Methods for lowering intraocular pressure

Abstract

Described herein is a method for reducing or preventing elevated intraocular pressure in a subject. The method involves administering a delta-9-tetrahydrocannabinol ester or a derivative thereof and a Rho kinase inhibitor to the subject. The combination of a delta-9-tetrahydrocannabinol ester or a derivative thereof and a Rho kinase inhibitor is effective in reducing intraocular pressure when compared to administration of a delta-9-tetrahydrocannabinol ester or a derivative thereof and a Rho kinase inhibitor alone.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 187,472, filed May 12, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] Delta-9-tetrahydrocannabinol (THC) is the main active ingredient of the plant Cannabis sativa (marijuana) and is responsible for most of its pharmacological effects. People have used the plant (containing numerous cannabinoids) since ancient times, both for medicinal purposes and for its addictive properties. Although marijuana is primarily known as a drug of abuse, the active ingredient THC has important pharmacological properties that, with the right delivery mechanisms, can be targeted for specific therapeutic effects. To date, the most promising clinical applications approved by the U.S. Food and Drug Administration (FDA) are the regulation of chemotherapy-induced nausea and vomiting and the increase in appetite in AIDS patients suffering from anorexia and wasting syndrome.

[0003] THC has numerous biological activities that may provide additional therapeutic applications. One potential application is the treatment of glaucoma. Glaucoma is a disease that causes progressive damage to the optic nerve through a variety of mechanisms, including increased intraocular pressure (IOP) in the eye caused by reduced blood flow or poor drainage of fluid, which can lead to vision loss and is the leading cause of irreversible blindness. Persistent elevated IOP leads to degeneration of retinal ganglion cells (RGCs). Once damaged, RGCs do not regenerate, and glaucoma is known as a silent disease because there are no major warning signs until vision loss begins. However, studies have shown that topical application of THC does not affect IOP. Furthermore, the American Glaucoma Society has taken the position that although marijuana reduces intraocular pressure, its side effects and short duration of action, as well as the lack of evidence that its use alters the course of glaucoma, preclude the recommendation of this drug in any form for the treatment of glaucoma.

[0004] Current IOP treatment drugs include Latanoprost and Rhopressor. Although these products provide relief with respect to IOP treatment, the number of treatment options is limited due to side effects or the development of resistance to current therapies, and therefore there remains a need for new treatments and therapies to lower IOP. Summary of the Invention

[0005] Described herein is the use of delta-9-tetrahydrocannabinol amino acid ester or its derivative and a Rho kinase inhibitor, such as netarsudil or its pharmaceutically acceptable salt, to reduce or prevent IOP elevation in a subject. The method includes co-administering delta-9-tetrahydrocannabinol amino acid ester or its derivative and a Rho kinase inhibitor, such as netarsudil or its pharmaceutically acceptable salt, to a subject. In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor can be administered to a subject sequentially. In another embodiment, the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor can be administered to a subject as a single pharmaceutical formulation. The combination of delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor is effective in reducing IOP to a greater extent than the administration of delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor separately.

[0006] Other systems, methods, features, and advantages of the present disclosure will become apparent to one of ordinary skill in the art upon examination of the following drawings and detailed description. All such additional systems, methods, features, and advantages are intended to be included within this specification, be within the scope of this disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments can be used in all aspects of the present disclosure taught herein. Moreover, the individual features of the dependent claims and all optional and preferred features and modifications of the described embodiments can be combined and exchanged with each other. [Brief description of the drawings]

[0007] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0008] [Figure 1] FIG. 1 shows the mean IOP (days 1, 3, and 5) versus time profiles in the test and contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or latanoprost formulations (mean ± SD, n=6).

[0009] [Diagram 2] FIG. 2 shows the mean % IOP reduction (days 1, 3, and 5) versus time profile in the test and contralateral eyes of DB rabbits following topical administration of the THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean ± SD, n=6).

[0010] [Diagram 3]FIG. 3 shows the IOP versus time profiles on day 1 in the study eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0011] [Figure 4] FIG. 4 shows IOP versus time profiles on day 1 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0012] [Diagram 5] FIG. 5 shows the % IOP reduction versus time profiles on day 1 in the test eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0013] [Figure 6] FIG. 6 shows the % IOP reduction vs. time profiles on day 1 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0014] [Figure 7] FIG. 7 shows the IOP versus time profiles on day 3 in the test eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0015] [Figure 8] FIG. 8 shows IOP versus time profiles on day 3 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0016] [Figure 9]FIG. 9 shows the % IOP reduction versus time profiles on day 3 in the test eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0017] [Figure 10] FIG. 10 shows the % IOP reduction versus time profiles on day 3 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0018] [Figure 11] FIG. 11 shows the IOP versus time profiles on day 5 in the study eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0019] [Figure 12] FIG. 12 shows the IOP versus time profiles on day 5 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0020] [Figure 13] FIG. 13 shows the % IOP reduction versus time profiles on day 5 in the study eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0021] [Figure 14] FIG. 14 shows the % IOP reduction versus time profiles on day 5 in the contralateral eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean±SD, n=6).

[0022] [Figure 15]FIG. 15 shows the mean and daily (days 1, 3, and 5) IOP versus time profiles in the test eyes of DB rabbits following topical administration of the THC-VHS-NEC formulation (mean±SD, n=6).

[0023] [Figure 16] FIG. 16 shows the mean and daily (days 1, 3 and 5) IOP versus time profiles in the contralateral eyes of DB rabbits following topical administration of the THC-VHS-NEC formulation (mean±SD, n=6).

[0024] [Figure 17] FIG. 17 shows the mean and daily (days 1, 3, and 5) % IOP reduction versus time profiles in the test eyes of DB rabbits following topical administration of the THC-VHS-NEC formulation (mean±SD, n=6).

[0025] [Figure 18] FIG. 18 shows the mean and daily (days 1, 3, and 5) % IOP reduction versus time profiles in the contralateral eyes of DB rabbits following topical administration of the THC-VHS-NEC formulation (mean±SD, n=6).

[0026] [Figure 19] FIG. 19 shows the mean and daily (days 1, 3 and 5) IOP versus time profiles in the study eyes of DB rabbits following topical administration of Rhopressa® formulations (mean±SD, n=6).

[0027] [Figure 20] FIG. 20 shows the mean and daily (days 1, 3 and 5) IOP versus time profiles in the contralateral eyes of DB rabbits following topical administration of Rhopressa® formulations (mean±SD, n=6).

[0028] [Figure 21] FIG. 21 shows the mean and daily (days 1, 3 and 5) % IOP reduction versus time profiles in the test eyes of DB rabbits following topical administration of Rhopressa® formulations (mean±SD, n=6).

