Indian Patents. 253760:PROCESS FOR PREPARATION OF RUBBER MIXTURES CONTAINING SILICON DIOXIDE

Title of Invention	PROCESS FOR PREPARATION OF RUBBER MIXTURES CONTAINING SILICON DIOXIDE
Abstract	A method for providing oxidatively stable ophthalmic compositions for removing at least 80% oxygen from an ophthalmically compatible solution comprising at least one oxidatively unstable ophthalmic compound wherein 11-dihydro- 11 (1-methyl-4- piperdinylidene-5H-imidazo[2.1 -b] [3]benzazepine-3-carboxaldehyde.

Full Text	Methods for Providing Oxidatively Stable Ophthalmic Compositions FIELD OF THE INVENTION The present invention relates to methods for providing ophthalmic compounds that display oxidative stability, during processing, autoclaving, packaging, shipping or storage. BACKGROUND OF THE INVENTION Therapeutic agents for topical administration to the eye are generally formulated in either a liquid or gel form and must be kept sterile until administration. Accordingly, ophthalmic therapeutic agents are either packaged asceptically, which is cumbersome and expensive or are heat sterilized. Unfortunately, many therapeutic agents are not oxidatively stable, especially at elevated temperatures. EDTA has been used to improve the stability of certain therapeutic agents during autoclaving. However, there remains a need for processes capable of stabilizing unstable therapeutic agents that are susceptible to oxidative degradation. SUMMARY OF THE INVENTION The present invention relates to a method comprising removing at least about 80% oxygen from an ophthalmically compatible solution comprising at least one oxidatively unstable ophthalmic compound. DETAILED DESCRIPTION OF THE INVENTION The present invention comprises, consists of and consists essentially of stabilizing at least one oxidatively unstable ophthalmic compound dissolved in an ophthalmically compatible solution by removing at least about 80% oxygen from said ophthalmically compatible solution comprising at least one oxidatively unstable ophthalmic compound. In some embodiments at least about 90% of said oxygen is removed. In some embodiments at least about 95% of said oxygen is removed and in still other embodiments at least about 99% of said oxygen is removed. As used herein, oxidatively unstable ophthalmic compound ("OUOC") is any therapeutic agent which shows greater than 10% degradation when autoclaved in solution with at least one oxidative catalyst, but shows less than 10% degradation when autoclaved under the same conditions without said at least one oxidative catalyst. Oxidative instability may be measured by forming a solution of 3 ml packing solution containing 25 ppm of the therapeutic agent to be evaluated, and exposing the solution, with and without oxidative catalysts (100 ppm Cu2O and 100 ppm FeSO4) to autoclave conditions (120°C for 20 minutes). Examples of OUOC include oxidatively unstable pharmaceutical and nutraceutical compounds. In one embodiment the OUOC comprises at least one pharmaceutically active amines. In one embodiment the at least one OUOC comprises at least one tertiary cyclic amine. In another embodiment the at least one OUOC comprises at least one tertiary cyclohexyl amine. In another embodiment the OUOC comprises at least one therapeutic agent selected from as acycylovir, adrenalone, aminocaproic acid, amoxicillin, amotriphene, amoxecaine, amodiaquin, antazoline, atrophine, betaxolol, bupivacaine, carbachol, carteolol, chlorampenicol, chlortetracycline, corynathine, cromalyn sodium, cyclopentolate, demecarium, dexamethasone, dichlorphenamide, dibutoline, diclophenac, dipivefrin, ephedrine, erythromycin, ethambutol, eucatropine, fluoromethalone, gentamycin, gramicidin, homatropine, indomethacin, ketotifen, levallorphan, levobunolol, levocabastine, lidocaine, lignocaine, lomefloxacin, medrysone, mepivacaine, methazolamide, naphazoline, natamycin, natamycin, neomycin, noradrenaline, ofloxacin, oxybuprocaine, oxymetazoline, pheniramine, phenylephrine, physostigmine, pilocarpine, polymyxin B, prednisolone, proparacaine, pyrilamine, scopolamine, sorbinil, sulfacetamide, tamoxifen, tetracaine, tetracycline, tetrahydozoline, timolol, trifluridine, tropicamide, vidarabine, and salts and mixtures thereof. Examples of nutriceutical compounds include vitamins and supplements such as vitamins A, D, E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids, such as omega 3 and omega 6 fatty acids, combinations thereof, combinations with pharmaceutical compounds and the like. In yet another embodiment the OUOC comprises at least one therapeutic agent selected from ketotifen fumarate, nor ketotifen fumarate, ,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1- b][3]benzazepine-3-carboxaldehyde (CAS# 147084-10-4, olapatadine and mixtures thereof. In yet another embodiment the OUOC comprises at least one therapeutic agent selected from ketotifen fumarate, 11-dihydro-l 1-(1-methyl-4- piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde (CAS# 147084-10-4 and mixtures thereof. The concentration of the OUOC in the ophthalmically compatible solutions of the present invention may range from about 10 ppm to about 100,000 ppm, in some embodiments from about 10 to about 10,000 ppm, in some embodiments from about 10 to about 1,000 ppm and some embodiments from about 10 to about 500 ppm. The process of the present invention