Novel method of applying zwitterions in ophthalmic topical cream compositions and preparations
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- GLAUKOS CORP
- Filing Date
- 2023-05-17
- Publication Date
- 2026-05-21
AI Technical Summary
Existing ophthalmic topical cream compositions face challenges in maintaining both physical and chemical stability of active pharmaceutical ingredients (APIs) due to issues with thickening agents and pH control, which affects their efficacy and shelf life.
Incorporating zwitterions, such as amino acids or zwitterionic polymers, into the ophthalmic topical cream compositions to enhance viscosity, stabilize the API, and adjust the pH, thereby maintaining the cream's texture and API stability.
The use of zwitterions significantly improves the chemical and physical stability of APIs in ophthalmic topical creams, maintaining their effectiveness over a longer period and ensuring a stable, semi-solid texture.
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Abstract
Description
Technical Field
[0001] Incorporation by reference to any priority application This application claims priority to U.S. Provisional Patent Application No. 63 / 364,914, filed May 18, 2022, entitled "NOVEL APPLICATIONS OF ZWITTERIONS IN OPHTHALMIC TOPICAL CREAM COMPOSITIONS AND PREPARATIONS," which is hereby incorporated by reference in its entirety for all purposes.
[0002] Field The present disclosure relates to ophthalmic topical cream compositions and methods of using them, particularly for treating eye disorders and diseases by administration to the outer surface of the eyelids of a patient's eye.
Background Art
[0003] Description of Related Art Eye drops are a typical way to administer ophthalmic medications to patients. For example, U.S. Patent No. 10,610,518 discloses pilocarpine formulations and methods of administering them as eye drops. This route is simple and non-invasive, but it only provides limited control over patient compliance, dosing schedules, and duration. Eye drops can result in undesirable efficacy and clinical outcomes if used inappropriately by the subject. See Souto, E. B., et al., "Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents", Pharmaceutics. 2019, 11, 460: 1-29 (Non-Patent Document 1). Other ophthalmic formulations have been developed that are said to be suitable for administration by topical application to the outer surface of the subject's eyelids. See U.S. Patent No. 9,034,830 (Patent Document 1). However, there is still a need for improved ophthalmic treatment compositions and methods. For example, it is extremely difficult to maintain both the physical and chemical stability of the active pharmaceutical ingredient (API) in a semi-solid dosage form. One difficulty is that the selected thickening agent used in the formulation may not be able to achieve and maintain the stable cream texture desired for an ophthalmic topical cream. Another challenge is to achieve and maintain the chemical stability of the active pharmaceutical ingredient (API) throughout the shelf life of the ophthalmic topical cream.
Prior Art Documents
Patent Documents
[0004]
Patent Document 1
Non-Patent Documents
[0005]
Non-Patent Document 1
Summary of the Invention
[0006] Summary Various aspects provide ophthalmic topical cream compositions. In one aspect, an ophthalmic topical cream composition includes a topical cream comprising at least one zwitterion and an active pharmaceutical ingredient (API) dispersed in the topical cream.
[0007] In some aspects, at least one zwitterion can be present in an amount effective to reduce degradation of the API and increase the viscosity of the topical cream. In some aspects, at least one zwitterion can have a concentration in the topical cream of from about 5 mM to about 600 mM. In some aspects, at least one zwitterion can have a concentration in the topical cream of from about 10 mM to about 500 mM. In some aspects, the topical cream can have a viscosity of from about 25,000 cPs to about 400,000 cPs. In some aspects, the topical cream can have a viscosity of from about 50,000 cPs to about 150,000 cPs.
[0008] In some embodiments, at least one zwitterion can include at least one of an amino acid, a peptide, a protein, phosphatidylcholine, and betaine. In some embodiments, the topical cream can be an oil-in-water emulsion system or a water-in-oil emulsion system. In some embodiments, at least one amino acid can include lysine, arginine, histidine, or a combination thereof. In some embodiments, at least one amino acid can include lysine and arginine. In some embodiments, lysine and arginine in the topical cream can each independently have a concentration of about 10 mM to about 500 mM. In some embodiments, at least one amino acid can include histidine and arginine. In some embodiments, histidine and arginine in the topical cream can each independently have a concentration of about 10 mM to about 500 mM. In some embodiments, at least one amino acid can include histidine and lysine. In some embodiments, histidine and lysine in the topical cream can each independently have a concentration of about 10 mM to about 500 mM.