[0029] [Figure 22] FIG. 22 shows the mean and daily (days 1, 3 and 5) % IOP reduction versus time profile in the contralateral eye of DB rabbits following topical administration of Rhopressa® formulation (mean±SD, n=6).

[0030] [Figure 23] FIG. 23 shows the mean and daily (days 1, 3 and 5) IOP versus time profiles in the test eyes of DB rabbits following topical administration of latanoprost formulations (mean±SD, n=6).

[0031] [Figure 24] FIG. 24 shows the mean and daily (days 1, 3 and 5) IOP versus time profiles in the contralateral eye of DB rabbits following topical administration of latanoprost formulations (mean±SD, n=6).

[0032] [Diagram 25] FIG. 25 shows the mean and each day (days 1, 3 and 5) IOP reduction versus time profile in the test eyes of DB rabbits following topical administration of latanoprost formulations (mean±SD, n=6).

[0033] [Figure 26] FIG. 26 shows the mean and daily (days 1, 3 and 5) IOP reduction versus time profile in the contralateral eye of DB rabbits following topical administration of latanoprost formulations (mean±SD, n=6).

[0034] [Figure 27] FIG. 27 shows the mean IOP (days 1, 3, and 5) vs. time profiles obtained after co-administration of the two formulations in the test eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations, compared to the mean IOP (days 1, 3, and 5) vs. time profiles obtained after single drug administration (mean±SD, n=6).

[0035] [Figure 28] FIG. 28 shows the mean IOP (days 1, 3, and 5) versus time profiles in the test and contralateral eyes of DB rabbits following topical co-administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations (mean ± SD, n=6).

[0036] [Figure 29] FIG. 29 shows the mean % IOP reduction (days 1, 3, and 5) versus time profiles following co-administration of the two formulations in the test eyes of DB rabbits following topical administration of THC-VHS-NEC, Rhopressa®, or Latanoprost formulations, compared to the mean IOP (days 1, 3, and 5) versus time profiles obtained following single-drug administration (mean±SD, n=6).

[0037] [Diagram 30] FIG. 30 shows the mean % IOP reduction (days 1, 3 and 5) vs. time profile obtained after co-administration of the two formulations compared to the mean % IOP reduction (days 1, 3 and 5) vs. time profile obtained after single agent administration in the test eye of DB rabbits (mean±SD, n=6).

[0038] [Diagram 31] FIG. 31 shows the IOP versus time profile on day 1 in the test eyes of DB rabbits following topical co-administration of the two formulations (mean±SD, n=6).

[0039] [Diagram 32] FIG. 32 shows the IOP versus time profile on day 1 in the contralateral eye of DB rabbits after topical co-administration of the two formulations (mean±SD, n=6).

[0040] [Diagram 33] FIG. 33 shows the % IOP reduction versus time profile on day 1 in the test eyes of DB rabbits following topical co-administration of the two formulations (mean±SD, n=6).

[0041] [Diagram 34] FIG. 34 shows the % IOP reduction vs. time profile on day 1 in the contralateral eye of DB rabbits following topical co-administration of the two formulations (mean±SD, n=6).

[0042] [Diagram 35] FIG. 35 shows the IOP versus time profile on day 3 in the test eyes of DB rabbits after topical co-administration of the two formulations (mean±SD, n=6).

[0043] [Diagram 36] FIG. 36 shows the IOP versus time profile on day 3 in the contralateral eye of DB rabbits after topical co-administration of the two formulations (mean±SD, n=6).

[0044] [Figure 37] FIG. 37 shows the % IOP reduction versus time profile on day 3 in the test eyes of DB rabbits following topical co-administration of the two formulations (mean±SD, n=6).

[0045] [Figure 38] FIG. 38 shows the % IOP reduction versus time profile on day 3 in the contralateral eye of DB rabbits after topical co-administration of the two formulations (mean±SD, n=6).

[0046] [Figure 39] FIG. 39 shows the IOP versus time profile on day 5 in the test eyes of DB rabbits after topical co-administration of the two formulations (mean±SD, n=6).

[0047] [Diagram 40] FIG. 40 shows the IOP versus time profile in the contralateral eye of DB rabbits on day 5 after topical co-administration of the two formulations (mean±SD, n=6).

[0048] [Diagram 41]FIG. 41 shows the % IOP reduction versus time profiles on day 5 in the study eyes of DB rabbits following topical co-administration of THC-VHS-NEC, Rhopressa® and Latanoprost formulations (mean±SD, n=6).

[0049] [Diagram 42] FIG. 42 shows the % IOP reduction versus time profile in the contralateral eye of DB rabbits on day 5 after topical co-administration of the two formulations (mean±SD, n=6).

[0050] [Diagram 43] FIG. 43 shows a comparison of mean IOP (days 1, 3, 5) versus time profiles in the study eyes of DB rabbits following topical administration of Rhopressa® alone, THC-VHS-NEC alone, and the combination of the two (THC-VHS-NEC + Rhopressa®) (mean ± SD, n=6).

[0051] [Diagram 44] FIG. 44 shows a comparison of mean IOP (days 1, 3, and 5) versus time profile to the IOP profiles on days 1, 3, and 5 in the contralateral eye of DB rabbits following topical co-administration of THC-VHS-NEC + Rhopressa® formulation (mean ± SD, n=6).

[0052] [Diagram 45] FIG. 45 shows a comparison of the mean % IOP reduction (days 1, 3, and 5) versus time profile in the test eyes of DB rabbits following topical administration of Rhopressa® alone, THC-VHS-NEC alone, and the combination of the two (THC-VHS-NEC + Rhopressa®) (mean ± SD, n=6).

[0053] [Figure 46]FIG. 46 shows a comparison of the mean IOP % reduction (days 1, 3, and 5) versus time profile to the % IOP reduction profiles on days 1, 3, and 5 in the contralateral eye of DB rabbits following topical co-administration of THC-VHS-NEC + Rhopressa® formulation (mean ± SD, n=6).

[0054] [Figure 47] FIG. 47 shows a comparison of mean IOP (days 1, 3, and 5) versus time profiles following topical administration of Rhopressa® alone, Latanoprost alone, and the combination of both (Rhopressa® + Latanoprost) in the study eyes of DB rabbits (mean ± SD, n=6).

[0055] [Figure 48] FIG. 48 shows a comparison of mean IOP (days 1, 3, and 5) versus time profile to the IOP profiles on days 1, 3, and 5 in the contralateral eye of DB rabbits following topical co-administration of Rhopressa® plus Latanoprost formulation (mean ± SD, n=6).

[0056] [Figure 49] FIG. 49 shows a comparison of the mean % IOP reduction (days 1, 3, and 5) versus time profile in the test eyes of DB rabbits following topical administration of Rhopressa® alone, Latanoprost alone, and the combination of the two (Rhopressa® + Latanoprost) (mean ± SD, n=6).

