Ophthalmic topical cream composition

Abstract

An ophthalmic therapeutic composition comprising a topical cream containing a cross-linked acrylic polymer, an acrylamide / sodium acryloyldimethyl taurate copolymer, and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream. The ophthalmic therapeutic compositions and APIs are formulated for topical administration and treatment of a variety of conditions, such as dry eye, presbyopia, intraocular pressure, and blepharitis.

Description

[0001] Incorporation by reference into any priority application

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 363,356, filed on April 21, 2022, entitled “Ophthalmic Topical Cream Compositions and Methods,” the entire contents of which are incorporated herein by reference and for all purposes. Background Art Technical Field

[0003] The present disclosure relates to ophthalmic therapeutic compositions, processes, and methods of using the same to treat ocular conditions and diseases, particularly by administration to the outer surface of the eyelid of a patient's eye.

[0004] illustrate

[0005] Eye drops are a typical way to administer ophthalmic drugs to patients. For example, U.S. Pat. No. 10,610,518 discloses a pilocarpine formulation and a method for administering it as an eye drop. This route is simple and non-invasive, but the control achieved in terms of patient compliance, dosage regimen, and duration is limited. If used improperly by an individual, eye drops may lead to undesirable efficacy and clinical outcomes. See Souto, EB et al., "Advanced Formulation Approachesfor Ocular Drug Delivery: State-Of-The-Art and Recent Patents", Pharmaceutics. 2019, 11, 460: 1-29. Other ophthalmic preparations have been developed, which are said to be suitable for administration by topical application to the outer surface of an individual's eyelid. See U.S. Pat. No. 9,034,830. However, there is still a need for improved ophthalmic therapeutic compositions and methods. SUMMARY OF THE INVENTION

[0007] Various embodiments provide ophthalmic therapeutic compositions. In one embodiment, the ophthalmic therapeutic composition comprises a topical cream comprising about 0% to about 8% (w / w) of a cross-linked acrylic acid polymer and about 0% to about 8% (w / w) of acrylamide / sodium acryloyldimethyltaurate copolymer; and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream.

[0008] In some embodiments, the ophthalmic therapeutic composition comprises about 0.001% to about 10% (w / w) API. In some embodiments, the ophthalmic therapeutic composition comprises about 2% to about 8% (w / w) API. In some embodiments, the topical cream comprises about 2% to about 4% (w / w) cross-linked acrylic acid polymer. In some embodiments, the topical cream comprises about 2% to about 4% (w / w) acrylamide / sodium acryloyldimethyltaurate copolymer.

[0009] In some embodiments, acrylamide / sodium acryloyldimethyltaurate copolymer is dispersed in isohexadecane containing polysorbate 80, polysorbate 20, polysorbate 40, or polysorbate 60. In some embodiments, the API comprises pilocarpine. In some embodiments, the ophthalmic therapeutic composition comprises an amount of API effective to reduce dry eye symptoms and / or treat presbyopia. In some embodiments, the API comprises travoprost. In some embodiments, the ophthalmic therapeutic composition comprises an amount of API that is safe and effective for treating intraocular pressure (IOP). In some embodiments, the API comprises atropine, physostigmine, and / or donepezil. In some embodiments, the ophthalmic therapeutic composition comprises an amount of API that is safe and effective for treating myopia and blepharitis.

[0010] In some embodiments, the pH of the ophthalmic therapeutic composition is in the range of about 3.0 to about 7.8. In some embodiments, the pH of the ophthalmic therapeutic composition is in the range of about 3.5 to about 5.5. In some embodiments, the viscosity of the ophthalmic therapeutic composition is in the range of about 4,000 centipoise to about 400,000 centipoise. In some embodiments, the viscosity of the ophthalmic therapeutic composition is in the range of about 5,000 centipoise to about 300,000 centipoise. In some embodiments, the viscosity of the ophthalmic therapeutic composition is in the range of about 7,500 centipoise to about 250,000 centipoise.

[0011] In some embodiments, the ophthalmic therapeutic composition is thixotropic. In some embodiments, the ophthalmic therapeutic composition has less than about 5% (w / w) API degradation when measured after storage at 40°C for 60 days after preparation of the ophthalmic therapeutic composition. In some embodiments, the ophthalmic therapeutic composition has less than about 10% (w / w) API degradation when measured after storage at 40°C for 24 months after preparation of the ophthalmic therapeutic composition.

