodine, merbromin, and chlorhexidene.
In some embodiments, a device disclosed herein comprises less than
about 20 ppm of each of acetic acid, iodine, merbromin, and
chlorhexidene. In some embodiments, a device disclosed herein
comprises less than about 10 ppm of each of acetic acid, iodine,
merbromin, and chlorhexidene. In some embodiments, a device
disclosed herein comprises less than about 5 ppm of each of acetic
acid, iodine, merbromin, and chlorhexidene. In some embodiments, a
device disclosed herein comprises less than about 1 ppm of each of
acetic acid, iodine, merbromin, and chlorhexidene.
[0223] Further, otic preparations require particularly low
concentrations of several potentially-common contaminants that are
known to be ototoxic. Other dosage forms, while seeking to limit
the contamination attributable to these compounds, do not require
the stringent precautions that otic preparations require. For
example, the following contaminants should be absent or nearly
absent from otic preparations: arsenic, lead, mercury, and tin.
Thus, in some embodiments, a device disclosed herein is free or
substantially free of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 50
ppm of each of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 25
ppm of each of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 20
ppm of each of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 10
ppm of each of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 5
ppm of each of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 1
ppm of each of arsenic, lead, mercury, and tin.
[0224] To prevent ototoxicity, ciprofloxacin compositions or
formulations or devices disclosed herein are optionally targeted to
distinct regions of the targeted auris structures, including but
not limited to the tympanic cavity.
[0225] Otic Surgery and Implants
[0226] In some embodiments, the pharmaceutical formulations,
compositions or devices described herein are used in combination
with (e.g., implantation, short-term use, long-term use, or removal
of) implants (e.g., cochlear implants). As used herein, implants
include auris-interna or auris-media medical devices, examples of
which include cochlear implants, hearing sparing devices,
hearing-improvement devices, short electrodes, tympanostomy tubes,
micro-prostheses or piston-like prostheses; needles; stem cell
transplants; drug delivery devices; any cell-based therapeutic; or
the like. In some instances, the implants are used in conjunction
with a patient experiencing hearing loss. In some instances, the
hearing loss is present at birth. In some instances, the hearing
loss is associated with conditions such as AIED, bacterial
meningitis or the like that lead to osteoneogenesis and/or nerve
damage with rapid obliteration of cochlear structures and profound
hearing loss.
[0227] In some instances, an implant is an immune cell or a stem
cell transplant in the ear. In some instances, an implant is a
small electronic device that has an external portion placed behind
the ear, and a second portion that is surgically placed under the
skin that helps provide a sense of sound to a person who is
profoundly deaf or severely hard-of-hearing. By way of example,
such cochlear medical device implants bypass damaged portions of
the ear and directly stimulate the auditory nerve. In some
instances cochlear implants are used in single sided deafness. In
some instances cochlear implants are used for deafness in both
ears.
[0228] In some embodiments, administration of ciprofloxacin
composition described herein in combination with an otic
intervention (e.g., an intratympanic injection, a stapedectomy, a
tympanostomy, a medical device implant or a cell-based transplant)
delays or prevents collateral damage to auris structures, e.g.,
irritation, inflammation and/or infection, caused by the external
otic intervention (e.g., installation of an external device and/or
cells in the ear). In some embodiments, administration of
ciprofloxacin composition described herein in combination with an
implant allows for a more effective restoration of hearing loss
compared to an implant alone.
[0229] In some embodiments, administration of ciprofloxacin
composition described herein reduces damage to cochlear structures
caused by underlying conditions (e.g., bacterial meningitis,
autoimmune ear disease (AIED)) allowing for successful cochlear
device implantation. In some embodiments, administration of a
composition or device described herein, in conjunction with otic
surgery, medical device implantation and/or cell transplantation,
reduces or prevents cell damage and/or inflammation associated with
otic surgery, medical device implantation and/or cell
transplantation.
[0230] In some embodiments, administration of ciprofloxacin
composition described herein (e.g., a composition or device
comprising a corticosteriod) in conjunction with a cochlear implant
or stem cell transplant has a trophic effect (e.g., promotes
healthy growth of cells and/or healing of tissue in the area of an
implant or transplant). In some embodiments, a trophic effect is
desirable during otic surgery or during intratympanic injection
procedures. In some embodiments, a trophic effect is desirable
after installation of a medical device or after a cell transplant.
In some embodiments, a medical device is coated with a composition
described herein prior to implantation in the ear.