[0057] [Figure 50] FIG. 50 shows a comparison of the mean IOP % reduction (days 1, 3, and 5) versus time profile to the % IOP reduction profiles in the contralateral eyes of DB rabbits on days 1, 3, and 5 after topical co-administration of Rhopressa® + Latanoprost formulation (mean ± SD, n=6).

[0058] [Figure 51]FIG. 51 shows a comparison of mean IOP (days 1, 3, and 5) versus time profiles following topical administration of THC-VHS-NC alone, Latanoprost alone, and the two combination (Latanoprost + THC-VHS-NEC) formulations (mean ± SD, n=6).

[0059] [Figure 52] FIG. 52 shows a comparison of mean IOP (days 1, 3, and 5) versus time profile to the IOP profiles on days 1, 3, and 5 in the contralateral eye of DB rabbits following topical co-administration of Latanoprost+THC-VHS-NEC formulation (mean ± SD, n=6).

[0060] [Diagram 53] FIG. 53 shows a comparison of the mean % IOP reduction (days 1, 3, and 5) versus time profile following topical administration of THC-VHS-NC alone, Latanoprost alone, and the two combination (Latanoprost + THC-VHS-NEC) formulations (mean ± SD, n=6).

[0061] [Figure 54] FIG. 54 shows a comparison of the mean IOP reduction % (days 1, 3, and 5) versus time profile for IOP on days 1, 3, and 5 in the contralateral eye of DB rabbits following topical co-administration of Latanoprost+THC-VHS-NEC formulation (mean±SD, n=6).

[0062] Additional advantages of the invention will be set forth in part in the description which follows and in part will be obvious from the description or may be learned by the practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. DETAILED DESCRIPTION OF THE DISCLOSURE

[0063] Many modifications and other embodiments disclosed herein will occur to those skilled in the art of the disclosed compositions and methods having the benefit of the teachings presented in the foregoing description and the associated drawings. It is therefore to be understood that the disclosure is not limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are intended to be included within the teachings of the present disclosure and to be encompassed within the scope of the claims herein.

[0064] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0065] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has separate components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0066] Any method described may be carried out in the order of events described or in any other order that is logically possible. That is, unless expressly stated otherwise, it is not intended that the methods or aspects described herein be construed as requiring that its steps be performed in a particular order. Thus, if a method claim does not specifically recite in the claim or description that the steps are limited to a particular order, no order is intended to be implied in any respect. This also applies to any possible non-express basis for interpretation, such as logical considerations regarding the arrangement of steps or the flow of operations, the plain meaning derived from grammatical construction and punctuation, the number and type of aspects described in the specification, etc.

[0067] All publications cited herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which they are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publications by virtue of prior invention. Further, the publication dates provided herein may be different from the actual publication dates, which may require independent confirmation.

[0068] It should also be understood that the terms used herein are for describing specific aspects and are not intended to be limiting.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosed compositions and methods belong.Furthermore, it should be understood that terms as defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of this specification and related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0069] Prior to describing the various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in this disclosure.

[0070] definition As used herein, "comprising" is to be construed as specifying the presence of the stated features, integers, steps, or components as used, but does not exclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Additionally, each of the terms "by," "comprising," "comprises," "comprised of," "including," "includes," "included," "involving," "involves," "involved," and "such as" are used in an open, non-limiting sense and may be used interchangeably. Additionally, the term "comprising" is intended to include examples and embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of."

[0071] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an amino acid" includes, but is not limited to, mixtures or combinations of two or more such amino acids, and the like.

[0072] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in a range format. It is further understood that the endpoints of each range are independent of the other endpoint in relation to the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as "about" one particular value and / or "about" another particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will be understood to provide that the particular value forms a further aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0073] When a range is expressed, a further embodiment includes from the one particular value and / or to the other particular value. For example, when the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, for example, a phrase "from x to y" includes a range from "x" to "y" as well as a range from greater than "x" to less than "y."

[0074] As used herein, the terms "about", "approximate", "at or about" and "substantially" mean that the amount or value in question may be an exact value or a value that provides an equivalent result or effect as claimed or taught herein. That is, it is understood that amounts, sizes, formulas, parameters, and other quantities and characteristics are not and need not be exact, but may be approximated and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, and other factors known to those skilled in the art that would provide an equivalent result or effect. In some circumstances, a value that would provide an equivalent result or effect may not be reasonably determined. In such cases, as used herein, "about" and "at or about" are generally understood to mean a variation of ±10% of the nominal value indicated, unless otherwise indicated or implied. In general, an amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximate," or "at or about," regardless of whether it is "about," "approximate," or "at or about." When "about," "approximate," or "at or about" is used in front of a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specified.

[0075] Unless otherwise stated, formulas in which chemical bonds are shown only as solid lines and not as wedges or dashes contemplate each possible isomer, for example each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or scalemic mixtures. Compounds described herein may contain one or more asymmetric centers, and thus may give rise to diastereomers and optical isomers. Unless otherwise stated, the present invention includes all such possible diastereomers, as well as their racemic mixtures, substantially pure resolved enantiomers, all possible geometric isomers, and pharma- ceutically acceptable salts thereof. Mixtures of stereoisomers, and isolated specific stereoisomers are also included. During the synthetic procedures used to prepare such compounds, or in the use of racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0076] Disclosed are the components used to carry out the methods of the invention, as well as the compositions themselves used within the methods disclosed herein. When these and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that each is specifically contemplated and described herein, although specific references to each of the various individual and collective combinations and permutations of these compounds cannot be explicitly disclosed. For example, when a particular compound is disclosed and discussed, and a number of modifications that can be made to a number of molecules including that compound are discussed, what is specifically contemplated is each and every combination and permutation of that compound and possible modifications, unless specifically indicated to the contrary. Thus, when a class of molecules A, B, and C, as well as a class of molecules D, E, and F, and an example of a combination molecule, AD, is disclosed, this means that the combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered to be disclosed, even if each is not individually described, and each is individually and collectively contemplated. Similarly, any subset or combination of these is also disclosed. Thus, for example, the subgroups AE, BF, and CE are considered to be disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, where there are various additional steps that may be performed, it is understood that each of these additional steps may be performed in any specific embodiment or combination of embodiments of the methods of the invention.

[0077] As used herein, the term "admixing" is defined as the mixing of two or more components in the absence of a chemical reaction or physical interaction. The term "admixing" also includes a chemical reaction or physical interaction between two or more components.

[0078] As used interchangeably herein, a "subject," "individual," or "patient" can refer to a vertebrate, such as a mammal (e.g., a human). A "subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably a human and components thereof.