[0012] In some embodiments, the ophthalmic therapeutic composition is formulated to be applied to the outer surface of the eyelid to deliver the API into the eye. In some embodiments, the ophthalmic therapeutic composition has less residue after application to the outer surface of the eyelid compared to application of an otherwise identical composition comprising hydroxypropylcellulose (HPC) instead of acrylamide / sodium acryloyldimethyltaurate copolymer.

[0013] In addition, various embodiments provide methods of administering an ophthalmic drug to an eye of a patient. In one embodiment, the method comprises applying an ophthalmic therapeutic composition to the outer surface of an eyelid of an eye of a patient, wherein the ophthalmic therapeutic composition comprises a topical cream comprising about 0.5% to about 8% (w / w) of a cross-linked acrylic acid polymer and about 0.25% to about 8% (w / w) of an acrylamide / sodium acryloyldimethyltaurate copolymer; and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream.

[0014] In some embodiments, the effective amount of the API is about 0.004% to about 10% (w / w). In some embodiments, the API comprises pilocarpine, travoprost, atropine, donepezil, or physostigmine. In some embodiments, the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye at least once a day.

[0015] In some embodiments, the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye up to four times a day. In some embodiments, applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye comprises applying with an applicator. In some embodiments, the method further comprises squeezing the ophthalmic therapeutic composition from the container onto the applicator and then applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a bar graph summarizing the results of a survey evaluating the residues of various ophthalmic therapeutic compositions that did not contain acrylamide / sodium acryloyldimethyltaurate copolymer or SEPINEO P600 after topical application.

[0017] Figure 2 is a bar graph summarizing the results of a survey evaluating the emolliency of various ophthalmic therapeutic compositions.

[0018] Figure 3 is a bar graph summarizing the findings of the texture evaluation of various ophthalmic therapeutic compositions.

[0019] Figure 4is a bar graph summarizing the findings from the residue acceptability evaluation following application of formulations containing either acrylamide / sodium acryloyldimethyltaurate copolymer or SEPINEO P 600.

[0020] Figure 5 The stability of an ophthalmic therapeutic composition (F2) having a pH of about 5 is illustrated as a function of storage time at room temperature and at 40°C.

[0021] Figure 6 The stability of an ophthalmic therapeutic composition (F15) having a pH of about 3.5 is illustrated as a function of storage time at room temperature and at 40°C.

[0022] Figure 7 The stability of an ophthalmic therapeutic composition (F23) having a pH of about 3.5 is illustrated as a function of storage time at room temperature and at 40°C.

[0023] Figure 8 The stability of an ophthalmic therapeutic composition (F24) having a pH of about 5 is demonstrated as a function of storage time at room temperature and at 40°C.

[0024] Fig. 9 The stability of an ophthalmic therapeutic composition (F27) having a pH of about 3.5 is illustrated as a function of storage time at room temperature and at 40°C.

[0025] Fig.10 The stability of an ophthalmic therapeutic composition (F28) having a pH of about 5 is illustrated as a function of storage time at room temperature and at 40°C. DETAILED DESCRIPTION OF THE INVENTION

[0027] An ophthalmic therapeutic composition has been developed that contains a topical cream comprising from about 0.0% to about 8% (w / w) of a cross-linked acrylic acid polymer and from about 0.0% to about 8% of an acrylamide / sodium acryloyldimethyltaurate copolymer, and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream. In various embodiments, this polymer combination imparts surprisingly high levels of desirable characteristics to the ophthalmic therapeutic composition, such as low residue after application, emollients, texture, and / or storage stability.

[0028] Ophthalmic therapeutic compositions

[0029] Various embodiments provide an ophthalmic therapeutic composition comprising:

[0030] A topical cream comprising from about 0.0% to about 8% (w / w), e.g., from about 0.05% to about 8% (w / w), of a cross-linked acrylic acid polymer and from about 0.0% to about 8% (w / w), e.g., from about 0.025% to about 8% (w / w), of an acrylamide / sodium acryloyldimethyltaurate copolymer; and

[0031] An effective amount of an active pharmaceutical ingredient (API) is dispersed in the topical cream.