comprises removing at least 80% oxygen from the ophthalmically compatible solution comprising at least one OUOC. In some embodiments the amount of oxygen removed is at least about 90%, at least about 95%, and even at least about 99%. The oxygen removal is conducted prior to heat sterilization, such as autoclaving. For example, oxygen removal may be conducted either before or after the OUOC is added to the ophthalmically compatible solution. If the oxygen removal is conducted before the OUOC is added to the ophthalmically compatible solution, the solution should be kept under conditions sufficient to prevent oxygen from being introduced into the ophthalmically compatible solution during mixing and autoclaving. The oxygen may be removed by a number of methods including sparging, alternating freezing and thawing cycles, vacuum removal, vacuum removal in combination with agitation, combinations thereof and the like. When sparging is used at least one inert gas which is capable of displacing oxygen is bubbled through the ophthalmically compatible solution under conditions suitable to remove the desired amount of oxygen. Suitable inert gasses include nitrogen, argon, helium, combinations thereof and the like. Suitable sparging conditions include volumes of ophthalmically compatible solution of at least about 1L, between about 1 and about 6L; and between about 1 and about 4L. In some embodiments a volume of about 2L is desirable. The inert gas flow rate may be selected based upon the selected volume and desired sparging time. So, for example, higher volumes may require higher inert gas flow rates, sparging times or a combination of both. Suitable inert gas flow rates include from about 10 to about 1000 standard cubic centimeter per minute (SCCM). In some embodiments an inert gas flow rate of about 370 SCCM is desirable. Sparging times may vary based upon the other conditions as described above. Suitable sparging times include at least about 5 minutes, from about 5 minutes to 24 hours, from 5 minutes to 12 hours and in some embodiments at least about 8 hours. Any temperature can be used for sparging so long as the ophthalmically compatible solution remains a liquid and the OUOC is soluble in the ophthalmically compatible solution at the selected temperature. Temperatures between about 0 to about 40°C may be used in some embodiments. Alternatively the oxygen may be removed by freeze thaw degassing. Suitable pressures for freeze thaw degassing include those less than about 660 mmHg. For degassing an aqueous solution at room temperature, pressures between 660 and 760mm Hg are desirable. Gentle agitation or sonication increases the efficiency of the process. When sparging is used the process of the present may also include agitation which may be provided by any known method such as, but not limited to sonication, stirring, rolling, shaking, combinations thereof and the like. Freeze thaw degassing comprises freezing the ophthalmically compatible solution to form a solid and then thawing the solid. This process may be repeated. Alternatively, the ophthalmically compatible solution may be exposed to degas conditions below its vapor pressure. For example, if an ophthalmically compatible solution's boiling point at a given pressure is 20°C, the solution is cooled to less than about 20°C prior to evacuating the system to the desired pressure. When placed under a vacuum, all dissolved gases are removed from the ophthalmically compatible solution, while little or none of the other components (solvents or solutes) are displaced. Once the gas bubbles cease to escape from the ophthalmically compatible solution, the system is placed under a positive pressure of an inert gas such as nitrogen or argon, and allowed to warm up to ambient temperature. The degassing cycle described above may be repeated once or more depending on how sensitive the ophthalmically compatible solution is to oxidative degradation, with solutions which are more susceptible to degradation being subjected to more cycles. The ophthalmically compatible solution may be formed from any suitable ophthalmically compatible carrier. Suitable carriers include water, saline solution, mineral oil, petroleum jelly, water soluble solvents, such as C15-20 alcohols, C15-20 amides, C 15-20 alcohols substituted with zwitterions, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, methylhydroxypropyl-cellulose, hydroxypropylcellulose, chitosan and scleroglucan, acrylates or methacrylates, such as salts of poly(acrylic acid) or ethyl acrylate, polyacry lam ides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as poloxamers, e.g. Poloxamer F127, polyvinyl alcohol, polyvinyl methyl ether, polyethylene oxide, cross-linked poly(acrylic acid), such as neutral Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof. The concentration of the carrier is, for example, from 0.1 to 100000 times the concentration of the active ingredient combinations thereof and the like. When the ophthalmically compatible solution is an eye drop, suitable carriers include water, pH buffered saline solution, mixtures thereof and the like. The ophthalmically compatible solution of the present invention may also be used as the packaging or storage solution for an ophthalmic device, such as a contact lens. When the ophthalmically compatible solution is used as a packaging