[0079] As used herein, the terms "treating" and "treatment" may generally mean to obtain a desired pharmacological and / or physiological effect. The effect may be, but is not necessarily, prophylactic, in that it prevents or partially prevents a disease, symptom, or condition, such as glaucoma. The effect may be therapeutic, in that it partially or completely cures a disease, condition, symptom, or side effects caused by a disease, disorder, or condition. As used herein, the term "treatment" may include any treatment of glaucoma in a subject, particularly a human, and may include any one or more of the following: (a) preventing the disease from occurring in a subject who may have a predisposition to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., arresting its development; and (c) alleviating the disease, i.e., reducing or reversing the disease and / or its symptoms or conditions. As used herein, the term "treatment" may mean only therapeutic treatment, only prophylactic treatment, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need of treatment) can include those already with the disorder and / or those in whom the disorder is to be prevented. In one embodiment, "treating" and "treatment" include improved pharmacological and / or physiological effects when a compound described herein is administered compared to when the compound is not administered (i.e., a control).

[0080] As used herein, "dose," "unit dose," or "dosage" may mean physically discrete units suitable for use in subjects, each unit containing a predetermined quantity of a disclosed compound and / or pharmaceutical composition thereof calculated to produce a desired response or reaction associated with its administration.

[0081] As used herein, "therapeutic" can mean treating, curing, and / or ameliorating a disease, disorder, condition, or side effect, or slowing the rate of progression of a disease, disorder, condition, or side effect.

[0082] As used herein, "effective amount" may refer to an amount of the disclosed compounds or pharmaceutical compositions provided herein sufficient to produce a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective amount may be administered in one or more administrations, applications, or dosages. The term may also include within its scope an amount effective to enhance or restore substantially normal physiological function.

[0083] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on undesired symptoms, but generally insufficient to cause adverse side effects. A particular therapeutically effective dose level for a particular patient will depend on a variety of factors, including the disease and severity of the disease being treated, the particular composition utilized, the age, weight, general health, sex, and diet of the patient, the time of administration, the route of administration, the rate of excretion of the particular compound utilized, the duration of treatment, drugs used in combination or concomitantly with the particular compound utilized, and factors within the knowledge and expertise of the medical practitioner and well known in the medical arts. When treating a particular disease or condition, in some cases the desired response may be to inhibit the progression of the disease or condition. In this case, it only involves temporarily slowing the progression of the disease. However, in other cases, it may be desired to permanently stop the progression of the disease. This may be monitored by routine diagnostic methods known to those skilled in the art for the particular disease. The desired response to the treatment of a disease or condition may be to slow or even prevent the onset of the disease or condition.

[0084] As used herein, the term "prophylactically effective amount" means an amount effective to prevent the development or onset of a disease or condition.

[0085] As used herein, the term "prevent" or "preventing" means to prevent, avoid, remove, prevent, stop, or hinder something from happening, especially by prior action. Where reduce, inhibit, or prevent is used herein, it is understood that the use of the other two words is expressly disclosed unless specifically indicated otherwise.

[0086] As used herein, the term "pharmaceutical acceptable salts" refers to salts of active ingredients prepared with acids or bases that are tolerated by biological systems or tolerated by subjects when administered in therapeutically effective amounts, or that are tolerated by biological systems and tolerated by subjects.When a compound of the present disclosure contains a relatively acidic functionality, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired base in a suitable or suitable inert solvent.Examples of pharmaceutical acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or similar salts.When a compound of the present disclosure contains a relatively basic functionality, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired acid in a suitable or suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid salts, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginic acid, and salts of organic acids such as glucuronic acid and galactunoric acid.

[0087] The term "ophthalmically suitable" refers to a material that is not biologically or otherwise undesirable, i.e., that does not cause unacceptable levels of undesirable biological effects or interact in a harmful manner with respect to the eye.

[0088] As used herein, "intraocular pressure" (IOP) refers to the ocular fluid pressure exerted by the aqueous humor of the eye on the surface area of ​​the anterior segment of the eye. In one aspect, high intraocular pressure is a risk factor for glaucoma and can result from inflammation, anatomical problems or differences, genetics, side effects of medications, and the like. In a further aspect, in humans, normal intraocular pressure is typically between 10-22 mmHg, while IOP in common mammals typically varies between 8-35, with different but overlapping ranges depending on the species.

[0089] In one embodiment, a "tonometer" is a device used to measure IOP in humans or other mammals. There are various types of tonometers. Applanation tonometers are designed based on the assumption that the pressure inside a dry, thin-walled sphere is equal to the force required to flatten its surface divided by the area flattened, and the cornea is flattened during use. Examples include the Goldmann applanation tonometer and the Perkins tonometer. Non-contact tonometry also flattens the cornea, and air-puff tonometers and ocular response analyzers use a column of air with increased strength. Indentation tonometry is based on the idea that a softer eyeball will sink more than a harder one when force is applied, and includes, for example, the Schiotz tonometer, pneumotonometer, and Tono-Pens (also including the applanation process). In rebound tonometry, a plastic ball on a wire is rebounded against the eye, which is held in place by an electromagnetic field, and the IOP correlates to the rate at which the eye decelerates through the device. The Pascal dynamic contour tonometer measures dynamic variations in IOP using a piezoelectric sensor in the tonometer. Some soft contact lens sensors may be used to measure changes in eye dimensions over the course of a day, and have been shown to correlate with IOP. In one embodiment, multiple tonometers can be used on humans or other mammals to measure IOP. In another embodiment, the change in IOP can be measured by taking an initial measurement with a tonometer or other sensor as described herein, administering a treatment, and taking a second measurement with the same tonometer or other sensor, with the difference between the first and second measurements indicating the change in IOP.

[0090] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (ie, 1 atmosphere).

[0091] Methods for reducing intraocular pressure Herein, a method for reducing or preventing IOP in a subject is described. The method includes administering delta-9-tetrahydrocannabinol amino acid ester or its derivative and a Rho kinase inhibitor to a subject. The combination of delta-9-tetrahydrocannabinol amino acid ester or its derivative and a Rho kinase inhibitor is more effective in reducing IOP than the independent use of delta-9-tetrahydrocannabinol amino acid ester or its derivative and netarsudil or its pharma-ceutical acceptable salt. As demonstrated herein, the co-administration of delta-9-tetrahydrocannabinol amino acid ester or its derivative and a Rho kinase inhibitor can enhance the initial reduction in IOP after administration and provide a sustained reduction in IOP compared to the administration of a Rho kinase inhibitor alone.

[0092] In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester has the structure I [ka] where R 1 comprises one or more amino acid residues. In another embodiment, the amino acid residues comprise valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine, and 4(4-aminophenyl)butyric acid, or a salt thereof, or any combination thereof.

