U.S. patent application number 09/902844 was filed with the patent office on 2002-03-21 for pharmaceutical compositions containing tobramycin and xanthan gum.
This patent application is currently assigned to Alcon Universal Ltd.. Invention is credited to Cabello, Gemma Torrella, Perdiguer, Nuria Carreras, Vallet Mas, Jose Alberto.
Application Number | 20020035088 09/902844 |
Document ID | / |
Family ID | 22828757 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020035088 |
Kind Code |
A1 |
Perdiguer, Nuria Carreras ;
et al. |
March 21, 2002 |
Pharmaceutical compositions containing tobramycin and xanthan
gum
Abstract
Topically administrable aqueous solution compositions containing
tobramycin and xanthan gum are disclosed. The solution compositions
contain a buffering agent and a pH-adjusting agent in an amount
sufficient to achieve a pH above 7.8 in order to minimize or avoid
compatibility problems between tobramycin and xanthan gum.
Inventors: |
Perdiguer, Nuria Carreras;
(Barcelona, ES) ; Vallet Mas, Jose Alberto;
(Barcelona, ES) ; Cabello, Gemma Torrella;
(Barcelona, ES) |
Correspondence
Address: |
Alcon Universal Ltd., c/o Alcon Research, Ltd.
Patrick M. Ryan(Q-148)
R&D Counsel
6201 So. Freeway
Fort Worth
TX
76134-2099
US
|
Assignee: |
Alcon Universal Ltd.
|
Family ID: |
22828757 |
Appl. No.: |
09/902844 |
Filed: |
July 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60221660 |
Jul 28, 2000 |
|
|
|
Current U.S.
Class: |
514/54 ;
514/61 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 9/0048 20130101; Y10S 514/912 20130101; A61K 31/7036 20130101;
A61K 9/0014 20130101; A61P 27/00 20180101; A61K 9/0043 20130101;
A61K 47/44 20130101; A61P 31/00 20180101; A61P 31/04 20180101; A61K
47/36 20130101 |
Class at
Publication: |
514/54 ;
514/61 |
International
Class: |
A61K 031/736; A61K
031/715 |
Claims
We claim:
1. A topically administrable solution composition comprising
tobramycin, xanthan gum, a buffering agent and a pH-adjusting
agent, wherein the composition has a pH greater than pH 7.8.
2. The composition of claim 1 wherein the composition has a pH of
about 7.9 - 8.6.
3. The composition of claim 2 wherein the composition has a pH of
about 7.9 - 8.2.
4. The composition of claim 1 wherein tobramycin is present in an
amount of about 0.5%(w/v) or less and xanthan gum is present in an
amount of about 0.4 - 0.8%(w/v).
5. The composition of claim 1 wherein the buffering agent is
tromethamine and the pH-adjusting agent is sulfuric acid.
6. The composition of claim 1 wherein the composition further
comprises one or more ingredients selected from the group
consisting of active agents; preservatives; tonicity-adjusting
agents; surfactants; solubilizing agents; stabilizing agents;
comfort-enhancing agents; emollients; and lubricants.
7. A topically administrable solution composition consisting
essentially of tobramycin, xanthan gum, tromethamine, sulfuric
acid, mannitol, boric acid, polysorbate 80, benzododecinium
bromide, and purified water, wherein the composition has a pH of
about 7.9 - 8.2.
Description
[0001] This application claims priority from co-pending U.S.
Provisional Application, U.S. Ser. No. 60/221,660, filed Jul. 28,
2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to pharmaceutical compositions
suitable for topical administration to the eye, ear or nose. In
particular, this invention relates to pharmaceutical compositions
formulated so that tobramycin and xanthan gum are compatible.
[0004] 2. Description of Related Art
[0005] Xanthan gum is a polysaccharide known to be useful in
ophthalmic compositions as a viscosity-enhancing agent. U.S. Pat.
No. 4,136,177 discloses ophthalmic compositions containing an
ophthalmic drug and from about 0.01 to 2.5% (w/v) of xanthan gum.
The '177 patent teaches that if the concentration of xanthan gum is
from about 0.02 to about 1.0% (w/v), the composition is suitable
for "dropwise" ophthalmic applications. In contrast, at
concentrations of xanthan gum above about 1.0% and up to about 2.5%
(w/v), "a gel-like consistency is attained." Thus, the '177 patent
discloses compositions that are formulated to be either non-gelled
liquids or gels before instillation in the eye. The '177 patent
does not describe any xanthan gum-containing compositions as
capable of being administered as a liquid and gelling upon contact
with the eye. According to the '177 patent, any ophthalmic drug can
be added to the xanthan gum-containing compositions. The '177
patent does not include tobramycin when it lists examples of
suitable antibacterial drugs (see Col. 3, lines 54 - 58).