solution for a contact lens the carrier comprises a buffered saline solution. Any contact lens could be packaged with the ophthalmically compatible solution of the present invention, including conventional and silicone hydrogel contact lenses, such as but not limited to commercially available hydrogel formulations such as etafilcon, polymacon, vifilcon, genfilcon A, lenefilcon A, galyfilcon, senofilcon, balafilcon, lotrafilcon A, lotrafilcon B and the like. The ophthalmically compatible solution of the present invention may further comprise additional components such as antioxidants, demulcents, antibacterial agents, solubilizers, surfactants, buffer agents, tonicity adjusting agents, chelating agents, preservatives, wetting agents, thickeners, stabilizers, combinations thereof and the like. An example of a suitable stabilizer includes EDTA. The ophthalmically compatible solution of the present invention are ophthalmically compatible, and have a pH between about 5 and about 9, in some embodiments between about 6 to about 8 is desired. The ophthalmically compatible solution of the present invention may be formed by mixing the OUOC and any additional components with the selected carrier. When a liquid composition, such as an eye drop or packaging solution for a contact lens, the OUOC and any additional components are dissolved in the carrier. It is generally desirable that the shelf life of the ophthalmically compatible solution be in excess of about 6 months, and in some instances greater than about 1 year, or even more than about 2 years. During the shelf life of the ophthalmically compatible solution it is desirable that at least about than 80% of the original concentration of the OUOC remains, and in some embodiments greater than about 90%. The ophthalmically compatible solution of the present invention may in some embodiments further comprise at least one electron rich polymer. Suitable electron rich polymers are water-soluble, comprise at least one group with a free electron pair, have a weight average molecular weight, Mw, between about 1000 and about 2,000,000, and are substantially free from transition metal containing species. In some embodiments the electron rich polymers are substantially free from copper and iron containing species. As used herein, "substantially free from" means that transition metal containing species are present in the electron rich polymer in amounts which are insufficient to cause further degradation of the OUOC. Preferably the transition metal containing species are present in the electron rich polymer in amounts less than about 100 ppm, in some embodiments less than about 50 ppm and in some embodiments less than about 20 ppm. As used herein, water soluble means that the selected electron rich polymer does not precipitate or form visible gel particles at the concentrations selected and across the temperatures and pH regimes common for manufacturing, sterilizing and storing ophthalmic solutions. For purposes of the invention, the molecular weight is determined using a gel permeation chromatograph with a 90° light scattering and refractive index detectors. Two columns of PW4000 and PW2500, a methanol-water eluent of 75/25 wt/wt adjusted to 50mM sodium chloride and a mixture of polyethylene glycol and polyethylene oxide molecules with well defined molecular weights ranging from 325,000 to 194 are used. Suitable examples of electron rich polymers include polymers comprising esters, acids, amines, carbonates, carboxylates, thiols, lactates, amides, carbamates, phosphates, nitriles, lactams, and combinations thereof. Polymers which do not have groups with at least one free electron pair, such as polymers comprising only ether groups, alcohol groups or combinations thereof are not electron rich polymers are defined herein. A wide concentration of electronic donating groups may be included, however, the higher the concentration of electron donating groups, the less electron rich polymer will need to be used. Specific examples include homopolymers and random or block copolymers of methacrylic acid, acrylic acid, itaconic acid, fumaric acid, maleic acid, vinylpyrollidone, vinylmethacetimide, combinations thereof and the like. More specific examples include poly(acrylic acid), poly(vinylpyrollidone) and poly(vinylmethylacetamide) and combinations thereof and the like. In one embodiment the electron rich polymer comprises poly(acrylic acid). The electron rich polymer is present in the ophthalmically compatible solution in stabilizing effective amounts. A stabilizing effective amount will vary depending upon the OUOC, the concentration of the OUOC and the concentration of other components in the ophthalmically compatible solution, but generally stabilizing effective amounts are those sufficient to provide at least about a 5% improvement in stability. Suitable amounts of'electron rich polymer include between about 10 and about 5,000 ppm, in some embodiments between about 100 and about 5,000 ppm, in some embodiments between about 500 and about 3,000 ppm. These examples do not limit the invention. They are meant only to suggest a method of practicing the invention. Those knowledgeable in contact lenses as well as other specialties may find other methods of practicing the invention. However, those methods are deemed to be within the scope of this invention. Examples 1 