[0093] In another embodiment, derivatives of delta-9-tetrahydrocannabinol amino acid esters may be used herein. In one embodiment, the delta-9-tetrahydrocannabinol amino acid esters may be reacted with an anhydride or a dicarboxylic acid to produce a derivative of the delta-9-tetrahydrocannabinol amino acid ester. In one embodiment, the anhydride is succinic anhydride or glutaric anhydride. In another embodiment, the dicarboxylic acid is malonic acid, malic acid, glutaric acid, succinic acid, or phthalic acid. In one embodiment, the derivative of the delta-9-tetrahydrocannabinol amino acid ester has the following structure: [ka] where n is an integer from 1 to 8.

[0094] In one embodiment, the derivative is delta-9-tetrahydrocannabinol-valine-hemisuccinic acid, the structure of which is: [ka] Methods for the synthesis of delta-9-tetrahydrocannabinol amino acid esters and derivatives thereof are provided in U.S. Patent Application Publication No. 2011 / 0275555, which is incorporated by reference in its entirety. In one aspect, the disclosed formulations and / or nanoemulsions may contain about 0.01% w / v to about 5% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or about 5% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, or any combination of the foregoing values, or a range encompassing any of the foregoing values.

[0095] The delta-9-tetrahydrocannabinol amino acid ester or its derivative is formulated as an ophthalmic composition.In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester or its derivative is formulated as a nanoemulsion.The delta-9-tetrahydrocannabinol amino acid ester or its derivative can be formulated with one or more additional ingredients to produce a nanoemulsion.

[0096] In one embodiment, the nanoemulsion comprises an ophthalmically suitable oil. Examples of such oils include, but are not limited to, castor oil, cottonseed oil, soybean oil, or sesame oil. In another embodiment, the oil is in an amount of about 1% w / v to about 10% w / v of the composition, or about 1% w / v, 1.5% w / v, 2% w / v, 2.5% w / v, 3% w / v, 3.5% w / v, 4% w / v, 4.5% w / v, 5% w / v, 5.5% w / v, 6% w / v, 6.5% w / v, 7% w / v, 7.5% w / v, 8% w / v, 8.5% w / v, 9% w / v, 9.5% w / v, or 10% w / v, either of which may be the lower and upper limits of the range (e.g., 1.5% w / v to 4% w / v).

[0097] In one embodiment, the nanoemulsion comprises an ophthalmologically suitable non-ionic surfactant. In one embodiment, the non-ionic surfactant is a poloxamer, which is a non-ionic triblock copolymer consisting of a central hydrophobic chain of polyoxypropylene (e.g., poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (e.g., poly(ethylene oxide)). In one embodiment, the poloxamer has the formula HO(C2H4O) b (C3H6O) a (C2H4O) b OH where a is 10-100, 20-80, 25-70, or 50-70, and b is 5-250, 10-225, 20-200, 50-200, 100-200, or 150-200. In another embodiment, the poloxamer has a molecular weight (MW) of 2,000-15,000, 3,000-14,000, or 4,000-12,000. Poloxamers useful herein are sold under the trade name Pluronic® by BASF. Non-limiting examples of poloxamers useful herein include, but are not limited to, those in the following table. In one embodiment, the poloxamer is F-407 (Pluronic® F-127). Useful poloxamers are listed in Table 1. [Table 1]

[0098] In another embodiment, the non-ionic surfactant is a polysorbate. A polysorbate is an oily liquid derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Examples of polysorbates include polysorbate 20, 40, 60, or 80.

[0099] In one embodiment, the non-ionic surfactant comprises a combination of a poloxamer and a polysorbate. In one embodiment, the poloxamer is in an amount of about 0.01% w / v to about 1% w / v of the composition, or about 0.01% w / v, 0.05% w / v, 0.1% w / v, 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.9% w / v, or 1% w / v, either of which may be the lower and upper limits of the range (e.g., 0.2% w / v to 0.4% w / v). In another embodiment, the polysorbate is in an amount of about 0.5% w / v to about 5% w / v of the composition, or about 1% w / v, 1.5% w / v, 2% w / v, 2.5% w / v, 3% w / v, 3.5% w / v, 4% w / v, 4.5% w / v, or 5% w / v, either of which can be the lower and upper limits of the range (e.g., 1.5% w / v to 4% w / v).

[0100] In one embodiment, the nanoemulsion includes an ophthalmologically suitable polymer to modify certain properties of the nanoemulsion. In one embodiment, the polymer is a cross-linked polyacrylic acid, such as Lubrizol's Carbopol 940. In one embodiment, the polymer is in an amount of about 0.1% w / v to about 2% w / v, or about 0.1% w / v, 0.2% w / v, 0.4% w / v, 0.6% w / v, 0.8% w / v, 1.0% w / v, 1.2% w / v, 1.4% w / v, 1.6% w / v, 1.8% w / v, or 2.0% w / v of the composition, either of which may be the lower or upper limit of the range (e.g., 0.4% w / v to 1.2% w / v).

[0101] In one embodiment, the nanoemulsion includes an ophthalmically suitable polyol, which is a compound having two or more hydroxyl groups. In one embodiment, the polyol is glycerin. In one embodiment, the polyol is in an amount of about 1% w / v to about 5% w / v of the composition, or about 1% w / v, 1.5% w / v, 2% w / v, 2.5% w / v, 3% w / v, 3.5% w / v, 4% w / v, 4.5% w / v, or 5% w / v, either of which may be the lower and upper limits of the range (e.g., 1.5% w / v to 4% w / v).

[0102] In one embodiment, the nanoemulsion comprises an ophthalmologically suitable ethoxylated tocopherol or tocotrienol. In one embodiment, the ethoxylated tocopherol or tocotrienol is D-alpha-tocopherol polyethylene glycol. In one embodiment, the nanoemulsion comprises Vitamin E polyethoxylated succinate (TPGS). In one embodiment, the ethoxylated tocopherol or tocotrienol is in an amount of about 0.0001% w / v to about 0.01% w / v of the composition, or about 0.0001% w / v, 0.0005% w / v, 0.001% w / v, 0. 002% w / v, 0.003% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, 0.01% w / v, either of which may be the lower or upper limit of the range (e.g., 0.001% w / v to 0.007% w / v).

[0103] In one embodiment, the nanoemulsion is composed of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, an oil, a poloxamer, a polysorbate, a cross-linked polyacrylic acid, a polyol, an ethoxylated tocopherol or tocotrienol, and water.

