阅读说明：本技术 用于将药物持续递送至视网膜的滴眼剂制剂和方法 (Eye drop formulations and methods for sustained drug delivery to the retina ) 是由 V·G·翁 G·T·黄 于 2019-05-01 设计创作，主要内容包括：本发明实施方案提供了用于治疗影响眼的后部(例如视网膜)的眼部病症或疾病的组合物、方法和药盒。(Embodiments of the invention provide compositions, methods, and kits for treating ocular disorders or diseases affecting the posterior portion of the eye (e.g., the retina).)

1. A fluid reservoir for sustained release of an active agent at the posterior portion of the eye, the fluid reservoir comprising: a tocopherol; an ocular film forming excipient; and an active agent; wherein the liquid reservoir has a viscosity of about 850cP to about 1100cP, inclusive.

2. The fluid reservoir of claim 1, wherein said tocopherol is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol, or alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, or delta-tocotrienol.

3. The fluid reservoir of any of claims 1-2, wherein said tocopherol is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol.

4. The fluid reservoir of any of claims 1-3 wherein the tocopherol is tocopherol acetate.

5. The fluid reservoir of any of claims 1-4, wherein the ocular film-forming excipient comprises at least one triglyceride.

6. The liquid reservoir of any of claims 1-5 wherein the triglyceride is comprised of medium chain triglycerides.

7. The fluid reservoir of any of claims 1-6 wherein said at least one active agent is a corticosteroid.

8. The fluid reservoir of claim 7 wherein the corticosteroid is a member selected from dexamethasone, prednisolone, prednisone, loteprednol etabonate, triamcinolone, and fluorometholone.

9. The fluid reservoir of claim 8, wherein said fluid reservoir comprises, in weight percent, (a) about 10% -30% dexamethasone; and (b) from about 70% to about 90% of a mixture of tocopherol acetate to medium chain triglycerides in a weight ratio of from about 85: 15 to about 70: 30.

10. The fluid reservoir of claim 8 wherein said fluid reservoir comprises, in weight percent, (a) about 10% prednisolone; and (b) about 90% of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of about 80: 20.

11. The fluid reservoir of claim 8 wherein the fluid reservoir comprises, in weight percent, (a) about 10% loteprednol etabonate; and (b) about 90% of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of about 80: 20.

12. The liquid reservoir of any of claims 1-6, wherein said at least one of said active agents is an anti-infective agent.

13. The fluid reservoir of any of claims 1-11, further comprising an anti-infective agent.

14. The fluid reservoir of claim 12 or 13, wherein said anti-infective agent is moxifloxacin.

15. The fluid reservoir of claim 12 wherein said fluid reservoir comprises, in weight percent, (a) about 10% -20% moxifloxacin; and (b) from about 80% to about 90% of a mixture of tocopherol acetate to medium chain triglycerides in a ratio of about 70: 30.

16. The fluid reservoir of claim 12 wherein said fluid reservoir comprises, in weight percent, (a) about 15% ciprofloxacin; and (b) about 85% of a mixture of tocopherol acetate to medium chain triglycerides in a ratio of about 70: 30.

17. The fluid reservoir of claim 12 wherein said fluid reservoir comprises, in weight percent, (a) about 10% gatifloxacin; and (b) about 90% of a mixture of tocopherol acetate to medium chain triglycerides in a ratio of about 70: 30.

18. The fluid reservoir of any of claims 1-7 comprising dexamethasone and moxifloxacin in a mixture of tocopherol acetate medium chain triglycerides in a weight ratio of about 85: 15 to about 70: 30.

19. The fluid reservoir of any of the preceding claims, wherein the fluid reservoir is sterile and is disposed within a disposable dispenser configured to dispense the fluid reservoir into an eye.

20. A kit comprising at least one disposable dispenser, wherein the at least one disposable dispenser comprises the fluid reservoir of any one of claims 1-19.

21. The kit of claim 20, wherein the fluid reservoir consists of, in weight percent: (a) about 10% to 30% dexamethasone; and (b) from about 70% to about 90% of a mixture of tocopherol acetate to medium chain triglycerides in a ratio of from about 70: 30 to about 85: 15.

22. The kit of claim 20, wherein (a) consists of about 10% dexamethasone; and (b) consists of a 70: 30 mixture of tocopherol acetate and medium chain triglycerides.

23. The kit of claim 20, wherein the medium chain triglyceride isMedium chain triglycerides.

24. A method of treating a retina in an eye of a subject, comprising topically administering to the eye of the subject a fluid reservoir comprising, consisting of, or consisting essentially of: (a) about 10% -30% (wt%) dexamethasone; and (b) from about 70% to about 90% (wt%) of a mixture of tocopherol acetate to medium chain triglycerides in a weight ratio of from about 85: 15 to about 70: 30.

25. The method of claim 24, wherein the fluid reservoir comprises, consists of, or consists essentially of: (a) about 10% dexamethasone; and (b) about 90% of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of about 70: 30.

26. The method of claim 24, wherein the fluid reservoir comprises, consists of, or consists essentially of: (a) about 10% dexamethasone; and (b) about 90% of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of about 85: 15.

27. The method of claim 24, wherein the fluid reservoir comprises, consists of, or consists essentially of: (a) about 30% dexamethasone; and (b) about 70% of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of about 70: 30.

28. The method of any one of claims 24-27, wherein the administration is intermittent.

29. The method of claim 28, wherein the intermittent administration is for at least about 24 hours, 48 hours, 72 hours (3 days), 4 days, 5 days, 6 days, 7 days (1 week), 14 days (2 weeks), or 21 days (3 weeks).

30. The method of any one of claims 24-27, wherein the administration is specified as a frequency of no more than once every three (3) days.

31. The method of any one of claims 24-27, wherein the administration is specified as a frequency of no more than once every seven (7) days.

Technical Field

Embodiments of the present invention provide compositions and methods for treating ocular disorders or diseases affecting the back of the eye (e.g., the retina).

Background

There remains a need for non-invasive, sustained delivery of agents to tissues and fluid portions of the posterior segment of the eye, such as the retina or vitreous.

Summary of The Invention

Embodiments of the present invention provide compositions and methods for treating or preventing ocular diseases (ailment) by non-invasive fluid reservoirs that deliver at least one agent to the eye for days or weeks. The fluid reservoir is biocompatible and conforms to the shape of the eye, forms a thin film or a flattened bleb covering the external tissues of the eye (e.g., conjunctiva, corneal surface), and is resistant to tearing (e.g., tears); although the film remains in place for days or more during the delivery of the one or more agents, it does not impair vision after the initial instillation; and instillation of the fluid reservoir is mediated at least in part by the viscosity of the fluid reservoir. Notably, while the fluid reservoir remains external to the eye, one or more agents are delivered to the internal ocular tissues (e.g., retina) and fluids (e.g., vitreous humor) in the posterior portion of the eye for at least three (3) days, and in some embodiments, at least seven (7) days. Thus, in contrast to the typical multiple daily doses currently required for conventional commercial ophthalmic formulations, embodiments of the present invention enable effective intermittent administration (e.g., once every 3 days or longer) of a single-dose liquid reservoir containing at least one pharmaceutical agent.

The fluid reservoirs described herein provide sustained release of one or more agents at a more stable release rate (i.e., reduced "spikes"), fewer side effects, and/or greater efficacy as compared to current aqueous-based (aquouus-based) eye drops. In some embodiments, the continuous level of agent released from the fluid reservoir of embodiments of the invention is at a lower C than previously thought necessary to achieve clinical benefit based on comparison to current water-based eye drops_maxConcentration of C_maxProvides an effective benefit at concentrations.

Brief Description of Drawings

Fig. 1A and 1B are illustrations of human eye anatomy, more specifically showing the left eye (1A) and the right eye (1B) viewed from above. The back of the eye typically includes the retina (including the macula) and the vitreous humor (vitreous or vitreous gel).

Figure 2 shows the average amount of vitamin E acetate in tear samples collected from rabbit eyes on days 1, 4, 7 and 12 after administration of a single 50 μ Ι _ reservoir of vitamin E acetate. No vitamin E acetate was observed in the aqueous humor samples over the same time course. x-axis, days; y-axis, vitamin E acetate ng/mL.

FIG. 3 shows 5mg dexamethasone powder (. tangle-solidup.),Schematic of in vitro release of 5mg dexamethasone (. diamond-solid.) in (E) or 5mg dexamethasone (■) in vitamin E acetate in saline. A50. mu.L sample of the powder or liquid reservoir formulation was placed in 100mL saline (exchange 50mL) and the percent dexamethasone release was determined by UPLC. x-axis, days; y-axis, percentage of total dexamethasone released into saline.