[0231] In some embodiments, administration of an anti-inflammatory
or immunosuppressant composition (e.g., a composition comprising an
immunosuppressant such as a corticosteroid) reduces inflammation
and/or infections associated with otic surgery, implantation of a
medical device or a cell transplant. In some instances, perfusion
of a surgical area with ciprofloxacin formulation described herein
and/or an anti-inflammatory formulation described herein reduces or
eliminates post-surgical and/or post-implantation complications
(e.g., inflammation, cell damage, infection, osteoneogenesis or the
like). In some instances, perfusion of a surgical area with a
formulation described herein reduces post-surgery or
post-implantation recuperation time.
[0232] In one aspect, the formulations described herein, and modes
of administration thereof, are applicable to methods of direct
perfusion of the middle ear compartments. Thus, the formulations
described herein are useful in combination with otic interventions.
In some embodiments, an otic intervention is an implantation
procedure (e.g., implantation of a hearing device in the cochlea).
In some embodiments, an otic intervention is a surgical procedure
including, by way of non-limiting examples, cochleostomy,
labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy,
tympanostomy, endolymphatic sacculotomy or the like. In some
embodiments, the middle ear compartments are perfused with a
formulation described herein prior to otic intervention, during
otic intervention, or after otic intervention, or a combination
thereof.
[0233] In some embodiments, when perfusion is carried out in
combination with otic intervention, the ciprofloxacin compositions
are immediate release compositions (e.g., a composition comprising
ciprofloxacin). In some of such embodiments, the immediate release
formulations described herein are non-thickened compositions and
are substantially free of extended release components (e.g.,
gelling components such as polyoxyethylene-polyoxypropylene
copolymers). In some of such embodiments, the compositions contain
less than 5% of the extended release components (e.g., gelling
components such as polyoxyethylene-polyoxypropylene triblock
copolymers) by weight of the formulation. In some of such
embodiments, the compositions contain less than 2% of the extended
release components (e.g., gelling components such as
polyoxyethylene-polyoxypropylene triblock copolymers) by weight of
the formulation. In some of such embodiments, the compositions
contain less than 1% of the extended release components (e.g.,
gelling components such as polyoxyethylene-polyoxypropylene
triblock copolymers) by weight of the formulation. In some of such
embodiments, a composition described herein that is used for
perfusion of a surgical area contains substantially no gelling
component and is an immediate release composition.
[0234] In certain embodiments, a composition described herein is
administered before an otic intervention (e.g., before implantation
of a medical device or a cell-based therapeutic). In certain
embodiments, a composition described herein is administered during
an otic intervention (e.g., during implantation of a medical device
or a cell-based therapeutic). In other embodiments, a composition
described herein is administered after an otic intervention (e.g.,
after implantation of a medical device or a cell-based
therapeutic). In some of such embodiments, a composition described
herein that is administered after the otic intervention is an
intermediate release or extended release composition (e.g., a
composition comprising an antibiotic, a composition comprising an
anti-inflammatory agent, a composition comprising a an antibiotic
and an anti-inflammatory agent or the like) and contains gelling
components as described herein. In some embodiments, an implant
(e.g., a tympanostomy tube) is coated with a composition or device
described herein prior to insertion in the ear.
[0235] Dosing Methods and Schedules
[0236] Drugs delivered to the middle or inner ear have been
administered systemically via oral, intravenous or intramuscular
routes. However, systemic administration for pathologies local to
the middle or inner ear increases the likelihood of systemic
toxicities and adverse side effects and creates a non-productive
distribution of drug in which high levels of drug are found in the
serum and correspondingly lower levels are found at the middle or
inner ear.
[0237] Intratympanic injection of therapeutic agents is the
technique of injecting a therapeutic agent behind the tympanic
membrane into the middle and/or inner ear. In one embodiment, the
formulations described herein are administered directly into the
tympanic cavity via transtympanic injection. In another embodiment,
the auris-acceptable ciprofloxacin formulations described herein
are administered onto the tympanic cavity via a non-transtympanic
approach to the middle or inner ear.
[0238] In one embodiment the delivery system is a syringe and
needle apparatus that is capable of piercing the tympanic membrane
and directly accessing the tympanic cavity. In some embodiments,
the needle on the syringe is wider than an 18 gauge needle. In
another embodiment, the needle gauge is from 18 gauge to 31 gauge.