[0104] In another embodiment, the nanoemulsion may comprise from about 0.01% w / v to about 2% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, from about 1% to about 10% w / v of an ophthalmically suitable oil, from about 0.51% w / v to about 6% w / v of an ophthalmically suitable surfactant, from about 0.1% w / v to about 2% w / v of an ophthalmologically suitable polymer, from about 1% to about 5% w / v of an ophthalmologically suitable polyol, from about 0.0001% w / v to about 0.01% w / v of an ophthalmologically suitable ethoxylated tocopherol or tocotrienol, and water.

[0105] In some embodiments, the formulation and / or nanoemulsion may further comprise a Rho kinase inhibitor. In one embodiment, the Rho kinase inhibitor may be netarsudil or a pharma- ceutically acceptable salt thereof. In one embodiment, the formulation may comprise about 0.005% w / v to about 0.05% w / v of a Rho kinase inhibitor, or about 0.005%, 0.01%, 0.015%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or about 0.5% of a Rho kinase inhibitor, or any combination of the aforementioned values, or a range encompassing any of the aforementioned values.

[0106] In one embodiment, nanoemulsions can be produced by sonication. For example, delta-9-tetrahydrocannabinol amino acid ester or derivatives are mixed with oil and then heated to produce a hot lipid phase. Poloxamer, polysorbate and polyol are mixed with water and heated to produce a hot aqueous phase. The hot aqueous phase is added to the heated lipid phase under constant mixing to form a coarse emulsion. The coarse emulsion is then homogenized using a T 25 digital Ultra-Turrax (IKA, Germany), for example, at 11,000 rpm and 65°C for 5 minutes to form a fine emulsion. The fine emulsion is slowly cooled and then placed in an ice bath and sonicated (SONICS® Vibra-Cell™, Newtown, Connecticut, USA) using a 3 mm step microtip probe (amplitude 40%; pulse on: 10 seconds, pulse off: 15 seconds; time: 10 minutes).

[0107] The physical properties of the nanoemulsion can be modified and fine-tuned as necessary. In one embodiment, the nanoemulsion has an average droplet size (z-average) of about 200 nm to about 250 nm, or about 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 225 nm, 230 nm, 235 nm, 240 nm, 245 nm, or 250 nm, as measured by dynamic light scattering (e.g., Zetasizer Nano ZS Zen3600), with any value being the lower and upper limit of the range (e.g., 210 nm to 240 nm).

[0108] In one embodiment, the nanoemulsion has a polydispersity index, as measured by dynamic light scattering (e.g., Zetasizer Nano ZS Zen3600), of about 0.15 to about 0.25, or about 0.15, 0.16, 0.17, 0.18, 0.15, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25, either of which can be the lower and upper limits of the range (e.g., 0.18 to 0.23).

[0109] In one embodiment, the nanoemulsion has a zeta potential, as measured by dynamic light scattering (e.g., Zetasizer Nano ZS Zen3600), of about -20 mV to about -60 mV, or about -20 mV, -25 mV, -30 mV, -35 mV, -40 mV, -45 mV, -50 mV, -55 mV, or -60 mV, either of which can be the lower and upper limits of the range (e.g., -25 mV to -35 mV).

[0110] In some embodiments, the nanoemulsion can be sterilized before administration. In one embodiment, the nanoemulsion can be filtered. In one embodiment, the nanoemulsion can be filtered through a micrometer filter membrane (e.g., a 0.22 μm filter). In another embodiment, the nanoemulsion can be moist heat sterilized. The methods described herein also include co-administration of a Rho kinase inhibitor. In one embodiment, the Rho kinase inhibitor is AT-13148, BA-210, β-elemene DJ4, fasudil, GSK-576371, GSK429286A, H-1152, hydroxyfasudil, LX-7101, RKI-1447, ripasudil, TCS-7001, thiazovivin, berosudil Y-30141, Y-33075, or Y-39983. In another embodiment, the Rho kinase inhibitor is netarsudil or a pharma-ceutically acceptable salt thereof.

[0111] In one embodiment, netarsudil mesylate, also known as Rhopressor (registered trademark), a commercially available eye drop, may be used herein. In one embodiment, the ophthalmic composition of netarsudil or its pharma- ceutically acceptable salt may be formulated with ophthalmologically suitable buffers and excipients. In one embodiment, netarsudil or a pharma- ceutically acceptable salt thereof can be formulated as an ophthalmic composition having a concentration of about 0.005% w / v to about 0.05% w / v, or about 0.005% w / v, 0.010% w / v, 0.015% w / v, 0.020% w / v, 0.025% w / v, 0.030% w / v, 0.035% w / v, 0.040% w / v, 0.045% w / v, or 0.050% w / v, with either value being the lower or upper limit of the range (e.g., 0.010% w / v to 0.030% w / v). In one embodiment, the ophthalmic composition comprises netarsudil or a pharma- ceutically acceptable salt thereof at a concentration of 0.02% w / v.

[0112] In one embodiment, the nanoemulsion containing the Rho kinase inhibitor and delta-9-tetrahydrocannabinol amino acid ester or derivative thereof can be formulated with both the Rho kinase inhibitor or its lipophilic derivative and the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof dissolved in the lipid phase of the emulsion. In another embodiment, the Rho kinase inhibitor or its salt is dissolved in the aqueous phase of the emulsion, while the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof is dissolved in the lipid phase of the emulsion. In addition, excipients such as solubilizers, surfactants, buffers, tonicity agents, penetration enhancers, mucoadhesives, viscosity enhancers, emulsion stabilizers, etc., can be added at concentrations suitable for ophthalmic formulations.

[0113] The delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and Rho kinase inhibitor of the present invention may be administered locally to the eye of a subject in need of treatment or prevention of IOP. Methods for topical administration include eye droppers and other suitable devices for applying eye drops to the surface of the eye. The order in which the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and netarsudil or a pharma-ceutically acceptable salt thereof may be administered may vary. In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof is administered before administration of the Rho kinase inhibitor. In another embodiment, the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof is administered after administration of the Rho kinase inhibitor. In another embodiment, the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof is administered simultaneously with administration of the Rho kinase inhibitor. In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor may be formulated into a single pharmaceutical formulation.

[0114] Depending on the condition of the subject, the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor may each be administered multiple times over a period of time. For example, the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor may be administered every day, every 2 days, every 3 days, or every 5 days. In another embodiment, the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor may be administered once a day or twice a day. The dosage and duration of the delta-9-tetrahydrocannabinol amino acid ester or its derivative and the Rho kinase inhibitor may vary depending on the condition of the subject. In one embodiment, the delta-9-tetrahydrocannabinol amino acid ester or its derivative is administered once a day for at least 5 days, or once a day for 10 days or more.

