U.S. patent application number 09/863294 was filed with the patent office on 2001-10-11 for ophthalmic compositions.
Invention is credited to Bowman, Lyle M., Memarzadeh, Eric B., Pfeiffer, James F., Roy, Samir.
Application Number | 20010029269 09/863294 |
Document ID | / |
Family ID | 26755646 |
Filed Date | 2001-10-11 |
United States Patent
Application |
20010029269 |
Kind Code |
A1 |
Bowman, Lyle M. ; et
al. |
October 11, 2001 |
Ophthalmic compositions
Abstract
An ophthalmic composition containing a divalent salt and a
non-steroidal anti-inflammatory agent as a precipitate. The
composition reduces or eliminates the risk of stinging and burning
the eye from topical application. Additionally a preservative
system comprising a perborate salt, a polyphosphonic acid peroxy
stabilizer and EDTA provides stable preservation of a variety of
aqueous ophthalmic compositions.
Inventors: |
Bowman, Lyle M.;
(Pleasanton, CA) ; Pfeiffer, James F.; (Oakland,
CA) ; Memarzadeh, Eric B.; (San Carlos, CA) ;
Roy, Samir; (San Ramon, CA) |
Correspondence
Address: |
ARNOLD & PORTER
555 12TH STREET, N.W.
WASHINGTON
DC
20004
US
|
Family ID: |
26755646 |
Appl. No.: |
09/863294 |
Filed: |
May 24, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09863294 |
May 24, 2001 |
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09074419 |
May 8, 1998 |
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6265444 |
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09074419 |
May 8, 1998 |
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08863015 |
May 23, 1997 |
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Current U.S.
Class: |
514/569 ;
514/567 |
Current CPC
Class: |
A61K 33/06 20130101;
A61K 33/06 20130101; A61K 33/06 20130101; Y10S 514/912 20130101;
A61K 33/06 20130101; A61K 9/0048 20130101; A61P 27/02 20180101;
A61K 31/19 20130101; A61K 31/195 20130101; A61K 2300/00 20130101;
A61K 31/38 20130101; A61P 29/00 20180101; A61K 33/06 20130101 |
Class at
Publication: |
514/569 ;
514/567 |
International
Class: |
A61K 031/196; A61K
031/192 |
Claims
We claim:
1. An ophthalmic composition comprising an aqueous medium
containing an effective amount of a non-steroidal anti-inflammatory
agent, wherein at least about 80 mol. % of said agent is in the
form of a precipitate, and at least about 0.5 mole equivalents of a
pharmacologically acceptable divalent cation per mole of said
non-steroidal anti-inflammatory agent precipitate; said aqueous
medium having a pH in the range of from 4.0 to 6.7.
2. The composition according to claim 1, wherein said non-steroidal
anti-inflammatory agent is selected from the group consisting of
diclofenac, suprofen, and flurbiprofen.
3. The composition according to claim 2, wherein said non-steroidal
anti-inflammatory agent is diclofenac.
4. The composition according to claim 1, wherein said
pharmacologically acceptable divalent cation is a Group IIA
metal.
5. The composition according to claim 4, wherein said Group IIA
divalent metal cation is calcium or magnesium.
6. The composition according to claim 1, wherein said precipitate
is in a free-acid form.
7. The composition according to claim 6, wherein said divalent
cation is present as a solute in said aqueous medium.
8. The composition according to claim 7, wherein said divalent
cation is present from 1 to 5 times the stoichiometric amount
equivalent to the molar amount of said non-steroidal
anti-inflammatory agent precipitate.
9. The composition according to claim 8, wherein 85 to 95% of said
non-steroidal anti-inflammatory agent is in said precipitate
form.
10. The composition according to claim 9, wherein said NSAI agent
is diclofenac and said divalent cation is Mg.sup.++.
11. The composition according to claim 1, further comprising a
polymer.
12. The composition according to claim 11, wherein said polymer is
water insoluble and water swellable.
13. The composition according to claim 12, wherein said polymer is
a crosslinked carboxy-containing polymer.
14. The composition according to claim 13, wherein said polymer is
a polycarbophil.
15. The composition according to claim 13, wherein said polymer is
a Carbopol.
16. The composition according to claim 15, wherein said polymer is
Carbopol 974P
17. The composition according to claim 13, further comprising
EDTA.
18. The composition according to claim 1, wherein said aqueous
medium has a pH of from 4.0 to 6.5.
19. The composition according to claim 1, wherein said
non-steroidal anti-inflammatory agent is contained in an amount of
from 0.01 to 5.0% by weight of the entire composition.
20. The composition according to claim 1, further comprising a
perborate salt.
21. A method for treating an eye, which comprises administering to
an eye in need thereof an effective amount of the composition
according to claim 1.
22. A method for making the composition according to claim 1, which
comprises: combining a non-steroidal anti-inflammatory agent and a
divalent cation source in an aqueous medium to form a
precipitate-containing solution.
23. The method according to claim 22, wherein said non-steroidal
anti-inflammatory agent is added to an aqueous solution containing
a polymer dispersed therein and said divalent cation source.
24. The method according to claim 23, wherein said aqueous solution
further comprises EDTA and said dispersed polymer is a water
insoluble, water-swellable crosslinked carboxy-containing
polymer.
25. The method according to claim 24, wherein said non-steroidal
anti-inflammatory agent comprises diclofenac and said divalent
cation source is CaCl.sub.2 MgCl.sub.2 or MgSO.sub.4.
26. An ophthalmic composition obtained by combining at least (1)
sodium diclofenac, (2) a divalent metal salt, (3) a water
insoluble, water-swellable polymer, and (4) water.
27. The composition according to claim 26, which further comprises
EDTA and wherein said divalent metal salt is CaCl.sub.2, MgCl.sub.2
or MgSO.sub.4.
28. The composition according to claim 26, wherein said sodium
diclofenac is added to an aqueous suspension comprising said
divalent metal salt, said water-swellable polymer and said
water.
29. The composition according to claim 1, further comprising
benzalkonium chloride.
30. An ophthalmic composition comprising an aqueous suspension of a
crosslinked carboxyl-containing polymer, solid diclofenac in
free-acid form, dissolved diclofenac, and dissolved Mg.sup.++ or
Ca.sup.++ cations in an amount of from about 1 to 5 times the
stoichiometric equivalent amount per mole of said solid diclofenac;
said composition having a pH of from about 4.0 to about 6.7 and the
total amount of diclofenac being a pharmaceutically effective
amount and said solid diclofenac comprising 85 to 95 mol % of the
total amount of diclofenac.