In a further embodiment, the needle gauge is from 25 gauge to 30
gauge. Depending upon the thickness or viscosity of the
ciprofloxacin compositions or formulations, the gauge level of the
syringe or hypodermic needle may be varied accordingly. In another
embodiment, the internal diameter of the needle can be increased by
reducing the wall thickness of the needle (commonly referred as
thin wall or extra thin wall needles) to reduce the possibility of
needle clogging while maintaining an adequate needle gauge.
[0239] In another embodiment, the needle is a hypodermic needle
used for instant delivery of the gel formulation. The hypodermic
needle may be a single use needle or a disposable needle. In some
embodiments, a syringe may be used for delivery of the
pharmaceutically acceptable gel-based ciprofloxacin-containing
compositions as disclosed herein wherein the syringe has a
press-fit (Luer) or twist-on (Luer-lock) fitting. In one
embodiment, the syringe is a hypodermic syringe. In another
embodiment, the syringe is made of plastic or glass. In yet another
embodiment, the hypodermic syringe is a single use syringe. In a
further embodiment, the glass syringe is capable of being
sterilized. In yet a further embodiment, the sterilization occurs
through an autoclave. In another embodiment, the syringe comprises
a cylindrical syringe body wherein the gel formulation is stored
before use. In other embodiments, the syringe comprises a
cylindrical syringe body wherein the pharmaceutically acceptable
gel-based ciprofloxacin compositions as disclosed herein is stored
before use which conveniently allows for mixing with a suitable
pharmaceutically acceptable buffer. In other embodiments, the
syringe may contain other excipients, stabilizers, suspending
agents, diluents or a combination thereof to stabilize or otherwise
stably store the ciprofloxacin or other pharmaceutical compounds
contained therein.
[0240] In some embodiments, the syringe comprises a cylindrical
syringe body wherein the body is compartmentalized in that each
compartment is able to store at least one component of the
auris-acceptable ciprofloxacin gel formulation. In a further
embodiment, the syringe having a compartmentalized body allows for
mixing of the components prior to injection into the auris media or
auris interna. In other embodiments, the delivery system comprises
multiple syringes, each syringe of the multiple syringes contains
at least one component of the gel formulation such that each
component is pre-mixed prior to injection or is mixed subsequent to
injection. In a further embodiment, the syringes disclosed herein
comprise at least one reservoir wherein the at least one reservoir
comprises ciprofloxacin, or a pharmaceutically acceptable buffer,
or a viscosity enhancing agent, such as a gelling agent or a
combination thereof. Commercially available injection devices are
optionally employed in their simplest form as ready-to-use plastic
syringes with a syringe barrel, needle assembly with a needle,
plunger with a plunger rod, and holding flange, to perform an
intratympanic injection.
[0241] In some embodiments, the delivery device is an apparatus
designed for administration of therapeutic agents to the middle
and/or inner ear. By way of example only: GYRUS Medical Gmbh offers
micro-otoscopes for visualization of and drug delivery to the round
window niche; Arenberg has described a medical treatment device to
deliver fluids to inner ear structures in U.S. Pat. Nos. 5,421,818;
5,474,529; and 5,476,446, each of which is incorporated by
reference herein for such disclosure. U.S. patent application Ser.
No. 08/874,208, which is incorporated herein by reference for such
disclosure, describes a surgical method for implanting a fluid
transfer conduit to deliver therapeutic agents to the inner ear.
U.S. Patent Application Publication 2007/0167918, which is
incorporated herein by reference for such disclosure, further
describes a combined otic aspirator and medication dispenser for
intratympanic fluid sampling and medicament application.
[0242] The auris-acceptable compositions or formulations containing
ciprofloxacin described herein are administered for prophylactic
and/or therapeutic treatments. In therapeutic applications, the
ciprofloxacin compositions are administered to a patient already
suffering from an autoimmune disease, condition or disorder, in an
amount sufficient to cure or at least partially arrest the symptoms
of the disease, disorder or condition. Amounts effective for this
use will depend on the severity and course of the disease, disorder
or condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0243] Frequency of Administration
[0244] In some embodiments, a composition disclosed herein is
administered to an individual in need thereof once. In some
embodiments, a composition disclosed herein is administered to an
individual in need thereof more than once. In some embodiments, a
first administration of a composition disclosed herein is followed
by a second administration of a composition disclosed herein. In
some embodiments, a first administration of a composition disclosed
herein is followed by a second and third administration of a
composition disclosed herein. In some embodiments, a first
administration of a composition disclosed herein is followed by a
second, third, and fourth administration of a composition disclosed
herein. In some embodiments, a first administration of a
composition disclosed herein is followed by a second, third,
fourth, and fifth administration of a composition disclosed herein.