[0115] Also disclosed herein are methods for treating or reducing IOP in a subject, the methods comprising at least administering to the subject the disclosed formulations and / or nanoemulsions. In one embodiment, performing the method can result in a reduction in IOP in the subject of about 15% to about 35%, or about 15, 20, 25, 30, or about 35%, or a combination of any of the aforementioned values, or a range encompassing any of the aforementioned values, compared to the IOP in the subject before performing the method. In another embodiment, after performing the method, the reduction in IOP remains at least about 15%. In another embodiment, performing the method can result in a reduction in IOP in the subject of about 5 to about 10 mmHg, or about 5, 6, 7, 8, 9, or about 10 mmHg, or a combination of any of the aforementioned values, or a range encompassing any of the aforementioned values, compared to the IOP in the subject before performing the method. In one embodiment, the maximum reduction in IOP relative to the IOP before performing the method occurs from about 4 hours to about 7 hours, or about 4, 5, 6, or about 7 hours, or a combination of any of the preceding values, or a range encompassing any of the preceding values, after performing the method. In one embodiment, the reduction in IOP occurs in the eye to which the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor are administered, or in the contralateral eye, or both.

[0116] As demonstrated in the Examples, the combination of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof with a Rho kinase inhibitor is more effective at lowering IOP than the use of the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor independently. In one embodiment, the combination of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof with a Rho kinase inhibitor can increase IOP reduction by up to 40%, up to 50%, or up to 60% compared to the use of the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor alone.

[0117] Aspects The present disclosure can be described according to the following numbered aspects, which should not be confused with the claims.

[0118] Embodiment 1. A method for the treatment or prevention of elevated intraocular pressure (IOP) in a subject in need thereof, comprising administering to the subject a delta-9-tetrahydrocannabinol amino acid ester or a derivative thereof and a Rho kinase inhibitor.

[0119] The method of embodiment 1, wherein the Rho kinase inhibitor is netarsudil or a pharma- ceutically acceptable salt thereof.

[0120] Aspect 3. A delta-9-tetrahydrocannabinol amino acid ester having structure I [ka] R 1 3. The method of embodiment 1 or 2, wherein comprises valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine, 4(4-aminophenyl)butyric acid, or a salt thereof.

[0121] Aspect 4. A derivative of delta-9-tetrahydrocannabinol amino acid ester has the structure II [ka] and n is an integer from 1 to 9.

[0122] Embodiment 5. The method of embodiment 1 or 2, wherein the derivative of delta-9-tetrahydrocannabinol amino acid ester is delta-9-tetrahydrocannabinol-valine-hemisuccinic acid.

[0123] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof comprises a component of a nanoemulsion.

[0124] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor are each administered locally to the eye of the subject.

[0125] Embodiment 8. The method of any one of embodiments 1 to 7, wherein the method is performed once a day for at least five days.

[0126] Embodiment 9. A nanoemulsion comprising a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, an ophthalmically suitable oil, an ophthalmically suitable surfactant, and water.

[0127] Aspect 10. A delta-9-tetrahydrocannabinol amino acid ester having structure I [ka] R 1 10. The nanoemulsion of embodiment 9, wherein comprises valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine, 4(4-aminophenyl)butyric acid, or a salt thereof.

[0128] Aspect 11. A derivative of delta-9-tetrahydrocannabinol amino acid ester has the structure II [ka] 10. The nanoemulsion according to embodiment 9, having the formula:

[0129] Embodiment 12. A nanoemulsion according to embodiment 9 or 10, wherein the derivative of delta-9-tetrahydrocannabinol amino acid ester is delta-9-tetrahydrocannabinol-valine-hemisuccinic acid.

[0130] Embodiment 13. An emulsion according to any one of embodiments 9 to 12, wherein the nanoemulsion comprises from about 0.01% w / v to about 2% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof.

[0131] Embodiment 14. A nanoemulsion according to any of embodiments 9 to 13, wherein the ophthalmically suitable oil comprises castor oil, cottonseed oil, soybean oil, sesame oil, or any combination thereof.

[0132] Embodiment 15. A nanoemulsion according to any of embodiments 9 to 14, wherein the nanoemulsion comprises from about 1% to about 10% w / v of an ophthalmically suitable oil.

[0133] Embodiment 16. A nanoemulsion according to any of embodiments 9 to 15, wherein the ophthalmically suitable surfactant comprises a non-ionic surfactant.

[0134] Embodiment 17. A nanoemulsion according to any of embodiments 9 to 16, wherein the ophthalmologically suitable surfactant comprises a poloxamer, a polysorbate, or any combination thereof.

[0135] Embodiment 18. The nanoemulsion of embodiment 17, wherein the nanoemulsion comprises from about 0.01% w / v to about 1% w / v of poloxamer and from about 0.5% w / v to about 5% w / v of polysorbate.

[0136] Embodiment 19. A nanoemulsion according to any of embodiments 9 to 18, further comprising an ophthalmologically suitable polymer.

[0137] Embodiment 20. The nanoemulsion of embodiment 19, wherein the ophthalmically suitable polymer comprises crosslinked polyacrylic acid.

[0138] Embodiment 21. A nanoemulsion according to any of embodiments 9 to 20, further comprising an ophthalmologically suitable polyol.

[0139] Aspect 22. The nanoemulsion of aspect 21, wherein the ophthalmically suitable polyol comprises glycerin.

[0140] Embodiment 23. A nanoemulsion according to any of embodiments 9 to 22, further comprising an ophthalmologically suitable ethoxylated tocopherol or tocotrienol.

[0141] Aspect 24. A nanoemulsion according to aspect 23, wherein the ophthalmically suitable ethoxylated tocopherol or tocotrienol is D-alpha-tocopherol polyethylene glycol, vitamin E polyethoxylated succinate, or any combination thereof.

[0142] Aspect 25. The nanoemulsion of aspect 23 or 24, wherein the nanoemulsion comprises from about 0.0001% w / v to about 0.01% w / v of an ophthalmically suitable ethoxylated tocopherol or tocotrienol.

[0143] 26. About 0.01% w / v to about 2% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof. about 1% to about 10% w / v of an ophthalmically suitable oil; from about 0.51% w / v to about 6% w / v of an ophthalmically suitable surfactant; about 0.1% w / v to about 2% w / v of an ophthalmically suitable polymer; about 1% to about 5% w / v of an ophthalmically suitable polyol; about 0.0001% w / v to about 0.01% w / v of an ophthalmically suitable ethoxylated tocopherol or tocotrienol, and water, A nanoemulsion comprising:

[0144] Embodiment 27 The nanoemulsion of any of embodiments 9 to 26, further comprising a Rho kinase inhibitor.

[0145] Embodiment 28 The nanoemulsion of embodiment 27, wherein the Rho kinase inhibitor is netarsudil or a pharma- ceutically acceptable salt thereof.