31. The composition according to claim 30, further comprising 0.03
to 0.3 wt. % sodium perborate, 0.003 to 0.03 wt. % polyphosphonic
acid peroxy stabilizer and 0.01 to 0.1 wt. % EDTA.
32. The composition according to claim 31, wherein said sodium
perborate is contained in an amount of about 0.28 wt. % and said
polyphosphonic acid peroxy stabilizer is diethylene triamine
penta(methylene-phosphonic acid).
33. A preserved ophthalmic composition comprising water, about 0.01
to 0.5 wt. % of a perborate salt, about 0.001 to 0.06 wt. % of a
polyphosphonic acid peroxy stabilizer, and about 0.01 to 0.1 wt. %
of ethylenediaminetetraacetic acid.
34. The composition according to claim 33, wherein said water is
sterile water, said perborate is sodium perborate contained in an
amount of from 0.03 to 0.3 wt. %, and said polyphosphonic acid
peroxy stabilizer is a compound of formula I or II: 3wherein x is
an integer of 0 to 3 and k, m, n, o, and p are each independently
an integer of 1 to 4; 4wherein q, r, s, and t are each
independently an integer of 0 to 4.
Description
[0001] This application is a Continuation-in-Part of prior
co-pending application Ser. No. 08/863,015, filed May 23, 1997, the
entire contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to ophthalmic compositions and
more particularly, to ophthalmic compositions containing a divalent
cation and a non-steroidal anti-inflammatory agent and/or to
ophthalmic compositions containing a preservative system.
[0004] 2. Description of the Related Art
[0005] Non-steroidal anti-inflammatory agents can be used in a
variety of ophthalmic treatments such as for treating ocular tissue
inflammation and its associated pain. Additional uses include (i)
preventing particular side-effects from surgical trauma (e.g., on
the pupil preventing surgical meiosis), (ii) preventing fluid
accumulation in the back of the eye after cataract surgery
(post-surgical macular edema) and (iii) preventing the appearance
of inflammatory cells and vessel leakage in the anterior chamber.
Diclofenac, suprofen, and flurbiprofin are specific examples of
non-steroidal anti-inflammatory agents that have been used for the
treatment of postoperative inflammation in patients who have
undergone cataract extraction. Topical application of non-steroidal
anti-inflammatory agents in the eye also appears to relieve some of
the itching due to allergic conjunctivitis.
[0006] In the past, anti-inflammatory agents, in general, have been
administered in solutions at neutral pH. Injection of
anti-inflammatory agents in the form of a suspension has also been
proposed. Suspensions have been used for topical ophthalmic
applications when the drug is not very soluble. However, when the
drug is soluble, at an acceptable pH, solutions are normally used
to avoid potential irritation caused by the particles of the
suspension. The following patents illustrate ophthalmic solutions
containing non-steroidal anti-inflammatory agents, including
diclofenac.
[0007] U.S. Pat. No. 4,960,799 to Nagy concerns a storage stable
aqueous solution of sodium
ortho-(2,6-dichlorophenyl)aminophenylacetate acid, which is the
chemical name for diclofenac sodium, for topical treatment of
ocular inflammation. The solution taught by Nagy has a pH of about
7.0 to 7.8.
[0008] U.S. Pat. No. 4,829,088 to Doulakas also relates to an
ophthalmic medicament containing diclofenac sodium in aqueous
solution. The solution contains
2-amino-2-hydroxymethyl-1,3-propanediol as a preservative.
[0009] U.S. Pat. No. 5,110,493 to Cherng-Chyi et al. relates to
ophthalmic non-steroidal anti-inflammatory drug formulations
containing a quaternary ammonium preservative and a non-ionic
surfactant.
[0010] Patent Abstracts of Japan, Vol. 8, No. 7, Abs. Gp. C-204,
concerning Japanese published application 58-174309 (pub. Oct. 13,
1983) relates to an antiphlogistic eye drop composition containing
(1) a non-steroidal antiphlogistic agent having a carboxyl group in
its structure and (2) a physiologically permissible calcium or
magnesium salt. The salt is described as an irritation mitigating
agent and is normally added in an amount of 1-1.5 mol per 1 mol of
the non-steroidal agent. Sodium diclofenac is specifically
mentioned as the non-steroidal antiphlogistic agent and the pH of
the composition is preferably maintained in the 7-8 range.
[0011] However, a problem with the use of non-steroidal
anti-inflammatory agents, as recognized in the above-mentioned
Japanese published application, is that stinging or burning
sensations are commonly experienced during the first few minutes
after topical administration on the eye. Not only are patients who
experience such stinging likely to avoid regularly taking their
medication, they also receive less benefit from each application.
Specifically, the stinging causes tearing which washes away the
drug. Having physically removed a portion of the drug from the eye
by tearing, the bioavailability of the drug is reduced.
[0012] In addressing the stinging problem, it has been proposed to
supply a portion of the non-steroidal anti-inflammatory agent in
suspension form, as is described in commonly assigned co-pending
application Ser. No. 08/248,500, filed May 24, 1994 (the entire
contents of which are hereby incorporated by reference). The
particle must dissolve before it can treat the eye. By providing
some of the active agent as a particle, the flow of the drug onto
the eye is delayed; i.e., providing some of the active agent as a
particle reduces the initial concentration of the drug contacting
the eye. This delay in drug delivery contrasted with the prior
compositions wherein all of the agent was in solution, owing to a
pH of 7-8, thereby immediately providing to the cornea a high
concentration of the drug. The high concentration of the drug on
the eye was believed to aggravate the burning and stinging effects
of the drug.
[0013] While some improvements have been made with respect to the
stinging problem by such a technique, there is still a segment of
the population that will experience stinging when topically
administering non-steroidal anti-inflammatory ophthalmic
compositions. Accordingly, further improvements are desirable.
[0014] Additionally, preserving an ophthalmic composition that
contains a non-steroidal anti-inflammatory agent can be
problematic. Conventional broad spectrum antimicrobial agents like
benzalkonium chloride (BAK) tend to interact with the non-steroidal
anti-inflammatory agents over time and thereby reduce the efficacy
of the medication. Indeed, as a general matter, preservatives in
ophthalmic compositions are not entirely satisfactory. Effective,
broad spectrum antimicrobials tend to reduce the storage stability
of the composition and/or have adverse interactions with other
components.