FIG. 4 is a graph showing the release of a liquid depot formulation (10% dexamethasone, 72% vitamin E acetate, and 18% vitamin E acetate) from 200mL saline (100mL exchange)(medium chain triglycerides)) in vitro release of dexamethasone from a 50 μ L sample. 6 replicates were tested: y-axis, percent dexamethasone released; x-axis, days; ●: GTH-83A; o: GTH 83B; ■: GTH-83C; □: GTH-83D; a tangle-solidup: GTH 83E; and (delta): GTH-83F.

FIG. 5 is a graph showing a depot formulation from a liquid placed in 100gm of water (10% prednisolone and 90% tocopherol acetate in a weight ratio of about 80: 20)Of (medium chain triglycerides)Mixture) in vitro release of prednisolone. For each time point, a 60ml sample was taken for sampling and replaced with 60ml saline. 6 replicates were tested: y-axis, percent prednisolone released; x-axis, days; ●: GTH-64A; o: GTH 64B; ■: GTH-64C; □: GTH-64D; a tangle-solidup: GTH 64E; and (delta): GTH-64F.

FIG. 6 is a graph showing a depot formulation from a liquid placed in 100gm of water (10% prednisolone and 90% tocopherol acetate in a weight ratio of about 80: 20)(mixture of medium chain triglycerides) in vitro release of prednisolone. For each time point, a 50ml sample was taken for sampling and replaced with 50ml saline. 6 replicates were tested: y-axis, percent prednisolone released; x-axis, days; ●: 5A; o: 5B; ■: 5C; □: 5D; a tangle-solidup: 5E, performing filtration; and (delta): 5F; h: average number.

Figure 7 is a graph showing the release of loteprednol etabonate from a liquid depot formulation containing loteprednol etabonate (10% loteprednol etabonate and 90% tocopherol acetate in a weight ratio of about 80: 20(mixture of medium chain triglycerides) in vitro release of loteprednol etabonate. A50 mL sample was taken and replaced with 50mL of 40% methanol/water. 2 replicates were tested: y-axis, percentage loteprednol etabonate released; x-axis, days; ●: 66-A; o: 66-B; h: average number.

FIG. 8 is a graph showing the depot formulation from ciprofloxacin (15% ciprofloxacin and 85% tocopherol acetate in a weight ratio of about 70: 30(mixture of medium chain triglycerides) in vitro release of ciprofloxacin. 25ml of each sample was sampled and replaced with 25ml of saline. 6 replicates were tested: y-axis, percent ciprofloxacin released; x-axis, hours; ●: 24-A; o: 24-B; ■: 24-C; □: 24-D; a tangle-solidup: 24-E; and (delta):24-F; h: average number.

FIG. 9 is a graph showing the depot formulation from ciprofloxacin (15% ciprofloxacin and 85% tocopherol acetate in a weight ratio of about 70: 30(mixture of medium chain triglycerides) another in vitro release profile of ciprofloxacin. 25ml of each sample was sampled and replaced with 25ml of saline. 6 replicates were tested: y-axis, percent ciprofloxacin released; x-axis, hours; ●: 25-A; o: 25-B; ■: 25-C; □: 25-D; a tangle-solidup: 25-E; and (delta): 25-F; h: average number.

FIG. 10 is a graph showing the release of gatifloxacin from a liquid depot formulation containing gatifloxacin (10% ciprofloxacin and 90% tocopherol acetate in a weight ratio of about 70: 30(mixture of medium chain triglycerides) in vitro release of gatifloxacin. 20ml of each sample was sampled and replaced with 20ml of saline. 6 replicates were tested: y-axis, percent gatifloxacin released; x-axis, hours; ●: 90-A; o: 90-B; ■: 90-C; □: 90-D; a tangle-solidup: 90-E; and (delta): 90-F; h: average number.

Figure 11 is a graph showing the results of an in vivo PK study on diclofenac drug levels in tear samples. And a y axis: diclofenac/mg tear; the x axis is as follows: and (5) day.

FIG. 12 is a graph showing the ratio of tocopherol acetate to tocopherol acetate at 90: 10(. mu.l.) or 70: 30 tocopheryl acetate(■) schematic representation of in vitro release of cyclosporin from two fluid reservoirs containing 2% cyclosporin in an excipient mixture. And a y axis: total release of cyclosporin a%; the x axis is as follows: and (5) day.

Detailed Description

It is to be understood that this invention is not limited to the particular methodology, protocols, reagents, etc. described herein, and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined only by the claims.

All patents and other publications mentioned are incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications, which might be used in connection with the present invention, but which would not provide a definition of terms inconsistent with that described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

As used herein and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Throughout this specification, unless the context requires otherwise, the words "comprise", "comprising" and "contain" are used inclusively rather than exclusively, so that the integer or group of integers may include one or more other non-recited integers or groups of integers. The term "or" is inclusive, unless modified by, for example, "either". Thus, unless the context indicates otherwise, the word "or" means any member of a particular list and also includes any combination of members of that list. Except in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as being modified in all instances by the term "about," which generally allows for a variation of ± 1, unless the context dictates otherwise. Generally, amounts or levels expressed as "%" are based on weight (i.e., wt% or wt/wt) unless otherwise indicated or clarified by context.

Headings are provided for convenience only and are not to be construed as limiting the invention in any way. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined only by the claims. In order that the disclosure may be more readily understood, certain terms are first defined. Additional limitations are set forth throughout the detailed description.

Diseases affecting the back of the eye (e.g., the retina) (see fig. 1A and 1B) are difficult to treat. Retinal diseases may be associated with aging, diabetes or other diseases, ocular trauma or family history. Treatment of retinal diseases can be complex and sometimes urgent, with the primary treatment goal being to stop or slow the progression of the disease and to maintain, improve, or restore vision. For example, diabetic retinopathy occurs when the presence of or new abnormal capillaries in the back of the eye worsens and leaks fluid into and under the retina, causing retinal swelling. Scattered laser photocoagulation is one technique used to constrict these blood vessels, but widespread use of this treatment can lead to decreased peripheral or night vision. Because capillary formation and leakage are associated with inflammation, anti-inflammatory agents are beneficial in the treatment of diabetic retinopathy as well as macular degeneration. Thus, injection of drugs (e.g., steroids) into the vitreous of the eye is another technique for treating retinal diseases, including diabetic retinopathy, macular degeneration, cystoid macular edema, or intraocular vascular rupture. Injectable and implantable sustained release formulations are becoming an important choice for drug therapy of the eye. However, injection into the eye is not without risk and must be performed by a skilled ophthalmologist using at least local anesthesia, a sterile technique. Thus, topical formulations that can effectively deliver agents into tissues and fluids in the posterior portion of the eye clearly represent a long-standing but unmet need in the art.

Topical formulations currently available for ophthalmic use include aqueous solutions, aqueous suspensions, ointments and inserts (insert). However, in current eye drop formulations, transcorneal delivery (i.e., drug penetration into the eye) is not an effective process, since one-tenth of the dose is estimated to penetrate into the eye. Moreover, current commercially available eye drops do not provide sustained release over a long period of time (e.g., over several days). In contrast to currently marketed ophthalmic formulations, embodiments of the present invention provide a fluid reservoir that rapidly forms a film on the eye that is not damaged by blinking and does not impair vision (except for brief damage upon administration). Furthermore, without being bound by theory, because the fluid reservoirs of the present invention deliver an active agent to ocular tissue, at least some ocular tissues can act as a reservoir (repositivity) for the active agent, prolonging the release or therapeutic benefit. Importantly and surprisingly, embodiments of the present invention deliver an agent to the posterior portion of the eye (e.g., the retina) effectively, efficiently, and continuously via a local fluid reservoir.

In addition, the slow release liquid reservoir has a physical consistency that avoids run-off and allows the patient to wear eye make-up and comfortably wear contact lenses. Due to the long-acting release and therapeutic benefits, this fluid reservoir can be provided in a single-dose dispenser that is easy to use because the patient (or healthcare provider) can focus all of their attention on dispensing the formulation into the eye without having to divert attention to avoid all contact with the dispenser tip. Furthermore, embodiments of the present invention enable instillation from a disposable dispenser such that no preservatives are required in the formulation. Thus, at least one embodiment provides a disposable dispenser comprising a unit dose of a liquid reservoir. Further embodiments provide kits comprising at least one disposable dispenser pre-loaded with a single dose unit (i.e., a single fluid reservoir).