In some embodiments, a first administration of a composition
disclosed herein is followed by a drug holiday.
[0245] The number of times a composition is administered to an
individual in need thereof depends on the discretion of a medical
professional, the disorder, the severity of the disorder, and the
individual's response to the formulation. In some embodiments, a
composition disclosed herein is administered once to an individual
in need thereof with a mild acute condition. In some embodiments, a
composition disclosed herein is administered more than once to an
individual in need thereof with a moderate or severe acute
condition. In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of
ciprofloxacin may be administered chronically, that is, for an
extended period of time, including throughout the duration of the
patient's life in order to ameliorate or otherwise control or limit
the symptoms of the patient's disease or condition.
[0246] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of
ciprofloxacin may be administered chronically, that is, for an
extended period of time, including throughout the duration of the
patient's life in order to ameliorate or otherwise control or limit
the symptoms of the patient's disease or condition.
[0247] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of ciprofloxacin may be
given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended
for a certain length of time (i.e., a "drug holiday"). The length
of the drug holiday varies between 2 days and 1 year, including by
way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50
days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The
dose reduction during a drug holiday may be from 10%-100%,
including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and
100%.
[0248] Once improvement of the patient's otic conditions has
occurred, a maintenance ciprofloxacin dose is administered if
necessary. Subsequently, the dosage or the frequency of
administration, or both, is optionally reduced, as a function of
the symptoms, to a level at which the improved disease, disorder or
condition is retained. In certain embodiments, patients require
intermittent treatment on a long-term basis upon any recurrence of
symptoms.
[0249] The amount of ciprofloxacin that will correspond to such an
amount will vary depending upon factors such as the particular
compound, disease condition and its severity, according to the
particular circumstances surrounding the case, including, e.g., the
route of administration, the autoimmune condition being treated,
the target area being treated, and the subject or host being
treated. In general, however, doses employed for adult human
treatment will typically be in the range of 0.02-50 mg per
administration, preferably 1-15 mg per administration. The desired
dose is presented in a single dose or as divided doses administered
simultaneously (or over a short period of time) or at appropriate
intervals.
[0250] Pharmacokinetics of Otic Formulations
[0251] In one embodiment, the formulations disclosed herein
additionally provides an immediate release of ciprofloxacin from
the composition, or within 1 minute, or within 5 minutes, or within
10 minutes, or within 15 minutes, or within 30 minutes, or within
60 minutes or within 90 minutes. In other embodiments, a
therapeutically effective amount of ciprofloxacin is released from
the composition immediately, or within 1 minute, or within 5
minutes, or within 10 minutes, or within 15 minutes, or within 30
minutes, or within 60 minutes or within 90 minutes. In certain
embodiments the composition comprises an auris-pharmaceutically
acceptable gel formulation providing immediate release of
ciprofloxacin. Additional embodiments of the formulation may also
include an agent that enhances the viscosity of the formulations
included herein.
[0252] In other or further embodiments, the formulation provides an
extended release formulation ciprofloxacin. In certain embodiments,
diffusion of ciprofloxacin from the formulation occurs for a time
period exceeding 5 minutes, or 15 minutes, or 30 minutes, or 1
hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day,
or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days,
or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25
days, or 30 days, or 45 days, or 2 months or 3 months or 4 months
or 5 months or 6 months or 9 months or 1 year. In other
embodiments, a therapeutically effective amount of ciprofloxacin is
released from the formulation for a time period exceeding 5
minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6
hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or
4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or
14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45
days, or 2 months or 3 months or 4 months or 5 months or 6 months
or 9 months or 1 year.
[0253] In other embodiments, the formulation provides both an
immediate release and an extended release formulation of
ciprofloxacin. In yet other embodiments, the formulation contains a
0.25:1 ratio, or a 0.5:1 ratio, or a 1:1 ratio, or a 1:2 ratio, or
a 1:3, or a 1:4 ratio, or a 1:5 ratio, or a 1:7 ratio, or a 1:10
ratio, or a 1:15 ratio, or a 1:20 ratio of immediate release and
extended release formulations. In a further embodiment the
formulation provides an immediate release of a first ciprofloxacin
and an extended release of a second ciprofloxacin or other
therapeutic agent. In yet other embodiments, the formulation
provides an immediate release and extended release formulation of
ciprofloxacin, and at least one therapeutic agent. In some
embodiments, the formulation provides a 0.25:1 ratio, or a 0.5:1
ratio, or a 1:1 ratio, or a 1:2 ratio, or a 1:3, or a 1:4 ratio, or
a 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a
1:20 ratio of immediate release and extended release formulations
of a first ciprofloxacin and second therapeutic agent,
respectively.