[0009] In some embodiments, at least one zwitterion can include a zwitterionic polymer or a polymeric zwitterion.
[0010] In some embodiments, the topical cream can further comprise a cross-linked acrylic acid polymer. In some embodiments, the topical cream can comprise less than about 1% (w / w) of the cross-linked acrylic acid polymer. In some embodiments, the topical cream can have a pH of from about 3.0 to about 7.8. In some embodiments, the topical cream can comprise from about 0.002% to about 10% (w / w) of an API. In some embodiments, the API can comprise pilocarpine, atropine, travoprost, physostigmine, donepezil, timolol, loteprednol, brimonidine, and / or salts thereof. In some embodiments, the topical cream can comprise an effective amount of the API to reduce the symptoms of dry eye, presbyopia, myopia, blepharitis, glaucoma, and / or edema.
[0011] Furthermore, various embodiments of a method for administering an ophthalmic topical cream composition to a patient's eye are also provided. In one embodiment, a method of treating dry eye, presbyopia, glaucoma, and / or myopia comprises administering an effective amount of the ophthalmic topical cream composition to a subject in need thereof. In some embodiments, the ophthalmic topical cream composition is applied to the outer surface of the eyelid of the subject's eye.
Brief Description of the Drawings
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Mode for Carrying Out the Invention
[0013] Detailed Description An ophthalmic topical cream composition is currently being developed that includes at least one zwitterion and an active pharmaceutical ingredient (API) dispersed in the topical cream. In some embodiments, the at least one zwitterion can include at least one positively charged functional group and at least one negatively charged functional group. In some embodiments, the at least one zwitterion can include both a positive charge and a negative charge. In some embodiments, the net charge of the at least one zwitterion can be zero. In some embodiments, the net charge of the at least one zwitterion can be negative in a neutral pH environment. For example, some amino acids such as glutamic acid and aspartic acid can be negatively charged in a neutral pH environment. In some embodiments, the net charge of the at least one zwitterion can be positive in a neutral pH environment. For example, some amino acids such as lysine, arginine, and histidine can be positively charged in a neutral pH environment. In various embodiments, this at least one zwitterion can impart a surprisingly high level of desirable characteristics to the ophthalmic treatment composition, such as improved chemical and physical stability of the API, skin softening properties, and a desirable stable texture.
[0014] The ophthalmic topical cream composition can typically include an active pharmaceutical ingredient (API), a thickening substance, a stabilizer, an osmotic pressure regulator, and an antimicrobial preservative. In some embodiments, the ophthalmic topical cream can be an oil-in-water (o / w) emulsion system. This o / w emulsion system delivers the active pharmaceutical ingredient (API) to the local skin at a designated site, such as the eyelid area.
[0015] The process of achieving a semi-solid texture for an ophthalmic topical cream has been observed to be complex and difficult. Further, it is difficult to maintain both the physical and chemical stability of the API in the semi-solid texture and matrix. One difficulty is that the selected thickener used in the ophthalmic topical cream composition may not be able to achieve and maintain a stable and desirable cream texture of the ophthalmic topical cream over a long period such as the shelf life of the product. Another difficulty can be achieving and maintaining the chemical stability of the API throughout the shelf life of the ophthalmic topical cream. Surprisingly, the presence of at least one zwitterion in the ophthalmic topical cream composition can help increase the viscosity of the ophthalmic topical cream to a level where the ophthalmic topical cream is a semi-solid or creamy texture or matrix. Further, including at least one zwitterion can help adjust the pH of the ophthalmic topical cream composition and can also help maintain the chemical and physical stability of the API.
[0016] Ophthalmic topical cream composition Various aspects provide an ophthalmic topical cream composition, the ophthalmic topical cream composition comprising a topical cream comprising at least one zwitterion; and an active pharmaceutical ingredient (API) dispersed in the topical cream comprising.