More specifically, the ophthalmic product must be sterile in the final container to prevent microbial contamination of the eye. Whether the current ophthalmic treatments are formulated as solutions, suspensions or ointments, a large number of current formulations are administered via a dropper or cuvette, and care must be taken not to touch the tip of the dropper or cuvette with the eyelid or any other surface that may contaminate the dispenser. Contamination of the tip or cap of the dropper, solution, suspension or cuvette can lead to serious ocular infections. Typically, preservatives are added to current eye drop formulations to maintain sterility once the container is opened. The FDA Advisory Review Panel on OTC Ophthalmic Drug Products (1979) determined preservatives and concentrations in formulations for direct contact with the eye. However, many of these preservatives react with the active agent or plastic, or increase the irritation of the eye drop formulation. Because the fluid reservoirs of the present invention provide sustained release and therapeutic benefits, the fluid reservoirs can be advantageously supplied in at least one embodiment in an easy-to-use single-dose dispenser that does not require a preservative.

In addition, the oxygen sensitivity of many agents leads to instability. For this reason, current eye drops typically contain a preservative (e.g., sodium bisulfate) to increase the stability of such active agents. The sustained release liquid reservoirs described herein are capable of releasing the active agent at therapeutic levels for at least about 24 hours, more preferably at least about 48 hours, more preferably at least about 72 hours (3 days), even though the reservoir is exposed to oxygen from air exposure and sustained cleansing of the liquid in the eye. Unexpectedly, the active agent remains stable during delivery, for example, for at least 3 days. Without being bound by theory, the stability observed in these embodiments may be due to the antioxidant properties of the tocopherols or tocotrienols, which are not overly diluted or diminished by the presence of the ocular film forming excipient.

At least one embodiment includes at least one pharmaceutical agent present in a sustained release fluid reservoir comprising, consisting of, or consisting essentially of: a biocompatible and biodegradable mixture of tocopherol and an ocular film-forming excipient having low solubility in aqueous solutions.

In at least one embodiment, the sustained release fluid reservoir comprises: at least one active agent, from about 60% to 90% (wt%) tocopherol (e.g., tocopherol acetate) and from about 10% to 40% (wt%) ocular film forming excipient (e.g., caprylic/capric glyceride). In at least one embodiment, the fluid reservoir comprises from about 70% to 85% (wt%) tocopherol (e.g., tocopherol acetate) and from about 15% to 30% (wt%) of an ocular film-forming excipient (e.g., caprylic capric glyceride). In at least one embodiment, the liquid film-forming vehicleThe agent modulates (e.g., increases or decreases) the viscosity of the fluid reservoir. For example, the fluid reservoir comprises 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% (wt%) or any interval therebetween, tocopherol; and comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40% (wt%) or any interval therebetween. In at least one embodiment, the film forming excipient is a triglyceride. In at least one embodiment, the triglyceride isMedium chain triglycerides. In at least one embodiment, the active agent is dexamethasone. In at least one embodiment, the fluid reservoir consists essentially of a mixture of (a) 10% -30% (wt%) dexamethasone and (b) 70% -90% (wt%) tocopherol acetate to medium chain triglycerides in a weight ratio of about 85: 15 to about 70: 30.

With respect to viscosity, this characteristic describes resistance to deformation exhibited between molecules moving in a fluid, or a form of internal friction that resists fluid flow when a stress is applied. The viscosity of the solution is usually expressed in poise (P), centipoise (cP), or millipascal seconds (mPas). For example, water has a viscosity of 1.00 mPas or 1.00cP at 20 ℃, while engine oil (SAE 40) has a viscosity of 319 mPas. Many fluids exhibit a low viscosity when heated: for example, water has a viscosity of 0.890 mPas at 25 ℃. See, for example, Elert, Physics Hypertextbook (1998-) 2017). Typically, current water-based eye drop solutions have viscosities in the range of 25cP to 50cP (at 20 ℃); and some of these ophthalmic solutions may contain added viscosity enhancers to increase viscosity and possibly enable the solution to remain in the eye for a longer period of time. Typical compounds added to increase viscosity in current eye drops are available in various grades (e.g., 15cP, 100cP, etc.) and include compounds such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinyl pyrrolidone. In preferred embodiments, the fluid reservoirs described herein do not contain these viscosifying compounds.

In one embodiment, the sustained release liquid reservoir of the invention is comprised of tocopherol acetate,And dexamethasone, the liquid reservoir having a viscosity of 850cP-1100cP, e.g., about 850cP, 851cP, 852cP, 853cP, 854cP, 855cP, 856cP, 857cP, 858cP, 859cP, 860cP, 899cP, 990cP, 994cP, 995cP, 996cP, 997cP, 998cP, 999cP, 1000cP, 1001cP, 1002cP, 1003cP, 1004cP, 1005cP, 1006cP, 1007cP, 1008cP, 1009cP, 1010cP, 1011cP, 1020cP, 1021cP, 1022cP, 1023cP, 1024cP, 1025cP 108108108, 1027cP, 1028cP, 1029, 1030cP, 1031cP, 1032cP, 1075cP, 1076cP, 1077cP, 1078cP, 1079cP, 1080cP, 1081, 1082cP, 1083cP, 1100cP, or any value therebetween. In another embodiment, the sustained release liquid reservoir of the invention is comprised of tocopherol acetate,And dexamethasone, said fluid reservoir having a viscosity of 1027 cP. In another embodiment, the sustained release liquid reservoir of the invention is comprised of tocopherol acetate,And dexamethasone, said fluid reservoir having a viscosity of 1027cP ± 32 cP.

In at least one embodiment, the sustained release fluid reservoir comprises, consists of, or consists essentially of: tocopherol and an ocular film forming excipient. As used herein, "tocopherol" includes tocopherol, tocotrienol, their esters, and mixtures thereof. Tocopherols are commonly referred to as "vitamin E". See, e.g., WO 2014100327; lee et al, Methods for influencing analysis of tocophenols, tocotrienols & their metabolites in animal samples with HPLC-EC, J.food Drug anal.1-12 (2017). The term "tocopherol" may be used herein to denote liquid tocopherol or tocotrienol or derivatives thereof as provided herein and suitable for use as described herein. In one embodiment, the tocopherol is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol, or alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol. In another embodiment, the tocopherol is alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol. In at least one embodiment, the tocopherol is tocopherol acetate.

In addition, the tocopherol component of the present embodiment remains in liquid form in the reservoir and does not undergo a phase transition to a solid, crystalline or liquid crystalline form upon contact with water or aqueous body fluids (e.g., tears). Tocopherols are highly viscous liquids and their ability to flow under different conditions related to temperature and flow rate is an essential characteristic of tocopherols.

In at least one embodiment, the tocopherol is tocopherol acetate (also known as tocopherol acetate, vitamin E acetate, or "EA"), which is an ester of tocopherol and acetic acid. More specifically, the IUPAC name for tocopheryl acetate is "[ (2R) -2,5,7, 8-tetramethyl-2- [ (4R,8R) -4,8, 12-trimethyltridecyl ] chroman-6-yl ] acetate" (CAS Reg. No. 58-95-7), which has low solubility in aqueous solution (< 0.1g/100mL water solubility at 17 ℃), viscosity of 6.31Pa · s-6.59Pa · s (20 ℃), and refractive index of 1.496n 20/D. In contrast, the average refractive index value for human tears is approximately 1.33698. Craig et al, reflective index & osmology of human tears, 72(10) Optom. Vis. Sci.718-24 (1995). In one embodiment, the tocopherol is tocopherol acetate. In at least one embodiment, the fluid reservoir comprises tocopherol acetate in any amount from 60% to 90% (inclusive), e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% (wt%).

In addition to tocopherol, the sustained release liquid reservoirs described herein comprise additional ocular film forming excipients that are generally biocompatible and safe for use in the human eye, have low solubility in aqueous solutions, do not impair vision (e.g., have a suitable refractive index at least when combined with tocopherol), and do not adversely affect tocopherol stability in the eye or release of the agent from the liquid reservoir. It is to be understood that while tocopherol is generally capable of forming a film in the eye and providing sustained release, tocopherol may be considered too viscous for practical use in the fluid reservoirs described herein; the ocular film-forming excipient improves the spreadability of the fluid reservoir described herein or facilitates its application. Generally, the viscosity of tocopherol is reduced by the ocular film-forming excipient. In other words, the additional ocular film forming component provides a fluid reservoir that is relatively less viscous, sticky or tacky than tocopherol (e.g., tocopherol acetate) as the sole component of the fluid reservoir. The eye film forming vehicle helps to quickly and smoothly cover the cornea and also changes the viscosity of the tocopherol component (e.g., tocopherol acetate). It should be noted, however, that inclusion of too much film forming excipient results in insufficient membrane reservoir and increased active agent washout from the eye.