[0006] WO 99/51273 discloses gel-forming compositions containing
xanthan gum where the xanthan gum has an initial bound acetate
content of at least about 4% and an initial bound pyruvate content
of at least about 2.5%. The entire contents of WO 99/51273 are
hereby incorporated by reference.
[0007] Tobramycin is an antibiotic drug known to be useful in
pharmaceutical compositions. For example, a TOBREX.RTM. brand of
tobramycin ophthalmic solution and ointment products is marketed by
Alcon Laboratories, Inc. (Fort Worth, Tex.).
SUMMARY OF THE INVENTION
[0008] The present invention is directed toward pharmaceutical
aqueous solutions of tobramycin and xanthan gum that are topically
administrable to the eye, ear or nose. According to the present
invention, the solution compositions are formulated a certain pH in
order to minimize or eliminate compatibility problems between
tobramycin and xanthan gum. The solution compositions have a pH
greater than 7.8.
[0009] Among other factors, the present invention is based upon the
finding that 0.3% tobramycin and 0.6% xanthan gum are incompatible
at pH 5 - 7.8 despite the fact that both tobramycin and xanthan gum
are independently sufficiently soluble in aqueous solution to give
0.3% and 0.6% solutions, respectively, but are compatible at a pH
greater than 7.8.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Unless otherwise indicated, all ingredient concentrations
are listed as % (w/v).
[0011] Xanthan gum is a well-known polysaccharide that is
commercially available from a variety of sources. The amount of
xanthan gum contained in the compositions of the present invention
will depend upon the properties desired for the final composition
and the identity and concentration of other ingredients in the
composition, but will generally range from about 0.4 to about 0.8%,
preferably 0.5 - 0.7%. Most preferred is a xanthan gum
concentration of about 0.6%.
[0012] Xanthan gum is generally available in at least two grades
from some commercial suppliers, a food or industrial grade and a
pharmaceutical grade. Even pharmaceutical grade materials should be
polish-filtered so that the finished pharmaceutical product will
have increased clarity. As one skilled in the art appreciates, the
appropriate filter size for polish filtration depends upon the size
of the undesired impurities contained in raw material. For example,
in the case of a solution composition, it has been found that the
Rhodigel Clear grade of xanthan gum from Rhone- Poulenc Inc. should
be filtered through a 0.45 .mu.m filter in order to remove cell
debris and impurities. Multiple stages of filters can be used to
increase the overall efficiency of the polish filtration
process.
[0013] Tobramycin is a known antibiotic drug. See, for example, The
Merck Index, Twelfth Edition, page 1619. The concentration of
tobramycin in the solution compositions of the present invention
will generally be about 0.5% or less. In topically administrable
ophthalmic compositions, the preferred concentration of tobramycin
is 0.3%.
[0014] In addition to xanthan gum and tobramycin, the solution
compositions of the present invention contain a buffer agent and a
pH-adjusting agent so that the pH is above 7.8. Preferably, the pH
of the solution compositions is about 7.9 - 8.6, more preferably,
7.9 - 8.2, and most preferably 8.0. Suitable buffering agents
include tromethamine; phosphate and borate. The most preferred
buffering agent is tromethamine. Suitable pH-adjusting agents
include sulfuric acid and hydrochloric acid. The most preferred
pH-adjusting agent is sulfuric acid.
[0015] The solution compositions of the present invention may
include other components. For example, the compositions may include
a second active agent (not limited to anti-infective agents). The
compositions may also contain one or more pharmaceutically
acceptable excipients, including, but not limited to, preservatives
(including preservative adjuncts), tonicity-adjusting agents
including salts containing monovalent cations, surfactants,
solubilizing agents, stabilizing agents, comfort-enhancing agents,
emollients, agents and lubricants.
[0016] The following examples are presented to illustrate further
various aspects of the present invention, but are not intended to
limit the scope of the invention in any respect.
EXAMPLES
Example 1
[0017] Each of the formulations shown in Table 1 was prepared as
follows. To the required amount of xanthan gum solution (obtained
from a polish-filtered stock solution), the remaining ingredients
indicated for Part A were added. Tromethamine was added from a 2%
stock solution (Formulation #'s 4 and 7) or in the form of a powder
(all other Formulations). L-Lysine was added from a 50% stock
solution. The formulations were then autoclaved at 124.degree. C.
for 45 minutes. After autoclaving, the required amount of
tobramycin was added (from a 2.5% stock solution of tobramycin
containing sulfuric acid so that the pH was 8.4 - 8.5). Purified
water and additional sulfuric acid, if necessary, were added to
achieve final batch size and target pH.