[0015] A useful preservative system that seeks to overcome some of
these deficiencies is disclosed in U.S. Pat. Nos. 5,576,028 and
5,607,698. These systems use a low amount of hydrogen peroxide, or
a hydrogen peroxide source, as a preservative in combination with a
peroxy stabilizer. The stabilizer is preferably a phosphonic acid
such as diethylene triamine penta(methylene-phosphonic acid) and
the like which are commercially available from Monsanto under the
DEQUEST brand name. Although this system is quite useful, certain
improvements in storage stability would be desirable.
SUMMARY OF THE INVENTION
[0016] It is an object of the present invention to provide an
ophthalmic composition that contains a topically effective amount
of a non-steroidal anti-inflammatory agent and that is no more
irritating than conventional eye drops.
[0017] It is another object of the present invention to provide a
non-steroidal anti-inflammatory agent-containing ophthalmic
composition that can be taken by a large segment of the population
without experiencing stinging or irritation.
[0018] A further object of the present invention is to provide a
preserved ophthalmic composition that exhibits good stability
during storage.
[0019] Another object of the present invention is to provide a
method for treating diseases of the eye, including inflammation, by
topically applying to eyes in need of such treatment a
non-steroidal anti-inflammatory agent-containing ophthalmic
composition.
[0020] Preferred forms of the invention contemplated accomplish at
least some of the above objects. One embodiment of the invention is
an ophthalmic composition comprising an aqueous medium containing
an effective amount of a non-steroidal anti-inflammatory agent,
wherein at least about 80 mol. % of said agent is in the form of a
precipitate, and at least about 0.5 equivalents of a
pharmacologically acceptable divalent cation per mole of said
non-steroidal anti-inflammatory agent; said aqueous medium having a
pH of from about 4.0 to 6.7. Another embodiment of the invention
relates to a method for treating an eye, which comprises
administering to an eye in need thereof an effective amount of such
an ophthalmic composition. A further aspect of the present
invention relates to a method for making such an ophthalmic
composition. Another preferred embodiment of the present invention
relates to an ophthalmic composition that is formed by combining at
least (1) sodium diclofenac, (2) a divalent metal salt, (3) a water
insoluble, water-swellable polymer, and (4) water.
[0021] A further embodiment of the invention is an ophthalmic
composition which comprises water, about 0.01 to 0.5 wt. % of a
perborate salt, about 0.001 to 0.06 wt. % of a polyphosphonic acid
peroxy stabilizer, and about 0.01 to 0.1 wt. % of
ethylenediaminetetraacetic acid. The composition in this embodiment
may further comprise a pharmaceutically active agent such as a
non-steroidal anti-inflammatory agent.
BRIEF DESCRIPTION OF THE DRAWING
[0022] FIG. 1 shows the illustrious results of Example 21 regarding
release rate curves for an inventive and a comparative ophthalmic
composition.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present inventors have discovered that by providing the
non-steroidal anti-inflammatory (NSAI) agent as a solid and in the
presence of a divalent cation, the dissolution of the NSAI agent
during the first several minutes at neutral pH is sufficiently
slowed so as to further avoid stinging the eye. For reasons that
are not entirely clear, stinging and burning irritation are
typically only induced during the first minutes after contact with
a sufficiently high concentration of NSAI agent. After this initial
time period, the eye is apparently no longer sensitive to the NSAI
agent, regardless of its concentration level. Thus, by delaying the
dissolution of the NSAI agent during the first few minutes, the
initial NSAI agent concentration on the eye can be sufficiently low
to avoid irritation. Afterward, the high concentration caused by
the dissolution of the solid NSAI agent precipitate is too late to
cause irritation. In this way the stinging problem is effectively
avoided while still providing a topically effective dose of NSAI
agent.
[0024] In contrast, the typical prior art composition would supply
all of the NSAI agent as a solute and thus apply an immediate high
concentration to the surface of the eye. Such a technique has the
greatest chance of inducing stinging in the patient. While the use
of sodium diclofenac in both suspension and solution form,
simultaneously, is described in the above-mentioned co-pending
application and provides good results, the presence of a divalent
cation in accordance with the present invention improves the
avoidance of stinging. The divalent cation reduces the solubility
of the NSAI agent in the aqueous medium and thus reduces the
dissolution rate of the solid NSAI agent precipitate during the
first several minutes after administration.
[0025] As used in this application, the term "divalent cation"
means a cation having a +2 charge. The divalent cation can be in
either solid or dissolved form, or both. In solid form, the cation
is ionically bonded to an anion thereby making a salt. When in
solution, the cation is not required to be directly associated with
a specific anion. Typically the cation is, or contains, a metal;
i.e., a "metal divalent cation". Examples of suitable divalent
cations include Group IIA elements (alkaline earth metals) such as
calcium, magnesium, barium, etc. Particularly preferred divalent
cations are Ca.sup.++ and Mg.sup.++. The divalent cation and any
salts thereof in the composition are pharmacologically acceptable
so as to not harm the eye or the patient. Typical anions include
chlorides, sulfates, and the NSAI agent.
[0026] The divalent cation is only required to be present in the
composition and is not necessarily associated or otherwise bonded
with the NSAI agent. In one embodiment, all or essentially all of
the divalent cation is in solution with no cation present in the
solid NSAI agent.
[0027] The amount of divalent cation is at least about 0.5
equivalents and generally within the range of from about 0.5 to
about 10 equivalents, more preferably 1.0 to about 5.0 equivalents,
per mole of NSAI. Note that molar equivalents are specified since
NSAI agents may be monovalent and hence stoichiometrically require
only half as many moles of the divalent cation. Thus, for example,
one mole of Mg.sup.++ per one mole of diclofenac anion would be 2.0
equivalents of Mg.sup.++ (twice as much cation as is required).
[0028] "Non-steroidal anti-inflammatory agents" as used herein are
intended to mean any non-narcotic analgesic/non-steroidal
anti-inflammatory compound useful in treating or ameliorating a
disease or medical condition. They include drugs intended to
therapeutically treat conditions of the eye itself or the tissue
surrounding the eye and drugs administered via the ophthalmic route
to treat therapeutically a local condition other than that
involving the eye. Preferably the NSAI agent is useful as a
cyclooxygenase inhibitor. Cyclooxygenase is essential in the
biosynthesis of prostaglandins which have been shown in many animal
models to be mediators of intraocular inflammation. The NSAI agent
typically contains at least one carboxy group in its molecule.