A buffer solution was formed by dissolving 8.3 gm NaCl (from Sigma Aldrich), 9.1 gm boric acid (from Mallinckrodt) and 1 gm sodium borate (from Mallinckrodt) in 1L deionized water (from Milli Q). The resulting solution had a pH of 7.65. Ketotifen fumarate (from Sigma Aldrich) was added to prepare a solution of approximately 80 ppm in the buffer solution. The ketotifen solution (3 mL) was placed in vials, autoclaved for the number of cycles shown in Table 1, below and analyzed as a function of autoclave cycle (3 replicate per autoclave cycle) using HPLC using an HP 1100 and an Agilent Zorbax Eclipse XDB-C18 and Rapid Resolution HT 50 x 4.6 mm x 1.8 µ. column and the following conditions: Detector Wavelength : 299 nm Flow rate: 1.0 mL/min Injection Volume: 3 µL Mobile Phase: Eluent A: 17 % acetonitrile in 0.025 M dihydrogen potassium phosphate buffer 0.2 % triethylamine, 0.13 % o-phosphoric acid Eluent B: 50 % acetonitrile in 0.025 M dihydrogen potassium phosphate buffer 0.2 % triethylamine, 0.13 % o-phosphoric acid The results in Table 1 clearly show that even a single autoclave cycle has a substantial detrimental effect on the ketotifen concentration in a buffer solution. Example 2 Example 1 was repeated, except that the buffer solution was sparged (with nitrogen) overnight (-12 hrs) at about 370 standard cubic centimeter per minute (SCCM) and subsequently transferred to a nitrogen box ( ketotifen solution of about 90 ppm was prepared and placed in vials as described above, but in nitrogen box. The vials were autoclaved and analyzed as described in Example 1. The results are shown in Table 2, below. Comparing the results in Table 2 to those in Table 1, it is clear that sparging the buffer solution and maintaining the ketotifen solution under nitrogen significantly improved (from 0 to 98%) the ketotifen stability. Example 3 and 4 Examples 1 and 2 was repeated, except that 10 gm of poly(acrylic acid) (PAA, Mw, 225,000, from Polysciences, Inc., 20 % in water) was added to the buffer solution. The vials were autoclaved and analyzed as described in Example 1. The results are shown in Table 3, below. The results for Example 3 (inclusion of an electron rich polymer, such as PAA, with no sparging) are far superior to those of Example 1 (no electron rich polymer, no sparging). However, even with an electron rich polymer some ketotifen is lost after multiple autoclaving cycles. However, Example 4 (electron rich polymer and sparging) shows improved stability of the oxidatively unstable ophthalmic composition. Thus the foregoing examples clearly show that removing oxygen from the ophthalmically compatible solution significantly improves the stability of an oxidatively unstable ophthalmic composition, like ketotifen fumarate. We Claim: 1. A method for providing oxidatively stable ophthalmic compositions for removing at least 80% oxygen from an ophthalmically compatible solution comprising at least one oxidatively unstable ophthalmic compound wherein 11-dihydro- 11 (1- methyl-4-piperdinylidene-5H-imidazo[2.1 -b] [3]benzazepine-3-carboxaldehyde 2. The method as claimed in claim 1 wherein at least 90% of said oxygen is removed. 3. The method as claimed in claim 1 wherein at least 95% of said oxygen is removed. 4. The method as claimed in claim 1 wherein at least 99% of said oxygen is removed. 5. The method as claimed in claim 1 wherein said removing step is accomplished via a method selected from the group consisting of sparging, alternating freezing and thawing cycles, vacuum removal and vacuum removal in combination with agitation and combinations thereof. 6. The method as claimed in claim 5 wherein agitation is provided via sonication, stirring, rolling, shaking and combinations thereof. 7. The method as claimed in claim 5 wherein said removing step is accomplished by sparging. 8. The method as claimed in claim 7 wherein said sparging is conducted using an inert gas capable of displacing oxygen. 9. The method as claimed in claim 8 wherein said inert gas is selected from the group consisting of nitrogen, argon, helium and mixtures thereof. 10. The method as claimed in claim 9 wherein said sparging is conducted using conditions comprising a volume of ophthalmically compatible solution of about 2 L a flow rate of 370 SCCM (standard cubic centimeter per minute) and a sparging time of at least about 8 hours. 11. The method as claimed in claim 10 wherein said conditions further comprise a temperature from about 0 to about 40°C and a pressure of less than about 660 mmHg. 12. The method as claimed in claim 10 wherein said conditions further comprise room temperature and pressure between 660 and 760 mm Hg. 13. The method as claimed in claim 1 wherein said ophthalmically compatible solution further comprises at least one stabilizer. 14. The method as claimed in claim 13 wherein said stabilizer comprises at least one electron rich polymer. 15. The method as claimed in claim 13 wherein said stabilizer comprises EDTA. ABSTRACT Title: Methods for providing oxidatively stable ophthalmic compositions. A method for providing oxidatively stable ophthalmic compositions for removing at least 80% oxygen from an ophthalmically compatible solution comprising at least one oxidatively unstable ophthalmic compound wherein 11-dihydro- 11 (1-methyl-4- piperdinylidene-5H-imidazo[2.1 -b] [3]benzazepine-3-carboxaldehyde.