Generally, the ratio (e.g., weight ratio) of tocopherol to film-forming excipient can be adjusted to modulate (e.g., increase or decrease) the sustained release profile of the fluid reservoir. For example, reducing the amount of film forming excipients generally increases the time that the fluid reservoir stays in the eye and delivers the active agent, i.e., increases the sustained release profile. Alternatively or additionally, depending on the indication, the sustained release profile can be extended by increasing the amount of active agent in the fluid reservoir. Furthermore, depending on the indication, the concentration of the active agent can be increased to increase the amount of active agent delivered to the posterior portion of the eye (i.e., the retina) through the fluid reservoir.

Thus, for example, the sustained release fluid reservoir of embodiments of the invention that provide dexamethasone to the retina comprises, consists of, or consists essentially of: (a) 10% to 30% dexamethasone in (b) 70% to 90% of a mixture of (i) tocopherol and (ii) film forming excipient (wherein the ratio of tocopherol to film forming excipient is 85: 15 to 70: 10). In one embodiment, the amount of dexamethasone is about 10%, and the amount of dexamethasone can be increased from about 10% to about 30% (or the interval therebetween) in order to increase the length or amount of dexamethasone delivered to the retina; to increase the length of time that the fluid reservoir delivers dexamethasone to the retina, the ratio of tocopherol to film-forming excipient can be adjusted from about 70: 30 to about 85: 15; and these options are not mutually exclusive, such that increasing the concentration of dexamethasone and decreasing the amount of film-forming excipient can both be used to modulate the amount of dexamethasone delivered to the retina through the fluid reservoir. Generally, during delivery of dexamethasone to the retina, tocopherol and the film-forming excipient remain in the fluid reservoir in approximately the same ratio.

The use of specific ocular film forming excipients and the amount of each additional ocular film former contained in the sustained release fluid reservoir described herein has been determined through laborious and detailed experiments to provide the type of excipient with the desired characteristics and amounts needed to provide a non-tacky, nearly instantaneous coating on the cornea with sufficient tocopherol to provide sustained release of the agent from the fluid reservoir. Desirable beneficial characteristics of ophthalmic film forming excipients include safety of use in the eye, chemical and physical stability over time, chemical compatibility with other formulation ingredients, solubility in the formulation, the ability to enhance sustained release of the pharmaceutically active ingredient, inertness, and diffusion from the liquid reservoir after the desired effect is achieved.

A number of potential film forming excipients for inclusion in the fluid reservoirs of embodiments of the present invention are contemplated or evaluated, including castor oil, corn oil, triacetin, tributyrin (tributyrin), tricaprin (tricaprin), tricaprylin (tricaprylin), water, dermol esters, benzoflex, polyethylene and polypropylene glycols, long chain fatty alcohols, hydroxypropyl methylcellulose (HPMC), stearic acid, and stearates. However, these excipients do not provide the many beneficial features needed to perform the rigorous evaluation procedures employed to achieve the fluid reservoirs described herein. These excipients are not included in the fluid reservoirs described herein.

In at least one embodiment, the ocular film forming excipient is a mixture of triglycerides. In at least one embodiment, the ocular film forming excipient is one or more Medium Chain Triglycerides (MCTs). For example, mixed tricaprin and tricaprylin (e.g., CAS number 73398-61-5) comprise>95% of saturated fatty acid chains, and is a transparent, colorless or pale yellow liquid, immiscible in water, practically odorless and tasteless, having a specific gravity of 0.94 to 0.96(20 ℃), a refractive index of 1.440n20D to 1.452n20D (20 ℃), and a viscosity in the range of 24mPa s to 33mPa s (20 ℃) (14.9 cSt at 100 ℃). Synonyms for MCT include caprylic capric acid triglyceride, mixed capric acid triglyceride and caprylic acid triglyceride, tricaprylin/caprate, oleum neutrale, Bergabest, and, MCT oil;orThus, the film forming agent of embodiments of the present invention may include triglyceride (and triglyceride-like) excipients including caprylic capric glyceride (e.g., caprylic capric triglyceride)) Caprylic/capric triglyceride (e.g. caprylic/capric triglyceride)) And propylene glycol dicaprylate/dicaprate (triglyceride-like) (e.g.) And mixtures thereof.

In exemplary embodiments, in combination with tocopherolImparting the necessary beneficial characteristics to the fluid reservoirs described herein: such as beneficial regulation of viscosity, fluidity, inertness, clarity, solubility with other ingredients (e.g., tocopherols and active agents), and permeability.

Thus, in one embodiment, the film forming excipient is immiscible or has low solubility in water or aqueous solutions. In one embodiment, the film-forming excipient has a viscosity of from 27 mPa.s to 33 mPa.s (20 ℃), inclusive, such as about 27 mPa.s, 28 mPa.s, 29 mPa.s, 30 mPa.s, 31 mPa.s, 32 mPa.s, or about 33 mPa.s (20 ℃), inclusive. In one embodiment, the film forming excipient has a refractive index of 1.448n20D to 1.451n20D, for example about 1.448n20D, 1.449n20D, 1.450n20D, or about 1.451n20D or an interval therebetween. In one embodiment, the film forming excipient comprises, consists of, or consists essentially of caprylic capric glyceride. In one embodiment, the caprylin/caprin excipient isOr(neutral oil). In at least one embodiment, the fluid reservoir comprises any amount of caprylic capric glyceride from 10% to 30% (inclusive), for exampleOr

When the agent is absent (i.e., prior to loading the agent into the reservoir), the fluid reservoir may also be referred to as a blank, a control, an excipient component of the formulation, a biodegradable excipient, an excipient mixture, a carrier, and the like. The fluid reservoir remains in a liquid state under physiological conditions in vitro and in vivo, and does not polymerize or become solid after placement in the eye. The liquid reservoir can be loaded with highly concentrated active agents, yet remain liquid, safe and effective, while reducing the side effects typically associated with active agents administered in conventional eye drop formulations. Loading refers to any means of dispersing, dissolving, mixing, suspending, or otherwise incorporating at least one active agent into a liquid reservoir. Liquids are generally referred to as fluids, but also include suspensions of solids dispersed in liquids (dispersions, suspensions, colloidal mixtures), and gases dissolved in liquids or otherwise co-existing within liquids, wherein the fluidity of the liquid is maintained. The fluid reservoirs of embodiments of the present invention retain their fluidic properties (i.e., do not solidify) before and after placement in the eye, and biodegrade over time while remaining fluid. Furthermore, it is believed that during drug delivery to the retina, the tocopherol and the film-forming excipient remain in the fluid reservoir at approximately the same ratio.

In at least one embodiment, a single administration, e.g., instillation, of the fluid reservoir is about 20 μm³(20. mu.L) to about 70 μm³(70 μ L) (e.g., about 20 μ L, 25 μ L, 30 μ L, 35 μ L, 40 μ L, 45 μ L, 50 μ L, 55 μ L, 60 μ L, 65 μ L, or about 70 μ L, including intervals therebetween) provides for sustained release of the agent to the internal tissue of the eye (e.g., the retina) for at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, or at least about 3 weeks, including the intervals therebetween. In at least one embodiment, the fluid reservoir (e.g., about 20 μm)³(20. mu.L) to about 70 μm³(70 μ Ι _) (inclusive of the fluid reservoir) provides a sustained release of the active agent to the internal tissues of the eye (e.g., the retina) for at least about 24 hours, at least about 48 hours, at least about 72 hours (3 days), at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week (7 days), at least about 2 weeks (14 days), or at least about 3 weeks (21 days), including the intervals therebetween.

Many pharmaceutical agents are suitable for sustained release from the fluid reservoirs described herein. Such agents may have low solubility in water or aqueous solutions. For example, in one embodiment of the fluid reservoirs described herein, dexamethasone is safely and therapeutically delivered to the retina over a sustained period of time. In some embodiments, the stability of the active agent in the liquid reservoir is more stable than the stability of the active agent in current water-based eye drop formulations.