[0029] Examples of NSAI agents that are useful in the present
invention include aspirin, benoxaprofen, benzofenac, bucloxic acid,
butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac,
diclofenac, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen,
fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen,
furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac,
ketorolac, ketroprofen, lactorolac, lonazolac, metiazinic,
miroprofen, naproxen, oxaprozin, oxepinac, phenacetin, pirprofen,
pirazolac, protizinic acid, sulindac, suprofen, tiaprofenic acid,
tolmetin, and zomepirac. Preferably, the NSAI agent is selected
from the group consisting of diclofenac, suprofen, flurbiprofen and
mixtures thereof.
[0030] The composition of the present invention contains at least
80% of the NSAI agent in precipitate form. This means that 80%, by
mole, of the NSAI is in a solid state. The remainder, if any, is in
solution. In this regard the term "precipitate" is not meant to
require that the solid was formed by a precipitation process,
although such is usually the case. Preferably, 85% to 95% of the
NSAI agent is in precipitate form. The precipitate is usually
dispersed in the aqueous medium or carried on a dispersed carrier
such as a polymer particle, but such a dispersed form is not
required.
[0031] In one embodiment of the invention, the precipitate is the
free-acid form (or free-base form) and not a salt form of the NSAI
agent. Generally, the free-acid is almost always formed, even if
formed from an NSAI divalent salt solution. For example,
originally, a calcium or magnesium salt of diclofenac was believed
to have been formed as the precipitate. However, subsequent
investigations showed that the precipitate was in fact the
free-acid of diclofenac. The divalent cation remained in solution.
The presence of this divalent cation serves to reduce the
solubility of the NSAI agent: thereby causing the desired delayed
release. Alternatively, the precipitate can be a salt of the
divalent cation and the NSAI agent or a mixture of salt and the
free-acid forms.
[0032] The remaining portion, if any, of the NSAI agent is in
solution (a solute) and is typically in a salt form such as sodium
diclofenac or magnesium diclofenac for example.
[0033] The total amount of NSAI agent present in the composition is
an amount effective to treat the selected target condition.
Generally the concentration will be about 0.001 to about 5.0% by
weight of the composition. Preferably, the drug is about 0.005 to
about 3.0% by weight of the composition, and more preferably about
0.1 to about 1.0% by weight of the composition. These same ranges
of drug concentrations are believed to be appropriate for treating
a wide range of conditions, such as those discussed above, in
addition to treating inflammation.
[0034] The pH of the aqueous medium is set to be within the range
of 4.0 to 6.7. Importantly the pH is below that of the pH of the
eye. In this way, upon topical application of the composition to
the eye, an increase in pH occurs thereby changing the solubility
equilibrium of the NSAI agent and causing the precipitate to
dissolve. As slow dissolution during the first minutes after
administration is desired, the use of a lower pH is preferred, such
as from 4.0 to 6.5.
[0035] The most preferred composition contains solid diclofenac in
free-acid form and all of the divalent cation as well as the
remaining diclofenac in solution. The divalent cation is preferably
calcium or magnesium. One of the advantages of this composition is
the ability to fully (100%) redissolve at pH 7.0 or above with
adequate residence time in the eye. This means that all of the
diclofenac is recovered and made bioavailable when the composition
is placed into the eye.
[0036] The aqueous medium used in the present invention is made of
water that has no physiologically or ophthalmologically harmful
constituents. Typically purified or deionized water is used. The pH
is adjusted by adding any physiologically and ophthalmologically
acceptable pH adjusting acids, bases or buffers. Examples of acids
include acetic, boric, citric, lactic, phosphoric, hydrochloric,
and the like, and examples of bases include sodium hydroxide,
sodium phosphate, sodium borate, sodium citrate, sodium acetate,
sodium lactate, tromethamine, THAM
(trishydroxymethylamino-methane), and the like. Salts and buffers
would include citrate/dextrose, sodium bicarbonate, ammonium
chloride and mixtures of the aforementioned acids and bases.
[0037] The osmotic pressure (.pi.) of the present composition is
preferably from about 10 milliosmolar (mOsM) to about 400 mOsM. If
necessary, the osmotic pressure can be adjusted by using
appropriate amounts of physiologically and ophthalmologically
acceptable salts or excipients. When needed, sodium chloride is
preferred to approximate physiologic fluid, and amounts of sodium
chloride ranging from about 0.01% to about 1% by weight, and
preferably from about 0.05% to about 0.45% 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, phosphate, 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. Sugars like
mannitol, dextrose, glucose or other polyols may be added to adjust
osmolarity.
[0038] The composition of the present invention may contain water
soluble polymers or water insoluble polymers as a suspending agent.
Examples of such soluble polymers are dextran, polyethylene
glycols, polyvinylpyrolidone, polysaccaride gels, Gelrite.RTM., and
cellulosic polymers like hydroxypropyl methylcellulose as well as
other polymeric demulcents. Water insoluble polymers are preferably
crosslinked carboxy-vinyl polymers.
[0039] A preferred embodiment of the invention provides the
ophthalmic composition as either gel or liquid drops that contain
water insoluble, water-swellable polymers which release the drug
over time; i.e., over one or more hours. Preferably, the polymer is
contained in an amount of about 0.1 to about 6.5%, more preferably
about 0.5 to about 1.3% by weight based on the total weight of the
composition. These polymer carriers include lightly crosslinked
carboxy-containing polymers (such as polycarbophil (Noveon AA-1) or
Carbopol.RTM.) which typically have an average dry particle size of
not more than about 50 .mu.m in equivalent spherical diameter, more
preferably not more than 20 .mu.m in equivalent spherical diameter.
The crosslinked carboxy-containing polymers can be formed from
carboxy-containing monoethylenically unsaturated monomers such as
acrylic acid, methacrylic acid, crotonic acid, and the like and
from suitable crosslinking agents such as difunctional crosslinkers
including divinyl glycol, divinyl benzene,
2,5-dimethyl-1,5-hexadiene, and polyalkenyl polyether compounds.
The carboxy-containing polymer backbone can be a homopolymer or a
copolymer comprised of two or more monomer species. When two or
more monomers are used, non-carboxy-containing monomers may be
employed, such as acrylic acid esters and methacrylic acid esters
(ethyl acrylate, methyl methacrylate, etc.), vinyl acetate,
N-vinylpyrrolidone, and the like. These non-carboxy-containing
comonomers are preferably present in an amount of not more than 40
wt. %, more preferably 0 to 20 wt. %, based on the total weight of
monomers present. The amount of crosslinker employed is preferably
from about 0.01 to 5%, more preferably from 0.1 to 1.0%, based on
the total weight of monomers present. Suitable carboxy-containing
polymers for use in the present invention and methods for making
them are described in U.S. Pat. No. 5,192,535 to Davis et al. which
is hereby incorporated by reference. A suitable carboxy-containing
polymer system for use in the present composition is known by the
tradename DuraSite.RTM., containing polycarbophil, which is a
sustained release topical ophthalmic delivery system that releases
the drug at a controlled rate.