Full Text

Methods for Providing Oxidatively Stable Ophthalmic Compositions
FIELD OF THE INVENTION
The present invention relates to methods for providing ophthalmic
compounds that display oxidative stability, during processing, autoclaving,
packaging, shipping or storage.
BACKGROUND OF THE INVENTION
Therapeutic agents for topical administration to the eye are generally
formulated in either a liquid or gel form and must be kept sterile until
administration. Accordingly, ophthalmic therapeutic agents are either packaged
asceptically, which is cumbersome and expensive or are heat sterilized.
Unfortunately, many therapeutic agents are not oxidatively stable, especially at
elevated temperatures.
EDTA has been used to improve the stability of certain therapeutic agents
during autoclaving. However, there remains a need for processes capable of
stabilizing unstable therapeutic agents that are susceptible to oxidative degradation.
SUMMARY OF THE INVENTION
The present invention relates to a method comprising removing at least about 80%
oxygen from an ophthalmically compatible solution comprising at least one
oxidatively unstable ophthalmic compound.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises, consists of and consists essentially of
stabilizing at least one oxidatively unstable ophthalmic compound dissolved in an
ophthalmically compatible solution by removing at least about 80% oxygen from
said ophthalmically compatible solution comprising at least one oxidatively unstable

ophthalmic compound. In some embodiments at least about 90% of said oxygen is
removed. In some embodiments at least about 95% of said oxygen is removed and
in still other embodiments at least about 99% of said oxygen is removed.
As used herein, oxidatively unstable ophthalmic compound ("OUOC") is any
therapeutic agent which shows greater than 10% degradation when autoclaved in
solution with at least one oxidative catalyst, but shows less than 10% degradation
when autoclaved under the same conditions without said at least one oxidative
catalyst. Oxidative instability may be measured by forming a solution of 3 ml
packing solution containing 25 ppm of the therapeutic agent to be evaluated, and
exposing the solution, with and without oxidative catalysts (100 ppm Cu2O and 100
ppm FeSO4) to autoclave conditions (120°C for 20 minutes).
Examples of OUOC include oxidatively unstable pharmaceutical and
nutraceutical compounds. In one embodiment the OUOC comprises at least one
pharmaceutically active amines. In one embodiment the at least one OUOC
comprises at least one tertiary cyclic amine. In another embodiment the at least one
OUOC comprises at least one tertiary cyclohexyl amine. In another embodiment the
OUOC comprises at least one therapeutic agent selected from as acycylovir,
adrenalone, aminocaproic acid, amoxicillin, amotriphene, amoxecaine, amodiaquin,
antazoline, atrophine, betaxolol, bupivacaine, carbachol, carteolol, chlorampenicol,
chlortetracycline, corynathine, cromalyn sodium, cyclopentolate, demecarium,
dexamethasone, dichlorphenamide, dibutoline, diclophenac, dipivefrin, ephedrine,
erythromycin, ethambutol, eucatropine, fluoromethalone, gentamycin, gramicidin,
homatropine, indomethacin, ketotifen, levallorphan, levobunolol, levocabastine,
lidocaine, lignocaine, lomefloxacin, medrysone, mepivacaine, methazolamide,
naphazoline, natamycin, natamycin, neomycin, noradrenaline, ofloxacin,
oxybuprocaine, oxymetazoline, pheniramine, phenylephrine, physostigmine,
pilocarpine, polymyxin B, prednisolone, proparacaine, pyrilamine, scopolamine,
sorbinil, sulfacetamide, tamoxifen, tetracaine, tetracycline, tetrahydozoline, timolol,

trifluridine, tropicamide, vidarabine, and salts and mixtures thereof. Examples of
nutriceutical compounds include vitamins and supplements such as vitamins A, D,
E, lutein, zeaxanthin, lipoic acid, flavonoids, ophthalmicially compatible fatty acids,
such as omega 3 and omega 6 fatty acids, combinations thereof, combinations with
pharmaceutical compounds and the like. In yet another embodiment the OUOC
comprises at least one therapeutic agent selected from ketotifen fumarate, nor
ketotifen fumarate, ,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-
b][3]benzazepine-3-carboxaldehyde (CAS# 147084-10-4, olapatadine and mixtures
thereof. In yet another embodiment the OUOC comprises at least one therapeutic
agent selected from ketotifen fumarate, 11-dihydro-l 1-(1-methyl-4-
piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde (CAS#
147084-10-4 and mixtures thereof.
The concentration of the OUOC in the ophthalmically compatible solutions
of the present invention may range from about 10 ppm to about 100,000 ppm, in
some embodiments from about 10 to about 10,000 ppm, in some embodiments from
about 10 to about 1,000 ppm and some embodiments from about 10 to about 500
ppm.
The process of the present invention comprises removing at least 80%
oxygen from the ophthalmically compatible solution comprising at least one OUOC.
In some embodiments the amount of oxygen removed is at least about 90%, at least
about 95%, and even at least about 99%. The oxygen removal is conducted prior
to heat sterilization, such as autoclaving. For example, oxygen removal may be
conducted either before or after the OUOC is added to the ophthalmically
compatible solution. If the oxygen removal is conducted before the OUOC is added
to the ophthalmically compatible solution, the solution should be kept under
conditions sufficient to prevent oxygen from being introduced into the
ophthalmically compatible solution during mixing and autoclaving.