1TABLE 1 INGREDIENT FORMULATION # Part A: 1 2 3 4 5 Xanthan Gum 0.6
0.6 0.6 0.6 0.6 Mannitol -- -- -- -- 4.5 Tromethamine -- -- -- q.s.
to pH 8.35 0.9 L-Lys -- -- q.s. to pH 9.54 -- -- NaOH 1N q.s. to pH
8.58 q.s. to pH 8.58 -- -- -- Boric Acid -- -- -- -- 0.3
Benzododecinium Bromide -- -- -- -- 0.012 Part B: 2.5% Tobramycin
0.3 0.3 0.3 0.3 0.3 (+H.sub.25O.sub.4 q.s. pH 8.4-8.5) Final pH pH
5.65 pH 7.27 pH 7.76 pH 7.80 pH 8.12 Purified Water q.s. to 100
q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100 Result:
Precipitation Yes -- -- -- -- White Filaments* -- Yes Yes Yes --
Clear & Colorless -- -- -- -- Yes INGREDIENT FORMULATION # Part
A: 6 7 8 9 10 Xanthan Gum 0.6 0.6 0.6 0.6 0.6 Mannitol 4.5 -- 3.75
-- -- Tromethamine 1.0 q.s. to pH 8.35 1.2 -- -- L-Lys -- -- --
q.s. to pH 9.54 -- NaOH 1N -- -- -- -- q.s. to pH 8.58 Boric Acid
0.3 -- 0.3 -- -- Benzododecinium Bromide 0.012 -- 0.012 -- -- Part
B: 2.5% Tobramycin 0.3 0.3 0.3 0.3 0.3 (+H.sub.25O.sub.4 q.s. pH
8.4-8.5) Final pH pH 8.15 pH 8.36 pH 8.40 pH 8.44 pH 8.57 Purified
Water q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100 q.s. to 100
Result: Precipitation -- -- -- -- -- White Filaments* -- -- -- --
-- Clear & Colorless Yes Yes Yes Yes Yes *White filaments
disappeared after stirring
[0018] A representative compound procedure is listed below for
Formulation #8.
[0019] 1. Tare a suitable container, pour the required amount of
purified water and heat to about 70.degree. C. in a water bath.
[0020] 2. Weigh out and slowly add the required amount of xanthan
gum with stirring to prepare a stock solution of 0.8%, by using an
overhead mixer with a suitable blade.
[0021] 3. Allow the xanthan gum to hydrate for 1 hour, maintaining
the temperature at 70.degree. C.
[0022] 4. Adjust water to volume and clarify the stock solution:
filter through a 1.2.mu. prefilter at pressure 1-1.5 kg/cm.sup.2
maintaining the unfiltered stock solution and the filter and the
receiving vessel at high temperature. Filter through a 0.45.mu.
final filter at pressure about 3 kg/cm.sup.2. It is recommended to
perform filtration in two steps since a lack of pressure may occur
in the second filter, if a clarifying filter set-up is used, and
the process slows down.
[0023] 5. Tare a suitable container and weigh in the appropriate
amount of clarified xanthan gum stock solution.
[0024] 6. Weight out and add mannitol with vigorous stirring. Allow
to fully dissolve with stirring.
[0025] 7. Separately, weigh out and dissolve an appropriate amount
of purified water boric acid with vigorous stirring. Allow to fully
dissolve with stirring (magnetic stirring).
[0026] 8. Weight out and add to the previous solution (step 7)
tromethamine. Allow to fully dissolve with stirring.
[0027] 9. Weigh out and add Polysorbate 80 to the solution of step
8. Allow to fully dissolve with stirring.
[0028] 10. Weigh out and add benzododecinium bromide to the
solution of step 9. Allow to fully dissolve with stirring.
[0029] 11. Add the resulting solution of step 10, prefiltered
through a polishing filter, to the vessel containing the xanthan
gum and mannitol mixture. Allow to fully incorporate with stirring
(overhead mixer).
[0030] 12. Adjust to volume with purified water and transfer to a
suitable bottle (tare full with magnetic bar inside and close the
vessel).
[0031] 13. Autoclave at 124.degree. C. for 45 min and allow to cool
to room temperature.
[0032] 14. Separately, weigh out and add tobramycin to the
appropriate amount of purified water (2.5% stock solution). Allow
to fully dissolve with stirring.
[0033] 15. Adjust to pH 8.4 by slowly adding sulfuric acid.
[0034] 16. Aseptically add the tobramycin solution obtained in step
15 to the first portion of the formulation after sterile
filtration, with stirring. Stir until homogeneous.
[0035] 17. Adjust to final weight of the formulation with sterile
purified water.
Example 2
[0036] Each of the formulations shown in Table 2 was prepared
according to the method described in Example 1.
