U.S. patent application number 12/855096 was filed with the patent office on 2010-12-02 for concentrated aqueous azalide formulations.
This patent application is currently assigned to INSITE VISION INCORPORATED. Invention is credited to Roy Duane Archibald, Lyle Bowman, S. Kumar Chandrasekaran, David Mufson, Stephen Pham.
Application Number | 20100305054 12/855096 |
Document ID | / |
Family ID | 40523785 |
Filed Date | 2010-12-02 |
United States Patent
Application |
20100305054 |
Kind Code |
A1 |
Bowman; Lyle ; et
al. |
December 2, 2010 |
CONCENTRATED AQUEOUS AZALIDE FORMULATIONS
Abstract
The present invention relates to formulations of concentrated
azalide antibiotics and methods for making and using them.
Specifically, the invention relates to a method of treating an
infection comprising administering to a patient in need thereof, an
effective amount of a concentrated aqueous azalide antibiotic
formulation made according to the method comprising dissolving an
azalide antibiotic in an aqueous solution comprising a strong acid.
The invention also relates to methods for making concentrated
aqueous azalide antibiotic formulations for use in pulmonary
infection, a nasopharyngeal infection, an otic infection, an ocular
infection, a dermal or a vaginal infection. The invention also
relates to concentrated aqueous azalide antibiotic formulations
made by dissolving an azalide antibiotic in an aqueous solution
comprising a strong acid.
Inventors: |
Bowman; Lyle; (Pleasanton,
CA) ; Chandrasekaran; S. Kumar; (Moraga, CA) ;
Archibald; Roy Duane; (Sonora, CA) ; Pham;
Stephen; (Sacramento, CA) ; Mufson; David;
(San Francisco, CA) |
Correspondence
Address: |
MCDERMOTT WILL & EMERY LLP
600 13TH STREET, N.W.
WASHINGTON
DC
20005-3096
US
|
Assignee: |
INSITE VISION INCORPORATED
Alameda
CA
|
Family ID: |
40523785 |
Appl. No.: |
12/855096 |
Filed: |
August 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11905854 |
Oct 4, 2007 |
7795231 |
|
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12855096 |
|
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Current U.S.
Class: |
514/29 |
Current CPC
Class: |
A61K 47/38 20130101;
A61P 33/02 20180101; A61K 47/32 20130101; A61K 9/0043 20130101;
A61K 9/008 20130101; A61K 47/26 20130101; A61K 9/0014 20130101;
A61K 9/0056 20130101; A61K 9/0051 20130101; A61P 31/00 20180101;
A61K 31/573 20130101; A61K 9/0034 20130101; A61P 31/04 20180101;
A61K 9/0058 20130101; A61K 31/351 20130101; A61K 9/0078 20130101;
A61K 9/0048 20130101; A61K 31/7052 20130101; A61K 9/0046 20130101;
A61K 31/00 20130101; A61K 9/0063 20130101; A61K 47/10 20130101;
A61P 29/00 20180101; A61K 31/00 20130101; A61K 2300/00 20130101;
A61K 31/351 20130101; A61K 2300/00 20130101; A61K 31/573 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/29 |
International
Class: |
A61K 31/7052 20060101
A61K031/7052; A61P 33/02 20060101 A61P033/02; A61P 31/04 20060101
A61P031/04; A61P 29/00 20060101 A61P029/00 |
Claims
1. A method of treating an infection comprising administering to a
patient in need thereof, an effective amount of a concentrated
aqueous azalide antibiotic formulation made according to the method
comprising dissolving an azalide antibiotic in an aqueous solution
comprising a strong acid.
2. The method of claim 1 wherein the azalide antibiotic is
azithromycin.
3. The method of claim 2 wherein the aqueous azalide antibiotic
formulation has about 2% to about 5% azithromycin.
4. The method of claim 2 wherein the aqueous azalide antibiotic
formulation has about 3% azithromycin.
5. The method of claim 1 wherein the strong acid is hydrochloric
acid.
6. The method of claim 1 wherein the aqueous solution has a pH of
about 5 to about 6.
7. The method of claim 1 wherein the method further comprises the
step of adding to the aqueous solution a second solution comprising
a strong base.
8. The method of claim 7 wherein the strong base is sodium
hydroxide.
9. The method of claim 7 wherein the second solution is added in an
amount sufficient to bring the combined solutions to a pH from
about 6 to about 7.
10. The method of claim 7 wherein the second solution is added in
an amount sufficient to bring the combined solutions to a pH from
about 6.3.
11. The method of claim 7 wherein the second solution comprises a
polymeric agent.
12. The method of claim 11 wherein the polymeric agent is Noveon
AA-1.
13. The method of claim 1 wherein the aqueous azalide antibiotic
formulation comprises an anti-inflammatory agent.
14. The method of claim 16 wherein the anti-inflammatory agent is a
dexamethasone.
15. The method of claim 14, wherein the dexamethasone is at
concentration of about 0.1%.
16. The method of claim 15 wherein the azalide antibiotic is
azithromycin at a concentration of about 3%.
17. The method of claim 1 wherein the infection a pulmonary
infection.
18. The method of claim 1 wherein the infection is a nasopharyngeal
infection.
19. The method of claim 1 wherein the infection is an ocular
infection.
20. The method of claim 1, wherein the infection is a dermal
infection.
21. The method of claim 1, wherein the infection is an otic
infection.
22. A method of making a concentrated aqueous azalide antibiotic
formulation comprising dissolving an azalide antibiotic in an
aqueous solution comprising a strong acid.
23. The method of claim 22 wherein the method further comprises the
step of adding to the aqueous solution a second solution comprising
a strong base.
24. A concentrated topical aqueous azalide antibiotic formulation
made by the method comprising dissolving an azalide antibiotic in
an aqueous solution comprising a strong acid.
25. The formulation of claim 24 wherein the method further
comprises the step of adding to the aqueous solution a second
solution comprising a strong base.
Description
RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application
Ser. No. 11/905,854, filed on Oct. 4, 2007, the disclosure of which
Application is incorporated by reference herein.
FIELD OF THE DISCLOSURE
[0002] The present invention relates to formulations of
concentrated azalide antibiotics and methods for making and using
them.
BACKGROUND OF THE INVENTION
[0003] The human body is susceptible to bacterial and parasitic
infections arising from both traumatic and non-traumatic related
events. Infections are a concern after surgery, and precautions are
correspondingly taken to prevent the onset of infection. However,
even without the invasive trauma of a surgical procedure,
infections in the eye, ears, mouth, skin and other superficial
tissues can occur.
[0004] Treating infections in superficial tissues can be
challenging and/or problematic because of the difficulty in
delivering an antibiotic to the affected tissue. The simple and
direct approach of topically applying the antibiotic has several
benefits, including the avoidance of side effects, bypassing the
hepatic first pass, and the reduced chance of developing resistant
strains of bacteria as compared to systemic administration.
However, for a variety of reasons, many antibiotics are not
amenable or suitable for topical application.
[0005] For example, in order for a topical application to be
effective, the antibiotic must be able to penetrate the desired
tissue. Also, the permeability must be sufficient to impart an
effective dose. Many drugs do not possess a requisite solubility or
permeability with regard to superficial tissues. It should be noted
that the permeability of the superficial tissues are quite
different from that of the tissues encountered in the stomach and
intestinal tract. Thus, while a certain drug may be readily
absorbed in the intestines and introduced into the blood supply for
systemic administration, the same drug may be incapable of being
absorbed by or passing through the substantially avascular outer
layers of superficial tissues at a minimally acceptable therapeutic
concentration. Moreover, the mechanism of transport or uptake of
the drug is entirely different for topical administration than for
oral administration.
[0006] Azithromycin (U.S. Pat. No. 4,517,359) is a well-known
antibiotic belonging to the macrolide class (of which erythromycin
is the precursor). Notwithstanding the structural similarity,
azithromycin can be considered as unique within the macrolides
class, such as to be included in a new class of antibiotics known
as azalides. In particular, the specific characteristics of
azithromycin make this molecule more stable, tolerated and
effective than its precursor erythromycin (S. Alvarez-Elcoro, M. J.
Enzler, "The macrolides: Erythromycin, clarithromycin, and
azithromycin", Mayo Clinic Proceeding, 1999, 74: 613-634).
[0007] Azithromycin, even in comparison to other recent macrolides,
shows a superior antibacterial activity against some gram-negative
organisms, while retaining the same efficacy against gram-positive
organisms. Moreover azithromycin has an extensive intracellular
distribution into specific tissues after oral administration [R. P.
Glaude et al., Antimicrob. Agents and Chemother., 1989, 33(3):
277-82]. The extended half-life of azithromycin makes it
potentially suitable for once-daily administration against
infections of the respiratory tract, skin and soft tissues [A. P.
Ball et al., J. Int. Med. Res., 1991, 19(6): 446-50; A. E. Girard
et al., Antimicrob. Agents and Chemother., 1987, 31(12):
1948-1954].
[0008] Efficient methods for preparing high concentration and well
tolerated aqueous azalide formulations have been elusive.
Generally, azalide antibiotics are poorly soluble in water. The
aqueous solubility at pH 7.4 at 37.degree. C. is 39 mg/ml. Aqueous
solubility can be improved when the antibiotic is converted to a
salt form. For example, azithromycin dihydrochloride has good water
solubility. However, there are potential safety problems associate
with the topical use of its salts.
[0009] U.S. Pat. No. 6,277,829 discloses a process for the
preparation of an aqueous ophthalmic formulation containing
azithromycin which comprises the ophthalmically acceptable
polybasic phosphate in a concentration range from 7.8 to 68.6 g/l,
citric acid monohydrate in an amount ranging from 0.9 to 35.94 g/l,
and azithromycin in an amount ranging from 0.1 to 100 g/l, within a
temperature range from 15 to 25.degree. C., wherein the molar ratio
of azithromycin to citric acid is about 1:0.67 to 1:1.5; wherein pH
is adjusted to a value of 5.5-7.6, and up to a final osmolality
between about 130 to about 300 mOsm/Kg. However, these solutions
utilize phosphate buffer system comprising of phosphoric acid in
combination with a polymeric suspending agent with increased
residence time can be irritating to the eye. Additionally,
phosphate buffered system can promote fungus growth in the
formulation.
[0010] As such there remains a need for concentrated yet well
tolerated aqueous formulations of azalide antibiotics for topical
application.
[0011] All documents scientific and patent, cited herein are
incorporated by reference in their entirety.
SUMMARY OF THE DISCLOSURE
[0012] The present invention relates to aqueous formulations of
azalide antibiotics. Such formulations can be topically
administered to a variety of tissues either prophylactically or to
treat bacterial or parasitic infections of susceptible organisms.
Topical routes of administration include but are not limited to
oral, otic, ophthalmic, dermal, periodontal, vaginal, respiratory
and nasal.