The oxygen may be removed by a number of methods including sparging,
alternating freezing and thawing cycles, vacuum removal, vacuum removal in
combination with agitation, combinations thereof and the like.
When sparging is used at least one inert gas which is capable of displacing
oxygen is bubbled through the ophthalmically compatible solution under conditions
suitable to remove the desired amount of oxygen. Suitable inert gasses include
nitrogen, argon, helium, combinations thereof and the like. Suitable sparging
conditions include volumes of ophthalmically compatible solution of at least about
1L, between about 1 and about 6L; and between about 1 and about 4L. In some
embodiments a volume of about 2L is desirable. The inert gas flow rate may be
selected based upon the selected volume and desired sparging time. So, for
example, higher volumes may require higher inert gas flow rates, sparging times or a
combination of both. Suitable inert gas flow rates include from about 10 to about
1000 standard cubic centimeter per minute (SCCM). In some embodiments an inert
gas flow rate of about 370 SCCM is desirable.
Sparging times may vary based upon the other conditions as described
above. Suitable sparging times include at least about 5 minutes, from about 5
minutes to 24 hours, from 5 minutes to 12 hours and in some embodiments at least
about 8 hours.
Any temperature can be used for sparging so long as the ophthalmically
compatible solution remains a liquid and the OUOC is soluble in the ophthalmically
compatible solution at the selected temperature. Temperatures between about 0 to
about 40°C may be used in some embodiments.
Alternatively the oxygen may be removed by freeze thaw degassing.
Suitable pressures for freeze thaw degassing include those less than about 660
mmHg. For degassing an aqueous solution at room temperature, pressures between
660 and 760mm Hg are desirable. Gentle agitation or sonication increases the
efficiency of the process.

When sparging is used the process of the present may also include agitation
which may be provided by any known method such as, but not limited to sonication,
stirring, rolling, shaking, combinations thereof and the like.
Freeze thaw degassing comprises freezing the ophthalmically compatible
solution to form a solid and then thawing the solid. This process may be repeated.
Alternatively, the ophthalmically compatible solution may be exposed to
degas conditions below its vapor pressure. For example, if an ophthalmically
compatible solution's boiling point at a given pressure is 20°C, the solution is cooled
to less than about 20°C prior to evacuating the system to the desired pressure. When
placed under a vacuum, all dissolved gases are removed from the ophthalmically
compatible solution, while little or none of the other components (solvents or
solutes) are displaced. Once the gas bubbles cease to escape from the
ophthalmically compatible solution, the system is placed under a positive pressure of
an inert gas such as nitrogen or argon, and allowed to warm up to ambient
temperature.
The degassing cycle described above may be repeated once or more
depending on how sensitive the ophthalmically compatible solution is to oxidative
degradation, with solutions which are more susceptible to degradation being
subjected to more cycles.
The ophthalmically compatible solution may be formed from any suitable
ophthalmically compatible carrier. Suitable carriers include water, saline solution,
mineral oil, petroleum jelly, water soluble solvents, such as C15-20 alcohols, C15-20
amides, C 15-20 alcohols substituted with zwitterions, vegetable oils or mineral oils
comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate,
carboxymethylcellulose, polyvinylpyrrolidone and other non-toxic water-soluble
polymers for ophthalmic uses, such as, for example cellulose derivatives, such as
methylcellulose, alkali metal salts of carboxy-methylcellulose,
hydroxymethylcellulose, methylhydroxypropyl-cellulose, hydroxypropylcellulose,

chitosan and scleroglucan, acrylates or methacrylates, such as salts of poly(acrylic
acid) or ethyl acrylate, polyacry lam ides, natural products, such as gelatin, alginates,
pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch
derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic
products, such as poloxamers, e.g. Poloxamer F127, polyvinyl alcohol, polyvinyl
methyl ether, polyethylene oxide, cross-linked poly(acrylic acid), such as neutral
Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose
derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and
hydroxypropylcellulose, neutral Carbopol, or mixtures thereof. The concentration of
the carrier is, for example, from 0.1 to 100000 times the concentration of the active
ingredient combinations thereof and the like. When the ophthalmically compatible
solution is an eye drop, suitable carriers include water, pH buffered saline solution,
mixtures thereof and the like.
The ophthalmically compatible solution of the present invention may also be
used as the packaging or storage solution for an ophthalmic device, such as a contact
lens. When the ophthalmically compatible solution is used as a packaging solution
for a contact lens the carrier comprises a buffered saline solution. Any contact lens
could be packaged with the ophthalmically compatible solution of the present
invention, including conventional and silicone hydrogel contact lenses, such as but
not limited to commercially available hydrogel formulations such as etafilcon,
polymacon, vifilcon, genfilcon A, lenefilcon A, galyfilcon, senofilcon, balafilcon,
lotrafilcon A, lotrafilcon B and the like.
The ophthalmically compatible solution of the present invention may further
comprise additional components such as antioxidants, demulcents, antibacterial
agents, solubilizers, surfactants, buffer agents, tonicity adjusting agents, chelating
agents, preservatives, wetting agents, thickeners, stabilizers, combinations thereof
and the like. An example of a suitable stabilizer includes EDTA. The