[0032] A variety of suitable cross-linked acrylic polymers are commercially available and / or can be readily synthesized by one skilled in the art. In some embodiments, the acrylic polymer is a homopolymer of acrylic acid. In other embodiments, the acrylic polymer is a copolymer consisting primarily of acrylic acid units and a small amount (usually <10%) of acrylic acid and a compatible comonomer such as acrylic acid C. 10 -C 30 The crosslinking of acrylic acid polymers can be carried out in various ways, for example, by copolymerization with crosslinking agents such as allyl sucrose or allyl pentaerythritol. In various embodiments, the molecular weight and degree of crosslinking of the crosslinked acrylic acid polymers result in a solution viscosity (measured at 0.5 wt % and pH 7.5) of about 4,000 centipoise to about 80,000 centipoise, for example, about 40,000 centipoise to about 60,000 centipoise. Suitable acrylic acid polymers from commercial sources include those available from Lubrizol Corporation under the trade name CARBOPOL. In a non-limiting example, the crosslinked acrylic acid polymer is carbomer homopolymer C 980 type (Carbomer Homopolymer Type C 980).

[0033] The amount of the cross-linked acrylic polymer in the topical cream is generally in the range of about 0.0% to about 8% (w / w), such as about 0.05% to about 8% (w / w), such as about 0.5% to about 8% (w / w), about 2% to about 6% (w / w), about 2% to about 4% (w / w), or about 3% to about 5% (w / w). The amount of the cross-linked acrylic polymer can be adjusted according to the viscosity. For example, for a cross-linked acrylic polymer having a viscosity in the range of about 40,000 centipoise to about 60,000 centipoise, a suitable amount can be in the range of about 3% to about 5% (w / w). Those skilled in the art will appreciate the relationship between viscosity and concentration, so that a cross-linked acrylic polymer of higher viscosity can be used in smaller amounts, while in some embodiments, a larger amount of a lower viscosity polymer may be suitable.

[0034] Various acrylamide / sodium acryloyldimethyl taurate copolymers are commercially available and / or can be readily synthesized by one skilled in the art. In some embodiments, the acrylamide / sodium acryloyldimethyl taurate copolymer is a copolymer of acrylamide and sodium acryloyldimethyl taurate. In other embodiments, the acrylamide / sodium acryloyldimethyl taurate copolymer may contain a small amount (usually <10%) of other units formed by copolymerization of acrylamide and sodium acryloyldimethyl taurate with compatible comonomers such as methacrylamide and / or sodium methacryloyldimethyl taurate.

[0035] The amount of acrylamide / sodium acryloyldimethyl taurate copolymer in the topical cream is generally in the range of about 0.0% to about 8% (w / w), such as 0.025% to about 8% (w / w), about 0.25% to about 8% (w / w), about 2% to about 6% (w / w), about 2% to about 4% (w / w), or about 3% to about 5% (w / w). The amount of acrylamide / sodium acryloyldimethyl taurate copolymer can be adjusted according to the viscosity in a similar manner as the cross-linked acrylic acid polymer described above.

[0036] Likewise, the type, amount, and viscosity of the polymer components (e.g., cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyl taurate copolymer) can be adjusted or selected to impart desired rheological properties (e.g., viscosity and / or thixotropy) to the ophthalmic therapeutic composition. In one embodiment, the viscosity of the ophthalmic therapeutic composition is in the range of about 4,000 centipoise to about 400,000 centipoise, e.g., about 5,000 centipoise to about 300,000 centipoise or about 7,500 centipoise to about 250,000 centipoise.

[0037] In one embodiment, the ophthalmic therapeutic composition is formulated for application to the outer surface of the eyelid to deliver the API to the eye. The ophthalmic therapeutic composition can be formulated to be surprisingly thixotropic. This high degree of thixotropy is desirable from a patient compliance perspective because the lower viscosity during flow facilitates squeezing the ophthalmic therapeutic composition from the container to the applicator, which is then applied to the outer surface of the eyelid of the patient's eye. After such application, the higher viscosity of the ophthalmic therapeutic composition after application on the eyelid enables it to remain in place, thereby providing the individual with additional time before being rubbed into the eye.

[0038] Acrylamide / sodium acryloyldimethyl taurate copolymers are typically provided by commercial sources in the form of emulsion gels. See G. Bonacucina et al., "Characterization and Stability of Emulsion Gels Based on Acrylamide / Sodium Acryloyldimethyl Taurate Copolymer" AAPS Pharma Sci Tech. 2009 Jun; 10 (2): 368-375. In a non-limiting example, the acrylamide / sodium acryloyldimethyl taurate copolymer is SEPINEO P 600, which is commercially available from Seppic, a subsidiary of Air Liquide Healthcare, as a concentrated dispersion in isohexadecane containing polysorbate 80.

[0039] In various embodiments, cross-linked acrylic acid polymers and acrylamide / sodium acryloyldimethyl taurate copolymers are combined to form a topical cream. In addition to common ingredients such as water, the topical cream may also contain small amounts of other ingredients that can be used for preparation and / or formulation. Non-limiting examples include: oils such as mineral oil and polyoxyl castor oil, glycols such as propylene glycol and polyethylene glycol, alcohols such as sorbitol and cetyl alcohol, parabens such as methylparaben and propylparaben, stabilizers such as disodium edetate, salts such as magnesium chloride, pH adjusters such as citric acid and sodium hydroxide, etc. The non-limiting examples in Table 1 illustrate suitable amounts of such small amounts of formulation ingredients.

[0040] Table 1

[0041] Element Amount(%w / w) Pilocarpine Hydrochloride 1-10 Kolliphor ELP 2-8 Propylene glycol 1-6 Cetyl Alcohol 0-3 Polysorbate 80 1-5 Mineral oil 5-20 Sorbitol 2-10 Polyethylene glycol 8000 0-5 Methylparaben 0.03-0.45 Propylparaben 0-0.1 caffeine 0-0.5 Magnesium chloride 0-0.1 Carbomer Homopolymer C Type 980 0-8 Edetate Disodium 0-0.3 Purified water The remainder Sepineo P600 0-8 Sodium hydroxide (pH adjuster) Adequate

[0042] Surprisingly, in some embodiments, the combination of cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyltaurate copolymer provides unexpectedly high levels of one or more desirable properties that enhance patient acceptance, thereby promoting patient compliance. For example, Figure 1 Illustrated is a bar graph summarizing the results of a survey of residual evaluations of various ophthalmic therapeutic compositions after topical application. Table 2 summarizes the major ingredients and pH values ​​of the formulations.

[0043] Table 2

[0044] Serial number Carbomer (weight %) HPC (wt%) Pilocarpine (weight %) pH 1 4 0 4 3.5 2 4 0 4 5 3 4 0 8 3.5 4 4 0 8 5 5 4 2 4 3.5 6 4 2 4 5 7 4 2 8 3.5 8 4 2 8 5 11 2 0 4 3.5 12 2 0 4 5 13 2 0 8 3.5 14 2 0 8 5 15 2 2 4 3.5 16 2 2 4 5 17 2 2 8 3.5 18 2 2 8 5

[0045] As shown in Table 2, no acrylamide / sodium acryloyldimethyltaurate copolymer or SEPINEO P 600 was present in Formulations 1-18. In addition, hydroxypropylcellulose (HPC) was present in Formulations 5-11 and 15-18. Figure 1 Data summarized in showed that topical application of a formulation containing a combination of a cross-linked acrylic acid polymer (carbomer) and hydroxypropylcellulose (HPC) to the skin of test subjects resulted in undesirable levels of residue perceived on the skin. Figure 2 ) and texture ( Figure 3 ) were observed in the evaluation.

[0046] In contrast, when the combination with the cross-linked acrylic acid polymer comprised acrylamide / sodium acryloyldimethyl taurate copolymer in place of HPC, test subjects were surprisingly more satisfied with the skin residue level, emolliency, and / or texture. Figure 4 The data summarized in the paper show that compared with HPC (see Figure 1 ), topical application of a different formulation containing a combination of a cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyl taurate copolymer to the skin of a test subject resulted in a more desirable feel of residue on the skin than the formulation containing a combination of a cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyl taurate copolymer. Similarly, better evaluations of emolliency and texture were observed for the formulation containing a combination of a cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyl taurate copolymer. Table 3 summarizes Figure 4 Main ingredients and pH values ​​of the indicated formulations.

[0047] In various embodiments, the pH of the ophthalmic therapeutic composition is in the range of about 3.0 to about 7.8, such as in the range of about 3 to about 5.5, about 3 to about 5, about 3.5 to about 5.5, or about 3.5 to 5. In one embodiment, the pH is less than 5, such as in the range of about 3.0 to less than 5 or about 3.5 to less than 5. For example, in one embodiment, the pH is in the range of about 3.5 to about 4.5. In another embodiment, the pH is in the range of about 3.5 to about 4.

[0048] Surprisingly, in some embodiments, the combination of cross-linked acrylic acid polymer and acrylamide / sodium acryloyldimethyltaurate copolymer provides unexpectedly high levels of physical stability and API chemical stability, particularly when stored at a pH of less than 5. In various embodiments, degradation of the ophthalmic therapeutic composition is measured at 40°C or at room temperature. Room temperature refers to a temperature of about 15°C to about 25°C. In some embodiments, room temperature is 25°C. Degradation at 40°C may be accelerated compared to degradation at room temperature. For example, Figure 5 The chemical stability of an ophthalmic therapeutic composition (F2) having a pH of about 5 is illustrated as a function of storage time at room temperature and 40°C. The impurities exemplified are degradation products of pilocarpine. In contrast, Figure 6 Another ophthalmic therapeutic composition (F15) shows significantly improved stability data at pH 3.5 rather than pH 5. An otherwise identical formulation (F24) at pH 5 ( Figure 8 ), a similar trend was observed in the evaluation of the ophthalmic therapeutic composition (F23) at pH 3.5 ( Figure 7 ). Similarly, an otherwise identical formulation (F28) at pH 5 ( Fig.10 ), the stability data of the ophthalmic therapeutic composition (F27) at pH 3.5 was significantly improved ( Fig. 9 ). Table 3 summarizes the main ingredients and pH values ​​of the formulations. The amounts shown are weight % of the ingredients.

[0049] Table 3

[0050] Serial number Carbomer (weight %) SEPINEO (wt%) Pilocarpine (weight %) pH F2 4 0 4 5 F15 2 0 (using 2% HPC) 4 3.5 F21 2 4 4 3.5 F22 2 4 4 5 F23 4 4 4 3.5 F24 4 4 4 5 F25 2 4 8 3.5 F26 2 4 8 5 F27 4 4 8 3.5 F28 4 4 8 5 F29 3 3 4 3.5 F30 3 3 8 3.5

[0051] In various embodiments, the ophthalmic therapeutic composition has less than about 5% (w / w) API degradation when measured after storage at 40°C for 60 days after preparation of the ophthalmic therapeutic composition. In some embodiments, the ophthalmic therapeutic composition has less than about 4.5% (w / w) API degradation when measured after storage at 40°C for 60 days after preparation of the ophthalmic therapeutic composition. In some embodiments, the ophthalmic therapeutic composition has less than about 4% (w / w) API degradation when measured after storage at 40°C for 30 days after preparation of the ophthalmic therapeutic composition. In one embodiment, the ophthalmic therapeutic composition has less than about 10% (w / w) API degradation when measured after storage at 40°C for 4 months after preparation of the ophthalmic therapeutic composition.

[0052] The ophthalmic therapeutic composition comprises an effective amount of an active pharmaceutical ingredient (API) dispersed in a topical cream. In one embodiment, the ophthalmic therapeutic composition comprises about 0.001% to about 10% (w / w) of API. In some embodiments, the API comprises pilocarpine, travoprost, atropine, donepezil, physostigmine, or a combination thereof. In some embodiments, the API may be pilocarpine, travoprost, atropine, donepezil, physostigmine, or a combination thereof. For example, in one embodiment, the ophthalmic therapeutic composition comprises about 0.004% to about 10% (w / w), about 1% to about 8% (w / w), or about 2% to about 8% (w / w) of API. For any particular API, the effective amount in the composition can be adjusted based on the disease or condition to be treated. For example, in one embodiment, the API is pilocarpine, and its effective amount is generally in the range of about 1% to about 8% (w / w). In one embodiment, the ophthalmic therapeutic composition comprises an amount of API (e.g., pilocarpine) that is effective in alleviating dry eye symptoms. In one embodiment, the ophthalmic therapeutic composition comprises an API (e.g., pilocarpine) in an amount effective to treat presbyopia. In one embodiment, the API comprises travoprost. In one embodiment, the ophthalmic therapeutic composition comprises an API (e.g., travoprost) in an amount effective to treat intraocular pressure (IOP). In one embodiment, the API comprises physostigmine. In one embodiment, the ophthalmic therapeutic composition comprises an API (e.g., physostigmine) in an amount effective to treat blepharitis. In one embodiment, the API comprises donepezil. In one embodiment, the ophthalmic therapeutic composition comprises an API (e.g., donepezil) in an amount effective to treat blepharitis.

[0053] The ophthalmic therapeutic composition disclosed herein can be prepared in various ways, for example, by fully mixing the various ingredients to form a topical cream. In one embodiment, acrylamide / sodium acryloyldimethyl taurate copolymer is added to the other ingredients and fully mixed, and then a cross-linked acrylic acid polymer is added. When EDTA is present in the formula, it is found that the opposite mixing order (i.e., first adding a cross-linked acrylic acid polymer, then adding acrylamide / sodium acryloyldimethyl taurate copolymer) can lead to the formation of EDTA crystallites. In another embodiment, when a strong base (e.g., NaOH) is used to adjust the pH of the ophthalmic therapeutic composition, the strong base is added to the other ingredients and fully mixed, and then the API is added. It is found that the opposite order of addition (i.e., adding the strong base to the other ingredients after adding the API) leads to a higher level of API degradation.

[0054] In various embodiments, the ophthalmic therapeutic composition is sterilized. For example, in one embodiment, the ophthalmic therapeutic composition is sterilized by electron beam treatment. As shown in the data in Table 4, such electron beam sterilization tends to increase the viscosity of the ophthalmic therapeutic composition to some extent, but the viscosity remains within the desired range.

[0055] Table 4

[0056]

[0057] Treatment

[0058] Various embodiments provide methods of treating an ocular disease or condition by topical administration of an ophthalmic therapeutic composition described herein.

[0059] For example, one embodiment provides a method of administering an ophthalmic drug to a patient's eye, the method comprising applying an ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye, wherein the ophthalmic therapeutic composition comprises a topical cream comprising about 0.5% to about 8% (w / w) of a cross-linked acrylic acid polymer and about 0.25% to about 8% of acrylamide / sodium acryloyldimethyltaurate copolymer; and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream. The amounts and types of various ingredients and indications are described above with respect to the ophthalmic therapeutic composition.

[0060] In various embodiments, the API is pilocarpine and the treatment method is effective for reducing dry eye symptoms. In another embodiment, the API is pilocarpine and the treatment method is effective for treating presbyopia. In one embodiment, the API comprises travoprost and the treatment method is effective for treating intraocular pressure (IOP). In one embodiment, the API comprises physostigmine or donepezil and the treatment method is effective for treating blepharitis. In one embodiment, the API comprises travoprost or pilocarpine and the treatment method is effective for treating blepharitis.

[0061] In one embodiment, the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye by applying with an applicator. For example, in one embodiment, the treatment comprises squeezing the ophthalmic therapeutic composition from a container onto an applicator (e.g., a tube connected to the container), and then applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye using the applicator, such as by further squeezing the container to push the ophthalmic therapeutic composition from the applicator onto the eyelid.

[0062] In various embodiments, the method of treatment comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye at least once a day. For example, in one embodiment, the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye up to four times a day, for example, once a day, twice a day, three times a day, or four times a day.

[0063] In addition, although the above content has been described in some detail by way of illustration and example for the purpose of clarity and understanding, it will be appreciated by those skilled in the art that many and various modifications may be made without departing from the spirit of the invention. Therefore, 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 also encompass all modifications and alternatives related to the true scope and spirit of the present disclosure.

[0064] Exemplary embodiments

[0065] 1. An ophthalmic therapeutic composition comprising:

[0066] a topical cream comprising from about 0.0% to about 8% (w / w) of a cross-linked acrylic acid polymer and from about 0.0% to about 8% (w / w) of an acrylamide / sodium acryloyldimethyl taurate copolymer; and

[0067] An effective amount of an active pharmaceutical ingredient (API) is dispersed in the topical cream.

[0068] 2. The ophthalmic therapeutic composition of embodiment 1, wherein the ophthalmic therapeutic composition comprises about 0.001% to about 10% (w / w) API.

[0069] 3. The ophthalmic therapeutic composition of embodiment 2, wherein the ophthalmic therapeutic composition comprises about 2% to about 8% (w / w) API.

[0070] 4. The ophthalmic therapeutic composition of any one of embodiments 1 to 3, wherein the topical cream comprises from about 2% to about 4% (w / w) of the cross-linked acrylic acid polymer.

[0071] 5. The ophthalmic therapeutic composition of any one of embodiments 1 to 4, wherein the topical cream comprises from about 2% to about 4% (w / w) acrylamide / sodium acryloyldimethyltaurate copolymer.

[0072] 6. The ophthalmic therapeutic composition of any one of embodiments 1 to 5, wherein the acrylamide / sodium acryloyldimethyltaurate copolymer is dispersed in isohexadecane containing polysorbate 80.

[0073] 7. The ophthalmic therapeutic composition of any one of embodiments 1 to 6, wherein the API comprises pilocarpine.

[0074] 8. The ophthalmic therapeutic composition of embodiment 7, wherein the ophthalmic therapeutic composition comprises an amount of API effective for alleviating dry eye symptoms and / or treating presbyopia.

[0075] 9. The ophthalmic therapeutic composition of any one of embodiments 1 to 6, wherein the API comprises travoprost.