[0013] The present invention includes and provides a topical
composition comprising water and an azalide antibiotic; wherein
said composition has a pH of about 6.0 to about 7.0. The present
invention also includes and provides an formulations comprising
about 0.1% to about 1.0% sodium chloride; about 0.1% to about 1.0%
citric acid; about 0.1% to about 2.0% sodium citrate, about 2% to
about 30.0% azithromycin, more preferably about 2% to about 20%,
most preferably about 2% to about 10% and even more preferably
about 2% to about 5%; wherein the composition has a pH of about 6.0
to about 7.0 or more preferably from a pH of about 6.0 to about
6.5, most preferably about 6.1 to about 6.4 and even more
preferably about 6.2 to about 6.3.
[0014] One aspect of the invention relates to a method of treating
an infection comprising administering to a patient in need thereof,
an effective amount of a concentrated aqueous azalide antibiotic
formulation made according to the method comprising dissolving an
azalide antibiotic in an aqueous solution comprising a strong acid.
In one embodiment the azalide antibiotic is azithromycin. In
another embodiment of this aspect of the invention, the aqueous
azalide antibiotic formulation has about 2% azithromycin. In a
further embodiment, the aqueous azalide antibiotic formulation has
about 3% azithromycin. In yet another embodiment, the aqueous
azalide antibiotic formulation has about 4% azithromycin. In still
another embodiment, the aqueous azalide antibiotic formulation has
about 5% azithromycin. In still a further embodiment, the strong
acid is hydrochloric acid. In yet a further embodiment, the aqueous
solution has a pH of about 5 to about 6. In still a further
embodiment, the pH is about 5.5 to about 6. In yet another
embodiment, the aqueous solution comprises citrate and citric acid.
In yet a further embodiment, the method further comprises the step
of adding to the aqueous solution a second solution comprising a
strong base. In another embodiment, the strong base is sodium
hydroxide. In still another embodiment, the second solution is
added in an amount sufficient to bring the combined solutions to a
pH from about 6 to about 7. In still another embodiment, the second
solution is added in an amount sufficient to bring the combined
solutions to a pH from about 6.2 to about 6.5. In still another
embodiment, the second solution is added in an amount sufficient to
bring the combined solutions to a pH from about 6.3. In yet a
further embodiment, the second solution comprises a polymeric
agent. In still a further embodiment, the polymeric agent is Noveon
AA-1. In another embodiment, the aqueous azalide antibiotic
formulation comprises an anti-inflammatory agent. In a further
embodiment, the anti-inflammatory agent is a dexamethasone. In yet
another embodiment, the dexamethasone is at a concentration of
about 0.1% and wherein the azalide antibiotic is azithromycin at a
concentration of about 3%. In another embodiment, the infection a
pulmonary infection, a nasopharyngeal infection, an otic infection,
an ocular infection, a dermal or a vaginal infection.
[0015] Another aspect of the invention relates to a method of
making a concentrated aqueous azalide antibiotic formulation
comprising dissolving an azalide antibiotic in an aqueous solution
comprising a strong acid according to the aforementioned
methods.
[0016] Yet another aspect of the invention relates to a topical
aqueous azalide antibiotic formulation made by the method
comprising dissolving an azalide antibiotic in an aqueous solution
comprising a strong acid according to the aforementioned
methods.
[0017] Another aspect of the invention relates to a method for
making an aqueous azalide antibiotic formulation comprising:
dissolving an azalide antibiotic in a first aqueous solution
comprising a strong acid and adding to the aqueous solution
comprising the azalide antibiotic a second solution comprising a
strong base in an amount sufficient to bring the pH of the aqueous
solution comprising the azalide antibiotic to about 6 to about 7,
to obtain an aqueous azalide antibiotic formulation. In one
embodiment of this aspect of the invention, the azalide antibiotic
is azithromycin. In another embodiment, the first aqueous solution
is buffered. In yet another embodiment, the first aqueous solution
comprises sodium citrate and citric acid. In still a further
embodiment, the second solution comprises a polymeric agent. In yet
another embodiment, the second aqueous solution comprises a
crosslinked carboxy-vinyl polymer. In still another embodiment, the
second solution comprises Noveon AA-1. In yet another embodiment,
the strong acid is hydrochloric acid. In yet a further embodiment,
the first aqueous solution has a pH of about 5 to about 6. In still
a further embodiment, the strong base is sodium hydroxide. In
another embodiment, the aqueous azalide antibiotic formulation has
about 2% to about 10% azithromycin. In yet a further embodiment,
the aqueous azalide antibiotic formulation has about 2% to about 5%
azithromycin. In another embodiment, the aqueous azalide antibiotic
formulation has a pH of about 6 to about 7. In a further
embodiment, the aqueous azalide antibiotic formulation has a pH of
about 6.2 to about 6.8. In yet a further embodiment, the aqueous
azalide antibiotic formulation has a pH of about 6.2 to about 6.5.
In still another embodiment, the aqueous azalide antibiotic
formulation has a pH of about 6.3. In still another embodiment, the
aqueous azalide antibiotic formulation has an osmolality of about
300 mOsm/kg. In still another embodiment, the aqueous azalide
antibiotic formulation comprises an anti-inflammatory agent. In yet
another embodiment, the anti-inflammatory agent is
dexamethasone.
[0018] Another aspect of the invention relates to a topical
antibiotic formulation comprising the aqueous azalide antibiotic
formulation made according to the method comprising dissolving an
azalide antibiotic in a first aqueous solution comprising a strong
acid and having a pH of about 6 and adding to the aqueous solution
comprising the azalide antibiotic a second solution comprising a
strong base in an amount sufficient to bring the pH of the aqueous
solution comprising the azalide antibiotic to about 6 to about 7,
to obtains an aqueous azalide antibiotic formulation. In one
embodiment of this aspect of the invention, the topical antibiotic
formulation is an otic formulation. In another embodiment, the
topical antibiotic formulation is an ophthalmic formulation. In
another embodiment, the topical antibiotic formulation is a nasal
formulation. In another embodiment, the topical antibiotic
formulation is a dermal formulation. In another embodiment, the
topical antibiotic formulation is a periodontal formulation. In
another embodiment, the topical antibiotic formulation is an
inhalational formulation. In another embodiment, the topical
antibiotic formulation is a vaginal formulation.
[0019] Another aspect of the invention relates to method of
treating an infection comprising administering to a patient in need
thereof, an effective amount of the aqueous azalide antibiotic
formulation made according to the methods disclosed herein. In one
embodiment of this aspect of the invention, the infection is an
otic infection. In another embodiment, the infection is an
ophthalmic infection. In another embodiment, the infection is a
nasopharyngeal infection. In another embodiment, the infection is a
dermal infection. In another embodiment, the infection is a
periodontal or oral infection. In another embodiment, the infection
is a vaginal infection. Yet in another embodiment, the infection is
a pulmonary infection.
[0020] Additional advantages of the present disclosure will become
readily apparent to those skilled in this art from the following
detailed description, wherein only the preferred embodiment of the
invention is shown and described, simply by way of illustration of
the best mode contemplated of carrying out the invention. As will
be realized, the invention is capable of other and different
embodiments, and its several details are capable of modifications
in various obvious respects, all without departing from the
invention. The present invention may be practiced without some or
all of these specific details. In other instances, well known
process operations have not been described in detail to avoid
unnecessarily obscure the present disclosure. Accordingly, the
description is to be regarded as illustrative in nature, and not as
restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Table 1 describes exemplary ophthalmic formulation
compositions with respect to the percentage of various formulation
components.
[0022] Table 2 describes exemplary otic formulation compositions
with respect to the percentage of various formulation
components.
[0023] Table 3 describes exemplary nasal formulation compositions
with respect to the percentage of various formulation
components.
[0024] Table 4 describes exemplary inhalation formulation
compositions with respect to the percentage of various formulation
components.
[0025] Table 5 describes exemplary dermal formulation compositions
with respect to the percentage of various formulation
components.
[0026] Table 6 describes exemplary periodontal formulation
compositions with respect to the percentage of various formulation
components.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0027] Azalides are a known subclass of macrolide antibiotics. For
the present invention and as used in this specification, an
"azalide antibiotic" means a derivitized erythromycin A structure
having a nitrogen atom inserted into the lactone ring. Additional
variations from the erythromycin structure are also embraced within
the term "azalide antibiotic." Such additional variations include
the conversion of a hydroxyl group to an alkoxy group, especially
methoxy (so-called "O-methylated" forms), for example at the 6
and/or 12 position. Such compounds are described in U.S. Pat. No.
5,250,518. Other variations relate to derivatives of the sugar
moieties, for example, 3' desmethoxy derivatives and the formation
of oxo or oxime groups on the sugar ring such as at the 4' position
as described in U.S. Pat. No. 5,441,939. This patent also teaches
that the adjacent hydroxyl groups at the 11 and 12 position of the
lactone ring can be replaced with a single carbonate or
thiocarbonate group. In short, an azalide antibiotic for purposes
of the present invention is any derivative of the erythromycin
structure that contains a 15-member lactone ring having a ring
nitrogen, preferably at the 9 position, and a sugar group attached
via a glycosidic bond to the lactone ring at the 5 position and at
the 3 position, and which still exhibits bacteriostatic or
bactericidal activity.
[0028] Preferred azalide antibiotics are represented by formula (I)
and pharmaceutically acceptable salts thereof.
##STR00001##
wherein R.sup.1 and R.sup.2 each independently represent a hydrogen
atom or methyl group.
[0029] Preferably at least one of R.sup.1 and R.sup.2 is a hydrogen
atom. Azithromycin, the common name for
N-methyl-1'-aza-10-deoxo-10-dihydroerythromycin, corresponds to the
compound of formula (I) where both R.sup.1 and R.sup.2 are hydrogen
atoms. Azithromycin was disclosed in U.S. Pat. Nos. 4,474,768 and
4,517,359, and is the most preferred azalide antibiotic. In
particular, the monohydrate form of azithromycin is especially
contemplated for use in the present invention, although other forms
are also suitable.
[0030] Azithromycin has been used as an oral antibiotic and is sold
worldwide under the brand name Zithromax.TM. by Pfizer Inc.
Azithromycin is a broad spectrum antibiotic that is generally more
effective in vitro than erythromycin. Moreover, because
azithromycin is an azalide and thus has a ring nitrogen atom, it
exhibits improved acid-stability, half-life, and cellular uptake in
comparison to erythromycin. The high uptake and retention of
azithromycin into cells, including phagocytic blood cells, allows
systemically administered azithromycin to be nonetheless
preferentially delivered to the site of the infection. The
mechanism has been reported to be as follows. The ingested
azithromycin is absorbed through the intestine into the blood
stream from which it enters most cells of the body including, inter
alia, the white blood cells. In response to an infection within the
body, white blood cells, including those containing azithromycin,
are attracted to the infectious site. When the white blood cells
die, the azithromycin is released. As more and more white blood
cells arrive at the infectious site and die, the concentration of
azithromycin in the surrounding tissue increases, eventually
surpassing the minimum inhibitory concentration (MIC). Once at the
infectious site, the azithromycin remains in the tissue for a
prolonged period of time. Due to its long half-life, an effective
concentration of azithromycin is present at the infected site for
many days after cessation of administration. While typically
administered via the oral route, Azalide antibiotics are also
amenable to topical and parenteral administrations.
[0031] One aspect of the invention relates to methods of preparing
a concentrated aqueous azalide antibiotic formulation. The process
generally involves dissolving an azalide antibiotic in a strongly
acidic aqueous and preferably a buffered solution, and then adding
a strong bases to the solution and adjusting the pH to about 6.0 to
about 7.0, more preferably from about 6.0 to about 6.6, more
preferably of about 6.2 to about 6.4, more preferably of about 6.25
to 6.35, and even more preferably about 6.3. Previously,
azithromycin antibiotics has been discovered to have a maximum
stability over a pH interval of about 6.0 to about 7.0, preferably
with a maximum at a pH of about 6.3 (See U.S. Pat. No. 7,056,893).
Given this teaching, the skilled artisan would have sought to avoid
pH ranges below 6 and above 7 when formulating aqueous formulations
of azalide antibiotics. However, it was surprisingly discovered
that concentrated aqueous azalide antibiotic formulations can be
made by dissolving the azalide antibiotic in a strong acid and then
bringing the pH to a range of about 6.0 to about 7.0 with a base.
Notwithstanding concerns that the strongly acidic conditions would
cause degradation of the azalide antibiotic, it was found that
dissolving azalide antibiotic in a strong acid and subsequent pH
adjustment did not have a deteriorative effect on the azalide
antibiotic.
[0032] The term "concentrated" aqueous azalide antibiotic
formulation refers to an aqueous solution of an azalide antibiotic
having a concentration of about 2%, about 3%, about 4%, about 5%,
about 6%, about 7%, about 8%, about 9%, 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%, about 25%, about 26% about 27%, about 28%, about 29% or about
30%. Preferably, the concentrated formulation is about 1% to about
30%, 2% to about 25%, about 2% to about 20%, more preferably about
2% to about 8%.
[0033] "Strong acid" as used herein refers to an acid that
dissociates completely in an aqueous solution (not in the case of
sulfuric acid as it is diprotic), or in other terms, with of about
pKa<-1.74. This generally means that in aqueous solution at
standard temperature and pressure, the concentration of hydronium
ions is equal to the concentration of strong acid introduced to the
solution. The preferred strong acids include but are not limited to
sulfuric, acetic, nitric, and perchloric acids. The most preferred
strong acid is hydrochloric acid.
[0034] "Strong base" as used herein refers to a basic chemical
compound that is able to deprotonate very weak acids in an
acid-base reaction. Preferably, such compounds have a pKa of more
than about 13. Common examples of strong bases are the hydroxides
of alkali metals and alkaline earth metals like NaOH. Very strong
bases are even able to deprotonate very weakly acidic C--H groups
in the absence of water. Strong bases include but are not limited
to potassium hydroxide, barium hydroxide, cesium hydroxide, sodium
hydroxide, strontium hydroxide, lithium hydroxide and rubidium
hydroxide. The preferred strong base is NaOH.
[0035] Although azithromycin can reach many of tissues by oral
administration, it has been discovered that azalide antibiotics in
general and azithromycin in particular are amenable to topical
administration. U.S. Pat. Nos. 6,239,113, 6,569,443, 7,056,893, all
of which are incorporated by reference in their entirety.
[0036] "Topical administration" refers to a route of administration
which is the path by which the azalide antibiotic is brought into
contact with the body. Preferably, in topical administration the
effect of the azalide antibiotic is local and the composition is
applied directly where its action is desired. Topical application
is application directly to superficial tissues such as for example
in tact or compromised skin (epicutaneous/dermal), tissues of the
mouth (buccal/periodontal), airway and lungs (inhalation), rectal
(by enema), eye (ocular), ear (otic), nose (intranasal), and vagina
(vaginal). Preferably, topical application is to mucous membrane,
also called mucosa, lining all body passages that communicate with
the exterior such as the respiratory, genitourinary, and alimentary
tracts, and having cells and associated glands that secrete
mucus.
[0037] A multitude of appropriate topical formulations can be found
in the formulary known to all pharmaceutical chemists: Blaug, S.,
Ch. 87 in Remington's Pharmaceutical Sciences (15th Ed., 1975, Mack
Publishing Company, Easton, Pa. 18042). These compositions include
for example, powders, pastes, ointments, jelly, waxes, oils,
lipids, anhydrous absorption bases, oil-in-water or water-in-oil
emulsions, emulsions carbowax (polyethylene glycols of a variety of
molecular weights), semi-solid gels, and semi-solid mixtures
containing carbowax. Preferred formulations of the invention are
concentrated aqueous azalide antibiotic for otic, dermal,
ophthalmic, nasal, pulmonary, vaginal or periodontal
administration.
[0038] The preferred formulations of the invention may be
formulated as drops, sprays, ointments, creams, lotions, gels,
emulsions or other aqueous solutions or dispersions. Preferably,
the primary vehicle is water or a biocompatible solvent that is
substantially neutral or that has been rendered substantially
neutral. The liquid vehicle can include other materials, such as
alcohols, glycerin, polyethylene glycol, and mineral oils with
various emulsifiers or dispersing agents as known in the art to
obtain the desired pH, consistency and viscosity. In a further
embodiment, the composition is an irrigating solution for use in a
process of irrigating a surgical site.
[0039] The amount of azalide antibiotic topically supplied is
preferably effective to treat or prevent infection in a superficial
tissue. This means that the conditions of application result in a
retardation or suppression of the infection. Typically at least
about MIC.sub.90 for the targeted bacteria or parasite is delivered
to the target tissue by the topical application of an effective
amount. More concretely, the concentration within the tissue is
desired to be at least about 1 .mu.g/g, preferably at least about
10 .mu.g/g, and more preferably at least about 20 .mu.g/g. The
amount of azalide actually applied to the tissue surface will
almost always be higher than the tissue concentration. This
reflects the permeability of the azalide antibiotic through the
outer layers of the tissue and that penetration is, to some extent,
concentration gradient. Thus, applying greater amounts to the
exterior will drive more antibiotic into the tissues. Delivery of
formulations as a depot will advantageously maintain the
concentration of the azalide antibiotic in the affected tissues at
or above the MIC.sub.90 for a period of at least about 2 hours, or
more preferably at least about 4 hours, more preferably at least
about 8 hours, or more preferably at least about 12 hours and more
preferably at least 18 hours.
[0040] Where a series of applications are typically employed in a
topical administration dosing regimen, it is possible that one or
more of the earlier applications will not achieve an effective
concentration in the tissue, but that a later application in the
regimen will achieve an effective concentration. This is
contemplated as being within the scope of topically applying an
azalide antibiotic in an effective amount.
[0041] The concentration of azalide antibiotic present in the
inventive formulations depends upon the dosage form, the release
rate, the dosing regimen, and the location and type of infection.
Generally speaking, the concentration is from about 2% to about
12.0% although it is possible to prepare and utilize formulations
with higher concentrations of azalide antibiotics such as 15%, 20%,
25% or even about 30%. In one embodiment of the invention, the
concentration is about 2% to about 20%. In another embodiment of
the invention, the concentration is about 2% to about 10%. In
another embodiment of the invention, the concentration is about 2%
to about 5%. In another embodiment of the invention, the
concentration is about 2% to about 3%. In another embodiment of the
invention, the concentration is about 2% to about 2.5%.
[0042] Azalide antibiotic formulations of this invention suitable
for topical administration may include one or more
"pharmaceutically acceptable carriers," such as for example an
otically, ophthalmically, dermally, nasally, pulmonary, vaginally
or buccally acceptable carrier. Typically the pharmaceutically
acceptable carriers are aqueous-based solution or suspension.
Generally, azalide antibiotics are poorly soluble in water.
However, the methods disclosed herein overcome this problem and
allow for the preparation of concentrated azalide antibiotic
formulations.
[0043] The aqueous formulations (solutions or suspensions) for use
in the present invention preferably use water that has no
physiologically harmful constituents. Typically purified or
deionized water is used. The pH is adjusted by adding any
physiologically and acceptable pH adjusting acids, bases, or
buffers to within the range of about 5.0 to about 7.0, more
preferably from about 5.8 to about 6.8, more preferably about 6.0
to about 6.5, more preferably at a pH of about 6.2 to about 6.4,
more preferably about 6.25 to about 6.35, or even more preferably
about 6.3. Any of the aforementioned ranges can be used with any of
the formulations of the present invention, including, without
limitation. Examples of acids include acetic, boric, citric,
lactic, hydrochloric, and the like, and examples of bases include
potassium hydroxide, sodium hydroxide, sodium borate, sodium
citrate, sodium acetate, sodium lactate, tromethamine, THAM
(trishydroxymethylamino-methane), and the like. Salts and buffers
include but are not limited to citrate/dextrose, sodium
bicarbonate, ammonium chloride and mixtures of the aforementioned
acids and bases. The pH is preferably adjusted by adding sodium
hydroxide. The preferred buffer is citric acid and amounts of
citric acid of about 0.01% to about 5% by weight, preferably about
0.05% to about 0.4% by weight, based on the total weight of the
composition, are typically used.
[0044] The formulations of the present invention suitable for
topical administration, including both ointments and suspensions,
have a viscosity that is suited for the selected route of
administration. Such viscosity enhancing agents include, for
example, polyvinyl alcohol, polyvinyl pyrrolidone, povidone,
polyethylene glycol, Carbomer 940/934P, methyl cellulose,
hydroxypropyl methylcellulose, hydroxyethyl cellulose,
carboxymethyl cellulose. The azalide antibiotic formulations of the
instant invention containing aqueous polymeric suspensions may be
formulated so that they retain the same or substantially the same
viscosity that they had prior to administration to the tissue.
Alternatively, in preferred embodiments for they may be formulated
so that there is increased gelation upon contact with a superficial
tissue or bodily fluid, e.g., tears.
[0045] The osmotic pressure (t) of the aqueous composition of this
invention is generally from about 10 milliosmolar (mOsM) to about
400 mOsM, more preferably from about 260 to about 340 mOsM and most
preferably about 280 to about 320 or about 300 mOsM. If necessary,
the osmotic pressure can be adjusted by using appropriate amounts
of physiologically acceptable salts or excipients. Sodium chloride
is preferred to approximate physiologic fluid, and amounts of
sodium chloride from about 0.01% to about 0.9% by weight, and
preferably from about 0.1% to about 0.9% by weight, and more
preferably about 0.2% to about 0.5% by weight based on the total
weight of the composition, are typically used. Equivalent amounts
of one or more salts made up of cations such as potassium, ammonium
and the like and anions such as chloride, citrate, ascorbate,
borate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium
bisulfate, ammonium sulfate, and the like can also be used in
addition to or instead of sodium chloride to achieve osmolalities
within the above-stated range. Similarly, a sugar such as mannitol,
dextrose, sorbitol, glucose and the like can also be used to adjust
osmolality.
[0046] The solubility of the components of the present formulations
may also be enhanced by a surfactant or other appropriate
co-solvent in the composition or solubility enhancing agents like
cyclodextrins such as hydroxypropyl, hydroxyethyl, glucosyl,
maltosyl and maltotriosyl derivatives of alpha-, beta-, and
gamma-cyclodextrin. A particularly preferred solubility enhancer is
hydroxypropyl-beta cyclodextrin (HPBC). In one embodiment, the
composition comprises 0.1% to 20% hydroxypropyl-beta-cyclodextrin,
more preferably 1% to 15% hydroxypropyl-beta-cyclodextrin, and even
more preferably from 2.5% to 10% hydroxypropyl-beta-cyclodextrin.
Co-solvents include polysorbates (for example, polysorbate 20, 60,
and 80), polyoxyethylene/polyoxypropylene surfactants (e.g.,
Pluronic F-68, F 84 and P-103), cyclodextrin, fatty-acid
glycerol-polyethylene glycol esters, other solubilizing agents such
as Octoxynol 40, Tyloxapol and Pluronics, or other agents known to
those skilled in the art and mixtures thereof. The amount of
solubility enhancer used will depend on the amount of azalide
antibiotic in the composition, with more solubility enhancer used
for greater amounts of azalides. Typically solubility enhancers are
employed at a level of from 0.01% to 20% by weight depending on the
ingredient. Preferable ranges are 1% to 5% and 0.1% to 2%. Wetting
agents include polyvinyl pyrolidone, polyvinyl alcohol,
polyethylene glycol. The solubilizing agents may help keep the
other components of the topical composition in solution, including
the azalide antibiotic in solution. The wetting agent helps the
formulation to spread over the tissue.
[0047] If necessary, free divalent metal ions may be removed from
the solution by using appropriate amounts of a chelating agent.
EDTA disodium is preferred to remove excess free metal ions. Citric
acid is another preferred chelating agent. The amounts of citric
acid of about 0.01% to about 1% by weight, preferably about 0.05%
to about 0.5% by weight, and more preferably about 0.1% to about
0.2% by weight based on the total weight of the composition, are
typically used. In addition to EDTA and citric acid, other
chelating agents including organic phosphonic acids such as Dequest
2060 may also be employed. Useful phosphonic include, but are not
limited to diethylene triamine penta(methylene-phosphonic acid) and
the like which are commercially available from Monsanto under the
DEQUEST brand name.
[0048] The inventive formulations may contain one or more of the
following: surfactants, adjuvants including additional medicaments,
buffers, antioxidants, tonicity adjusters, preservatives,
thickeners or viscosity modifiers, and the like. Additives in the
formulation may include sodium chloride, EDTA (disodium edetate),
and/or BAK (benzalkonium chloride), sorbic acid, methyl paraben,
propyl paraben, chlorhexidine, and sodium perborate. Suitable
preservatives also include: polyquaternium-1, thimerosal,
chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,
sorbic acid, or other agents known to those skilled in the art.
Typically such preservatives are employed at a level of from 0.001%
to 1.0% by weight.
[0049] The formulations of this invention may also advantageously
employ one or more stabilizing agents including antioxidants.
Useful antioxidants include but are not limited to sodium
bisulfate, butylated hydroxy toluene (BHT), thiourea, and sodium
formaldehyde sulfoxylate.
[0050] Preferably, the formulations of the present invention should
also achieve a sufficiently high tissue concentration with a
minimum number of doses so that a simple dosing regimen can be used
to treat or prevent bacterial or parasitic infections. To this end,
a preferred technique involves forming or supplying a depot of
azalide antibiotic in contact with the superficial tissue. A depot
refers to a source of azalide antibiotic that is not rapidly
removed by the physiologic clearance mechanisms, e.g., tears,
saliva, mucous. This allows for continued, sustained high
concentrations of azalide antibiotic to be present in the fluid on
the surfaces of the tissue by a single application. In general, it
is believed that absorption is dependent on both the dissolved drug
concentration and the contact duration of the external tissue with
the drug-containing fluid. As the drug is removed by clearance of
the fluid and/or absorption into the tissue, more drug is provided,
e.g. dissolved, into the replenished fluid from the depot.
[0051] Accordingly, the use of a depot more easily facilitates
loading of the tissue in view of the typically slow and low
penetration rate of the generally or poorly soluble azalide
antibiotics. The depot, which retains a bolus of concentrated drug,
can effectively slowly "pump" the azalide antibiotic into the
tissue. As the azalide antibiotic penetrates the tissue, it is
accumulated therein and not readily removed due to its long
half-life. As more azalide antibiotic is "pumped" in, the tissue
concentration increases and the minimum inhibitory concentration
threshold is eventually reached or exceeded, thereby loading the
tissue with azalide antibiotic. By significantly exceeding the
MIC.sub.50, more preferably the MIC.sub.90 level, provided the
toxicity limit is not exceeded, a therapeutically effective
concentration will remain active in the tissue for an extended
period of time due to the low clearance rate of the azalide
antibiotic from the tissue. Thus, depending on the depot, one or
two applications may provide a complete dosing regimen. Indeed,
such a simple dosing regimen may provide a 6 to 14 day treatment
concentration within the ocular tissue. A preferred dosing regimen
involves one to two doses per day over a one to three day period,
more preferably one or two doses in a single day, to provide in
vivo at least a 6 day treatment and more typically a 6 to 14 day
treatment.
[0052] A depot can take a variety of forms so long as the azalide
antibiotic can be provided in sufficient concentration levels
therein and is releasable therefrom, and that the depot is not
readily removed from the tissue. A depot generally remains for at
least about 30 minutes after administration, preferably at least 2
hours, and more preferably at least 4 hours. The term "remains"
means that neither the depot composition nor the azalide antibiotic
is exhausted or cleared from the tissue prior to the indicated
time. In some embodiments, the depot can remain for up to eight
hours or more. Typical ophthalmic depot forms include aqueous
polymeric suspensions, ointments, and solid inserts. Polymeric
suspensions are the most preferred form for the present
invention.
[0053] A preferred form of the azalide formulations for
administration of azalide antibiotics to the ocular, nasal,
pulmonary, periocular, dermal, buccal, vaginal or otic tissues is
an aqueous polymeric suspension. Here, at least one of the azalide
antibiotic or the polymeric suspending agent is suspended in an
aqueous medium having the properties as described above. The
azalide antibiotic may be in suspension, although in the preferred
pH ranges the azalide antibiotic will be in solution (water
soluble), or both in solution and in suspension. It is possible for
significant amounts of the azalide antibiotic to be present in
suspension. The polymeric suspending agent is preferably in
suspension (i.e. water insoluble and/or water swellable), although
water soluble suspending agents are also suitable for use with a
suspension of the azalide antibiotic. The suspending agent serves
to provide stability to the suspension and to increase the
residence time of the dosage form on the tissue. It can also
enhance the sustained release of the drug in terms of both longer
release times and a more uniform release profile.
[0054] Examples of polymeric suspending agents include dextrans,
polyethylene glycols, polyvinylpyrolidone, polysaccharide gels,
Gelrite.TM., cellulosic polymers like hydroxypropyl
methylcellulose, and carboxy-containing polymers such as polymers
or copolymers of acrylic acid, as well as other polymeric
demulcents. A preferred polymeric suspending agent is a water
swellable, water insoluble polymer, especially a crosslinked
carboxy-containing polymer.
[0055] Crosslinked carboxy-containing polymers used in practicing
this invention are, in general, well known in the art. In a
preferred embodiment such polymers may be prepared from at least
about 90%, and preferably from about 95% to about 99.9% by weight,
based on the total weight of monomers present, of one or more
carboxy-containing monoethylenically unsaturated monomers (also
occasionally referred to herein as carboxy-vinyl polymers). Acrylic
acid is the preferred carboxy-containing monoethylenically
unsaturated monomer, but other unsaturated, polymerizable
carboxy-containing monomers, such as methacrylic acid, ethacrylic
acid, .beta.-methylacrylic acid (crotonic acid),
cis-.alpha.-methylcrotonic acid (angelic acid),
trans-.alpha.-methylcrotonic acid (tiglic acid),
.alpha.-butylcrotonic acid, .alpha.-phenylacrylic acid,
.alpha.-benzylacrylic acid, .alpha.-cyclohexylacrylic acid,
.beta.-phenylacrylicacid (cinnamic acid), coumaric acid
(o-hydroxycinnamic acid), umbellic acid (p-hydroxycoumaric acid),
and the like can be used in addition to or instead of acrylic
acid.
[0056] Such polymers may be crosslinked by a polyfunctional
crosslinking agent, preferably a difunctional crosslinking agent.
The amount of crosslinking should be sufficient to form insoluble
polymer particles, but not so great as to unduly interfere with
sustained release of the azalide antibiotic. Typically the polymers
are only lightly crosslinked. Preferably the crosslinking agent is
contained in an amount of from about 0.01% to about 5%, preferably
from about 0.1% to about 5.0%, and more preferably from about 0.2%
to about 1%, based on the total weight of monomers present.
Included among such crosslinking agents are non-polyalkenyl
polyether difunctional crosslinking monomers such as divinyl
glycol; 2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene;
divinylbenzene; N,N-diallylacrylamide; N,N-diallymethacrylamide and
the like. Also included are polyalkenyl polyether crosslinking
agents containing two or more alkenyl ether groupings per molecule,
preferably alkenyl ether groupings containing terminal
H.sub.2C.dbd.C<groups, prepared by etherifying a polyhydric
alcohol containing at least four carbon atoms and at least three
hydroxyl groups with an alkenyl halide such as allyl bromide or the
like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the
like; see, e.g., Brown U.S. Pat. No. 2,798,053, the entire contents
of which are incorporated herein by reference. Diolefinic
non-hydrophilic macromeric crosslinking agents having molecular
weights of from about 400 to about 8,000, such as insoluble di- and
polyacrylates and methacrylates of diols and polyols,
diisocyanate-hydroxyalkyl acrylate or methacrylate reaction
products of isocyanate terminated prepolymers derived from
polyester diols, polyether diols or polysiloxane diols with
hydroxyalkylmethacrylates, and the like, can also be used as the
crosslinking agents; see Mueller et al. U.S. Pat. Nos. 4,192,827
and 4,136,250, the entire contents of each patent being
incorporated herein by reference.
[0057] The crosslinked carboxy-vinyl polymers may be made from a
carboxy-vinyl monomer or monomers as the sole monoethylenically
unsaturated monomer present, together with a crosslinking agent or
agents. Preferably the polymers are ones in which up to about 40%,
and preferably from about 0% to about 20% by weight, of the
carboxy-containing monoethylenically unsaturated monomer or
monomers has been replaced by one or more non-carboxyl-containing
monoethylenically unsaturated monomer or monomers containing only
physiologically and ophthalmically innocuous substituents,
including acrylic and methacrylic acid esters such as methyl
methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate,
octyl methacrylate, 2-hydroxyethyl-methacrylate,
3-hydroxypropylacrylate, and the like, vinyl acetate,
N-vinylpyrrolidone, and the like; see Mueller et al. U.S. Pat. No.
4,548,990 for a more extensive listing of such additional
monoethylenically unsaturated monomers.
[0058] Particularly preferred polymers are lightly crosslinked
acrylic acid polymers wherein the crosslinking monomer is
2,3-dihydroxyhexa-1,5-diene or 2,3-dimethylhexa-1,5-diene.
Preferred commercially available polymers include polycarbophil
(Noveon AA-1) and Carbopol.TM.. Most preferably, a
carboxy-containing polymer system known by the tradename
DuraSite.RTM., containing polycarbophil, which is a sustained
release topical delivery system is used in the aqueous polymeric
suspension composition of the present invention.
[0059] The crosslinked carboxy-vinyl polymers used in practicing
this invention are preferably prepared by suspension or emulsion
polymerizing the monomers, using conventional free radical
polymerization catalysts, to a dry particle size of not more than
about 25 .mu.m in equivalent spherical diameter; i.e., to provide
dry polymer particles ranging in size from about 1 to about 25
.mu.m, preferably from about 3 to about 20 .mu.m, and more
preferably 1 .mu.m to 10 .mu.m in equivalent spherical diameter. In
general, such polymers will have a molecular weight which has been
variously reported as being from about 250,000 to about 4,000,000,
and from 3,000,000,000 to 4,000,000,000. Using polymer particles
that were obtained by mechanically milling larger polymer particles
to this size is preferably avoided.
[0060] In a more preferred embodiment of the invention for topical
administration, the particles of crosslinked carboxy-vinyl polymer
are monodisperse, meaning that they have a dry particle size
distribution such that at least 80% of the particles fall within a
10 .mu.m band of major particle size distribution. More preferably,
at least 90% and most preferably at least 95%, of the particles
fall within a 10 .mu.m band of major particle size distribution.
Also, a monodisperse particle size means that there is no more than
20%, preferably no more than 10%, and most preferably no more than
5% particles of a size below 1 .mu.m. The use of monodispersed
particles will give maximum viscosity and an increased eye
residence time of the ophthalmic medicament delivery system for a
given particle size. Monodisperse particles having a dry particle
size of 10 .mu.m and below are most preferred. Good particle
packing is aided by a narrow particle size distribution.
[0061] The aqueous polymeric suspension normally contains azalide
antibiotics in an amount from about 0.05% to about 25%, preferably
about 0.1% to about 20%, more preferably about 0.5% to about 15%,
more preferably about 1% to about 12%, more preferably about 2% to
about 10.0%, and polymeric suspending agent in an amount from about
0.05% to about 10%, preferably about 0.1% to about 5% and more
preferably from about 0.1% to about 1.0% polymeric suspending
agent. In the case of the above described water insoluble,
water-swellable crosslinked carboxy-vinyl polymer, another
preferred amount of the polymeric suspending agent is an amount
from about 0.5% to about 2.0%, preferably from about 0.5% to about
1.2%, and in certain embodiments from about 0.5% to about 1.0%,
based on the weight of the composition. Although referred to in the
singular, it should be understood that one or 25 more species of
polymeric suspending agent, such as the crosslinked
carboxy-containing polymer, can be used with the total amount
falling within the stated ranges. In one preferred embodiment, the
composition contains about 0.5% to about 1.0% of the polymeric
suspending agent such as Noveon AA-1 (polycarbophil).
[0062] In one embodiment, the amount of insoluble lightly
crosslinked carboxy-vinyl polymer particles, the pH, and the
osmolality can be correlated with each other and with the degree of
crosslinking to give a composition having a viscosity in the range
of from about 50 to about 100,000 centipoise, and preferably from
about 1,000 to about 30,000 or about 1,000 to about 10,000
centipoise, as measured at room temperature (about 25.degree. C.)
using a Brookfield Digital LVT Viscometer equipped with a number 25
spindle and a 13R small sample adapter at 12 rpm (Brookfield
Engineering Laboratories Inc.; Middleboro, Mass.). Alternatively,
when the viscosity is within the range of 500 to 3000 centipoise,
it may be determined by a Brookfield Model DV-11+, choosing a
number cp-52 spindle at 6 rpm.
[0063] When water soluble polymers are used as the suspending
agent, such as hydroxypropyl methylcellulose, the viscosity will
typically be about 10 to about 400 centipoise, more typically about
10 to about 200 centipoises or about 10 to about 25 centipoise.
[0064] A further aspect of the present invention involves the use
of additional medicaments in combination with the azalide
antibiotic. A composition comprising a concentrated azalide
antibiotic, an additional medicament, and a pharmaceutically
acceptable carrier can advantageously simplify administration and
allow for treating or preventing multiple conditions or symptoms
simultaneously. The "additional medicaments," which can be present
in any of the compositional forms described herein including fluid
and solid forms, are pharmaceutically active compounds having
efficacy in topical applications and which are compatible with an
azalide antibiotic and with the particular target tissue.
Typically, the additional medicaments include other antibiotics (an
antibiotic that is different than an azalide antibiotic),
antivirals, antifungals, anesthetics, anti-inflammatory agents,
including steroidal and non-steroidal anti-inflammatories, and
anti-allergic agents.
[0065] Examples of suitable medicaments include aminoglycosides
such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin,
and kanamycin; fluoroquinolones such as gatifloxacin, moxifloxacin,
ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,
levofloxacin, and telithromycin, enoxacin; naphthyridine;
sulfonamides; polymyxin; chloramphenicol; neomycin; paramomomycin;
colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and
its derivatives ("rifampins"); cycloserine; beta-lactams;
cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;
miconazole; ketoconazole; corticosteroids; diclofenac;
flurbiprofen; ketorolac; suprofen; comolyn; lodoxamide;
levocabastin; naphazoling; antazoline; and pheniramimane. These
other medicaments are generally present in a pharmaceutically
effective amount as is understood by workers of ordinary skill in
the art. These amounts are generally within the range of from about
0.01 to 5%, more typically 0.1 to 2%, for fluid formulations and
from 0.5 to 50% for solid dosage forms.
[0066] The steroidal anti-inflammatory agents of the present
invention include glucocorticoids, such as dexamethasone,
loteprednol, rimexolone, prednisolone, prednisolone acetate,
fluticasone propionate, busesonide, triamcinolone, beclomethasone,
mometasone furoate, fluorometholone, and hydrocortisone.
Dexamethasone derivatives such as U.S. Pat. No. 5,223,493, herein
incorporated by reference, may also be used. Particular compounds
include "21-ether derivatives of dexamethasone", such as a
21-benzyl ether derivatives of dexamethasone."
[0067] The preferred non-steroidal anti-inflammatory agents are:
diclofenac, flurbiprofen, ketorolac, and suprofen. Other
non-steroidal anti-inflammatory agents useable in the present
invention include: prostaglandin H synthetase inhibitors (Cox I or
Cox II), also referred to as cyclooxygenase type I and type II
inhibitors, such as nepafenac, amfenac, indomethacin, naproxen,
ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam,
sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin,
fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone,
aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456,
tenoxicam and carprofen; cyclooxygenase type II selective
inhibitors, such as NS-398, vioxx, celecoxib, P54, etodolac,
L-804600 and S-33516; PAF antagonists, such as SR-27417, A-137491,
ABT-299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant
and modipafant; PDE IV inhibitors, such as ariflo, torbafylline,
rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-11294A,
CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636,
BAY-19-8004, and roflumilast; inhibitors of cytokine production,
such as inhibitors of the NFkB transcription factor; or other
anti-inflammatory agents known to those skilled in the art.
[0068] The concentrations of the anti-inflammatory agents contained
in the formulations of the present invention will vary based on the
agent or agents selected and the type of inflammation being
treated. The concentrations will be sufficient to reduce
inflammation in the targeted tissues following topical application
of the formulations to those tissues. Such an amount is referred to
herein as "an anti-inflammatory effective amount". The formulations
of the present invention may contain one or more anti-inflammatory
agents in an amount of from about 0.01 to about 5% or in a range of
from about 0.1 to about 2%, as discussed above for the additional
medicaments, or in a range of from about 0.01 to about 1.0 wt
%.
[0069] The concentrated azalide antibiotic formulations of the
instant invention are preferably formulated for administration via
topical administration. The formulations can be administered to
humans and a variety of non-human animals, the latter including but
not limited to cows, sheep, horses, pigs, goats, rabbits, dogs,
cats, and other mammals.
1. Otic Formulations
[0070] Examples of otic conditions that may be treated with the
formulations of the present invention include otitis externa and
otitis media, ear inflammation, ear infections and ear trauma.
Examples of bacteria believed to act as pathogens in acute otitis
externa infections include "corneforms" or "idphtheroids". They
have previously been identified as being present both in healthy
ears and in ears afflicted with acute otitis externa
infections.
[0071] With respect to the treatment of otitis media, the
formulations of the present invention may be useful in cases where
the tympanic membrane has ruptured or tympanostomy tubes have been
implanted. The formulations may also be used to treat infections
associated with otic surgical procedures, such as tympanostomy, or
to prevent such infections which is acute otitis media with a
tympanostomy tube (AOMT). Additionally, the formulations and
methods of the present invention may be useful in the treatment of
acute infections of the external ear canal, which are commonly
referred to as "acute otitis externa" or "AOE". The antibiotics
utilized in the present invention have a high level of
antimicrobial activity against otic pathogens, and therefore may be
useful in the treatment of acute otitis externa infections
involving these pathogens.
[0072] The azalide antibiotic can be supplied to otic tissue in a
variety of ways, including as an aqueous otic solution or
suspension. Any delivery technique and any topical otic composition
containing a dosage form that supplies an azalide antibiotic to
otic tissues is included within the notion of topically applying,
although the external surface of the ear is typically the ear
canal.
[0073] The prevention of infection preferably includes
pre-operative treatment prior to surgery as well as other suspected
infectious conditions or contact, for example. Examples of
prophylaxis situations include treatment prior to surgical
procedures and other operative procedures involving ear trauma or
ear damage. Topical application of azalide antibiotic can be used
to treat acute otitis externa and acute otitis media with a
tympanostomy.
[0074] Generally, the inventive azalide antibiotic formulations can
be used to treat or prevent infections caused by a variety of
bacteria or parasites, including but not limited to one or more of
the following organisms: Staphylococcus including Staphylococcus
aureus and Staphylococcus epidermidis; Streptococcus including
Streptococcus pneumoniae and Streptococcus pyogenes as well as
Streptococci of Groups C, F, and G and Viridans group of
Streptococci; Haemophilus influenza including biotype III (H.
Aegyptius); Haemophilus ducreyi; Moraxella catarrhalis; Neisseria
including Neisseria gonorrhoeae and Neisseria meningitidis;
Chlamydia including Chlamydia trachomatis, Chlamydia psittaci, and
Chlamydia pneumoniae; Mycobacterium including Mycobacterium
tuberculosis and Mycobacterium avium-intracellular complex as well
as a typical mycobacterium including M. marinum, M. fortuitm, and
M. chelonae; Bordetella pertussis; Campylobacter jejuni; Legionella
pneumophila; Bacteroides bivius; Clostridium perfringens;
Peptostreptococcus species; Borrelia burgdorferi; Mycoplasma
pneumoniae; Treponema pallidum; Ureaplasma urealyticum; toxoplasma;
malaria; and nosema.
[0075] For otic formulations, a viscosity in the range of from
about 10 to 1000 centipoise is useful for a drop. Preferably about
50 to about 500 centipoise, more preferably about 50 to about 400
and most preferably about 50 to about 150 centipoise. The use of
viscosity enhancing agents to provide the formulations of the
invention with viscosities greater than the viscosity of simple
aqueous solutions may be desirable to increase absorption of the
active compounds by the target tissues or to increase the retention
time in the ear, for example.