[0040] The ophthalmic compositions of the present invention have a
viscosity that is suited for the selected route of administration.
A viscosity up to about 30,000 centipoise is useful for a drop.
About 30,000 to about 100,000 centipoise is an advantageous
viscosity range for ophthalmic administration in ribbon form. The
viscosity can be controlled in many ways known to the worker
skilled in the art.
[0041] In one embodiment, the amount of insoluble lightly
crosslinked polymer particles, the pH, and the osmotic pressure 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
500 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. Alternatively, when water soluble
polymers are used, 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.
[0042] Ophthalmic compositions of the present invention may be
formulated so that they retain the same or substantially the same
viscosity in the eye that they had prior to administration to the
eye. Alternatively, ophthalmic compositions of the present
invention may be formulated so that there is increased gelation
upon contact with tear fluid. For instance, when a formulation
containing DuraSite.RTM. is administered to the eye at a lower pH,
the DuraSite.RTM. system swells upon contact with tears. This
gelation or increase in gelation leads to entrapment of the
suspended drug particles, thereby extending the residence time of
the composition in the eye. The drug is released slowly as the
suspended particles dissolve over time as the solubility of the
drug is higher in the tear fluid. All these events eventually lead
to increased patient comfort, increase in the time the drug is in
contact with the eye tissues, thereby increasing the extent of drug
absorption and duration of action of the formulation in the
eye.
[0043] The viscous gels that result from fluid eye drops typically
have residence times in the eye ranging from about 2 to about 12
hours, e.g., from about 3 to about 6 hours. The agents contained in
these drug delivery systems will be released from the gels at rates
that depend on such factors as the drug itself and its physical
form, 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.
Preferably, the compositions provide a sustained concentration of
the NSAI agent of between 10.sup.-8 and 10.sup.-4 M, and more
preferably between 10.sup.-7 and 10.sup.-5 M, in the aqueous or
treated tissue of the eye for at least two hours, preferably at
least three hours.
[0044] The composition of the present invention will ordinarily
contain surfactants and, if desired, adjuvants, including
additional medicaments, buffers, antioxidants, tonicity adjusters,
preservatives, thickeners or viscosity modifiers, and the like.
Additives in the formulation may desirably include sodium chloride,
EDTA (disodium edetate), phosphonic acid, BAK (benzalkonium
chloride), perborate salt, sorbic acid, methyl paraben, propyl
paraben, and/or chlorhexidine. It should be noted that BAK was
found to be unexpectedly compatible with diclofenac in the present
ophthalmic composition. While the reasons for this are not entirely
clear, and without wishing to be bound by any theory, the presence
of the divalent cation is believed to prevent the BAK from
complexing the diclofenac out of the system.
[0045] The preferred preservative in the divalent cation
non-steroidal anti-inflammatory ophthalmic composition is sodium
perborate in an amount of from about 0.01 to 0.5 wt. %. more
preferably from 0.03 to 0.3 wt. %.
[0046] In this connection, applicants have also discovered that a
perborate salt can be effectively stabilized by the presence of
both a polyphosphonic acid peroxy stabilizer and EDTA. This
discovery was surprising in that the presence of EDTA would have
been expected to interfere with the complexing action of the
polyphosphonic acid stabilizer. Moreover, the presence of EDTA
surprisingly enhances the stability of the composition. This three
component preservative system is applicable to any aqueous
ophthalmic composition including saline solutions, eye lubricants,
medicated compositions, etc. and is not limited to use in
combination with a non-steroidal anti-inflammatory agent. The
preservative system comprises (1) about 0.01 to 0.5 wt. %,
preferably 0.03 to 0.3 wt. %, of a perborate salt; (2) about 0.001
to 0.06 wt. %, preferably 0.003 to 0.3 wt. %, of a polyphosphonic
acid peroxy stabilizer; and (3) about 0.01 to 0.1 wt. % of EDTA,
based on the total weight of the composition. The preservative
system may additionally comprise 0.05 to 0.2 parts of BAK. The
perborate salt is preferably sodium perborate.
[0047] A "polyphosphonic acid peroxy stabilizer" means any compound
containing at least two --PO.sub.3H.sub.2 moieties or the
pharmacologically acceptable salt thereof, and that is capable of
stabilizing a peroxy compound. Such compounds are generally well
known in the prior art. Preferably the polyphosphonic acid peroxy
stabilizer is a compound of the formula I or II or a
pharmacologically acceptable salt thereof: 1
[0048] wherein x is an integer of 0 to 3 and k, m, n, o, and p are
each independently an integer of 1 to 4. Preferably x is 2 and k,
m, n, o, and p are each 1 or 2. 2
[0049] wherein q, r, s, and t are each independently an integer of
0 to 4. Preferably q, r, s, and t are 0 or 1, and most preferably
all are zero.
[0050] Many of the compounds of formulas I and II are sold by
Monsanto under the DEQUEST brand name. A preferred compound is
diethylene triamine penta(methylene-phosphonic acid), which
corresponds to formula I, and is sold as DEQUEST 2060.
[0051] The water used in the preserved ophthalmic composition of
the present invention is normally sterilized. The preserved
ophthalmic composition can contain additional ingredients including
any of the ingredients discussed previously. For example, sodium
chloride can be present as part of a saline solution; a
carboxy-containing polymer, such as polycarbophil, can be present
to form a stably preserved suspension; etc. With respect to the
latter composition, a preferred form further includes magnesium
ions (Mg.sup.++) in addition to the polymer and the
perborate/polyphosphonic acid peroxy stabilizer/EDTA system. The
amount of magnesium is not particularly limited, but typically
ranges from about 0.005 to 0.5 wt. %, preferably 0.02 to 0.2 wt. %
(the amount of polymer being the same as described above). Such a
composition is well preserved and also exhibits a stable viscosity
during storage.
[0052] Alternatively, a pharmaceutically active agent may be
present as part of a medicated composition. In this regard, a
"pharmaceutically active agent" is broader in scope than an NSAI
agent and embraces any agent with pharmaceutical utility that can
be used to treat the eye or administered via the eye in treating a
disease or condition of the patient.