[0076] 10. The ophthalmic therapeutic composition of embodiment 9, wherein the ophthalmic therapeutic composition comprises an amount of API effective to treat intraocular pressure (IOP).

[0077] 11. The ophthalmic therapeutic composition of any one of embodiments 1 to 6, wherein the API comprises physostigmine and / or donepezil.

[0078] 12. The ophthalmic therapeutic composition of embodiment 11, wherein the ophthalmic therapeutic composition comprises an amount of the API effective to treat blepharitis.

[0079] 13. The ophthalmic therapeutic composition of any one of embodiments 1 to 12, wherein the pH of the ophthalmic therapeutic composition is in the range of about 3.0 to about 7.8.

[0080] 14. The ophthalmic therapeutic composition of embodiment 13, wherein the pH of the ophthalmic therapeutic composition is in the range of about 3.5 to about 5.5.

[0081] 15. The ophthalmic therapeutic composition of any one of embodiments 1 to 14, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 4,000 centipoise to about 400,000 centipoise.

[0082] 16. The ophthalmic therapeutic composition of embodiment 15, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 5,000 centipoise to about 300,000 centipoise.

[0083] 17. The ophthalmic therapeutic composition of any one of embodiments 1 to 11, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 7,500 centipoise to about 250,000 centipoise.

[0084] 18. The ophthalmic therapeutic composition of any one of embodiments 1 to 17, wherein the ophthalmic therapeutic composition is thixotropic.

[0085] 19. The ophthalmic therapeutic composition of any one of embodiments 1 to 18, wherein the ophthalmic therapeutic composition has less than about 5% (w / w) API degradation when measured after storage at 40°C for 60 days after preparation of the ophthalmic therapeutic composition.

[0086] 20. The ophthalmic therapeutic composition of any one of embodiments 1 to 19, wherein the ophthalmic therapeutic composition has less than about 10% (w / w) API degradation when measured after storage at 40°C for 4 months after preparation of the ophthalmic therapeutic composition.

[0087] 21. The ophthalmic therapeutic composition of any one of embodiments 1 to 20, wherein the ophthalmic therapeutic composition is formulated for application to the outer surface of the eyelid to deliver the API into the eye.

[0088] 22. The ophthalmic therapeutic composition of embodiment 21, wherein less residue remains after the ophthalmic therapeutic composition is applied to the outer surface of the eyelid compared to applying a composition comprising hydroxypropylcellulose (HPC) instead of acrylamide / sodium acryloyldimethyl taurate copolymer but being the same in all other aspects.

[0089] 23. A method of administering an ophthalmic medicament to an eye of a patient, the method comprising applying an ophthalmic therapeutic composition to the outer surface of an eyelid of an eye of the patient,

[0090] The ophthalmic therapeutic composition comprises a topical cream comprising about 0.5% to about 8% (w / w) of a cross-linked acrylic acid polymer and about 0.25% to about 8% of an acrylamide / sodium acryloyldimethyl taurate copolymer; and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream.

[0091] 24. The method of embodiment 23, wherein the effective amount of the API is from about 0.001% to about 10% (w / w).

[0092] 25. The method of embodiment 23 or 24, wherein the API comprises pilocarpine, travoprost, atropine, donepezil, or physostigmine.

[0093] 26. The method of any one of embodiments 23 to 25, wherein the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye at least once a day.

[0094] 27. The method of embodiment 26, wherein the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye up to four times per day.

[0095] 28. The method of any one of embodiments 23 to 27, wherein applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye comprises applying with an applicator.

[0096] 29. The method of embodiment 28, wherein the method further comprises squeezing the ophthalmic therapeutic composition from the container onto the applicator and then applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye.

Claims

1. An ophthalmic therapeutic composition comprising: a topical cream comprising from about 0.0% to about 8% (w / w) of a cross-linked acrylic acid polymer and from about 0.0% to about 8% (w / w) of an acrylamide / sodium acryloyldimethyl taurate copolymer; and An effective amount of an active pharmaceutical ingredient (API) is dispersed in the topical cream.

2. The ophthalmic therapeutic composition of claim 1, wherein the ophthalmic therapeutic composition comprises from about 0.001% to about 10% (w / w) API.

3. The ophthalmic therapeutic composition of claim 2, wherein the ophthalmic therapeutic composition comprises from about 2% to about 8% (w / w) API.

4. The ophthalmic therapeutic composition of any one of claims 1 to 3, wherein the topical cream comprises from about 2% to about 4% (w / w) of the cross-linked acrylic acid polymer.