2 TABLE 2 Formulation # Ingredient 11 12 13 Tobramycin 0.30 g + 5%
excess 0.30 g + 5% excess 0.30 g + 5% excess Xanthan Gum 0.60 g
0.60 g 0.60 g Mannitol 3.75 g 3.75 g 3.75 g Boric Acid 0.30 g 0.30
9 0.30 9 Polysorbate 80 -- 0.05 g 0.05 g Tromethamine 1.20 g 1.20 g
1.20 g Benzododecinium Bromide 0.012 g 0.012 g 0.012 g Edetate
Disodium -- -- 0.05 g Sulfuric Acid q.s. to pH 8.3 q.s. to pH 8.3
q.s. to pH 8.3 Purified Water q.s. to 100 g q.s. to 100 g q.s. to
100 g
[0037] All three formulations shown in Table 2 were placed on
stability (25.+-.2.degree. C./40% R. H. and 40.+-.2.degree. C./15%
R. H.) for six months. All three formulations showed no sign of
precipitation or tobramycin/xanthan gum compatibility problems.
Example 3
[0038] Each of the formulations shown in Table 3 was prepared as
follows. A solution of xanthan gum (from a clarified stock
solution), mannitol, tromethamine, benzododecinium bromide and
purified water was prepared, forming approximately 87% of the final
batch weight. This portion was autoclaved at 121.degree. C. for 45
minutes. Separately, a solution of tobramycin in purified water was
prepared and sulfuric acid added to obtain the indicated target pH.
This tobramycin portion was sterilized by sterile filtration (0.2
.mu.m) before being combined with the xanthan gum portion of the
formulation.
[0039] No precipitation was observed in any of the three
formulations shown in Table 3. Each of the three formulations was
evaluated against reference solutions of the European Pharmacopoeia
(3rd edition; 1997) for clarity using the following scale: RS I
(clearest) - RS IV (least clear). The clarity rating difference
between Formulation # 14 on the one hand and Formulation # 15 and
16 on the other could indicate a future precipitation or
tobramycin/xanthan gum compatibility problem.
3 TABLE 3 Formulation # Ingredient 14 15 16 Tobramycin 0.30 g + 5%
excess 0.30 g + 5% excess 0.30 g + 5% excess Xanthan Gum 0.60 g
0.60 g 0.60 g Mannitol 3.75 g 3.75 g 3.75 g Boric Acid 0.30 g 0.30
g 0.30 g Polysorbate 80 0.05 g 0.05 g 0.05 g Tromethamine 1.00 g
0.75 g 0.65 g Benzododecinium Bromide 0.012 g 0.012 g 0.012 g
Sulfuric Acid q.s. to pH 8.0 q.s. to pH 7.6 q.s. to pH 7.1 Purified
Water q.s. to 100 g q.s. to 100 g q.s. to 100 g Clarity .ltoreq.RS
III .ltoreq.RS IV .ltoreq.RS IV
Example 4
[0040] Formulation #s 4 and 8 were prepared as described in Example
1 and then divided into three portions. Sulfuric acid was added to
each portion to adjust the pH to approximately 7.0, 7.4 and 7.8,
respectively. White filaments were observed when the sulfuric acid
was added, but these filaments disappeared after stirring. Each of
the formulations was stored at 4.degree. C. Samples were e analyzed
for clarity (nephelos testing) after 11, 18 and 35 days. The
results (in NTU) are shown in Table 4.
4 TABLE 4 Initial 11 Days 18 Days 35 Days Formulation # pH NTU pH
NTU pH NTU pH NTU 4 7.85 14.7 7.66 11.8 7.67 13.4 -- -- 4 7.41 34.1
7.36 38.4 7.23 48.6 7.33 71.9 4 7.05 223 7.01 302 6.87 884 -- -- 8
7.84 14.7 7.76 18.2 7.72 15.7 7.91 14.2 8 7.45 19.9 7.42 21.4 7.33
39.3 -- -- 8 7.02 28.9 6.98 31.4 6.90 96.4 -- --
[0041] Xanthan gum and tobramycin incompatibility becomes greater
as final pH decreases since higher NTU values may indicate a
problem of future precipitation.
Example 5
[0042] A preferred solution composition according to the present
invention is shown in Table 5.
5 TABLE 5 Ingredient Amount (% w/v) Tobramycin 0.30 + 5% excess
Xanthan Gum 0.60 Mannitol 3.75 Boric Acid 0.30 Polysorbate 80 0.05
Tromethamine 1.00 Benzododecinium Bromide 0.012 + 5% excess
Sulfuric Acid q.s. to pH 8.0 Purified Water q.s. to 100
[0043] The invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its spirit or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *