U.S. patent application number 10/865639 was filed with the patent office on 2005-12-15 for stabilized compositions comprising a therapeutically active agent and an oxidizing preservative.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Jordan, Robert S., Lyons, Robert T..
Application Number | 20050276867 10/865639 |
Document ID | / |
Family ID | 34970420 |
Filed Date | 2005-12-15 |
United States Patent
Application |
20050276867 |
Kind Code |
A1 |
Lyons, Robert T. ; et
al. |
December 15, 2005 |
Stabilized compositions comprising a therapeutically active agent
and an oxidizing preservative
Abstract
Citric acid and conjugate bases thereof are useful for
stabilizing stabilized chlorine dioxide in the presence of
therapeutically active agents and excipients in a composition.
Ophthalmic compositions and methods related thereto are also
disclosed herein.
Inventors: |
Lyons, Robert T.; (Laguna
Hills, CA) ; Jordan, Robert S.; (Trabuco Canyon,
CA) |
Correspondence
Address: |
ALLERGAN, INC., LEGAL DEPARTMENT
2525 DUPONT DRIVE, T2-7H
IRVINE
CA
92612-1599
US
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
34970420 |
Appl. No.: |
10/865639 |
Filed: |
June 9, 2004 |
Current U.S.
Class: |
424/661 ;
514/574 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 2300/00 20130101; A61K 47/12 20130101; A61P 27/02 20180101;
A61K 9/0048 20130101; A61P 31/04 20180101; A61K 47/02 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/165 20130101;
A61K 31/19 20130101; A61K 47/02 20130101 |
Class at
Publication: |
424/661 ;
514/574 |
International
Class: |
A61K 033/14; A61K
031/19 |
Claims
1. An ophthalmic composition comprising an effective amount of a
therapeutically active agent having an oxidizable functional group,
an effective amount of stabilized chlorine dioxide to act as a
preservative, and an effective amount of citric acid and/or
conjugate bases thereof to stabilize said therapeutically active
agent in the presence of said stabilized chlorine dioxide.
2. The composition of claim 1 wherein said therapeutically active
agent comprises a sulfur atom.
3. The composition of claim 1 wherein said therapeutically active
agent comprises a carboxylic acid, a carboxylic acid ester, or a
carboxylic acid amide.
4. The composition of claim 1 comprising a prostaglandin or a
prostamide.
5. The composition of claim 1 which comprises bimatoprost.
6. The composition of claim 1 comprising a borate/boric acid
buffer.
7. The composition of claim 1 comprising from 0.01% to 0.10%
bimatoprost.
8. The composition of claim 1 comprising from 0.001% to 0.10%
citric acid and/or conjugate bases thereof.
9. The composition of claim 7 comprising about 0.02% citric acid
and/or conjugate bases thereof.
10. The composition of claim 8 comprising 0.03% bimatoprost, 0.39%
sodium chloride, 0.6% boric acid, 0.045% sodium borate decahydrate,
0.014% citric acid monohydrate, 0.5% carboxymethylcellulose, and
0.005% stabilized chlorine dioxide, wherein the pH is adjusted to
7.3 by the addition of hydrochloric acid or sodium hydroxide.
11. A method of stabilizing incompatible components of a
composition comprising adding an effective amount of citric acid
and/or conjugate bases thereof to said composition, wherein said
incompatible components comprise stabilized chlorine dioxide and a
second component.
12. The method of claim 11 wherein said second component is a
therapeutically active agent.
13. The method of claim 12 wherein said therapeutically active
agent is a prostaglandin or a prostamide.
14. The method of claim 13 wherein said therapeutically active
agent is bimatoprost.
15. The method of claim 14 wherein bimatoprost has a concentration
of about 0.03%.
16. A method of preserving an ophthalmic composition comprising
providing an effective amount of citric acid and/or conjugate bases
thereof and stabilized chlorine dioxide to said composition.
17. The composition of claim 8 comprising about 0.03% bimatoprost,
about 0.27% sodium phosphate dibasic heptahydrate, about 0.014%
citric acid monohydrate, about 0.83% sodium chloride, and about
0.01% Purite.RTM., wherein the pH is adjusted to 7.3 by the
addition of hydrochloric acid and/or sodium hydroxide.
18. The composition of claim 8 consisting essentially of about
0.03% bimatoprost, about 0.27% sodium phosphate dibasic
heptahydrate, about 0.014% citric acid monohydrate, about 0.83%
sodium chloride, and about 0.01% Purite.RTM., water, and a
sufficient quantity of hydrochloric acid and/or sodium hydroxide to
adjust the pH is adjusted to 7.3.
19. The composition of claim 8 consisting of about 0.03%
bimatoprost, about 0.27% sodium phosphate dibasic heptahydrate,
about 0.014% citric acid monohydrate, about 0.83% sodium chloride,
and about 0.01% Purite.RTM., water, and a sufficient quantity of
hydrochloric acid and/or sodium hydroxide to adjust the pH is
adjusted to 7.3.
20. The composition of claim 8 comprising from 30 ppm to 500 ppm
Purite.RTM..
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical
compositions. In particular, the present invention relates to
ophthalmic compositions containing an active drug and the use of
stabilized chlorine dioxide as a preservative in these
compositions.
BACKGROUND OF THE INVENTION
DESCRIPTION OF RELATED ART
[0002] Preservatives are used in multi-use ophthalmic formulations
to prevent microbial contamination of the composition after the
packaging has been opened. A number of preservatives have been used
including quaternary ammonium salts such as benzalkonium chloride;
mercury compounds such as phenylmercuric acetate and thimerosal;
alcohols such as chlorobutanol and benzyl alcohol; and others.
Recently, stabilized chlorine dioxide has also been disclosed as
being useful as a preservative in ophthalmic compositions, see for
example, U.S. Pat. No. 5,736,165; U.S. Pat. No. 5,424,078; and WO
9602264A2; all of which are expressly incorporated herein by
reference.
[0003] At least one commercial ophthalmic product, Alphagan P.RTM.,
marketed by Allergan, Inc., the assignee of the present patent
document uses stabilized chlorine dioxide as a preservative. The
active agent of Alphagan P.RTM. is brimonidine, an alpha
2-adrenoceptor agonist, and the product is used for the treatment
of glaucoma and other conditions associated with elevated
intraocular pressure.
SUMMARY OF THE INVENTION
[0004] One embodiment comprises an ophthalmic composition
comprising an effective amount of a therapeutically active agent,
stabilized chlorine dioxide, and citric acid and/or conjugate bases
thereof.
[0005] A method of stabilizing incompatible components of a
composition comprising adding an effective amount of citric acid
and/or conjugate bases thereof, wherein said incompatible
components comprise stabilized chlorine dioxide and a second
component, is also disclosed herein.
[0006] Another embodiment comprises a method of preserving an
ophthalmic composition comprising providing an effective amount of
citric acid and/or conjugate bases thereof and stabilized chlorine
dioxide to said composition.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0007] FIG. 1 shows the effect of citrate on bimatoprost stability
in the composition of Table 4 at 50.degree. C.
[0008] FIG. 2 shows the effect of citrate on Purite.RTM. stability
in the composition of Table 4 at 50.degree. C.
DETAILED DESCRIPTION OF THE INVENTION
[0009] We have found many therapeutically active agents and some
other components of many ophthalmic compositions are incompatible
with stabilized chlorine dioxide, which is a useful preservative
for ophthalmic compositions. Particularly, stabilized chlorine
dioxide and therapeutically active agents or other components of an
ophthalmic formulation are unstable in one another's presence. In
other words, if stabilized chlorine dioxide is in a composition
with certain therapeutically active agents, either the stabilized
chlorine dioxide, or the therapeutically active agent, or both, are
unstable. Similarly, if stabilized chlorine dioxide is in a
composition with certain other excipients, either the stabilized
chlorine dioxide, or the other excipient, or both, are unstable.
Surprisingly, citric acid and/or conjugate bases thereof have been
discovered to improve the stability of these combinations.
[0010] As used herein, the term "therapeutically active agent" is
understood in the broadest sense generally accepted in the art to
be a compound or compounds which are used to treat or prevent any
disease or undesirable condition which afflicts an animal.
[0011] The term "stabilized chlorine dioxide" is well known in the
industry and by those skilled in the art. The term "stabilized
chlorine dioxide" as used herein means, for example, one or more
chlorine dioxide-containing complexes disclosed in U.S. Pat. Nos.
4,696,811 and 4,689,215, which are incorporated herein by
reference. Chlorites include metal chlorite salts, particularly
alkali metal chlorites. A specific example of a chlorite salt which
is useful as a chlorine dioxide precursor is sodium chlorite. Among
the preferred stabilized chlorine dioxide complexes are carbonate
and bicarbonate complexes. The exact chemical composition of many
of these stabilized chlorine dioxide precursors is not completely
understood. The manufacture or production of certain chlorine
dioxide precursors is described in McNicholas U.S. Pat. No.
3,278,447, which is hereby incorporated in its entirety by
reference herein. A commercially available stabilized chlorine
dioxide which can be utilized in the compositions disclosed herein
is the proprietary stabilized chlorine dioxide of BioCide
International, Inc. of Norman, Okla., sold under the trademark
Purite.RTM.. Other suitable stabilized chlorine dioxide products
include that sold under the trademark Dura Klor.RTM. by Rio Linda
Chemical Company, Inc., and that sold under the trademark Antheium
Dioxide.RTM. by International Dioxide, Inc. The amount of
stabililized chlorine dioxide used depends upon the therapeutically
active agent, other excipients, and other aspects of the
formulation process. Such a determination can readily be made by a
person of ordinary skill in the art, without undue experimentation.
While the amount of stabilized chlorine dioxide may vary widely, a
concentration between 30 ppm and 500 ppm is useful in many
compositions. In other compositions, from 50 ppm and 150 ppm
stabilized chlorine dioxide is used.
[0012] The term "citric acid and/or conjugate bases thereof" refers
to citric acid and its monovalent (-1), divalent (-2), and
trivalent (-3) salts in any combination. Thus, any one of these
species and any combination thereof is considered to be within the
meaning of the phrase "citric acid and/or conjugate bases thereof".
The concentration of citric acid in the compositions disclosed
herein may vary. In some compositions, the concentration of citric
acid and/or conjugate bases thereof is from 0.001% to 0.10%. In
other compositions, the concentration of citric acid and/or
conjugate bases thereof is about 0.02%. Unless a specific amount of
a specific form is indicated, the concentration of citric acid
and/or conjugate bases thereof is determined as if all citric acid
and citrate species were citric acid.
[0013] U.S. Pat. No. 5,246,662 teaches that transition metals are
capable of catalyzing the conversion of stabilized chlorine dioxide
to the active form. Thus, while not intending to be limited or
bound in any way by theory as to the scope of the present
invention, it is believed that trace transition metals help to
accelerate the formation of active chlorine dioxide, which in turn
oxidizes the therapeutically active agent or an excipient. Thus, it
is believed that citric acid acts as a chelating agent to bind up
these trace metals, stabilizing the incompatible components in each
others' presence. While the trace metals are not deliberately
added, it is believed that sufficient quantities of these metals
are present in common ophthalmic excipients to effect the freeing
of chlorine dioxide. Furthermore, while not intending to be bound
in any way by theory, it is believed that the citric acid enhances
the preservative effectiveness because binding the metal deprives
microbial contaminants of nutrients, thus inhibiting their growth,
and/or helping to kill the pathogen.
[0014] While not intending to be bound in any way by theory, it is
believed that polyanions such as carboxymethylcellulose (CMC) have
a sufficient quantity of transition metal impurities to overcome
the chelating properties of these compounds, such that they do not
stabilize the incompatible components, but can actually destabilize
them. It is believed that this is because polymeric materials are
much more difficult to purify than small molecules, due to the fact
that these materials generally constitute a mixture, and are not a
pure, single compound. It is believed that this is the reason that
carboxymethylcellulose was observed to destabilize certain
incompatible components. By contrast citric acid is believed to be
sufficiently pure to stabilize the incompatible components
contemplated herein.
[0015] While not intending to be bound in any way by theory, it is
also believed that many chelating agents have oxidizable groups
which make them unsuitable for stabilizing chlorine dioxide. For
example, amines with amine functional groups such as EDTA and
ethylene diamine are oxidized by the stabilized chlorine dioxide,
and are thus not suitable chelating agents for the purposes
disclosed herein.
[0016] While not intending to be bound in any way by theory, other
potential chelating agents such as lactate, pyruvate, and oxalate,
are believed to either be too weak as metal chelating agents to be
effective, or susceptible to oxidation, or both, such that they do
not appear to stabilize the incompatible components of a
composition.
[0017] In one embodiment, the therapeutically active agent of the
compositions disclosed herein is bimatoprost which is a prostamide
compound. While not intending to be bound in any way by theory, it
is generally believed in the art that oxidation reactions are
generally nonselective reactions, the fact that stabilized chlorine
dioxide destabilizes bimatoprost suggests that a broad variety of
compounds will be oxidized by chlorine dioxide. Furthermore,
chlorine dioxide is a strong oxidant (as evidenced by the fact that
we are using "stabililized" chorine dioxide), and would thus be
even less selective than a "normal" oxidant. For comparison, the
standard reduction potential of chlorine dioxide to ClO.sub.2.sup.-
is 1.07 V, whereas the standard reduction potential of permanganate
to manganese dioxide is 0.6 V [Schriver, Atkins, Langford,
Inorganic Chemistry, New York: W.H. Freeman and Company, 1990, pp.
649 and 654]. Permanganate has been used as a reagent for many
oxidations in organic chemistry including the oxidative cleavage of
alkenes to ketones or carboxylic acids, the oxidative cleavage of
ketones to carboxylic acids, the oxidation of alcohols or aldehydes
to carboxylic acids, and various oxidations of amine and sulfur
containing functional groups. Thus, while not intending to be bound
in any way by theory, chlorine dioxide, being a stronger oxidizing
agent than permanganate, is expected to oxidize many functional
groups.
[0018] In one embodiment, the therapeutically active agent
comprises a carboxylic acid, a carboxylic acid ester, or a
carboxylic acid amide. In another embodiment, the therapeutically
active agent is a prostaglandin or prostamide such as bimatoprost,
latanoprost, travoprost, unoprostone isopropyl, and the like, which
have carboxylic acid, ester, or amide groups. In another
embodiment, the therapeutically active agent comprises a sulfur
atom. Other functional groups that may be susceptible to stabilized
chlorine dioxide are amines, phenols, alcohols, aromatic amino
acids, non-conjugated double bonds, and similar groups. While not
intending to be limiting, or to be bound by theory, non-active
excipients comprising one or more of the aforementioned functional
groups should be stabilized by citric acid such that they can be
used with stabilized chlorine dioxide.
[0019] As is known in the art, buffers are commonly used to adjust
the pH to a desirable range for ophthalmic use. Generally, a pH of
around 6-8 is desired, however, this may need to be adjusted due to
considerations such as the stability or solubility of the
therapeutically active agent or other excipients. Many buffers
including salts of inorganic acids such as phosphate, borate, and
sulfate are known. Although any buffer may be used in the
compositions disclosed herein, in certain situations it is
particularly useful to use a borate/boric acid buffer in the
compositions disclosed herein. The term "borate/boric acid buffer"
refers to any combination of boric acid and one or more of the
conjugate bases such that the pH is adjusted to the desired range.
While not intending to limit the scope of the invention in any way,
or be bound in any way by theory, it is believed that the
borate/boric acid buffer may boost the antimicrobial properties of
stabilized chlorine dioxide.
[0020] In another embodiment, the therapeutically active agent is a
prostaglandin or a prostamide. In another embodiment, the
therapeutically active agent is bimatoprost. One composition
comprises from 0.01% to 0.10% bimatoprost. In another embodiment,
the concentration of bimatoprost is about 0.03%.
[0021] Another commonly used excipient in ophthalmic compositions
is a viscosity-enhancing, or a thickening agent. Thickening agents
are used for a variety of reasons, ranging from improving the form
of the formulation for convenient administration to improving the
contact with the eye to improve bioavailability. The
viscosity-enhancing agent may comprise a polymer containing
hydrophilic groups such as monosaccharides, polysaccharides,
ethylene oxide groups, hydroxyl groups, carboxylic acids or other
charged functional groups. While not intending to limit the scope
of the invention, some examples of useful viscosity-enhancing
agents are sodium carboxymethylcellulose,
hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, and
polyethylene glycol.
[0022] Another composition comprises 0.03% bimatoprost, 0.39%
sodium chloride, 0.6% boric acid, 0.045% sodium borate decahydrate,
0.014% citric acid monohydrate, 0.5% carboxymethylcellulose, and
0.005% Purite.RTM. (stabilized chlorine dioxide), wherein the pH is
adjusted to 7.3 by the addition of hydrochloric acid (HCl) or
sodium hydroxide (NaOH).
[0023] In ophthalmic solutions, tonicity agents often are used to
adjust the composition of the formulation to the desired isotonic
range. Tonicity agents are well known in the art and some examples
include glycerin, mannitol, sorbitol, sodium chloride, and other
electrolytes.
[0024] The best mode of making and using the present invention are
described in the following examples. These examples are given only
to provide direction and guidance in how to make and use the
invention, and are not intended to limit the scope of the invention
in any way.
EXAMPLE 1
[0025] The following example is typical of the instability of
various common ophthalmic excipients in the presence of stabilized
chlorine dioxide. Each of the excipients was added, in the amounts
shown, to a proprietary composition comprising brimonidine as a
therapeutically active agent. The results, presented in Table 1,
show that none of the excipients appear to stabilize the chlorine
dioxide. In particular, EDTA and ethylene diamine, which are known
chelating agents, do not stabilize the chlorine dioxide. Also of
note is that some of the other compounds that might be viewed as
chelating agents, such as oxalate or pyruvate, are similarly
ineffective.
1TABLE 1 Effect of Chelating Agents on Stability of Chlorine
Dioxide Stabilized Chlorine Dioxide Concentration (ppm) Ingredient
(ppm) pH 0 Days 7 Days 14 Days None (control) 7.3 42 41 38 Sodium
Formate (100) 7.3 42 40 36 Sodium Lactate (100) 7.3 45 40 37 Sodium
Pyruvate(100) 7.3 41 15 0 Sodium Dihydroxyfurmarate (100) 7.1 37 13
0 Sodium Oxalate (100) 7.3 39 38 35 Ethylene diamine (100) 7.2 42
37 29 EDTA (100) 7.2 44 2 0 Sodium Oxalate (100) + Fe(III) (1) 7.3
43 38 39 Ethylene oxide (100) 7.3 43 40 35 Acetone (100) 7.3 43 38
35 Glucose (100) 7.3 43 41 34
EXAMPLE 2
[0026] Compositions A, B, and C were prepared according to Table 2.
All compositions were prepared in a similar manner. A composition
is manufactured on a volume basis at ambient temperatures from two
principal parts designated I and II. Each in-process part is
prepared separately and then combined. The resulting bulk
composition is pH adjusted and then brought to volume for final
mix.
[0027] Part I is manufactured in the main batch vessel. Water is
charged to the main mixing vessel at 50% of the final batch volume.
Mixing is initiated at a specified speed using a Rotosolver mixer
positioned off-center to produce a strong vortex, and CMC is added
directly into the vortex. The solution is mixed for a specified
time until complete dissolution is achieved.
[0028] Part II is manufactured in a separate mixing vessel equipped
with a top-entering variable-speed mixer and an appropriately sized
impeller. Water is charged to the tank at 35% of the batch volume
ad mixing is initiated at a specified speed. The ingredients for
Part II are added in the following order: boric acid, sodium
borate, sodium chloride, bimatoprost, and Purite.RTM.. Each
ingredient is allowed to completely dissolve before the next
ingredient is added.
[0029] With continued mixing in the main batch vessel, Part II is
quantitatively transferred into Part I. The combined parts are
mixed for a specified time to ensure homogeneity. The pH is
measured and adjusted to pH 7.3 with NaOH and/or HCl. Water is
added to final volume and the bulk solution is mixed until
homogeneous. The osmolality of the final solution is about 290
mOsm/kg.
[0030] The samples were held at 50.degree. C. for 13 weeks and the
concentration of bimatoprost was determined by high performance
liquid chromatography. The concentration of Purite.RTM. was
determined by titration and is reported as potential chlorine
dioxide (CDO) concentration in ppm. The Purite.RTM. analysis
procedure is based on the reduction of chlorite ion by iodide in
acidic medium. The liberated iodine is then back-titrated using
sodium thiosulfate to calculate the amount of sodium chlorite.
Results are reported as potential chlorine dioxide rather than in
terms of sodium chlorite (or Purite.RTM.) because CDO is the active
form of the preservative
[0031] While not intending to limit the scope of the invention in
any way, the results, presented in Table 3, demonstrate that the
addition of low viscosity carboxymethylcellulose polymer (CMC),
with or without NaCl, tends to destabilize both the bimatoprost and
the Purite.RTM..
2TABLE 2 Base Composition Comprising Bimatoprost and Purite .RTM..
Concentration (% w/w) Ingredient A B C Bimatoprost 0.03 0.03 0.03
Purite 0.015 0.015 0.015 Boric Acid 0.60 0.60 0.60 Sodium Borate
0.045 0.045 0.045 Sodium Chloride 0 0 0.39 Carboxymethylcellulose 0
0.50 0.50 HCl/NaOH pH to 7.3 pH to 7.3 pH to 7.3 Purified Water
q.s. 100% q.s. 100% q.s. 100%
[0032]
3TABLE 3 Bimatoprost and Purite .RTM. Content in Formulations of
Table 2 After 13 Weeks at 50.degree. C. Bimatoprost, % of Purite
.RTM., Composition Initial % of Initial Borate Buffer (A) 91.0
100.5 Borate + CMC (B) 84.5 95.7 Borate + CMC + NaCl (C) 82.2
96.0
EXAMPLE 3
[0033] Compositions D and E were prepared according to Table 4 by a
procedure similar to that described in Example 2. Citric acid was
added after the dissolution of sodium chloride and the pH was
measured and adjusted to pH 7.3 with NaOH and/or HCl before the
addition of bimatoprost and Purite.RTM.. The samples were stored at
50.degree. C. and the concentrations of bimatoprost (FIG. 1) and
Purite.RTM. (FIG. 2) were determined at 3, 6 and 10 weeks. While
not intending to limit the scope of the invention in any way, FIGS.
1 and 2 demonstrate that citrate stabilizes both bimatoprost and
Purite.RTM. in the composition.
4TABLE 4 Composition of Bimatoprost With and Without Citric Acid
Concentration (% w/w) Ingredient D E Bimatoprost 0.03 0.03 Purite
.RTM. 0.005 0.005 Citric Acid 0.014 -- Boric Acid 0.60 0.60 Sodium
Borate 0.045 0.045 Sodium Chloride 0.39 0.39 Carboxymethylcellulose
0.50 0.50 HCl/NaOH pH to 7.3 pH to 7.3 Purified Water q.s. 100%
q.s. 100%
EXAMPLE 4
[0034] A composition, prepared according to Table 5, was entirely
manufactured in a single batch vessel and was prepared as follows.
The ingredients are added into purified water with mixing in the
following order: sodium phosphate dibasic heptahydrate, citric acid
monohydrate, sodium chloride, bimatoprost, and Purite.RTM.. Each
ingredient was allowed to dissolve completely before the next
ingredient was added. The pH was then measured and adjusted to 7.3,
and purified water was added to bring the composition to final
volume. After storage for six months at 40.degree. C., 99.7% of
initial bimatoprost and 99.6% of initial Purite.RTM. remained in
the product. While not intending to limit the scope of the
invention in any way, these data demonstrate that the citrate
provides excellent storage stability for bimatoprost and
Purite.RTM..
5TABLE 5 Composition of Bimatoprost in Phosphate/Citrate Buffer
Concentration (% w/w) Ingredient E Bimatoprost 0.03 Purite .RTM.
0.01 Sodium Phosphate Dibasic 0.268 Citric Acid 0.014 Sodium
Chloride 0.83 HCl/NaOH pH to 7.3 Purified Water q.s. 100%
EXAMPLE 5
[0035] A composition according to example 4 is administered
topically once a day to the eyes of a patient suffering from
glaucoma. Reduction of the patient's intraocular pressure is
observed shortly after administration, and continues for as long as
the composition is administered.
* * * * *