[0076] Aqueous polymeric suspensions of the present invention may
be formulated so that they retain the same or substantially the
same viscosity before and after administration. Because of the
higher viscosity of the formulation, the administered dose is
retained at the affected site for a longer period of time. This
affords the azalide antibiotic to be released into the affected
tissue over a longer period of time. All these events eventually
lead to increased patient comfort and increased azalide antibiotic
contact time with the tissues, thereby increasing the extent of
drug absorption and duration of action of the formulation.
[0077] The agents contained in these drug delivery systems will be
released from the gels at rates that depend on such factors as the
molecular weight of the drug, its ionization state, the extent of
drug loading and the pH of the system, as well as on any drug
delivery adjuvants, such as ion exchange resins compatible with the
otic surface, which may also be present.
[0078] The preferred otic azalide formulations disclosed herein are
preferably used to treat Otitis Media. The ideal otic formulations
should be formulated with a viscosity that is reasonably high to
render acceptable residence time at the site of action but at the
same time sufficiently low to allow the formulation to penetrate
through a tympanic tube upon administration. The preferred
concentration of Noveon AA-1 is about 0.5% to about 0.9% to
maintain the viscosity in the optimal range. The formulations
preferably use a citrate buffer and optionally contain
DuraSite.RTM. as the delivery vehicle. The preferred formulations
have about 2%, about 3% about 4% and about 5% Azithromycin.
Moreover, the preferred otic formulations contain an
anti-inflammatory agent such as dexamethasone. In this case the
preferred anti-inflammatory agent is dexamethasone in the range of
0.01 to 1%. In addition to Azithromycin content, the preferred
formulations have a pH of about 6 to about 7, preferably about 6.8
to about 6.2 and most preferably 6.3.+-.0.1; osmolality of about
250 to about 330 mOsm/kg, preferably about 270 to about 330 mOsm/kg
and most preferably about 300 mOsm/kg, and viscosity of about 10 to
about 200 cps, preferably about 50 to about 150 and most preferably
about 70 to about 130 cps.
2. Ocular Formulations
[0079] Any delivery technique and ocular dosage form that applies
an azalide antibiotic to the external eye surface is included
within the definition of "topically applying." Although the
external surface of the eye is typically the outer layer of the
conjunctiva, it is possible that the sclera, cornea, or other
ocular tissue could be exposed such as by rotation of the eye or by
surgical procedure, and thus be an external surface. For the
purposes of this application, periocular tissues are defined as
those tissues in contact with the lachrymal secretions, including
the inner surface of the eye lid, the tissues of the orbit
surrounding the eye, and the tissues and ducts of the lachrymal
gland.
[0080] Generally a single application, such as one or two drops,
provides a therapeutically effective concentration (i.e. one that
retards or suppresses the infection) of the azalide antibiotic
within a tissue. Indeed, although dependent on the amount and form
of the ophthalmic composition, a single application will typically
provide a therapeutically effective amount of the azalide
antibiotic within a tissue for at least about 2, more preferably
about 4, more preferably about 8, more preferably about 12, and
more preferably at least about 18 hours.
[0081] Azalide antibiotic formulations of this invention can be
used to treat or prevent a variety of conditions associated with
ocular infection. For example, conditions of the eyelids, including
blepharitis, blepharconjunctivies, meibomianitis, acute or chronic
hordeolum, chalazion, dacryocystitis, dacryoadenities, and acne
rosacea; conditions of the conjunctiva, including conjunctivitis,
ophthalmia neonatorum, and trachoma; conditions of the cornea,
including corneal ulcers, superficial and interstitial keratitis,
keratoconjunctivitis, foreign bodies, and post operative
infections; and conditions of the anterior chamber and uvea,
including endophthalmitis, infectious uveitis, and post operative
infections, are a few of the tissues and conditions that can be
treated by topical application of an azalide antibiotic. The
prevention of infection includes pre-operative treatment prior to
surgery as well as other suspected infectious conditions or
contact. Examples of prophylaxis situations include treatment prior
to surgical procedures such as blepharoplasty, removal of chalazia,
tarsorrhapy, procedures for the canualiculi and lacrimal drainage
system and other operative procedures involving the lids and
lacrimal apparatus; conjunctival surgery including removal of
ptyregia, pingueculae and tumors, conjunctival transplantation,
traumatic lesions such as cuts, burns and abrasions, and
conjunctival flaps; corneal surgery including removal of foreign
bodies, keratotomy, and corneal transplants; refractive surgery
including photorefractive procedures; glaucoma surgery including
filtering blebs; paracentesis of the anterior chamber; iridectomy;
cataract surgery; retinal surgery; and procedures involving the
extra-ocular muscles. The prevention of ophthalmia neonatorum is
also envisaged.
[0082] About 30,000 to about 100,000 centipoise is an advantageous
viscosity range for ophthalmic administration in ribbon form.
Alternatively, a viscosity in the range of from about 1,000 to
30,000 centipoise is useful for a drop. Preferably about 1200 to
about 20,000 centipoise, more preferably about 1500 to about 10,000
and most preferably about 1500 centipoise.
[0083] Depot of the azalide antibiotic can be formed by several
means within the eye. In one preferred embodiment a depot for
topical administration can be formed by including lightly
crosslinked carboxyl containing polymers in the formulation, which
causes the solution to undergo a rapid increase in viscosity upon a
pH rise associated with administration to tissues such as those of
the eye and surrounding region. In another embodiment, a depot of
the azalide antibiotic can be formed by injection of a bolus of the
antibiotic composition into an eye. In one preferred method of
ophthalmic administration the injection is intended to form a depot
of material within the sclera, to accommodate extended release of
the material to the surrounding tissues. Methods of intrascleral
administration are discussed in U.S. patent application Ser. No.
09/127,920, filed Aug. 3, 1998 now U.S. Pat. No. 6,378,526 and
copending U.S. patent application Ser. No. 09/366,072, filed Aug.
2, 1999, now U.S. Pat. No. 6,397,849. Other means of forming depot
include the use of inserts loaded with a bolus of the drug to be
delivered. Inserts placed under the eyelid have been used for
example to deliver therapeutics to the ocular and periocular
region.
[0084] In a preferred embodiment where the concentrated azalide
antibiotic formulation containing DuraSite.RTM. or other similar
polyacrylic acid-type polymer at a pH of about 6 to about 6.8, or
more preferably about 6.0 to about 6.5, or more preferably at a pH
of about 6.2 to about 6.4, or more preferably about 6.25 to about
6.35, or more preferably about 6.3 is administered to the eye, the
polymer will swell upon contact with tear fluid which has a higher
pH. This gelation or increase in gelation leads to entrapment of
the azalide antibiotic in the gel thereby extending the residence
time of the composition in the eye if the antibiotic is in
solution. If the azalide antibiotic is retained in the gel polymer
matrix, the antibiotic is released slowly to the affected tissue
over time. All these events eventually lead to increased patient
comfort and increased azalide antibiotic contact time with the eye
tissues, thereby increasing the extent of drug absorption and
duration of action of the formulation in the eye. These
antibiotics, display minimal degradation and relatively high
solubility in aqueous formulations at the pre-administration pH,
with the advantages of the gelling composition.
[0085] The viscous gels that result from fluid eye drops typically
have residence times in the eye ranging from about 2 to about 4
hours, e.g., from about 2 to about 3 hours. The agents contained in
these drug delivery systems will be released from the gels at rates
that depend on such factors as the molecular weight of the drug,
its ionization state, the extent of drug loading and the pH of the
system, as well as on any drug delivery adjuvants, such as ion
exchange resins compatible with the ocular surface, which may also
be present.
[0086] The preferred ophthalmic azalide formulations have about 2%,
about 3%, about 4% and about 5% Azithromycin with DuraSite.RTM. as
the delivery vehicle. Such formulations are intended for the
treatment of bacterial conjunctivitis. The formulations preferably
use a citrate buffer and optionally contain DuraSite.RTM. as the
delivery vehicle. Moreover, the preferred ophthalmic formulations
contain an anti-inflammatory agent such as dexamethasone. In
addition to Azithromycin content, the preferred formulations have a
pH of about 6 to about 7, preferably about 6.8 to about 6.2 and
most preferably 6.3.+-.0.2; osmolality of about 300 mOsm/kg,
preferably about 250 to about 330 mOsm/kg and most preferably 300
mOsm/kg, and viscosity of about 1000 to about 5000 cps, preferably
about 1000 to about 2000 cps and most preferably about 1500
cps.
3. Dermal Formulations
[0087] In embodiments of the invention, the vehicle for topical
application to the skin can include water, buffered solutions,
various alcohols, glycols such as glycerin, lipid materials such as
fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and
silicone based materials. Various cosolvents can be used as known
in the art to disperse the components and maintain the components
in solution or suspension. The vehicles used for formulations for
treating mucosa are limited primarily by the toxicity of the
vehicle to the tissue. The vehicle is an important component of
some topical formulations, because it can be selected to enhance
penetration, to prolong the duration of activity, or to meet
requirement of the site of application. For example, a formulation
for application to the callous parts of the body, such as the palms
of the hand or bottoms of the feet, can include a penetration
enhancing agent such as dimethylsulfoxide, propylene glycol or
AZONE.TM..
[0088] The preferred dermal azalide antibiotic formulations
disclosed herein are preferably used to treat infections of the
skin. The dermal formulations are formulated with a higher
viscosity in order to be able to stay on the skin surface. The
dermal formulation could be in the form of a lotion, ointment or
cream. The preferred formulations have about 2%, about 3%, about 4%
and about 5% Azithromycin. The formulations preferably use a
citrate buffer and optionally contain a polymer such as
polycarbophil as the delivery vehicle. Moreover, the preferred
dermal formulations contain an anti-inflammatory agent such as
dexamethasone. The formulation may contain structure building agent
like Cab-O-Sil. In addition to Azithromycin content, the preferred
formulations have a pH of about 6 to about 7, preferably about 6.8
to about 6.2 and most preferably 6.3.+-.0.2; osmolality of about
300 mOsm/kg, preferably about 250 to about 330 mOsm/kg and most
preferably 300 mOsm/kg, and viscosity of about 100,000 to about
1,000,000 cps, preferably about 250,000 to about 750,000 cps and
most preferably about 5,000,000 cps.
4. Nasal Formulations
[0089] The concentrated aqueous azalide formulations of the
invention are also envisaged for nasal administration in specific,
measured amounts, preferably in the form of an aqueous solution or
suspension, by use of a pump spray bottle such as the bottles used
to deliver VANCENASE AQ.TM.. The aqueous formulations of the
present invention may be prepared by admixing concentrated aqueous
azalide formulations with other pharmaceutically acceptable
excipients, for example. The aqueous formulations according to the
present invention may contain, inter alia, additional water,
auxiliaries and/or one or more of the excipients, such as:
suspending agents, e.g., microcrystalline cellulose, sodium
carboxymethylcellulose, hydroxypropyl-methyl cellulose; humectants,
e.g. glycerin and propylene glycol; acids, bases or buffer
substances for adjusting the pH, e.g., citric acid, sodium citrate,
and; surfactants, e.g. Polysorbate 20, Polysorbate 80, glyceryl
monoleate, lecithin, or Poloxamer 407 and antimicrobial
preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and
potassium sorbate.