ophthalmically compatible solution of the present invention are ophthalmically
compatible, and have a pH between about 5 and about 9, in some embodiments
between about 6 to about 8 is desired.
The ophthalmically compatible solution of the present invention may be
formed by mixing the OUOC and any additional components with the selected
carrier. When a liquid composition, such as an eye drop or packaging solution for a
contact lens, the OUOC and any additional components are dissolved in the carrier.
It is generally desirable that the shelf life of the ophthalmically compatible
solution be in excess of about 6 months, and in some instances greater than about 1
year, or even more than about 2 years. During the shelf life of the ophthalmically
compatible solution it is desirable that at least about than 80% of the original
concentration of the OUOC remains, and in some embodiments greater than about
90%.
The ophthalmically compatible solution of the present invention may in
some embodiments further comprise at least one electron rich polymer. Suitable
electron rich polymers are water-soluble, comprise at least one group with a free
electron pair, have a weight average molecular weight, Mw, between about 1000
and about 2,000,000, and are substantially free from transition metal containing
species. In some embodiments the electron rich polymers are substantially free from
copper and iron containing species. As used herein, "substantially free from" means
that transition metal containing species are present in the electron rich polymer in
amounts which are insufficient to cause further degradation of the OUOC.
Preferably the transition metal containing species are present in the electron rich
polymer in amounts less than about 100 ppm, in some embodiments less than about
50 ppm and in some embodiments less than about 20 ppm.
As used herein, water soluble means that the selected electron rich polymer
does not precipitate or form visible gel particles at the concentrations selected and

across the temperatures and pH regimes common for manufacturing, sterilizing and
storing ophthalmic solutions.
For purposes of the invention, the molecular weight is determined using a gel
permeation chromatograph with a 90° light scattering and refractive index detectors.
Two columns of PW4000 and PW2500, a methanol-water eluent of 75/25 wt/wt
adjusted to 50mM sodium chloride and a mixture of polyethylene glycol and
polyethylene oxide molecules with well defined molecular weights ranging from
325,000 to 194 are used.
Suitable examples of electron rich polymers include polymers comprising
esters, acids, amines, carbonates, carboxylates, thiols, lactates, amides, carbamates,
phosphates, nitriles, lactams, and combinations thereof. Polymers which do not
have groups with at least one free electron pair, such as polymers comprising only
ether groups, alcohol groups or combinations thereof are not electron rich polymers
are defined herein. A wide concentration of electronic donating groups may be
included, however, the higher the concentration of electron donating groups, the less
electron rich polymer will need to be used. Specific examples include
homopolymers and random or block copolymers of methacrylic acid, acrylic acid,
itaconic acid, fumaric acid, maleic acid, vinylpyrollidone, vinylmethacetimide,
combinations thereof and the like. More specific examples include poly(acrylic
acid), poly(vinylpyrollidone) and poly(vinylmethylacetamide) and combinations
thereof and the like. In one embodiment the electron rich polymer comprises
poly(acrylic acid).
The electron rich polymer is present in the ophthalmically compatible
solution in stabilizing effective amounts. A stabilizing effective amount will vary
depending upon the OUOC, the concentration of the OUOC and the concentration of
other components in the ophthalmically compatible solution, but generally
stabilizing effective amounts are those sufficient to provide at least about a 5%
improvement in stability. Suitable amounts of'electron rich polymer include

between about 10 and about 5,000 ppm, in some embodiments between about 100
and about 5,000 ppm, in some embodiments between about 500 and about 3,000
ppm.
These examples do not limit the invention. They are meant only to suggest a
method of practicing the invention. Those knowledgeable in contact lenses as well
as other specialties may find other methods of practicing the invention. However,
those methods are deemed to be within the scope of this invention.
Examples 1
A buffer solution was formed by dissolving 8.3 gm NaCl (from Sigma Aldrich), 9.1
gm boric acid (from Mallinckrodt) and 1 gm sodium borate (from Mallinckrodt) in
1L deionized water (from Milli Q). The resulting solution had a pH of 7.65.
Ketotifen fumarate (from Sigma Aldrich) was added to prepare a solution of
approximately 80 ppm in the buffer solution. The ketotifen solution (3 mL) was
placed in vials, autoclaved for the number of cycles shown in Table 1, below and
analyzed as a function of autoclave cycle (3 replicate per autoclave cycle) using
HPLC using an HP 1100 and an Agilent Zorbax Eclipse XDB-C18 and Rapid
Resolution HT 50 x 4.6 mm x 1.8 µ. column and the following conditions:
Detector Wavelength : 299 nm
Flow rate: 1.0 mL/min
Injection Volume: 3 µL
Mobile Phase:
Eluent A: 17 % acetonitrile in 0.025 M dihydrogen potassium phosphate
buffer
0.2 % triethylamine, 0.13 % o-phosphoric acid
Eluent B: 50 % acetonitrile in 0.025 M dihydrogen potassium phosphate
buffer
0.2 % triethylamine, 0.13 % o-phosphoric acid