[0017] A variety of suitable zwitterions are commercially available and / or can be readily synthesized by those skilled in the art. In some embodiments, at least one zwitterion is present in an amount effective to reduce the degradation of the API and increase the viscosity of the topical cream. In some embodiments, at least one zwitterion has a concentration in the topical cream of about 5 mM to about 600 mM, about 10 mM to about 500 mM, about 30 mM to about 60 mM, about 80 mM to about 120 mM, about 5 mM to about 30 mM, or any other amount within a range defined by any two of the foregoing concentration values as the end values. In some embodiments, the topical cream can have a viscosity of about 25,000 cPs to about 400,000 cPs, about 50,000 cPs to about 150,000 cPs, about 50,000 cPs to about 100,000 cPs, or any other amount within a range defined by any two of the foregoing viscosity values as the end values.
[0018] In one aspect, at least one zwitterion included in the ophthalmic topical cream composition can include at least one of an amino acid, a peptide, a protein, phosphatidylcholine, and betaine. In some aspects, at least one amino acid can include lysine, arginine, histidine, or a combination thereof. In some aspects, the ophthalmic topical cream composition can include or be lysine and arginine. In these aspects, lysine and arginine can each independently have a concentration of about 5 mM to about 500 mM, about 5 mM to about 100 mM, about 5 mM to about 50 mM, about 5 mM to about 30 mM, about 5 mM to about 15 mM, or any other amount within a range defined by any two of the foregoing concentration values as the end values. In some aspects, the ophthalmic topical cream composition can include or be lysine and histidine. In these aspects, lysine and histidine can each independently have a concentration of about 5 mM to about 500 mM, about 5 mM to about 100 mM, about 5 mM to about 50 mM, about 5 mM to about 30 mM, about 5 mM to about 15 mM, or any other amount within a range defined by any two of the foregoing concentration values as the end values. In some aspects, the ophthalmic topical cream composition can include or be arginine and histidine. In these aspects, arginine and histidine can each independently have a concentration of about 5 mM to about 500 mM, about 5 mM to about 100 mM, about 5 mM to about 50 mM, about 5 mM to about 30 mM, about 5 mM to about 15 mM, or any other amount within a range defined by any two of the foregoing concentration values as the end values.
[0019] In another aspect, at least one zwitterion included in the ophthalmic topical cream composition can include a zwitterionic polymer or a polymeric zwitterion.
[0020] In some embodiments, the topical cream can further comprise a crosslinked acrylic acid polymer. In some embodiments, the topical cream can comprise less than about 1% (w / w), about 0.5% (w / w), or about 0.2% (w / w) of the crosslinked acrylic acid polymer. In some embodiments, the topical cream can have a pH of about 3.0 to about 7.8, about 3.0 to about 7.0, about 3.0 to about 5.0, about 3.0 to about 4.0, about 3.5, about 3.7, or any other pH within a range defined by any two of the foregoing pH values as the end values.
[0021] In some embodiments, the topical cream can comprise from about 0.002% to about 10% (w / w) of an API. In some embodiments, the concentration of the API can be about 0.1% to about 10% (w / w), about 0.5% to about 8% (w / w), about 1% to about 8% (w / w), or any other amount within a range defined by any two of the foregoing concentration values as the end values. In some embodiments, the API can comprise pilocarpine, atropine, travoprost, physostigmine, donepezil, timolol, loteprednol, brimonidine, and / or any salt of any of the foregoing (e.g., a pharmaceutically acceptable salt). In some embodiments, the topical cream can comprise an effective amount of the API to reduce the symptoms of dry eye, presbyopia, myopia, blepharitis, glaucoma, and / or edema.
[0022] In various embodiments, the ophthalmic topical cream composition is formulated for treating dry eye, presbyopia, glaucoma, and / or myopia. In some embodiments, the ophthalmic topical cream composition can be administered in an effective amount to a subject in need thereof. In some embodiments, the ophthalmic topical cream composition can be applied to the outer surface of the eyelid of the subject's eye. After such application, due to the higher viscosity that the ophthalmic treatment composition comes to have after application to the eyelid, the composition remains in place, thereby providing the subject with a longer time before it is squeezed into the eye.