5. The ophthalmic therapeutic composition of any one of claims 1 to 4, wherein the topical cream comprises from about 2% to about 4% (w / w) acrylamide / sodium acryloyldimethyltaurate copolymer.

6. The ophthalmic therapeutic composition of any one of claims 1 to 5, wherein the acrylamide / sodium acryloyldimethyltaurate copolymer is dispersed in isohexadecane containing polysorbate 80.

7. The ophthalmic therapeutic composition of any one of claims 1 to 6, wherein the API comprises pilocarpine.

8. The ophthalmic therapeutic composition of claim 7, wherein the ophthalmic therapeutic composition comprises an amount of the API effective to reduce dry eye symptoms and / or treat presbyopia.

9. The ophthalmic therapeutic composition of any one of claims 1 to 6, wherein the API comprises travoprost.

10. The ophthalmic therapeutic composition of claim 9, wherein the ophthalmic therapeutic composition comprises an amount of the API effective to treat intraocular pressure (IOP).

11. The ophthalmic therapeutic composition of any one of claims 1 to 6, wherein the API comprises physostigmine and / or donepezil.

12. The ophthalmic therapeutic composition of claim 11, wherein the ophthalmic therapeutic composition comprises an amount of the API effective to treat blepharitis.

13. The ophthalmic therapeutic composition of any one of claims 1 to 12, wherein the pH of the ophthalmic therapeutic composition is in the range of about 3.0 to about 7.

8.

14. The ophthalmic therapeutic composition of claim 13, wherein the pH of the ophthalmic therapeutic composition is in the range of about 3.5 to about 5.

5.

15. The ophthalmic therapeutic composition of any one of claims 1 to 14, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 4,000 centipoise to about 400,000 centipoise.

16. The ophthalmic therapeutic composition of claim 15, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 5,000 centipoise to about 300,000 centipoise.

17. The ophthalmic therapeutic composition of any one of claims 1 to 11, wherein the viscosity of the ophthalmic therapeutic composition is in the range of about 7,500 centipoise to about 250,000 centipoise.

18. The ophthalmic therapeutic composition of any one of claims 1 to 17, wherein the ophthalmic therapeutic composition is thixotropic.

19. The ophthalmic therapeutic composition of any one of claims 1 to 18, wherein the ophthalmic therapeutic composition has less than about 5% (w / w) API degradation when measured after storage at 40°C for 60 days after preparation of the ophthalmic therapeutic composition.

20. The ophthalmic therapeutic composition of any one of claims 1 to 19, wherein the ophthalmic therapeutic composition has less than about 10% (w / w) API degradation when measured after storage at 40°C for 4 months after preparation of the ophthalmic therapeutic composition.

21. The ophthalmic therapeutic composition of any one of claims 1 to 20, wherein the ophthalmic therapeutic composition is formulated for application to the outer surface of the eyelid to deliver the API into the eye.

22. The ophthalmic therapeutic composition of claim 21, wherein less residue remains after application of the ophthalmic therapeutic composition to the outer surface of the eyelid compared to application of an otherwise identical composition comprising hydroxypropylcellulose (HPC) in place of acrylamide / sodium acryloyldimethyltaurate copolymer.

23. A method of administering an ophthalmic drug to an eye of a patient, the method comprising applying an ophthalmic therapeutic composition to the outer surface of an eyelid of the eye of the patient, The ophthalmic therapeutic composition comprises a topical cream comprising about 0.5% to about 8% (w / w) of a cross-linked acrylic acid polymer and about 0.25% to about 8% of an acrylamide / sodium acryloyldimethyl taurate copolymer; and an effective amount of an active pharmaceutical ingredient (API) dispersed in the topical cream.

24. The method of claim 23, wherein the effective amount of the API is from about 0.001% to about 10% (w / w).

25. The method of claim 23 or 24, wherein the API comprises pilocarpine, travoprost, atropine, donepezil, or physostigmine.

26. The method of any one of claims 23 to 25, wherein the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye at least once a day.

27. The method of claim 26, wherein the method comprises applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye up to four times per day.

28. The method of any one of claims 23 to 27, wherein applying the ophthalmic therapeutic composition to the outer surface of the eyelid of the patient's eye comprises applying with an applicator.

29. The method of claim 28, wherein the method further comprises squeezing the ophthalmic therapeutic composition from a container onto the applicator and then applying the ophthalmic therapeutic composition to the outer surface of an eyelid of the patient's eye.

Images