[0090] The preferred nasal azalide formulations disclosed herein
are preferably used to treat infections of the nasopharyngeal
passages. The nasal formulations have a lower viscosity in order to
be effectively administered to the nasal passages. The preferred
formulation have about 2%, about 3%, about 4% and about 5%
Azithromycin. The formulations preferably use a citrate buffer and
optionally contain DuraSite.RTM. or Noveon AA-1 as a
suspending/mucoadhesive agent and delivery vehicle. In order to
achieve a lower viscosity, the concentration of Noveon AA-1 may be
reduced from about 0.5% to about 0.9%. The formulations preferably
use a citrate buffer and optionally contain a surfactant such as
poloxamer. Moreover, the preferred nasal formulations contain an
anti-inflammatory agent such as dexamethasone. In addition, the
preferred formulations have a pH of about 6 to about 7, preferably
about 6.8 to about 6.2 and most preferably 6.3.+-.0.1; osmolality
of about 250 to about 330 mOsm/kg, preferably about 270 to about
330 mOsm/kg and most preferably about 300 mOsm/kg, and viscosity of
about 10 to about 200, preferably about 50 to about 150 and most
preferably about 70 to about 130 cps.
5. Inhalation Formulations
[0091] Preferably, inhalation formulations are useful in delivering
azalide antibiotic to the oral airway passages and lungs by oral
inhalation or intranasally by inhalation. The inhalation
formulations of the present invention may be prepared by admixing
concentrated aqueous azalide formulations with other
pharmaceutically acceptable excipients, for example. The aqueous
formulations according to the present invention may contain, inter
alia, additional water, auxiliaries and/or one or more of the
excipients, such as acids, bases or buffer substances for adjusting
the pH, e.g., hydrochloric acid, sodium hydroxide, citric acid,
sodium citrate, sulfuric acid and; surfactants, e.g. Polysorbate
80, sorbitan trioleate, or lecithin and antimicrobial
preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and
chlorobutanol.
[0092] The concentrated aqueous azalide formulations of the
invention are also envisaged for inhalational administration in
specific, measured amounts, preferably in the form of an aqueous
suspension, by use of a nebulizer such as the Pan LC.RTM. Plus or
the AeroEclipse.RTM.. In another embodiment, the concentrated
aqueous azalide formulations of the invention are delivered using a
metered dose inhaler (`MDP`). An MDI preferably delivers
aerosolized particles suspended in chlorofluorocarbon propellants
such as CFC-11, CFC-12, or the non-chlorofluorocarbons or alternate
propellants such as the fluorocarbons, HFC-134A or HFC-227 with or
without surfactants and suitable bridging agents.
[0093] The preferred inhalation azalide formulations disclosed
herein are preferably used to treat infections of the respiratory
system. The inhalation formulations have a lower viscosity in order
to be effectively nebulized into inhalation aerosol. The preferred
formulation have about 2%, about 3%, about 4% and about 5%
Azithromycin. The formulations preferably use a citrate buffer and
optionally contain DuraSite.RTM. or Noveon AA-1 as a
suspending/mucoadhesive agent and delivery vehicle. In order to
achieve a lower viscosity, the concentration of Noveon AA-1 may be
reduced from about 0.5% to about 0.9%. The formulations preferably
use a citrate buffer and optionally contain a surfactant such as
Polysorbate 80. Moreover, the preferred inhalation formulations
contain an anti-inflammatory agent such as dexamethasone. In
addition, the preferred formulations have a pH of about 6 to about
7, preferably about 6.8 to about 6.2 and most preferably
6.3.+-.0.1; osmolality of about 250 to about 330 mOsm/kg,
preferably about 270 to about 330 mOsm/kg and most preferably about
300 mOsm/kg, and viscosity of about 10 to about 200, preferably
about 50 to about 150 and most preferably about 70 to about 130
cps.
6. Buccal Formulations
[0094] The invention also includes topical buccal formulations.
Preferably such formulations are for application to the oral
mucosa, which includes the oral cavity, oral epithelium, palate,
gingival, and the nasal mucosa. In embodiments of the invention,
the oral composition is preferably an aqueous composition applied
to the tooth surface either alone or in combination with mechanical
application. One embodiment of the invention includes a component
that reduces or minimizes an unpleasant organoleptic property of
the compound. This may include a bitter taste in the mouth or
throat, or an unpleasant sensation in the nose. The invention is
thus further directed to a process of treating tissue or applying
an active agent to an area with little or no irritation. It has
been found that various natural and particularly artificial or
synthetic non-nutritive sweeteners are able to provide a temporary
suppression of pain and irritation to the area being treated when
applied topically.
[0095] Preferably, the buccal formulations include a carrier that
is solid or semi-solid at room temperature and is capable of
releasing the azalide antibiotic to the delivery area in the mouth.
In embodiments of the invention, suitable solid carriers included
sucrose, corn syrup solids, and other confectionery formulations.
The carrier may for example, be a lozenge, hard candy, lollipop or
gel and the like comprising an azalide antibiotic. Preferably, they
also have either a natural or artificial sweetener. Preferably, the
solid carrier is water soluble that can dissolve in the mouth to
release the active agent and anti-irritant. Preferred natural
sweeteners include sorbitol, mannitol and xylitol.
[0096] Examples of semi-solid carriers include gels, chewing gums
and other chewable compositions and compositions as known in the
art. The carrier can be a conventional toothpaste or dentifrice
gel. In one embodiment of the invention, the composition is in the
form of a chewing gum comprising a chewing gum base and an azalide
antibiotic. Oral formulations may also contain an effective amount
of a fluoride to treat the tooth surfaces.
[0097] The chewing gum base of the invention can be a conventional
gum base as known in art that can contain one or more solvents,
plasticizer, flavorants and colorants. The composition generally
contains up to about 50% by weight of a gum base based on the total
weight of the composition. Suitable chewing gum bases include
natural and synthetic elastomers and rubbers. Natural chewing gum
bases include natural rubber, chickle, jeluting, gutta percha and
croun gum. Other gum bases includes resins, such as comatone resin,
pontianak resin, copel gum, kauri gum, dammar gum, sweet bay gum,
spruce gum, and balsams. Synthetic elastomers includes
butadiene-styrene copolymers, isobutylene-isoprene copolymers,
polyethylene, polyisobutylene, polyvinylacetate and copolymers of
vinyl acetate.
[0098] The preferred buccal/peridontal azalide formulations
disclosed herein are used to treat infections of the mouth. The
buccal formulations have a higher viscosity in order to be retained
in the mouth. The preferred formulations have about 2%, about 3%,
about 4% and about 5% Azithromycin. The formulations preferably use
a citrate buffer and optionally contain a surfactant such as
poloxamer, and a polymer such as polycarbophil as a suspending and
mucoadhesive agent. Moreover, the preferred buccal formulations
contain an anti-inflammatory agent such as dexamethasone. The
preferred formulations have a pH of about 6 to about 7, preferably
about 6.8 to about 6.2 and most preferably 6.3.+-.0.2; osmolality
of about 300, preferably about 250 to about 330 mOsm/kg and most
preferably 300 mOsm/kg, and viscosity of about 50,000 to about
1.000,000 cps, preferably about 100,000 to about 500,00 cps and
most preferably about 250,000 cps. See for Example Table 6.
[0099] All of the percentages recited herein refer to weight
percent, unless otherwise indicated. The following non-limiting
examples serve to illustrate certain features of the present
invention.
Example 1
Ophthalmic Formulations Made at the 12L Scale
[0100] In a first step, EDTA, sodium chloride and Noveon (Solution
#1) are mixed for 30 minutes using an overhead mixer. The solution
is then transferred to a stainless steel pressure can. The solution
is transferred using pressure through a 100 mesh screen into the
12L vessel. In the second step, sodium hydroxide is added to the
vessel containing Solution #1. The volume of sodium hydroxide
required is based upon targeting a final batch pH of 6.3. This
solution is sterilized within the tank at 121.1.degree. C. for 30
minutes. The stainless steel pressure can and transfer line are
then rinsed with house DI water. In a third step, mannitol, citric
acid, sodium citrate, hydrochloric acid, azithromycin, benzalkonium
chloride (BAC), and Poloxamer 407 (Solution #2) are mixed together.
Hydrochloric acid is added to facilitate the dissolution of
azithromycin. After all of the solid components in Solution #2 are
fully dissolved, it is transferred aseptically into the 12L vessel
through a 0.2 .mu.m filter. Alternatively, the sodium hydroxide may
be added as the last step to insure a pH of 6.3 is achieved. The
stainless steel pressure can and filter are then rinsed with DI
water and the rinsate is added aseptically to the solution in the
12L vessel. The rinse volume is determined by targeting a final
batch volume of 12 liters. See Table 1.
Example 2
Otic Formulations Made at the 12L Scale
[0101] In a first step, EDTA, sodium chloride and Noveon AA-1
(Solution #1) are mixed for 30 minutes using an overhead mixer. The
solution is then transferred to a stainless steel pressure can. The
solution is transferred using pressure through a 100 mesh screen
into the 12L vessel. In the second step, sodium hydroxide is added
to the vessel containing Solution #1. The volume of sodium
hydroxide required is based upon targeting a final batch pH of 6.3.
This solution is sterilized within the tank at 121.1.degree. C. for
30 minutes. The stainless steel pressure can and transfer line are
then rinsed with DI water. In a third step, mannitol, citric acid,
sodium citrate, hydrochloric acid, azithromycin, BAC, and Poloxamer
407 (Solution #2) are mixed together. Hydrochloric acid is added to
facilitate the dissolution of azithromycin. After all of the solid
components in Solution #2 are fully dissolved, it is transferred
aseptically into the 12L vessel through a 0.2 .mu.m filter.
Alternatively, the sodium hydroxide may be added as the last step
to insure a pH of 6.3 is achieved. The stainless steel pressure can
and filter are then rinsed with DI water and the rinsate is added
aseptically to the solution in the 12L vessel. The rinse volume is
determined by targeting a final batch volume of 12 liters. See
Table 2.
Example 3
Nasal Formulations Made at the 12L Scale
[0102] In a first step, EDTA, sodium chloride and Noveon AA-1
(Solution #1) are mixed for 30 minutes using an overhead mixer. The
solution is then transferred to a stainless steel pressure can. The
solution is transferred using pressure through a 100 mesh screen
into the 12L vessel. In the second step, sodium hydroxide is added
to the vessel containing Solution #1. The volume of sodium
hydroxide required is based upon targeting a final batch pH of 6.3.