[0023] Stability of ophthalmic topical cream composition As described above, surprisingly, the addition of zwitterions makes it possible to adjust the pH of the ophthalmic topical cream composition, and thus this addition can help maintain the chemical and physical stability of the API. In some embodiments, the zwitterion can be dissolved in an aqueous solution as a buffer for adjusting the pH of the formulation. Advantageously, using a zwitterion as a buffer makes it possible to provide a synergistic effect on both physical and chemical stability in a cream-based matrix for controlled release of the API over a desired period. In some embodiments, the zwitterion can be an amino acid. In some embodiments, at least one zwitterion can include at least one of an amino acid, a peptide, a protein, phosphatidylcholine, and betaine. In some embodiments, at least one zwitterion can be at least one of an amino acid, a peptide, a protein, phosphatidylcholine, and betaine. In some embodiments, the amino acid can include lysine, arginine, histidine, or a combination thereof. In some embodiments, the amino acid can be lysine, arginine, histidine, or a combination thereof. In some embodiments, at least one amino acid can include lysine and arginine. In some embodiments, at least one amino acid can be lysine and arginine. In some embodiments, at least one amino acid can include lysine and histidine. In some embodiments, at least one amino acid can be lysine and histidine. In some embodiments, at least one amino acid can include arginine and histidine. In some embodiments, at least one amino acid can be arginine and histidine.
[0024] Non-limiting examples of suitable amounts of zwitterions and API for ophthalmic topical cream compositions are illustrated and summarized in Table 1 using pilocarpine as an exemplary drug (API).
[0025]
Table 1
[0026] As shown in Table 1, ophthalmic topical cream compositions of these non-limiting examples were formulated and then sterilized by electron beam sterilization at a dose of 25 kGy. However, composition F27 was not sterilized by electron beam. As shown in Table 1, the pH of various ophthalmic topical cream compositions was maintained at about 3.5. F27 is a control formulated using a non-buffered solution and is compared to ophthalmic topical cream compositions containing at least one zwitterion as a buffer to adjust the pH of the formulation. F105 (Figure 1) contains 10 mM histidine as a buffer, F106 (Figure 2) contains 10 mM arginine, F107 (Figure 3) contains 5 mM lysine and 5 mM histidine, F108 (Figure 4) contains 5 mM lysine and 5 mM arginine, F109 (Figure 5) contains 5 mM histidine and 5 mM arginine, F121 (Figure 6) contains 10 mM lysine, and F122 (Figure 7) contains 25 mM lysine. All of the examples of the compositions in Table 1 were formulated by the same process using the same concentration of thickener and the exemplary drug pilocarpine. However, composition F27 was not sterilized by electron beam.
[0027] Figures 1-7 show the stability of various ophthalmic topical cream compositions containing at least one functional amino acid in buffer as a function of storage period, compared to the stability of ophthalmic topical cream compositions formulated using a non-buffered solution at room temperature and 40°C. Room temperature is a temperature in the range of about 15°C to about 25°C. In some embodiments, room temperature is 25°C. The impurities measured are degradation products of the API, pilocarpine, in the studies described herein.
[0028] As shown in FIGS. 1-7, the total impurities derived from composition F27 (non-buffered solution) continued to increase over a four-month period. Further, the amount of impurities derived from composition F27 at a higher temperature (40°C) is more than the amount of impurities at a controlled room temperature. As shown in FIGS. 1-7, the amount of impurities derived from composition F27 at 40°C exceeds 5% at the end of the test period. In contrast, the amount of impurities derived from compositions containing one type of functional amino acid at a storage temperature of 40°C is less than the amount of impurities derived from compositions containing no amino acids in the buffer at both a storage temperature of 40°C and room temperature at the end of the test period. As shown in FIGS. 1-7, surprisingly, the amount of impurities derived from compositions containing one type of amino acid at a storage temperature of 40°C is controlled to about 3% or less.
[0029] As shown in FIGS. 8 and 9, among all examples of compositions containing one type of functional amino acid, the compositions containing 10 mM or 25 mM of lysine showed the lowest amount of total impurities. As shown in FIG. 9, it should be noted that the compositions containing 10 mM or 25 mM of lysine had similar amounts of total impurities when measured at different stability test time points.