[0053] The preservative system can used in a variety of aqueous
ophthalmic compositions such as saline solutions for cleaning
contact lenses, as an eye wash, as an eye lubricating or wetting
composition, and as a medicated composition. The preservative
system of the present invention is preferably combined with the
above-described divalent cation-containing ophthalmic
composition.
[0054] The compositions of the present invention can be prepared
from known materials through the application of known techniques by
workers of ordinary skill in the art without undue experimentation.
In general, compositions are formed by combining the NSAI agent, a
divalent cation source, optionally a polymer, and water. In one
embodiment, the divalent cation is first completely dissolved in an
aqueous solution, adjusting the pH or temperature if necessary. The
divalent cation source is typically in the form of a salt, but any
water soluble form is acceptable. Preferred divalent cation sources
are divalent metal salts such as CaCl.sub.2, MgCl.sub.2 and
MgSO.sub.4. The NSAI agent is then added, typically in the form of
a salt although such is not required, resulting in precipitation of
the NSAI agent. Generally the precipitation will be immediate
without adjustment of the solution. However, aids in causing
precipitation, such as seeding, may also be used, either alone, or
in addition to pH modifiers, in order to encourage or enhance
precipitate formation.
[0055] After the precipitation of the NSAI agent, the polymer, if
any, can be added to the aqueous composition by conventional
techniques. The resulting composition is sterilized and then the
remaining ingredients such as buffers, surfactants, etc. are added
thereto. It is not preferred to heat sterilize after the
precipitate is formed in that redisolving and recrystallization of
the precipitate can occur and may adversely effect the precipitate,
e.g. increasing the crystal size. Alternatively, the
precipitate-containing solution can be combined with a sterilized
aqueous polymer dispersion, optionally containing buffer,
surfactant, preservative and/or other ingredients.
[0056] In another embodiment, the NSAI agent is added to a solution
that contains the divalent cation source and optionally a dispersed
polymer to form the precipitate-containing composition. The
solution can be previously sterilized and preferably contains all
ingredients except the NSAI agent (and possibly a final portion of
water) at the time of NSAI agent addition.
[0057] If a carboxy-containing polymer is to be added to the
composition, then the amount of free divalent cation added should
be controlled so as not to significantly exceed the stoichiometric
amount. Specifically, a large excess of free calcium, magnesium,
divalent cations, etc., could react with and complex the polymer
thereby disrupting the suspension and preventing the release of the
NSAI agent. Alternatively a chelating agent such as EDTA should be
provided in the composition in order to chelate any excess divalent
cation (e.g., calcium, magnesium, etc.). Such a chelating agent can
be provided in the dispersed polymer-containing solution, if
desired. The amount of chelating agent depends in part on the
amount of NSAI agent and divalent cation source and need only be
sufficient to avoid the above-mentioned disruption.
[0058] Although the above described methods are suitable for making
the present ophthalmic composition, they are not the only methods.
Other methods for making the present composition can be used.
[0059] The ophthalmic compositions according to the present
invention can be topically administered in accordance with
techniques familiar to persons skilled in the art. The finished
formulations are preferably stored prior to use in opaque or brown
containers to protect them from light exposure, and under an inert
atmosphere. These compositions can be packaged in
preservative-free, single-dose non-reclosable containers. This
permits a single dose of the medicament to be delivered to the eye
as a drop or ribbon, with the container then being discarded after
use. Such containers eliminate the potential for
preservative-related irritation and sensitization of the corneal
epithelium, as has been observed to occur particularly from
ophthalmic medicaments containing mercurial preservatives. Multiple
dose containers can also be used, if desired, particularly since
relatively low viscosities can be obtained in compositions of the
invention which permit constant, accurate dosages to be
administered dropwise to the eye as many times each day as
necessary.
[0060] The following non-limiting example serves to illustrate
certain features of the present invention.
EXAMPLES 1-5
[0061] Hydrated polymer is prepared by adding 2.3 grams of
polycarbophil or 2.4 grams of Carbopol.RTM.974P to 100 grams of
purified water in a 600 ml beaker and mixing for 30 minutes with an
overhead stirrer. Then, 0.2 gram of edetate disodium is added and
mixed for 5 minutes followed by 1 gram of sodium chloride, which is
also mixed for 5 minutes. In a separate 50 ml beaker, different
amounts of poloxamer 407 is dissolved in 15 grams of purified
water. The solution is then added to the polycarbophil or Carbopol
dispersion and mixed for 5 minutes. After adjusting the pH of the
dispersion to 4 using 2N sodium hydroxide, it is sterilized by
autoclaving at 121.degree. C. for 20 minutes. The drug solution is
prepared by combining, in a separate 100 ml beaker, different
amounts of diclofenac sodium, 2 grams of mannitol and various
amounts of CaCl.sub.2 dihydrate in 40 grams of purified water. The
resulting suspension is then added to the polycarbophil or Carbopol
dispersion and mixed for 15 minutes. The formulation is neutralized
by adjusting the pH of the formulation to 6.0 using 2N sodium
hydroxide. This causes it to gel. Finally, the weight of the
solution is brought to 200 grams by adding purified water.
1TABLE 1 Amount Of Each Component Added to make the Formulations of
Examples 1-4 Example 1 Example 2 Example 3 Example 4 Ingredients
Wt. % Wt. % Wt. % Wt. % polycarbophil 1.15 1.15 1.15 1.15 edetate
disodium 0.1 0.1 0.1 0.1 sodium chloride 0.5 0.5 0.5 0.5 diclofenac
sodium 0.1 0.3 0.1 0.3 calcium chloride 0.0173 0.0519 0.0208 0.0623
dihydrate poloxamer 407 0.05 0.1 0.05 0.1 mannitol 1.0 1.0 1.0 1.0
purified water q.s. 100 100 100 100
[0062]
2 Amount of Each Component Added to make the Formulation of Example
5 Example 5 Ingredients Wt. % Carbopol .RTM. 974P 1.2 edetate
disodium 0.1 sodium chloride 0.5 diclofenac sodium 0.1 calcium
chloride dihydrate 0.0173 poloxamer 407 0.05 mannitol 1.0 purified
water q.s. 100
EXAMPLES 6-9
[0063] Hydrated polycarbophil (Noveon AA-1) is prepared by adding
2.3 grams of polycarbophil to 100 grams of purified water in a 600
ml beaker and mixing for 30 minutes with an overhead stirrer. Then
0.2 gram of edetate disodium is added and mixed for 5 minutes
followed by 1 gram of sodium chloride mixed for 5 minutes. In a
separate 50 ml beaker, different amounts of poloxamer 407 (a
commercially available surfactant) is dissolved in 15 grams of
purified water. The solution is then added to polycarbophil
dispersion and mixed for 5 minutes. After adjusting the pH of the
dispersion to 4 using 2N sodium hydroxide, it is sterilized by
autoclaving at 121.degree. C. for 20 minutes. The drug solution is
prepared by combining, in a separate 100 ml beaker, different
amounts of diclofenac sodium, 2 grams of mannitol and various
amounts of magnesium sulfate heptahydrate in 40 grams of purified
water. The resulting suspension is then added to the polycarbophil
dispersion and mixed for 15 minutes. The formulation is neutralized
by adjusting the pH of the formulation to 6.0 using 2N sodium
hydroxide. This causes it to gel. Finally, the weight of the
solution is brought to 200 grams by adding purified water. The
amount of each component in Examples 5-8 is listed in Table 2.