This solution is sterilized within the tank at 121.1.degree. C. for
30 minutes. The stainless steel pressure can and transfer line are
then rinsed with DI water. In the third step, dexamethasone,
Polysorbate 80, citric acid, sodium citrate, hydrochloric acid,
azithromycin, BAC, and Poloxamer 407 (Solution #2) are mixed
together. Hydrochloric acid is added to facilitate the dissolution
of azithromycin. After all of the solid components in Solution #2
are fully dissolved, it is transferred aseptically into the 12L
vessel through a 0.2 .mu.m filter. The stainless steel pressure can
and filter are then rinsed with DI water and the rinsate is added
aseptically to the solution in the 12L vessel. Alternatively, the
sodium hydroxide may be added as the last step to insure a pH of
6.3 is achieved. The rinse volume is determined by targeting a
final batch volume of 12 liters. See Table 3
Example 4
Inhalation Formulations Made at the 12L Scale
[0103] In a first step, EDTA, sodium chloride and Noveon AA-1
(Solution #1) are mixed for 30 minutes using an overhead mixer. The
solution is then transferred to a stainless steel pressure can. The
solution is transferred using pressure through a 100 mesh screen
into the 12L vessel. In the second step, sodium hydroxide is added
to the vessel containing Solution #1. The volume of sodium
hydroxide solution required is based upon targeting a final batch
pH of 6.3. This solution is sterilized within the tank at
121.1.degree. C. for 30 minutes. The stainless steel pressure can
and transfer line are then rinsed with DI water. In the third step,
dexamethasone, Polysorbate 80, citric acid, sodium citrate,
hydrochloric acid, azithromycin, and BAC, (Solution #2) are mixed
together. Hydrochloric acid is added to facilitate the dissolution
of Azithromycin. After all of the solid components in Solution #2
are fully dissolved, it is transferred aseptically into the 12L
vessel through a 0.2 .mu.m filter. The stainless steel pressure can
and filter are then rinsed with DI water and the rinsate is added
aseptically to the solution in the 12L vessel. Alternatively, the
sodium hydroxide may be added as the last step to insure a pH of
6.3 is achieved. The rinse volume is determined by targeting a
final batch volume of 12 liters. See Table 4.
Example 5
Dermal Formulations Made at the 12L Scale
[0104] In a first step, EDTA, sodium chloride, Cabosil, and Noveon
AA-1 (Solution #1) are mixed for 30 minutes using an overhead
mixer. The solution is then transferred to a stainless steel
pressure can. The solution is transferred using pressure through a
100 mesh screen into the 12L vessel. In the second step, sodium
hydroxide is added to the vessel containing Solution #1. The volume
of sodium hydroxide solution required is based upon targeting a
final batch pH of 6.3. This solution may or may not be sterilized
within the tank at 121.1.degree. C. for 30 minutes. The stainless
steel pressure can and transfer line are then rinsed with DI water.
In the third step, dexamethasone, Polysorbate 80, citric acid,
sodium citrate, hydrochloric acid, azithromycin, BAC, and Poloxamer
407 (Solution #2) are mixed together. Hydrochloric acid is added to
facilitate the dissolution of Azithromycin. After all of the solid
components in Solution #2 are fully dissolved, it is transferred
either non-aseptically or aseptically through a 0.2 .mu.m filter
into the 12L vessel. The stainless steel pressure can and filter
are then rinsed with DI water and the rinsate is added either
aseptically or non-aseptically to the solution in the 12L vessel.
Alternatively, the sodium hydroxide may be added as the last step
to insure a pH of 6.3 is achieved. The rinse volume is determined
by targeting a final batch volume of 12 liters. See Table 5.
[0105] In this disclosure there is described only the preferred
embodiments of the invention and but a few examples of its
versatility. It is to be understood that the invention is capable
of use in various other combinations and environments and is
capable of changes or modifications within the scope of the
inventive concept as expressed herein. Thus, for example, those
skilled in the art will recognize, or be able to ascertain, using
no more than routine experimentation, numerous equivalents to the
specific substances and procedures described herein. Such
equivalents are considered to be within the scope of this
invention. All references cited herein are incorporated by
reference in their entirety for all purposes.
TABLE-US-00001 TABLE 1 Ophthalmic Formulations Formulation
Formulation Composition Component T01T T02T T03T T04T U01T V04T
V05T EDTA 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% Sodium Chloride 0.3%
0.5% 0.25% 0.3% 0.4% 0.35% 0.35% Noveon AA-1 0.9% 0.9% 0.9% 0.9%
0.9% 1.0% 0.938% Mannitol 1.0% 1.0% 1.0% 0.5% 0.8% 0.8% 0.8%
Benzalkonium 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% Chloride
Sodium Citrate 0.3% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% Dihydrate Citric
Acid 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% Poloxamer 407 0.2% 0.2%
0.2% 0.2% 0.2% 0.2% 0.2% Azithromycin 2.1% 2.1% 3.1% 3.1% 2.1% 2.2%
2.2% HCl (6N) N/A 0.5% 0.9% 1.0% 0.5% 0.5% 0.5% NaOH (2N) 5.1% 4.9%
5.0% 5.1% 4.9% 5.3% 5.3% Dexamethasone 0.1%
TABLE-US-00002 TABLE 2 Otic Formulations Formulation Formulation
Composition Component U02T U03T U04T V01T V01T V01T V02T V03T EDTA
0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% Sodium Chloride 0.3% 0.3%
0.2% 0.3% 0.4% 0.5% 0.5% 0.5% Noveon AA-1 0.5% 0.5% 0.6% 0.6% 0.6%
0.6% 0.5% 0.6% Mannitol 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5%
Benzalkonium 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%
Chloride Sodium Citrate 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1%
Dihydrate Citric Acid 0.4% 0.4% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2%
Poloxamer 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% Azithromycin 3.1%
3.1% 3.2% 2.0% 2.0% 2.0% 2.0% 2.0% HCl (6N) 1.0% 1.0% 1.0% 0.5%
0.5% 0.5% 0.5% 0.5% NaOH (2N) 5.0% 2.9% 2.8% 3.0% 3.0% 3.0% 2.5%
2.9% Dexamethasone 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1%
TABLE-US-00003 TABLE 3 Nasal Formulations Formulation Concentration
Concentration Concentration Concentration Component Function w/w %
w/w % w/w % w/w % Formulation 1 2 3 4 Azithromycin Active
ingredient 3.0 3.0 2.0 2.0 monohydrate Dexamethasone Active
ingredient 0.1 0.1 Polycarbophil Suspending agent/ 0.525 0.525
0.525 0.525 mucoadhesive agent Hydrochloric acid (1N) pH adjusting
agent 6 6 3 3 Dextrose Osmolality 0.5 0.5 0.5 0.5 adjusting agent
Polysorbate 80 Surfactant 0.01 0.01 0.01 0.01 EDTA Chelator 0.1 0.1
0.1 0.1 Citric acid pH buffer 0.2 0.2 0.2 0.2 Sodium citrate
dihydrate pH buffer 0.14 0.14 0.14 0.14 Benzalkonium chloride
Preservative 0.011 0.011 0.011 0.011 Sodium chloride Osmolality 0.3
0.3 0.3 0.3 adjusting agent Sodium hydroxide pH adjusting agent
q.s. to pH 6.3 q.s. to pH 6.3 q.s. to pH 6.3 q.s. to pH 6.3
Purified Water Diluent q.s. to 100% q.s. to 100% q.s. to 100% q.s.
to 100%
TABLE-US-00004 TABLE 4 Inhalation Formulations Formulation
Concentration Concentration Concentration Concentration Component
Function w/w % w/w % w/w % w/w % Formulation 1 2 3 4 Azithromycin
Active ingredient 3.0 3.0 2.0 2.0 monohydrate Dexamethasone Active
ingredient 0.1 0.1 Polycarbophil Suspending agent/ 0.525 0.525
0.525 0.525 mucoadhesive agent Hydrochloric acid (1N) pH adjusting
agent 6 6 3 3 Dextrose Osmolality 0.5 0.5 0.5 0.5 adjusting agent
Polysorbate 80 Surfactant 0.01 0.01 0.01 0.01 EDTA Chelator 0.1 0.1
0.1 0.1 Citric acid pH buffer 0.2 0.2 0.2 0.2 Sodium citrate
dihydrate pH buffer 0.14 0.14 0.14 0.14 Benzalkonium chloride
Preservative 0.011 0.011 0.011 0.011 Sodium chloride Osmolality 0.3
0.3 0.3 0.3 adjusting agent Sodium hydroxide pH adjusting agent
q.s. to pH 6.3 q.s. to pH 6.3 q.s. to pH 6.3 q.s. to pH 6.3
Purified Water Diluent q.s. to 100% q.s. to 100% q.s. to 100% q.s.
to 100%
TABLE-US-00005 TABLE 5 Dermal Formulations Formulation
Concentration Concentration Concentration Concentration Component
Function w/w % w/w % w/w % w/w % Formulation 1 2 3 4 Azithromycin
Active ingredient 3.0 3.0 2.0 2.0 monohydrate Dexamethasone Active
ingredient 0.1 0.1 Polycarbophil Suspending agent/ 3.0 3.0 3.0 3.0
mucoadhesive agent Hydrochloric acid (1N) pH adjusting agent 6 6 3
3 Cab-O-Sil Structure Agent 1.0 1.0 1.0 1.0 Dextrose Osmolality 0.5
0.5 0.5 0.5 adjusting agent Polysorbate 80 Surfactant 0.01 0.01
0.01 0.01 EDTA Chelator 0.1 0.1 0.1 0.1 Citric acid pH buffer 0.2
0.2 0.2 0.2 Sodium citrate dihydrate pH buffer 0.14 0.14 0.14 0.14
Benzalkonium chloride Preservative 0.011 0.011 0.011 0.011 Sodium
chloride Osmolality 0.3 0.3 0.3 0.3 adjusting agent Sodium
hydroxide pH adjusting agent q.s. to pH 6.3 q.s. to pH 6.3 q.s. to
pH 6.3 q.s. to pH 6.3 Purified Water Diluent q.s. to 100% q.s. to
100% q.s. to 100% q.s. to 100%
TABLE-US-00006 TABLE 6 Peridontal Formulations Formulation
Concentration Concentration Concentration Concentration Component
Function w/w % w/w % w/w % w/w % Formulation 1 2 3 4 Azithromycin
Active ingredient 3.0 3.0 2.0 2.0 monohydrate Dexamethasone Active
ingredient 0.1 0.1 Polycarbophil Suspending agent/ 1.5 1.5 1.5 1.5
mucoadhesive agent Hydrochloric acid (1N) pH adjusting agent 6 6 3
3 Dextrose Osmolality 0.5 0.5 0.5 0.5 adjusting agent Poloxamer 407
Surfactant 0.01 0.01 0.01 0.01 EDTA Chelator 0.1 0.1 0.1 0.1 Citric
acid pH buffer 0.2 0.2 0.2 0.2 Sodium citrate dihydrate pH buffer
0.14 0.14 0.14 0.14 Benzalkonium chloride Preservative 0.01 0.01
0.01 0.01 Sodium chloride Osmolality 0.3 0.3 0.3 0.3 adjusting
agent Sodium hydroxide pH adjusting agent q.s. to pH 6.3 q.s. to pH
6.3 q.s. to pH 6.3 q.s. to pH 6.3 Purified Water Diluent q.s. to
100% q.s. to 100% q.s. to 100% q.s. to 100%
* * * * *