[0254] In a specific embodiment the formulation provides a
therapeutically effective amount of ciprofloxacin at the site of
disease with essentially no systemic exposure. In an additional
embodiment the formulation provides a therapeutically effective
amount of ciprofloxacin at the site of disease with essentially no
detectable systemic exposure. In other embodiments, the formulation
provides a therapeutically effective amount of ciprofloxacin at the
site of disease with little or no detectable systemic exposure.
[0255] The combination of immediate release, delayed release and/or
extended release ciprofloxacin compositions or formulations may be
combined with other pharmaceutical agents, as well as the
excipients, diluents, stabilizers, tonicity agents and other
components disclosed herein. As such, depending upon the thickness
or viscosity desired, or the mode of delivery chosen, alternative
aspects of the embodiments disclosed herein are combined with the
immediate release, delayed release and/or extended release
embodiments accordingly.
[0256] In certain embodiments, the pharmacokinetics of the
ciprofloxacin formulations described herein are determined by
intratympanic injection of the formulation into the test animal
(including by way of example, a guinea pig or a chinchilla). At a
determined period of time (e.g., 6 hours, 12 hours, 1 day, 2 days,
3 days, 4 days, 5 days, 6 days, and 7 days for testing the
pharmacokinetics of a formulation over a 1 week period), the test
animal is euthanized and the level of ciprofloxacin in the ear is
measured. In addition, the systemic level of ciprofloxacin is
measured by withdrawing a blood sample from the test animal. In
order to determine whether the formulation impedes hearing, the
hearing of the test animal is optionally tested.
[0257] FIG. 5 shows predicted tunable release of an active agent
from four compositions.
[0258] Kits/Articles of Manufacture
[0259] The disclosure also provides kits for preventing, treating
or ameliorating the symptoms of a disease or disorder in a mammal.
Such kits generally will comprise one or more of controlled-release
ciprofloxacin compositions or devices disclosed herein, and
instructions for using the kit. The disclosure also contemplates
the use of one or more of controlled-release ciprofloxacin
compositions, in the manufacture of medicaments for treating,
abating, reducing, or ameliorating the symptoms of a disease,
dysfunction, or disorder in a mammal, such as a human that has, is
suspected of having, or at risk for developing an ear disorder.
[0260] In some embodiments, kits include a carrier, package, or
container that is compartmentalized to receive one or more
containers such as vials, tubes, and the like, each of the
container(s) including one of the separate elements to be used in a
method described herein. Suitable containers include, for example,
bottles, vials, syringes, and test tubes. In other embodiments, the
containers are formed from a variety of materials such as glass or
plastic.
[0261] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products are also presented herein. See, e.g., U.S.
Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of
pharmaceutical packaging materials include, but are not limited to,
blister packs, bottles, tubes, inhalers, pumps, bags, vials,
containers, syringes, bottles, and any packaging material suitable
for a selected formulation and intended mode of administration and
treatment. A wide array of ciprofloxacin formulations compositions
provided herein are contemplated as are a variety of treatments for
any disease, disorder, or condition that would benefit by
controlled release administration of ciprofloxacin to the ear.
[0262] In some embodiments, a kit includes one or more additional
containers, each with one or more of various materials (such as
reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user standpoint for use of a
formulation described herein. Non-limiting examples of such
materials include, but not limited to, buffers, diluents, filters,
needles, syringes; carrier, package, container, vial and/or tube
labels listing contents and/or instructions for use and package
inserts with instructions for use. A set of instructions is
optionally included. In a further embodiment, a label is on or
associated with the container. In yet a further embodiment, a label
is on a container when letters, numbers or other characters forming
the label are attached, molded or etched into the container itself;
a label is associated with a container when it is present within a
receptacle or carrier that also holds the container, e.g., as a
package insert. In other embodiments a label is used to indicate
that the contents are to be used for a specific therapeutic
application. In yet another embodiment, a label also indicates
directions for use of the contents, such as in the methods
described herein.
[0263] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. In another
embodiment, the pack for example contains metal or plastic foil,
such as a blister pack. In a further embodiment, the pack or
dispenser device is accompanied by instructions for administration.
In yet a further embodiment, the pack or dispenser is also
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. In another embodiment, such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In yet another embodiment, compositions containing a
compound provided herein formulated in a compatible pharmaceutical
carrier are also prepared, placed in an appropriate container, and
labeled for treatment of an indicated condition.
EXAMPLES
Example 1
Form (Anhydrous/Hydrate) of Ciprofloxacin--Loss on Drying
[0264] To assess the form of ciprofloxacin samples described in the
present disclosure, a comparison experiment is conducted to
evaluate the sample's loss of weight upon heating. Loss of less
than 2% in weight generally indicates that the sample is in
anhydrous form. On the other hand, loss of more than 10% in weight
generally indicates that the sample is in hydrate form. The
conditions and results of the experiment are summarized below:
[0265] Experimental Setup--
[0266] Loss on Drying: [0267] If suspension: Pipette cipro
suspension onto filter on vacuum filter flask [0268] Transfer
filter/dry powder to 40.degree. C. oven, hold 24 hours [0269]
Transfer solid to pre-weighed aluminum pan and weigh solid [0270]
Transfer pan to 125.degree. C. oven, hold one hour [0271] Weigh
again and determine weight loss due to 125.degree. C.
TABLE-US-00001 [0271] TABLE 1 Form (Anhydrous/Hydrate) of
Ciprofloxacin - Loss on Drying Sample Weight Loss on No. Sample
Description Drying 1 Cipro anhydrous (dry powder; no suspension)
0.1% 2 Cipro hydrate (dry powder; no suspension) 11.1% 3 Cipro
suspension (5.degree. C. addition of Cipro 13.7% anhydrous powder
to water, homogenized) 4 Cipro suspension (135.degree. C. autoclave
of Sample 1.0% 3; hot suspension) 5 Cipro suspension (135.degree.
C. autoclave of Sample 15.9% 3; cooled down suspension)
[0272] The first entry indicates that ciprofloxacin anhydrous
losses less than 1% weigh upon oven heating. The second entry
indicates that ciprofloxacin hydrate losses more than 10% weigh
upon oven heating. The third entry indicates that ciprofloxacin
anhydrous is converted into hydrate form upon mixing with water (as
the solid isolated from the mixture losses more than 10% weigh upon
oven hearing). The fourth entry indicates that that the
ciprofloxacin hydrate suspension in third entry, upon heating at
high temperature, reverts back to anhydrous form in the hot
suspension. Finally, the last entry indicates that ciprofloxacin in
the hot suspension heated at high temperature is re-hydrated during
cool-down. Without wishing to be bound by any particular theory, it
is contemplated that the hydrate-anhydrous-hydrate transformation
contributes to the solidification of the ciprofloxacin suspension
described herein.
Example 2
Form (Anhydrous/Hydrate) of Ciprofloxacin--X-Ray
Characterization
[0273] FIG. 1 shows X-ray characterization of ciprofloxacin
anhydrous (bottom), ciprofloxacin hydrate (middle), and an aqueous
ciprofloxacin suspension formed according to the method disclosure
herein (top). FIG. 2 shows X-ray characterization of an aqueous
ciprofloxacin suspension after heat sterilization at 135.degree. C.
(without cooling down). In a non-limiting sterilization example,
dry powder ciprofloxacin free base anhydrate with the X-ray
characterization at the bottom of FIG. 1 is used. When this is
added to water, it immediately hydrates. Notably, ciprofloxacin
changes forms (showing increasing particle size and visually
showing long needles forming) and thickens (and can solidify)
during this step. This could be similar to the solidification
during cool-down, suggesting that the conversion from anhydrate at
high temperature back to hydrate at low temperature is involved in
causing the solidification.
[0274] Referring now to FIG. 1, the X-ray characterization at the
bottom represents ciprofloxacin anhydrous, and the X-ray
characterization in the middle represents ciprofloxacin hydrate.
Referring now to FIG. 2, the X-ray characterization represents an
aqueous ciprofloxacin suspension after heat sterilization at
135.degree. C. (without cooling down). Comparison of the X-ray
characterization of those non-limiting examples indicates the
presence of ciprofloxacin in anhydrous form when an aqueous
ciprofloxacin suspension is heated at high temperature (e.g.
135.degree. C.)
[0275] When this hot ciprofloxacin free base (anhydrous) suspension
is cooled down, it solidified. This solidified material is shown to
be the hydrate form.
[0276] Referring again to FIG. 1, the X-ray characterization at the
bottom represents ciprofloxacin anhydrous, and the X-ray
characterization in the middle represents ciprofloxacin hydrate.
The X-ray characterization at the top represents an aqueous
ciprofloxacin suspension after heat sterilization at the lower
temperature exposure (e.g. 100.degree. C. -120.degree. C.) after
cooling down. Comparison of the X-ray characterization of those
non-limiting examples indicates the presence of ciprofloxacin in
hydrate form when an aqueous ciprofloxacin suspension is heated at
the lower temperature exposure (e.g. 100.degree. C. -120.degree.
C.) after cooling down.
Example 3
Heat Sterilization of Ciprofloxacin
[0277] To demonstrate the features of the sterilization process
described herein, three manufacturing experiments are conducted by
Alliance Medical Products (9342 Jeronimo Rd, Irvine, Calif. 92618),
with results summarized below.
[0278] Engineering (Process Development) Manufacturing Run,
Protocol 14047: 105.degree. C. exposure for 2 hours; no
solidification of ciprofloxacin suspension.
[0279] Engineering (Process Development) Manufacturing Run,
Protocol 14047 addendum 1: 115.degree. C. exposure for 1 hour; no
solidification of ciprofloxacin suspension.
[0280] Engineering (Process Development) Manufacturing Run,
Protocol 13156: >121.5.degree. C. exposure for 20 minutes;
ciprofloxacin suspension solidified.
[0281] Changes in the form during manufacturing process also
results in changes in the particle size of ciprofloxacin API.
Ciprofloxacin free base anhydrous API powder has a typical particle
size of D90 under 15 .mu.m, upon conversion to the hydrate form,
particle size increases to D90 of around 60 .mu.m. The final drug
product has particle size of D90 of about 25 .mu.m. Without wishing
to be bound by any particular theory, one or more features of the
sterilization method described herein, including but not limited to
the use of a lower sterilization temperature and/or homogenization
of the suspension during the sterilization process, would
contribute to the particle size distribution of ciprofloxacin in
the suspension, and in the final product. In some embodiments, it
is the use of a lower sterilization temperature and homogenization
of the suspension during the sterilization process that contributes
to the particle size distribution of ciprofloxacin in the
suspension, and in the final product.
Example 4
Filtration Sterilization of a Diluent Composition
[0282] The heat sterilized ciprofloxacin suspension could be
further processed into a ready-to-use drug product, such as by
mixing with a diluent composition. In this example, the diluent
composition is an aqueous solution of a
polyoxyethylene-polyoxypropylene copolymer (e.g. poloxamer 407), a
buffering agent (tromethamine), an osmolarity adjusting agent (e.g.
sodium chloride), and a pH adjusting agent (hydrochloric acid)
prepared as follows.
[0283] A concentrated poloxamer 407 buffered solution is prepared
by mixing and dissolving all components with nitrogen sparging,
under pressure, at approximately 2-7.degree. C. The poloxamer 407
buffered diluents composition is sterile filtered through a 0.22
.mu.m filter for further combination with the ciprofloxacin
suspension.
Example 5
Determination of Manufacturing Conditions for Sterile
Filtration
[0284] The temperature of the room is maintained below 25.degree.
C. to retain the temperature of the solution at below 19.degree. C.
The temperature of the solution is maintained at below 19.degree.
C. up to 3 hours of the initiation of the manufacturing, without
the need to chill/cool the container.
[0285] Three different Sartoscale (Sartorius Stedim) filters with a
surface area of 17.3 cm.sup.2 are evaluated at 20 psi and
14.degree. C. of solution [0286] 1) Sartopore 2, 0.2 .mu.m
5445307HS-FF (PES), flow rate of 16 mL/min [0287] 2) Sartobran P,
0.2 .mu.m 5235307HS-FF (cellulose ester), flow rate of 12 mL/min
[0288] 3) Sartopore 2 XLI, 0.2 .mu.m 544530715-FF (PES), flow rate
of 15 mL/min
[0289] Sartopore 2 filter 5441307H4-SS is used, filtration is
carried out at the solution temperature using a 0.45, 0.2 .mu.m
Sartopore 2 150 sterile capsule (Sartorius Stedim) with a surface
area of 0.015 m.sup.2 at a pressure of 16 psi. Flow rate is
measured at approximately 100 mL/min at 16 psi, with no change in
flow rate while the temperature is maintained in the 6.5-14.degree.
C. range. Decreasing pressure and increasing temperature of the
solution causes a decrease in flow rate due to an increase in the
viscosity of the solution. Discoloration of the solution is
monitored during the process.
TABLE-US-00002 TABLE 2 Predicted filtration time for a 17%
poloxamer 407 diluent composition at a solution temperature range
of 6.5-14.degree. C. using Sartopore 2, 0.2 .mu.m filters at a
pressure of 16 psi of pressure Estimated flow rate Time to filter 8
L Filter Size (m.sup.2) (mL/min) (estimated) Sartopore 2, size 4
0.015 100 mL/min 80 min Sartopore 2, size 7 0.05 330 mL/min 24 min
Sartopore 2, size 8 0.1 670 mL/min 12 min
[0290] Viscosity, Tgel and UV/Vis absorption is checked before
filtration evaluation. UV/Vis spectra are obtained by an Evolution
160 UV/Vis (Thermo Scientific). A peak in the range of 250-300 nm
is attributed to BHT stabilizer present in the raw material
(poloxamer). Table 3 lists physicochemical properties of the above
solutions before and after filtration.
TABLE-US-00003 TABLE 3 Physicochemical properties of 17% poloxamer
407 diluent composition before and after filtration Tgel
Viscosity.sup.a @ 19.degree. C. Sample (.degree. C.) (cP)
Absorbance @ 274 nm Before filtration 22 100 0.3181 After
filtration 22 100 0.3081 .sup.aViscosity measured at a shear rate
of 37.5 s.sup.-1
[0291] The above process is applicable for manufacture of 17% P407
formulations, and includes temperature analysis of the room
conditions. Preferably, a maximum temperature of 19.degree. C.
reduces cost of cooling the container during manufacturing. In some
instances, a jacketed container is used to further control the
temperature of the solution to ease manufacturing concerns.
Example 6
Preparation of a Ready-to-Use Ciprofloxacin Poloxamer
Formulation
[0292] In this non-limiting example, a ciprofloxacin suspension
prepared as in Example 3 and a poloxamer 407 diluent are mixed
together at aseptic conditions to form a ready-to-use otic
formulation that meets the high sterility requirements for
intratympanic administered composition. An exemplary formulation is
provided below as a thermoreversible gel that is an injectable
liquid at room temperature and gels in the ear after intratympanic
delivery.
TABLE-US-00004 Quality Composition Composition Ingredient Standard
Function (mg/mL).sup.a (mg/vial).sup.b Ciprofloxacin USP Active 60
210 ingredient Poloxamer 407 NF Gel formation 157 549.5 Sodium USP
Osmolality 4.5 15.75 Chloride modifier Tromethanine USP Buffering
agent 5.8 20.3 Hydrochloric NF pH adjustment QS for pH QS for pH
Acid adjustment adjustment (37.5% w/w) (pH 7.0-8.0) (pH 7.0-8.0)
Water for USP Vehicle QS to 1040 QS to 3640 Injection (WFI)
.sup.aDensity of OTO-201 Drug Product containing 60 mg/mL
ciproflexacia USP has been determined to be 1.04 g/mL. .sup.bFill
volume is approximately 3.5 mL per vial.
[0293] The formulation has less than about 50 colony forming units
(cfu) of microbiological agents per gram of formulation, and has
less than about 5 endotoxin units (EU) per kg of body weight of a
subject. The composition is suitable for intratympanic
administration.
Example 7
Preparation of a Ready-to-Use Vial Containing Ciprofloxacin
Poloxamer Formulation
[0294] The formulation in Example 6 is filled into an aseptic
container (e.g. a vial), stoppered, and capped, all under aseptic
process conditions to form a ready-to-use medical/pharmaceutical
product that meets the sterility requires for intratympanic
administration. The formulation in the vial has less than about 50
colony forming units (cfu) of microbiological agents per gram of
formulation, and has less than about 5 endotoxin units (EU) per kg
of body weight of a subject.
Example 8
In Vivo Testing of Intratympanic Injection of Ciprofloxacin
Formulation in a Guinea Pig
[0295] A cohort of 21 guinea pigs (Charles River, females weighing
200-300 g) is intratympanically injected with 50 .mu.L of different
P407-ciprofloxacin formulation prepared in Example 6 or Example 7.
Animals are dosed on day 1. The release profile for the
formulations is determined based on analysis of the perilymph.
[0296] While preferred embodiments of the present invention have
been shown and described herein, such embodiments are provided by
way of example only. Various alternatives to the embodiments
described herein are optionally employed in practicing the
inventions. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
* * * * *
References