[0030] FIG. 10 shows the amount of impurities derived from an example of a composition containing two types of functional amino acids. As shown in FIG. 10, the exemplary drug pilocarpine is most stable in the composition containing 5 mM lysine and 5 mM arginine compared to the other two examples of compositions. Surprisingly, FIG. 10 shows that a combination of two different amino acids has a synergistic effect in stabilizing pilocarpine. Among various examples, the combination of 5 mM of arginine and 5 mM of lysine shows the most significant effect on the stabilization of pilocarpine under accelerated stability conditions.
[0031] The results shown in FIGS. 1 to 10 indicate that including at least one type of amino acid helps maintain the chemical stability of the API. Further, among the various examples of functional amino acids used in the composition, it should be noted that lysine may be the most effective stabilizer for the exemplary drug pilocarpine, followed by arginine and histidine. Furthermore, among the compositions containing two types of functional amino acids, the combinations of lysine and arginine, and lysine and histidine show strong chemical protection for pilocarpine over a 4-month test period under accelerated storage conditions.
[0032] Texture of ophthalmic topical cream composition As described above, in some embodiments, an ophthalmic treatment composition containing at least one zwitterion may include an oil-in-water emulsion system in which an oil phase is dispersed in an aqueous phase. It should be noted that maintaining such a semi-solid matrix or cream body matrix of the oil-in-water emulsion system is important for achieving desirable physical stability. Therefore, it is important to select a thickening agent having an appropriate concentration, polymer molecular weight, and polydispersity. Further, the selection of an appropriate medium and / or synergistic action of components may also play an important role in the product development process. It should be noted that in order to achieve the semi-solid texture and / or cream texture of the ophthalmic topical cream composition, the viscosity of the emulsion system can be about 50,000 cPs to 150,000 cPs.
[0033] To demonstrate the importance of an appropriate medium for an ophthalmic treatment composition, various examples of ophthalmic treatment compositions are shown in Table 2. In all examples, the drug exemplified is atropine sulfate, 4% carbomer is used as a thickening agent, and the pH of the formulation is adjusted to about 3.7 in all examples.
[0034] [Table 2]
[0035] As shown in Table 2, water (AS2R) can be a suitable medium for forming a lotion, but due to its viscosity being less than 3000 cPs, it may not be a suitable medium for forming a cream texture. In contrast, as shown in Table 2, various examples of buffer solutions or amino acid solutions, due to their viscosities being higher than about 50,000 cPs and lower than about 150,000 cPs, can be more suitable media for forming a cream texture. Further, as shown in Table 2, it should be noted that a medium containing an amino acid buffer can be a stronger viscosity enhancer than a non - amino acid buffer for forming the desired cream texture for an ophthalmic treatment composition. To achieve a viscosity of about 70,000 cPs, a citrate buffer or a potassium buffer having a concentration of about 200 mM may be required. In contrast, a solution containing lysine at a concentration of only 50 mM achieved a viscosity of about 71,130 cPs. When the concentration of lysine was increased to about 100 mM, the viscosity increased significantly to about 362,000 cPs (AS14). In some embodiments, lysine at a concentration of about 50 mM can provide a desirable viscosity such that the ophthalmic treatment composition can have a cream texture without phase separation being observed.
[0036] As shown by the results in Table 2, including at least one zwitterion can help increase the viscosity of an ophthalmic topical cream composition and make the texture of the ophthalmic topical cream composition semi - solid or creamy. In some embodiments, including at least one zwitterion can help maintain the physical stability of the ophthalmic topical cream composition and no phase separation is observed.
[0037] Method of treatment using ophthalmic topical cream composition Various embodiments provide a method of treating an eye disease or disorder by topical administration of the ophthalmic topical cream composition described herein.
[0038] For example, one aspect can provide a method for administering an ophthalmic pharmaceutical to a patient's eye, the method including applying an ophthalmic topical cream composition to the outer surface of the patient's eye eyelid, the topical cream including at least one zwitterion; and an active pharmaceutical ingredient (API) dispersed in the topical cream. The amounts and types of the various ingredients as well as the indications are as described above with respect to the ophthalmic topical cream composition.
[0039] In various aspects, the API can be pilocarpine and the method of treatment can be effective in reducing the symptoms of dry eye. In another aspect, the API can be pilocarpine and the method of treatment can be effective in treating presbyopia. In one aspect, the API can include or be travoprost and the method of treatment can be effective in treating intraocular pressure (IOP). In one aspect, the API can include or be physostigmine and the method of treatment can be effective in treating blepharitis. In one aspect, the API can include or be donepezil and the method of treatment can be effective in treating intraocular pressure (IOP).