Reference to "agent," "pharmaceutically active," "pharmaceutical," "drug," "active agent," "active drug," "biological agent," or "therapeutic agent" and the like refer in a general sense to a substance useful in the medical and scientific fields, including, for example, drugs, biologics, diagnostic agents (e.g., dyes or contrast agents), or other substances used for therapeutic, prophylactic, diagnostic, or research purposes. Exemplary agents include biological agents (e.g., insulin), chemotherapeutic agents, small molecules, antigens, interferons, polyclonal or monoclonal antibodies, anesthetics, interfering RNAs, gene vectors, contrast agents, or any combination thereof. Reference to general or specific agents or drugs includes pharmaceutically acceptable analogs, derivatives and salts thereof. For example, reference to triamcinolone (triamcinolone) includes triamcinolone acetonide (triamcinolone acetonide). For example, in U.S. patent No. 9,011,915, an active agent that can be included in a fluid reservoir as described herein is provided.

By "inactive" material is generally meant carriers, excipients, diluents, and the like, well known in the art, although such materials may have beneficial functions, such as stabilizing a pharmaceutical.

In one embodiment, the active agent is delivered to the eye in a manner that provides treatment or prevention (e.g., prophylactic treatment) of an ocular disease in the posterior (posterior) portion of the eye.

In some embodiments, ocular tissues and fluids are located in the posterior portion of the eye, such as the vitreous humor and the retina.

In one embodiment, one application of the sustained release liquid reservoir delivers the active agent to the posterior portion of the eye for at least 3 days

In another aspect, a method of treating a clinical condition associated with or affecting the posterior portion of the eye is provided, comprising intermittently administering (e.g., once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days, once every 2 weeks, or once every 3 weeks) a single dose of a drug-containing liquid reservoir described herein, wherein the dose is from about 20 μ Ι _ to about 70 μ Ι _ inclusive and amounts therebetween, e.g., 50 μ Ι _ are included. It is further understood that a single drip may include two microdroplets (e.g., 25 μ L) instilled in rapid succession to provide a single administration (e.g., 50 μ L). It will be appreciated that reference to an intermittent dosing schedule or an intermittent dosage schedule reflects a therapeutic dose over a prolonged period of time such that once every 3 days or longer means that sustained release has provided a therapeutic effect and thus more frequent dosing is not indicated.

In one embodiment, the clinical condition is inflammation, such as cystoid macular edema. In one embodiment, the clinical condition is an infection. However, it is understood that these indications may not be mutually exclusive; for example, infection is often associated with inflammation. Similarly, anti-infective agents (e.g., cyclosporine) are commonly administered to reduce inflammation. Thus, at least one embodiment provides a fluid reservoir formulation for the prevention of infection and inflammation, such as macular cystoid edema (CME), which can be a postoperative cataract.

In some embodiments, the sustained release fluid reservoir comprises a biologically active or therapeutic agent as the agent. The bioactive or therapeutic agents may have more than one activity or benefit, and thus the following embodiments are not mutually exclusive. For example, anti-inflammatory steroids may also have angiogenesis inhibiting activity. In some embodiments, the sustained release fluid reservoir comprises at least one anti-inflammatory agent. In some embodiments, the sustained release fluid reservoir comprises at least one anti-infective agent.

In another embodiment, the sustained release fluid reservoir contains two or more active agents, wherein at least one of the active agents provides a benefit in treating a disease of the posterior segment of the eye. For example, in one embodiment, each active agent is selected for its ability to remain associated with or pass through the cornea, such that one active agent resides on or in the cornea and the other active agent permeates into the interior of the eye to treat the retina. In one embodiment, the sustained release fluid reservoir comprises two or more active agents having a similar ability to penetrate the interior of the eye to provide the active agents to the retina.

An aspect of an embodiment of the invention relates to a method of treating a disease in the back of the eye, such as diabetic retinopathy, neovascular glaucoma, retinal vein occlusion, retinitis pigmentosa, macular degeneration (juvenile macular degeneration, age-related macular degeneration, wet macular degeneration, dry macular degeneration or myopic macular degeneration), macular edema (or cystoid macular edema), central serous chorioretinopathy, choroidal plication, macular dystrophy (Stargardt's disease or macular xanthosis, adult vitelliform macular dystrophy, familial drusen, dominant cystoid macular edema or cone degeneration (con degeneration)), Best's disease (vitelliform macular dystrophy), idiopathic polypoid choroidal vasculopathy, and systemic problems (angioid streaks associated with pseudoxanthoma elasticum), Ehlers-Danlos syndrome, rare bone Paget's disease and some hemoglobinopathies), cancer-related maculopathy, drug-induced maculopathy (e.g., chloroquine or hydroxychloroquine-induced retinal toxicity), or other retinal or vitreous disorders that benefit from local delivery of a drug to the back of the eye. In at least one embodiment, a method of treating a disease of the posterior segment of the eye comprises administering a fluid reservoir comprising a steroid in tocopherol and MCT. In some embodiments, the steroid is dexamethasone or triamcinolone. Another embodiment provides a method of treating retinitis pigmentosa comprising administering a sustained release fluid reservoir comprising valproic acid in tocopherol and MCT. In some embodiments, administration of the fluid reservoir is intermittent, e.g., once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days, once every 2 weeks, or once every 3 weeks.

At least one embodiment provides a fluid reservoir for delivery of anti-glaucoma therapy. Anti-glaucoma agents include inflow-arresting/inhibiting agents, such as beta blockers (e.g., timolol, betaxolol, carteolol, levobunolol, etc.); topical carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide); sympathomimetic agents (e.g., epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine); efflux promoters, including parasympathomimetics (e.g., cholinergic agonists such as pilocarpine); and prostaglandin analogs and related compounds (e.g., latanoprost, travoprost, bimatoprost, unoprostone, or tafluprost). Various agents (including, for example, bimatoprost, latanoprost, travoprost, tafluprost, brimonidine, betaxolol, levobunolol, metiprolol, or timolol) can be used alone or in combination to lower intraocular pressure.

Thus, one particular embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and timolol. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And timolol).

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and betaxolol. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And betaxolol.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and carteolol. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And carteolol).

Another embodiment is a fluid reservoir comprising tocopherol, an ophthalmic film-forming excipient, and levobunolol. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And levo-blonol.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and dorzolamide. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And dorzolamide.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and brinzolamide. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) ) and brinzolamide.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and epinephrine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) Adrenaline.

Another embodiment is a fluid reservoir comprising tocopherol, an ophthalmic film-forming excipient and dipivefrin. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) ) and dipivefrin.

Another embodiment is a fluid reservoir comprising tocopherol, an ophthalmic film-forming excipient, and clonidine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And clonidine).

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and apraclonidine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And apraclonidine.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and brimonidine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And brimonidine.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and pilocarpine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And pilocarpine.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and latanoprost. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And latanoprost.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film forming excipient, and travoprost. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And travoprost.

Another embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and bimatoprost. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And bimatoprost.

Another embodiment is a fluid reservoir comprising tocopherol, an ophthalmic film-forming excipient, and unoprostone. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And unoprostone.

Another embodiment is a composition comprising tocopherol, an ophthalmic film-forming excipient and a pharmaceutically acceptable carrierA liquid reservoir of fluoroprostinil. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And tafluprost.

At least one embodiment provides a sustained release fluid reservoir that releases an anti-inflammatory therapy, such as a non-steroidal anti-inflammatory drug (NSAID) or a steroidal anti-inflammatory drug such as a corticosteroid. The embodiments described herein support the use of a liquid reservoir in a wide range of clinical indications for the use of anti-inflammatory drugs. For example, although true antihistamines are often used as antiallergic eye drops, anti-inflammatory drugs (including, for example, loteprednol etabonate) can also be used to reduce allergies. For example, corticosteroids are used to treat allergic conjunctivitis. Indeed, the sustained release liquid reservoir formulations comprising anti-inflammatory drugs described herein may find clinical application in a number of different clinical indications, such as the treatment or prevention of (a) inflammation associated with ocular surgery, including but not limited to cataract surgery and vitrectomy, (b) uveitis, (c) Diabetic Macular Edema (DME), (d) macular cystic edema (CME), and (e) diabetic retinopathy.

In at least one embodiment, the sustained release fluid reservoir comprises a corticosteroid anti-inflammatory agent, such as dexamethasone, triamcinolone, prednisolone, prednisone, loteprednol or fluoromethalone, or pharmaceutically acceptable derivatives, analogs and salts thereof or combinations thereof. Other anti-inflammatory agents that may be included in the sustained release fluid reservoirs described herein include angiogenesis inhibiting steroids or anti-inflammatory steroids known in the art.