3TABLE 2 Amount Of Each Component Added to Make the Formulations of
Examples 6-9 Example 6 Example 7 Example 8 Example 9 Ingredients
Wt. % Wt. % Wt. % Wt. % polycarbophil 1.15 1.15 1.15 1.15 edetate
disodium 0.1 0.1 0.1 0.1 sodium chloride 0.5 0.5 0.5 0.5 diclofenac
sodium 0.1 0.3 0.1 0.3 magnesium sulfate 0.0387 0.116 0.0464 0.139
heptahydrate poloxamer 407 0.05 0.1 0.05 0.1 mannitol 1.0 1.0 1.0
1.0 purified water q.s. 100 100 100 100
EXAMPLES 10-13
[0064] Hydrated polycarbophil (Noveon AA-1) is prepared by adding
1.6 grams of polycarbophil to 100 grams of purified water in a 600
ml beaker and mixing for 30 minutes with an overhead stirrer. Then
0.2 gram of edetate disodium is added and mixed for 5 minutes
followed by 1 grams of sodium chloride mixed for 5 minutes. In a
separate 50 ml beaker, 0.02 grams of benzalkonium chloride is
dissolved in 20 grams of purified water. The solution is then added
to the polycarbophil dispersion and mixed for 5 minutes. In a
separate 50 ml beaker, different amounts of poloxamer 407 is
dissolved in 15 grams of purified water. The solution is then added
to polycarbophil dispersion and mixed for 5 minutes. After
adjusting the pH of the dispersion to 4 using 2N sodium hydroxide,
it is sterilized by autoclaving at 121.degree. C. for 20 minutes.
The drug solution is prepared by combining, in a separate 100 ml
beaker, different amounts of diclofenac sodium, 3.0 grams of
sorbitol, 0.4 grams of glycerin and various amounts of calcium
chloride dihydrate in 40 grams of purified water. The resulting
suspension is then added to the polycarbophil dispersion and mixed
for 15 minutes. The formulation is neutralized by adjusting the pH
of the formulation to 6.0 using 2N sodium hydroxide. This causes it
to gel. Finally, the weight of the solution is brought to 200 grams
by adding purified water. The amount of each component in Examples
9-12 is listed in Table 3.
4TABLE 3 Amount Of Each Component Added to Make the Formulations in
Examples 10-13 Example Example Example Example Ingredients 10 Wt. %
11 Wt. % 12 Wt. % 13 Wt. % polycarbophil 0.8 0.8 0.8 0.8 edetate
disodium 0.1 0.3 0.1 0.1 sodium chloride 0.25 0.25 0.25 0.25
diclofenac sodium 0.1 0.3 0.1 0.3 calcium chloride 0.0173 0.0519
0.0208 0.0623 dihydrate benzalkonium chloride 0.01 0.01 0.01 0.01
poloxamer 407 0.05 0.1 0.05 0.1 glycerin 0.2 0.2 0.2 0.2 sorbitol
1.5 1.5 1.5 1.5 purified water q.s. 100 100 100 100
EXAMPLES 14-17
[0065] Hydrated polycarbophil (Noveon AA-1) is prepared by adding
1.6 grams of polycarbophil to 100 grams of purified water in a 600
ml beaker and mixing for 30 minutes with an overhead stirrer. Then
0.2 gram of edetate disodium is added and mixed for 5 minutes
followed by 1 grams of sodium chloride mixed for 5 minutes. In a
separate 50 ml beaker, 0.02 grams of benzalkonium chloride is
dissolved in 20 grams of purified water. The solution is then added
to the polycarbophil dispersion and mixed for 5 minutes. In a
separate 50 ml beaker, different amounts of poloxamer 407 is
dissolved in 15 grams of purified water. The solution is then added
to polycarbophil dispersion and mixed for 5 minutes. After
adjusting the pH of the dispersion to 4 using 2N sodium hydroxide,
it is sterilized by autoclaving at 121.degree. C. for 20 minutes.
The drug solution is prepared by combining, in a separate 100 ml
beaker, different amounts of diclofenac sodium, 3.0 grams of
sorbitol, 0.4 grams of glycerin and various amounts of calcium
chloride dihydrate in 40 grams of purified water. The resulting
suspension is then added to the polycarbophil dispersion and mixed
for 15 minutes. The formulation is neutralized by adjusting the pH
of the formulation to 6.0 using 2N sodium hydroxide. This causes it
to gel. Finally, the weight of the solution is brought to 200 grams
by adding purified water. The amount of each component in Examples
13-16 is listed in Table 4.