The results in Table 1 clearly show that even a single autoclave cycle has a
substantial detrimental effect on the ketotifen concentration in a buffer solution.
Example 2
Example 1 was repeated, except that the buffer solution was sparged (with
nitrogen) overnight (-12 hrs) at about 370 standard cubic centimeter per minute
(SCCM) and subsequently transferred to a nitrogen box ( ketotifen solution of about 90 ppm was prepared and placed in vials as described
above, but in nitrogen box. The vials were autoclaved and analyzed as described in
Example 1. The results are shown in Table 2, below.

Comparing the results in Table 2 to those in Table 1, it is clear that sparging
the buffer solution and maintaining the ketotifen solution under nitrogen
significantly improved (from 0 to 98%) the ketotifen stability.
Example 3 and 4
Examples 1 and 2 was repeated, except that 10 gm of poly(acrylic acid)
(PAA, Mw, 225,000, from Polysciences, Inc., 20 % in water) was added to the
buffer solution. The vials were autoclaved and analyzed as described in Example 1.
The results are shown in Table 3, below.

The results for Example 3 (inclusion of an electron rich polymer, such as
PAA, with no sparging) are far superior to those of Example 1 (no electron rich
polymer, no sparging). However, even with an electron rich polymer some ketotifen
is lost after multiple autoclaving cycles. However, Example 4 (electron rich
polymer and sparging) shows improved stability of the oxidatively unstable
ophthalmic composition. Thus the foregoing examples clearly show that removing
oxygen from the ophthalmically compatible solution significantly improves the
stability of an oxidatively unstable ophthalmic composition, like ketotifen fumarate.

We Claim:
1. A method for providing oxidatively stable ophthalmic compositions for removing
at least 80% oxygen from an ophthalmically compatible solution comprising at
least one oxidatively unstable ophthalmic compound wherein 11-dihydro- 11 (1-
methyl-4-piperdinylidene-5H-imidazo[2.1 -b] [3]benzazepine-3-carboxaldehyde
2. The method as claimed in claim 1 wherein at least 90% of said oxygen is
removed.
3. The method as claimed in claim 1 wherein at least 95% of said oxygen is
removed.
4. The method as claimed in claim 1 wherein at least 99% of said oxygen is
removed.
5. The method as claimed in claim 1 wherein said removing step is accomplished via
a method selected from the group consisting of sparging, alternating freezing and
thawing cycles, vacuum removal and vacuum removal in combination with
agitation and combinations thereof.

6. The method as claimed in claim 5 wherein agitation is provided via sonication,
stirring, rolling, shaking and combinations thereof.
7. The method as claimed in claim 5 wherein said removing step is accomplished by
sparging.

8. The method as claimed in claim 7 wherein said sparging is conducted using an
inert gas capable of displacing oxygen.
9. The method as claimed in claim 8 wherein said inert gas is selected from the
group consisting of nitrogen, argon, helium and mixtures thereof.
10. The method as claimed in claim 9 wherein said sparging is conducted using
conditions comprising a volume of ophthalmically compatible solution of about 2
L a flow rate of 370 SCCM (standard cubic centimeter per minute) and a sparging
time of at least about 8 hours.
11. The method as claimed in claim 10 wherein said conditions further comprise a
temperature from about 0 to about 40°C and a pressure of less than about 660
mmHg.
12. The method as claimed in claim 10 wherein said conditions further comprise
room temperature and pressure between 660 and 760 mm Hg.
13. The method as claimed in claim 1 wherein said ophthalmically compatible
solution further comprises at least one stabilizer.
14. The method as claimed in claim 13 wherein said stabilizer comprises at least one
electron rich polymer.

15. The method as claimed in claim 13 wherein said stabilizer comprises EDTA.

ABSTRACT

Title: Methods for providing oxidatively stable ophthalmic compositions.
A method for providing oxidatively stable ophthalmic compositions for removing at least
80% oxygen from an ophthalmically compatible solution comprising at least one
oxidatively unstable ophthalmic compound wherein 11-dihydro- 11 (1-methyl-4-
piperdinylidene-5H-imidazo[2.1 -b] [3]benzazepine-3-carboxaldehyde.

PROCESS FOR PREPARATION OF RUBBER MIXTURES CONTAINING SILICON DIOXIDE

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