Thus, one particular embodiment is a sustained release fluid reservoir comprising tocopherol, an ocular film forming excipient, and dexamethasone. Exemplary embodiments comprise from about 70% to 85% (wt%) tocopherol (e.g., tocopherol acetate), from about 15% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) ) and dexamethasone. In some embodiments, the amount of dexamethasone is 10% to 30% of the liquid reservoir. Exemplary embodiments provide a sustained release fluid reservoir comprised of tocopherol acetate at 70% (wt. -%)Tocopherol acetate and tocopherol acetate in a ratio of 70: 3030% (wt%) dexamethasone in the mixture. Exemplary embodiments provide a sustained release fluid reservoir comprised of 90% (wt%) tocopherol acetateTocopherol acetate and tocopherol acetate in a ratio of 85: 1510% (wt%) dexamethasone in the mixture. Exemplary embodiments provide a sustained release fluid reservoir comprised of tocopherol acetate at 70% (wt. -%)Tocopherol acetate and tocopherol acetate in a ratio of 85: 1530% (wt%) dexamethasone in the mixture. These embodiments deliver a therapeutic dose of dexamethasone to the retina for at least about 3 days, at least about 7 days, or longer. In some embodiments, a sustained release fluid reservoir can be specified to be administered locally to the retina of an individual at a frequency of no more than once every 3 days or once every 7 days, the sustained release fluid reservoir comprising, consisting of, or consisting essentially of: (a) about 10% -30% (wt%) dexamethasone; and (b) from about 70% to about 90% (by weight) of a mixture of tocopherol acetate and medium chain triglycerides in a weight ratio of from about 85: 15 to about 70: 30)。

Another embodiment is a sustained release liquid reservoir comprising tocopherol, an ocular film forming excipient, and prednisolone. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And prednisolone.

Another embodiment is a sustained release liquid reservoir comprising tocopherol, an ocular film forming excipient, and prednisone. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And prednisone).

Another embodiment is a fluid reservoir comprising tocopherol, an ophthalmic film-forming excipient, and loteprednol etabonate. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And loteprednol etabonate.

Thus, a particular embodiment is a fluid reservoir comprising tocopherol, an ocular film-forming excipient, and fluorometholone. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And fluorometholone.

In at least one embodiment, the sustained release fluid reservoir comprises a non-steroidal anti-inflammatory agent, such as ketorolac, nepafenac, bromfenac, or diclofenac, or a combination thereof.

Thus, in one embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and ketorolac. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And ketorolac.

In one embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and nepafenac. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And nepafenac.

In another embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and bromfenac. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And bromfenac.

In yet another embodiment, the fluid reservoir contains tocopherol, an ocular film forming excipient, and diclofenac. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) Diclofenac acid, and diclofenac acid.

At least one embodiment provides a fluid reservoir for sustained release of an anti-infective agent that may be used to treat or prevent intraocular infections. In at least one embodiment, the fluid reservoir comprises an anti-infective agent, such as moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, gentamicin, tobramycin or chloramphenicol, or a combination thereof.

Thus, in one embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and moxifloxacin. Exemplary embodiments range from 70% to 90% of 65% to 90% (wt%) tocopherol (e.g., tocopherol acetate) and 10% to 35% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate and glyceryl caprate))) ) contains 10% to 30% (wt%) moxifloxacin. In other words, embodiments of the moxifloxacin liquid reservoir for sustained release of moxifloxacin contain 10% to 30% (wt%) moxifloxacin, 58.5% to 81% tocopherol, and 9% to 31.5% film forming excipients.

In one embodiment, the fluid reservoir contains tocopherol, an ocular film former, and gatifloxacin. Exemplary embodiments range from 70% to 90% of 65% to 90% (wt%) tocopherol (e.g., tocopherol acetate) and 10% to 35% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate and glyceryl caprate))) ) of 10% to 30% (wt%) gatifloxacin.

In one embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and levofloxacin. Exemplary embodiments range from 70% to 90% of 65% to 90% (wt%), inclusive, tocopherol (e.g., tocopherol acetate) and from about 10% to about 35% (wt%), inclusive, ocular film-forming excipient (e.g., caprylic capric glyceride (e.g., caprylic capric acid glyceride)) ) contains levofloxacin.

In one embodiment, the fluid reservoir contains tocopherol, an ocular film forming excipient, and ciprofloxacin. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., caprylic/capric acid)Glycerides (e.g. of) And ciprofloxacin.

In another embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and gentamicin. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) Gentamicin).

In one embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and tobramycin. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And tobramycin.

In yet another embodiment, the fluid reservoir contains tocopherol, an ocular film-forming excipient, and chloramphenicol. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient such as a fatty acid ester (e.g., caprylic capric glyceride (e.g., caprylic capric acid))) And chloramphenicol.

As noted above, anti-infective agents (e.g., cyclosporine) are commonly administered to reduce inflammation. Thus, in at least one embodiment, the liquid reservoir comprises cyclosporine. Exemplary embodiments comprise from about 70% to 80% (wt%) tocopherol (e.g., tocopherol acetate), from about 10% to 30% (wt%) of an ocular film-forming excipient (e.g., glyceryl caprylate caprite (e.g., glyceryl caprylate))) And cyclosporins.

At least one embodiment provides a liquid depot formulation for the prevention of infection and inflammation, such as Cystoid Macular Edema (CME) or uveitis, both of which may be associated with cataract surgery.

With respect to uveitis, the uveal tract (uvea) is the middle layer of the eye, which contains many of the blood vessels of the eye in addition to the iris, ciliary body, and choroid. Uveitis is a potentially blinding inflammation of this tissue that destroys vision by causing problems with the lens, retina, optic nerve, and vitreous. Uveitis can be anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis, and is often treated with steroids to reduce inflammation. A study comparing oral corticosteroid (prednisone) with surgically implanted slow release corticosteroid (0.59mg fluocinolone intravitreal implant) revealed that although both treatments reduced inflammation in the eye, corticosteroid implants produced more ocular problems such as cataracts, abnormally high intraocular pressure (IOP ≧ 21mmHg) and glaucomatous optic nerve damage. Essentially, 69% of patients assigned implants required IOP lowering therapy, while the systemic treatment group was 26%; the proportion of the two having an IOP peak of at least 40mmHg is 15% and 3%, respectively; the proportion of glaucoma optic nerve damage is 23 percent and 6 percent respectively; and the proportion of surgical intervention required was 32% and 5%, respectively. Importantly, studies conclude that current eye drop therapy does not control IOP elevation in most implanted patients. Friedman et al, Risk of elevated intraocular pressure & glaucoma in Patients with uvitis; results of the Multicenter Uvetis Steroid procedure Trial,120(8) Ophthalmol.1571-79 (2013).

With regard to cataract, which is characterized by the occurrence of lenticular opacity, cataract is a leading cause of blindness worldwide. Since the adverse sequelae of cataract surgery include CME and uveitis, cataract surgeons often prescribe prophylactic administration of steroidal and non-steroidal anti-inflammatory eye drops. Non-steroidal anti-inflammatory drugs are included prophylactically to avoid long-term, high dose exposure to corticosteroids, which can lead to elevated intraocular pressure and glaucoma as previously described. It is specified that the combination also exposes anterior and posterior tissues to prophylaxis. However, current eye drop formulations of corticosteroid anti-inflammatory agents at least temporarily elevate IOP, and in some patients, IOP may remain above normal levels.

In contrast to the above-mentioned IOP sequelae, the dexamethasone-loaded fluid reservoirs provided herein do not cause clinically significant elevated IOP. This result is surprising given that current steroidal eye drops that elevate IOP contain only 0.1% (wt) corticosteroid, as compared to 10% -15% (wt) corticosteroid (e.g., dexamethasone) that can be contained in the embodiments described herein. Importantly, as shown in the embodiments herein, the fluid reservoir of the embodiments provides an anti-inflammatory drug to the retina (posterior of the eye) for at least 7 days, so that prophylactic treatment for inflammatory disorders (e.g., uveitis) can be delivered to treat inflammation following cataract surgery. For example, a surgeon may administer a fluid reservoir post-operatively and make one additional application after about 7 days (1 week) to provide effective treatment and prophylactic treatment post-cataract surgery. Also, it is important that the sustained delivery of anti-inflammatory drugs to the posterior part of the eye can eliminate the need for both steroidal and non-steroidal agents, while replacing the non-steroidal agents with more effective steroidal dosage regimens.

In one embodiment, the sustained release fluid reservoir consists of about 10% dexamethasone, about 30% dexamethasone, or 10% -30% (e.g., about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or about 30% (% wt), or an interval therebetween) dexamethasone and the balance of a liquid mixture comprising, consisting of, or consisting essentially of: about 70% to about 85% (e.g., about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or about 85% (% wt), or an interval therebetween) of tocopherol and 20% to 30% (e.g., about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or about 30% (% wt), or an interval therebetween) of a film-forming excipientAnd (4) forming agent. In one embodiment, the tocopherol is tocopherol acetate and the film-forming excipient is tocopherol acetateIn one embodiment, the tocopherol is tocopherol acetate and the film-forming excipient is tocopherol acetate

Further, as for the film-forming excipient,is fractionated C₈And C₁₀Triglycerides of vegetable fatty acids (caprylic/capric/linoleic triglycerides); contains about 4% -5% linoleic acid. Viscosity of 30 mPa.s-35 mPa.s (20 ℃); is miscible in oil.

(caprylic/capric triglyceride); the ratio of caprylic acid to capric acid triglyceride is 65-80 percent to 20-35 percent, the ratio of caproic acid is less than or equal to 2 percent, and the ratio of myristic acid is less than or equal to 2 percent; refractive index 1.448n20D-1.451n 20D; a viscosity of about 27mPa s to 33mPa s (20 ℃); is insoluble in water. In at least one embodiment, the film-forming excipient portion of the fluid reservoir is

(caprylic/capric triglyceride); octanoic acid: the proportion of capric triglyceride is 50-65 percent to 30-45 percent, the caproic acid is less than or equal to 2 percent, and the myristic acid is less than or equal to 2 percent; refractive index 1.448n20D-1.451n 20D; viscosity 27mPa s-33mPa s (20 ℃ C.); is insoluble in water. In at least one embodiment, the film-forming excipient portion of the fluid reservoir isAt least oneIn one embodiment, the film-forming excipient portion of the fluid reservoir isAnda mixture of (a).

(caprylic/capric/succinic triglycerides); cross-linking with succinic acid to form a macromolecular glyceryl caprylate/caprate unit with unique properties; fractionated C₈And C₁₀Glycerides of vegetable fatty acids, in combination with succinic acid; viscosity of about 230mPa · s (20 ℃); 1.00g/cm³M-1.02g/cm³High density of M (20 ℃); almost immiscible in water.

(CAS #77466-09-2) is a compound having C₈And C₁₀Propylene glycol diesters of saturated vegetable fatty acids of chain length; mainly caprylic acid, less capric acid, less caproic acid, lauric acid and myristic acid; density 0.91g/cm³-0.93g/cm³(20 ℃ C.); viscosity of 9-12 mPas (20 ℃); refractive index 1.440n20D-1.442n 20D; is miscible in oil.

Is a fatty acid triester, has a refractive index of 1.4480dgf cIV 5-1.4500dgf cIV 5, and a viscosity of 27mPas-33mPas (20 ℃).Contains 33-41% of C₂₄(C₈ C₈) 41-66% of C₂₆(C₈ C₁₀+C₈ C₁₀ C₈) 13% -19% of C₁₈(C₁₀ C₈+C₁₀ C₈ C₁₀)、<4％C of (A)₃₀(C₁₀ C₁₀ C₁₀)。

OrIs a fully saturated triester, mainly caprylic/capric triglyceride, having a refractive index of 1.4485-1.4500(n 20D), low solubility in water, viscosity of 25-33 mPas (at 20 ℃), and 0.93g/cm³-0.96g/cm³Relative density (g/mL).

Is another fully saturated triester, mainly caprylic/capric triglyceride, having a refractive index of 1.4480-1.4510(n 20D), low solubility in water, viscosity of 25-33 mPas (20 ℃), and 0.94g/cm at 20 ℃³Relative density of (d).

Not all excipients are suitable film formers for use in the embodiments described herein. For example, although cholesterol (CAS #57-88-5) has a refractive index of 1.53n 20D, low solubility in water, and is used as a non-ionic emulsifier, and although cholesterol is included with cyclodextrins or petrolatum in formulations for the treatment of dry eye, cholesterol has been found to be unsuitable for use in the tocopherol-based liquid depot described herein.

Further, regarding tocopherol, α -tocopherol: refractive Index (RI) 1.503-1.507; is practically insoluble in water; density 0.947g/cm³-0.951g/cm³(ii) a And (3) oil. Tocopherols are incompatible with peroxides and metal ions (particularly iron, copper and silver); d- α -tocopherol: CAS 59-02-9; an oil; d-alpha-tocopherol is a naturally occurring form of alpha-tocopherol; d- α -tocopherol acetate: CAS 58-95-7; an oil; dl-alpha tocopherol acetate: CAS 7695-91-21; RI 1.4950-1.4972; density 0.953g/cm³Unstable to alkali, more stable than alpha-tocopherol, oil; beta-tocopherol: an oil; CAS 148-03-8; delta-tocopherol: CAS 119-13-1; oil(ii) a Gamma-tocopherol: CAS 7616-22-01; α -tocotrienol: refractive index: 1.523; beta-tocotrienol: refractive index: 1.52, oil.

Examples

EXAMPLE 1 fluid reservoir

To characterize the tocopherol-based fluid reservoir system, a single sample of 50 μ Ι _ of vitamin E acetate was instilled into the rabbit eyes. Subsequently, a tear sample was collected using a filter paper strip, and vitamin E acetate contained in the paper strip was extracted using methanol. The methanol extract was analyzed for the amount of vitamin E acetate by known methods using LC/MS/MS. As shown in table 1, vitamin E acetate was observed in tear samples collected on days 1, 4, 7 and 12, and the results are illustrated in fig. 2.

In addition, aqueous humor samples were collected from 4 eyes on day 1, day 4, day 7 and day 12 using a syringe, and then the amount of vitamin E acetate in each sample was analyzed using LC/MS/MC (limit of quantitation 1.0 ng/mL). No detectable vitamin E acetate was observed in the aqueous humor samples on day 1, day 4, day 7, or day 12.

The results show that measurable amounts of vitamin E acetate were present in the tears of rabbit eyes for at least 12 days, indicating that fluid reservoirs were present in the eyes for at least 12 days, despite normal lacrimal and ocular function; vitamin E acetate is not present in the anterior chamber of the eye, indicating that the fluid reservoir is not absorbed into the eye.

Example 2 comparison of in vitro Release of dexamethasone

From 5mg dexamethasone powder, in a 100mL physiological saline tank (exchange 50mL),10% (5mg) of dexamethasone or 10% (5mg) of dexamethasone in tocopherol acetate. The results are illustrated in fig. 3.

Example 3 fluid reservoir containing dexamethasone

Vitamin E is viscous, having a cP (mPas) of about 6000-6500(20 ℃). With liquid film-forming agentThe combination may achieve a sustained release fluid reservoir containing one or more of a plurality of agents. Miglyol is a stable neutral oil that can be used as a carrier or solvent and is Generally Recognized As Safe (GRAS) by the U.S. food and drug administration.

By mixing 10% dexamethasone, 72% vitamin E acetate and 18% vitamin E acetate(in the examples% means wt%) are mixed thoroughly to prepare the liquid reservoir. The dexamethasone-containing liquid reservoir has a viscosity of 850cP to 860 cP. A50. mu.L sample was placed in 200mL saline solution, then 100mL was taken at intervals (and replaced with 100mL fresh saline), and the amount of dexamethasone was determined by UPLC. The release profile of this formulation is shown in figure 4 (n-6, repeats a-F); dexamethasone was released within 10 days.

By mixing 10% dexamethasone, 72% vitamin E acetate and 18% vitamin E acetateAnd mixed thoroughly to prepare another embodiment of the fluid reservoir. Viscosity was measured in duplicate and indicated viscosities of 995cP and 1008cP (average 1001.5 cP); after 3 months, the viscosity was measured at 1079cP (average of 1027cP at all time points).

Example 4 delivery of dexamethasone to the interior of the eye by liquid reservoir

By mixing 80mg of tocopherol acetate with 20mg(neutral oil) was mixed well to prepare the liquid reservoir. 10mg dexamethasone was suspended in a 90mg liquid reservoir and the formulation was mixed into a homogeneous liquid. The dexamethasone fluid reservoir was radiation sterilized using standard protocols.

A 25 μ L unit depot of dexamethasone fluid was instilled into the eyes of female new zealand white rabbits. Subsequently, the amount of dexamethasone present in the posterior part of the eye was determined at time points from 8 hours to 21 days. Data are shown in table 2 (vitreous humor) and table 3 (retina):

these data show that one insertion of a fluid reservoir results in dexamethasone in the retina for at least 8 days (more than one week); and last at least 3 days in the vitreous humor.