5TABLE 4 Amount Of Each Component Added to Make the Formulations of
Examples 14-17 Example Example Example Example Ingredients 14 Wt. %
15 Wt. % 16 Wt. % 17 Wt. % polycarbophil (Noveon 0.8 0.8 0.8 0.8
AA-1) edetate disodium 0.1 0.3 0.1 0.1 sodium chloride 0.25 0.25
0.25 0.25 diclofenac sodium 0.1 0.3 0.1 0.3 magnesium sulfate
0.0387 0.116 0.0464 0.139 heptahydrate benzalkonium chloride 0.01
0.01 0.01 0.01 poloxamer 407 0.05 0.1 0.05 0.1 glycerin 0.2 0.2 0.2
0.2 sorbitol 1.5 1.5 1.5 1.5 purified water q.s. 100 100 100
100
EXAMPLES 18-19
[0066] Hydrated polycarbophil (Noveon AA-1) is prepared by adding
1.6 grams of polycarbophil to 100 grams of purified water in a 600
ml beaker and mixing for 30 minutes with an overhead stirrer. Then
0.2 gram of edetate disodium is added and mixed for 5 minutes
followed by 1 grams of sodium chloride mixed for 5 minutes. In a
separate 50 ml beaker, 0.02 grams of benzalkonium chloride is
dissolved in 20 grams of purified water. The solution is then added
to the polycarbophil dispersion and mixed for 5 minutes. In a
separate 50 ml beaker, different amounts of poloxamer 407 is
dissolved in 15 grams of purified water. The solution is then added
to polycarbophil dispersion and mixed for 5 minutes. After
adjusting the pH of the dispersion to 4 using 2N sodium hydroxide,
it is sterilized by autoclaving at 121.degree. C. for 20 minutes.
The drug solution is prepared by combining, in a separate 100 ml
beaker containing 40 grams of purified water, Suprofen or
Flurbiprofen sodium, 3.0 grams of sorbitol, 0.4 grams of glycerin
and an amount of either magnesium sulfate heptahydrate or calcium
chloride dihydrate sufficient to form a precipitate of the drug.
The resulting suspension is then added to the polycarbophil
dispersion and mixed for 15 minutes. The formulation is neutralized
by adjusting the pH of the formulation to 6.0 using 2N sodium
hydroxide. This causes it to gel. Finally, the weight of the
solution is brought to 200 grams by adding purified water.
EXAMPLE 20
[0067] Hydrated hydroxypropyl methyl cellulose (HPMC) is prepared
by adding 2.0 grams of HPMC to 100 grams of purified water in a 600
ml breaker and mixing for 4 hours with an overhead stirrer. Then, 1
gram of sodium chloride, 0.242 grams of dibasic sodium phosphate
and 0.055 grams of monobasic sodium phosphate are added and mixed
for 5 minutes. In a separate 50 ml beaker, 0.02 grams of
benzalkonium chloride is dissolved in 20 grams of purified water.
The solution is then added to the HPMC dispersion and mixed for 5
minutes. In a separate 50 ml beaker, different amounts of poloxamer
407 is dissolved in 15 grams of purified water. The solution is
then added to the HPMC dispersion and mixed for 5 minutes. It is
sterilized by autoclaving at 121.degree. C. for 20 minutes. The
drug solution is prepared by combining, in a separate 100 ml beaker
containing 40 grams of purified water, either Diclofenac sodium,
Suprofen or Flurbiprofen sodium with 3.0 grams of sorbitol, 0.4
grams of glycerin and an amount of either magnesium sulfate
heptahydrate or calcium chloride dihydrate sufficient to form a
precipitate of the drug. The resulting suspension is then added to
the HPMC dispersion and mixed for 15 minutes. The formulation is
neutralized by adjusting the pH of the formulation to 6.0 using 2N
sodium hydroxide. Finally, the weight of the solution is brought to
200 grams by adding purified water.
EXAMPLE 21
[0068] To demonstrate the surprising effect of the present
invention, two ophthalmic compositions are prepared, which
essentially differ from each other with respect to the presence or
absence of a divalent cation. Composition A, made in accordance
with the present invention, includes the presence of a divalent
cation (Mg.sup.++). Comparative Composition B does not have a
divalent cation, but does have a monovalent cation (Na.sup.+) and
is similar to the exemplified compositions set forth in the
above-mentioned co-pending application Ser. No. 08/248,500, filed
May 24, 1994. The compositions are prepared from the ingredients
listed in the table below.
6 Composition A Composition B Ingredient (wt. %) (wt. %) Diclofenac
sodium 0.033 0.033 Magnesium chloride 0.2 -- Sodium chloride -- 0.5
Sodium perborate 0.28 -- Polycarbophil 0.7 1.15 Phosphonic acid
0.006 -- (Dequest 2060) EDTA -- 0.1 Mannitol 1.5 1.0 Boric acid
0.75 -- Poloxamer 407 0.05 0.05 Sodium hydroxide q.s. to pH 6.1
q.s. to pH 6.0 Purified water q.s. to 100 q.s. to 100
[0069] Each composition is tested to determine its release rate
over time. Samples are placed into a buffer solution contained in a
cell. The cell size is 0.6 ml and the buffer is a phosphonate
buffered saline solution containing 0.9% NaCl and 10 mM phosphate
at pH 7.4. Additional buffer is then steadily passed through the
cell via a peristalic pump at an appropriate rate to model natural
liquid turnover in the eye; here 6 ml/hr. The temperature is
maintained at approximately 37.degree. C. (body temperature). The
concentration of the medicament in the eluted buffer is measured
over time by spectroscopy, to thereby form a release rate curve.
Illustrious results are depicted in FIG. 1.
[0070] The release rate curve shown for composition A according to
the present invention shows a delay in the initial release. In
contrast, the release rate curve shown for composition B displays a
higher peak during the initial release. Thus, the composition
according to the present invention provides for improved delayed
release during the important initial contact period with the eye
and thereby reduces the tendency of stinging.
EXAMPLE 22
[0071] Further embodiments of the present invention are obtained by
combining the ingredients set forth in the following table.
7 Composition Composition Ingredient 22A (wt. %) 22B (wt. %) Sodium
diclofenac 0.03 to 0.1 0.03 to 0.1 Magnesium chloride hexahydrate
0.02 to 0.2 0.02 to 0.2 Sodium perborate 0.28 0.28 BAK -- 0.01
Polycarbophil 0.825 0.825 Dequest 2060 0.006 0.006 EDTA 0.025 0.025
Mannitol 1.5 1.5 Sodium chloride 0.05 0.05 Boric acid 1.0 1.0
Poloxamer 407 0.05 0.05 Sodium hydroxide q.s. to pH 6.1 q.s. to pH
6.1 Purified water q.s. to 100 q.s. to 100
[0072] The ingredients, except for the sodium diclofenac, are
preferably combined so as to form a polymer suspension. Then the
sodium diclofenac is added resulting in the precipitation of the
diclofenac free-acid. A final portion of water is then added to
complete the composition.
[0073] The above discussion of this invention is directed primarily
to preferred embodiments and practices thereof. It will be readily
apparent to those skilled in the art that further changes and
modifications in actual implementation of the concepts described
herein can easily be made or may be learned by practice of the
invention, without departing from the spirit and scope of the
invention as defined by the following claims.
* * * * *