[0040] In one aspect, the method can include applying the ophthalmic topical cream composition to the outer surface of the patient's eye eyelid by using an applicator. For example, in one aspect, the treatment includes pushing the ophthalmic topical cream composition from a container onto an applicator (e.g., a tube attached to the container), and then, for example, further squeezing the container to extrude the ophthalmic topical cream composition from the applicator onto the eyelid, thereby applying the ophthalmic topical cream composition to the outer surface of the patient's eye eyelid using the applicator.
[0041] In various embodiments, the treatment method can include applying an ophthalmic topical cream composition to the outer surface of the patient's eyelid at least once a day. For example, in one embodiment, the method can include applying the ophthalmic topical cream composition to the outer surface of the patient's eyelid up to 4 times a day, such as once a day, twice a day, three times a day, or four times a day.
[0042] Furthermore, although the above has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Accordingly, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of the present disclosure, but rather are intended to embrace all modifications and alternatives that are properly within the true scope and spirit of the present disclosure.
[0043] Exemplary embodiments 1. A topical cream comprising at least one zwitterion; and An active pharmaceutical ingredient (API) dispersed in the topical cream An ophthalmic topical cream composition comprising. 2. The ophthalmic topical cream composition according to claim 1, wherein the zwitterion is present in an amount effective to reduce the degradation of the API and increase the viscosity of the topical cream. 3. The ophthalmic topical cream composition according to claim 1 or 2, wherein the at least one zwitterion has a concentration in the topical cream of about 5 mM to about 600 mM. 4. The ophthalmic topical cream composition according to any one of claims 1 to 3, wherein the at least one zwitterion has a concentration in the topical cream of about 10 mM to about 500 mM. 5. The ophthalmic topical cream composition according to any one of claims 1 to 4, wherein the topical cream has a viscosity of about 25,000 cPs to about 400,000 cPs. 6. The ophthalmic topical cream composition according to any one of claims 1 to 5, wherein the topical cream has a viscosity of about 50,000 cPs to about 150,000 cPs. 7. The ophthalmic topical cream composition according to any one of claims 1 to 6, wherein the at least one zwitterion comprises at least one of an amino acid, a peptide, a protein, phosphatidylcholine, and betaine. 8. The ophthalmic topical cream composition according to any one of claims 1 to 7, wherein the topical cream is an oil-in-water emulsion system or a water-in-oil emulsion system. 9. The ophthalmic topical cream composition according to claim 7 or 8, wherein the at least one amino acid comprises lysine, arginine, histidine, or a combination thereof. 10. The ophthalmic topical cream composition according to claim 9, wherein the at least one amino acid comprises lysine and arginine. 11. The ophthalmic topical cream composition according to claim 10, wherein the lysine and arginine in the topical cream each independently have a concentration of about 10 mM to about 500 mM. 12. The ophthalmic topical cream composition according to claim 9, wherein the at least one amino acid comprises histidine and arginine. 13. The ophthalmic topical cream composition according to claim 12, wherein the histidine and arginine in the topical cream each independently have a concentration of about 10 mM to about 500 mM. 14. The ophthalmic topical cream composition according to claim 9, wherein the at least one amino acid comprises histidine and lysine. 15. The ophthalmic topical cream composition according to claim 14, wherein the histidine and lysine in the topical cream each independently have a concentration of about 10 mM to about 500 mM. 16. The ophthalmic topical cream composition according to claim 1, wherein the at least one zwitterion comprises a zwitterionic polymer or a polymeric zwitterion. 17. The ophthalmic topical cream composition according to any one of claims 1 to 16, wherein the topical cream further comprises a cross-linked acrylic acid polymer. 18. The ophthalmic topical cream composition according to any one of claims 1 to 16, wherein the topical cream contains less than about 1% (w / w) of a crosslinked acrylic acid polymer. 19. The ophthalmic topical cream composition according to any one of claims 1 to 18, wherein the topical cream has a pH of about 3.0 to about 7.8. 20. The ophthalmic topical cream composition according to any one of claims 1 to 19, wherein the topical cream contains about 0.002% to about 10% (w / w) of the API. 21. The ophthalmic topical cream composition according to any one of claims 1 to 20, wherein the API contains pilocarpine, atropine, travoprost, physostigmine, donepezil, timolol, loteprednol, brimonidine, and / or any salt of the foregoing. 22. The ophthalmic topical cream composition according to any one of claims 1 to 21, wherein the topical cream contains an effective amount of the API to reduce symptoms of dry eye, presbyopia, myopia, blepharitis, glaucoma, and / or edema. 23. A method of treating dry eye, presbyopia, glaucoma, and / or myopia, comprising administering an effective amount of the ophthalmic topical cream composition according to any one of claims 1 to 22 to a subject in need thereof. 24. The method according to claim 23, wherein the ophthalmic topical cream composition is applied to the outer surface of the eyelid of the subject's eye.