Example 5 liquid reservoir containing prednisolone

By mixing 10% prednisolone in 80% vitamin E acetate and 20% prednisoloneI.e., 80: 20 tocopherol acetate at 90%Of prednisolone 10% of the mixture) to prepare a fluid reservoir. In vitro sustained release studies of prednisolone were performed using a Cabone ring (Wilton Brands LLC, Woodridge, il.) having an Outer Dimension (OD) of 0.5 inches and an Inner Dimension (ID) of 0.281 inches. Samples GTH-64A to GTH-64F, weighing 50.9mg, 48.6mg, 50.4mg, 48.7mg, 51.6mg and 49.3mg respectively (average weight 49.92; SD 1.24; RSD (relative standard deviation) ═ 2.47), were added to 125mL urine sample cups (with lids) containing 100gm of water, respectively. A0.5 "Cabone ring was placed in the cup. At each point in time of the operation of the motor,60ml of each of the 6 samples was sampled and replaced with 60ml of saline. The amount of prednisolone released was determined by UPLC. The release profiles of the prednisolone-containing liquid depot formulations are shown in table 4 and fig. 5; the prednisolone release was sustained for at least 5 days.

By mixing prednisolone 10%, vitamin E acetate 80%, and vitamin E acetate 20%(80: 20 Tocopherol acetate at 90%10% prednisolone in the mixture) is mixed thoroughly to prepare another prednisolone fluid reservoir. An in vitro sustained release study of prednisolone was performed using a 12.7mm Cabone ring. 6 samples 5A-5F weighing 48.2mg, 48.5mg, 48.1mg, 49mg, 51.7mg and 49.2mg (average weight 49.1 mg; SD ═ 1.24; RSD ═ 2.7), respectively, were incubated in 50ml saline at 40 ℃. At each time point, 25ml of each of the 6 samples was sampled and replaced with 25ml of saline. The amount of prednisolone released was determined by UPLC. The release profiles of the prednisolone-containing liquid depot formulations are shown in tables 5 to 7 and fig. 6. The prednisolone release was sustained for at least 5 days.

Example 6 liquid reservoir comprising loteprednol etabonate

By mixing loteprednol etabonate 10%, vitamin E acetate 80% and vitamin E acetate 20%(80: 20 Tocopherol acetate at 90%Of loteprednol etabonate 10%) is mixed thoroughly to prepare a liquid reservoir. An in vitro sustained release study of loteprednol etabonate was performed by incubating 2 samples 66-a and 66-B of weight approximately 71.8mg and 59.8mg, respectively, in 100mL of 40% methanol/water at 37 ℃. At each time point, 50ml each of the 2 samples was sampled and replaced with 50ml of 40% methanol/water. The amount of loteprednol etabonate released was determined by UPLC. The release profiles of the loteprednol etabonate-containing liquid reservoir formulation are shown in table 8, table 9 and figure 7; loteprednol etabonate release is sustained for at least 14 days.

Example 7 fluid reservoir containing prednisone or fluorometholone

Prednisone was loaded to tocopherol and as described in example 3In vitro and in vivo sustained release data were collected as described in examples 3-4.

Fluorometholone loading into tocopherols and Fluorometholone as described in example 3In vitro and in vivo sustained release data were collected as described in examples 3-4.

Example 8 fluid reservoir comprising ciprofloxacin

By mixing 15% ciprofloxacin hydrochloride, 70% vitamin E acetate and 30%(70: 30 Tocopherol acetate at 85%15% ciprofloxacin in the mixture) were mixed thoroughly to prepare a liquid reservoir. An in vitro sustained release study of ciprofloxacin was performed using a 12.7mm Cabone ring. 6 samples of Cipro-24A to Cipro-24F, weighing 50.2mg, 54.1mg, 56.3mg, 44mg, 62.3mg and 61mg (average weight 54.65mg, SD 6.857,% RSD 12.5), respectively, were incubated in 50ml saline at 40 ℃. At each time point, 25ml of each of the 6 samples was sampled and replaced with 25ml of saline. The amount of ciprofloxacin released was determined by UPLC. The release profiles of ciprofloxacin-containing liquid depot formulations are shown in table 10, table 11 and figure 8; ciprofloxacin release was sustained for at least 24 hours.

Example 9 liquid reservoir comprising ciprofloxacin

By mixing 15% ciprofloxacin hydrochloride, 70% vitamin E acetate and 30%(70: 30 Tocopherol acetate at 85%15% ciprofloxacin in the mixture) were mixed thoroughly to prepare another fluid reservoir containing ciprofloxacin similar to example 8. 12.7mm Cab was usedone ring was subjected to in vitro sustained release studies of ciprofloxacin. 6 samples of Cipro-25A to Cipro-25F, weighing 45.8mg, 48.5mg, 51.2mg, 48mg, 62.2mg and 49.3mg (average weight 50.83mg, SD 5.839,% RSD 11.5), respectively, were incubated in 50ml saline at 40 ℃. At each time point, 25ml of each of the 6 samples was sampled and replaced with 25ml of saline. The amount of ciprofloxacin released was determined by UPLC. The release profiles of ciprofloxacin-containing liquid depot formulations are shown in table 12, table 13 and figure 9; ciprofloxacin release was sustained for at least 24 hours.

Example 10 liquid reservoir comprising gatifloxacin

By mixing 10% of gatifloxacin, 70% of vitamin E acetate and 30% of vitamin E acetate(70: 30 tocopheryl acetate at 90%10% gatifloxacin in the mixture) are mixed thoroughly to prepare a liquid reservoir. An in vitro sustained release study of gatifloxacin was performed using a 12.7mm Cabone ring (Wilton Brands LLC, Woodridge, Ill.). 6 samples of Gati-90A to Gati-90F, weighing 48.2mg, 48mg, 48.9mg, 47mg, 49.1mg and 47.8mg respectively (average weight 48.17 mg; SD 0.766;% RSD 1.6), were incubated in 40mL saline at 40 ℃. At each time point, 20ml of each of the 6 samples was sampled and replaced with 20ml of saline. The amount of gatifloxacin released was determined by UPLC. The release profiles of the gatifloxacin-containing liquid depot formulations are shown in table 14, table 15 and figure 10. Gatifloxacin is released for at least 24 hours.

Example 11 liquid reservoir comprising an anti-infective agent

Moxifloxacin was loaded into tocopherols andin the reservoir. In vitro and in vivo sustained release data were collected as described in examples 3-4.

Levofloxacin was loaded into tocopherols and vitamin E as described in example 3In the reservoir. In vitro and in vivo sustained release data were collected as described in examples 3-4.

Gentamicin loading into tocopherols and gentamicin suspension as described in example 3In the reservoir. In vitro and in vivo sustained release data were collected as described in examples 3-4.

Tobramycin loading into tocopherols and Tobramycin as described in example 3In the reservoir. In vitro and in vivo sustained release data were collected as described in examples 3-4.

Chloramphenicol loading into tocopherols and Tocopherol as described in example 3In the reservoir. In vitro and in vivo sustained release data were collected as described in examples 3-4.

Example 12 fluid reservoir containing NSAID

By mixing 10% diclofenac with 90% 80: 20 tocopheryl acetateIs mixed thoroughly in the fluid depot mixture to produce a formulation of NSAID diclofenac. One administration of 50 μ L of this formulation was instilled into the eyes of NZW rabbits, and tear samples were collected and analyzed as described herein. As shown in fig. 11, the results indicate that diclofenac is detected in the rabbit tear film for at least 7 days.

EXAMPLE 13 cyclosporin-containing liquid reservoir

Two formulations comprising 2% cyclosporin a (csa) were prepared as provided herein. A preparation comprises 90: 10 of tocopherol acetateThe mixture of (2%) contained CsA. The other is 70: 30 of tocopherol acetateThe mixture of (2%) contained CsA. In vitro release (% CsA release) was monitored as described herein, and the% total CsA release was plotted over the course of at least 120 days, as shown in fig. 12.

Example 14 fluid reservoir administration

The sustained release fluid reservoir loaded with the therapeutic agent is administered in a single administration or provided to an individual wearing contact lenses or make-up in the form of a kit. Due to the physical consistency, no flow of the fluid reservoir was observed in the eye of the individual. In addition, the individual did not experience blurred vision or eye irritation. Accordingly, at least one embodiment provides a kit comprising at least one disposable dispenser, wherein the at least one disposable dispenser comprises a fluid reservoir as described herein.