Claims
1. A topical cream containing at least one zwitterion; and An active ingredient (API) dispersed in the topical cream, comprising pilocarpine, atropine, travoprost, physostigmine, donepezil, timolol, loteprednol, brimonidine, and / or a salt of any of the aforementioned. A topical cream composition for ophthalmic use, comprising:
2. The ophthalmic topical cream composition according to claim 1, wherein the zwitterion is present in an amount effective in reducing the degradation of the API and increasing the viscosity of the topical cream.
3. The ophthalmic topical cream composition according to claim 1 or 2, wherein the at least one zwitterion is present in the topical cream at a concentration of about 5 mM to about 600 mM.
4. The ophthalmic topical cream composition according to claim 1 or 2, wherein the topical cream has a viscosity of about 25,000 cPs to about 400,000 cPs.
5. The ophthalmic topical cream composition according to claim 1 or 2, wherein the at least one zwitterion comprises at least one of amino acids, peptides, proteins, phosphatidylcholine, and betaine.
6. The ophthalmic topical cream composition according to claim 1 or 2, wherein the topical cream is an oil-in-water emulsion or an oil-in-water emulsion.
7. The ophthalmic topical cream composition according to claim 5, wherein at least one of the aforementioned amino acids comprises lysine, arginine, histidine, or a combination thereof.
8. The ophthalmic topical cream composition according to claim 7, wherein at least one of the aforementioned amino acids comprises lysine and arginine.
9. The ophthalmic topical cream composition according to claim 8, wherein the lysine and arginine in the topical cream each have a concentration of about 10 mM to about 500 mM, independently.
10. The ophthalmic topical cream composition according to claim 7, wherein at least one of the aforementioned amino acids comprises histidine and arginine.
11. The ophthalmic topical cream composition according to claim 10, wherein the histidine and arginine in the topical cream each have a concentration of about 10 mM to about 500 mM, independently.
12. The ophthalmic topical cream composition according to claim 7, wherein at least one of the aforementioned amino acids comprises histidine and lysine.
13. The ophthalmic topical cream composition according to claim 12, wherein the histidine and lysine in the topical cream each have a concentration of about 10 mM to about 500 mM, independently.
14. The ophthalmic topical cream composition according to claim 1, wherein the at least one zwitterion comprises a zwitterionic polymer or a polymeric zwitterion.
15. The ophthalmic topical cream composition according to claim 1 or 2, further comprising a crosslinked acrylic acid polymer.
16. The ophthalmic topical cream composition according to claim 15, wherein the topical cream contains less than 1% (w / w) of a cross-linked acrylic acid polymer.
17. The ophthalmic topical cream composition according to claim 1 or 2, wherein the topical cream has a pH of about 3.0 to about 7.
8.
18. The ophthalmic topical cream composition according to claim 1 or 2, wherein the topical cream contains about 0.002% to about 10% (w / w) of the API.
19. The ophthalmic topical cream composition according to claim 1 or 2, wherein the API comprises atropine, physostigmine, donepezil, loteprednol, and / or a salt of any of the foregoing.
20. The ophthalmic topical cream composition according to claim 1 or 2, wherein the topical cream contains an amount of the API effective in relieving symptoms of dry eye, presbyopia, myopia, blepharitis, glaucoma, and / or edema.
21. An ophthalmic topical cream composition according to claim 1 or 2, formulated for application to the outer surface of the eyelid of the eye of the subject.