[0146] Embodiment 29. The nanoemulsion of embodiment 27 or 28, comprising about 0.005% w / v to about 0.05% w / v of a Rho kinase inhibitor.

[0147] Aspect 30. A nanoemulsion according to any one of aspects 9 to 29, having an average droplet size of about 200 nm to about 250 nm.

[0148] Aspect 31. A nanoemulsion according to any one of aspects 9 to 30, having a polydispersity index of about 0.15 to about 0.25.

[0149] Aspect 32. A nanoemulsion according to any one of aspects 9 to 31, having a zeta potential of about -20 mV to about -60 mV.

[0150] Embodiment 33 A method for treating or preventing elevated IOP, comprising administering to a subject a nanoemulsion according to any of embodiments 9 to 32. EXAMPLES

[0151] The following examples are presented to provide those skilled in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, are intended to be purely illustrative of the disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in ° C. or at ambient temperature, and pressure is at or near atmospheric pressure.

[0152] Development Overview The present series of studies was conducted to compare the IOP-lowering efficacy of latanoprost, netarsudil (Rhopressor®) formulations (Table 3) and THC-VHS-NEC formulations (Tables 4 and 5) in 28-week-old male pigmented (Dutch Belted; DB) rabbits with an average body weight of 2.0±0.3 kg. Rabbits were divided into three groups. Each group received a single formulation (THC-VHS-NEC, latanoprost or Rhopressor®) for the first 5 days and the two formulations combined for the next 5 days. The second formulation was administered 15 minutes after the first formulation. The treatment protocol is summarized in Table 2. [Table 2]

[0153] IOP was measured on days 1, 3, and 5 while rabbits were receiving single formulations, and on days 6, 8, and 10 while receiving combination treatment. All doses were administered topically (50 μL) once daily to the left eye, while the contralateral eye (right eye) was left untreated. [Table 3] [Table 4] [Table 5]

[0154] Single treatment multi-day application study IOP profiles after multiple day (QD, 5 days) exposure to a single formulation in pigmented DB rabbits are presented in Figures 1-26. Results include:

[0155] The THC-VHS-NEC (Figures 15-18) formulation demonstrated a mean maximum reduction in IOP of approximately 27.5±2.1% and maintained a mean reduction of 21.1±1.6% from 30 to 540 minutes. IOP returned to baseline within 24 hours. Time to maximum reduction in IOP varied from 60, 420, and 240 minutes (Days 1, 3, and 5), with mean maximum IOP decreasing by 7.2-6.0 mmHg over the 5 days. See also Table 6 below.

[0156] Rhopressor® (FIGS. 19-22) demonstrated a mean maximum reduction in IOP of approximately 30.6±1.4% and maintained a mean reduction of 25.4±2.9% from 30 minutes to 540 minutes. IOP returned to baseline within 24 hours. The maximum reduction in IOP occurred between 180 and 240 minutes. See also Table 7 below.

[0157] Latanoprost (Figures 23-26) demonstrated a mean maximum reduction in IOP of approximately 21.3±2.1% and maintained a mean reduction in IOP of 19.4±1.9% from 30 to 420 minutes. IOP returned to baseline within 480 minutes. Maximum reductions in IOP occurred at 60, 90, and 240 minutes on days 1, 3, and 5. Maximum IOP decreased by 6.0-4.7 mmHg over the 5 days. See also Table 8 below. [Table 6] [Table 7] [Table 8]

[0158] In terms of maximum IOP reduction, Rhopressa® was superior to the THC-VHS-NEC formulation. However, both showed a duration of action of at least 9 hours, with IOP remaining approximately 20% lower than baseline 9 hours after administration. Both Rhopressa® and THC-VHS-NEC formulations performed better than latanoprost in terms of maximum IOP reduction and duration of action. All formulations produced a corresponding IOP reduction in the contralateral eye. No irritation or redness (visual) was observed in any of the rabbits' eyes in the various treatment groups. The results are summarized in Table 9. [Table 9]

[0159] Combination administration multiple day application test Data from the co-administration studies are presented in Figures 27-54 (Figures 43-46: THC-VHS-NEC + Rhopressa®; Figures 47-50: Rhopressa® + Latanoprost; Figures 51-54: Latanoprost + THC-VHS-NEC). Comparative profiles from these studies are presented in Figures 27-52.

[0160] Dosing was topical, with each treatment applied in 50 μL. The left eye (treated eye) received a second dose of drug 15 minutes after the first. The right eye (contralateral eye) remained untreated. Results include:

[0161] When the THC-VHS-NEC formulation was followed by Rhopressor® (Figures 43-46), the mean maximum reduction in IOP was about 32.4±2.6%, and maintained a mean reduction of 26.5±4.4% from 30 to 540 minutes. IOP returned to baseline within 24 hours. The maximum reduction in IOP occurred between 240 and 420 minutes, but with a reduction in pressure intensity of 8.6-7.0 mmHg over the course of 5 days. However, at 30 minutes, IOP was already 20% lower than baseline on days 6 and 8, and by 90 minutes on day 10. Thus, the IOP reduction profile of the combination was better than either the THC-VHS-NEC formulation or Rhopressor® alone. See also Table 10 below.

[0162] When Rhopressa® was followed by Latanoprost (Figures 47-50), the mean maximum reduction in IOP was about 22.7±2.9%, and maintained a mean reduction of 19.0±2.1% from 30 to 540 minutes. The time to maximum IOP reduction showed some variation over the 3 days, being 180, 420, and 120 minutes on days 6, 8, and 10, respectively. A maximum IOP reduction of 25.7±0.8% was observed on day 6, compared with 22.5±1.3% and 19.9±2.6% on days 8 and 10, respectively. Thus, the combination was similar to Latanoprost alone, but the effect was significantly inferior to Rhopressa® alone. The duration of action was at least 540 minutes, at which point IOP remained about 15% below baseline, returning to baseline by 24 hours. Thus, the duration of action of Latanoprost was extended by combination with Rhopressa®, but Rhopressa® alone was better than the combination with Latanoprost. See also Table 11 below.

[0163] When the THC-VHS-NEC formulation was administered following latanoprost (Figures 51-54), the maximum IOP reduction was approximately 21.6±2.9%, with a mean reduction of 18.1±2.1% maintained from 30 to 480 minutes. The maximum IOP reduction occurred around 90 minutes on all three days measured. However, a larger maximum IOP reduction was observed on day 6, 26.1±2.6%, on day 8, 19.9±1.3%, and on day 10, 18.7±2.0%. IOP returns to baseline at 540 minutes. The IOP reduction profile of this combination was similar to that of latanoprost alone. Thus, activity of THC-VHS-NEC is not evident in combination with latanoprost. See also Table 12 below. [Table 10] [Table 11] [Table 12]

[0164] Thus, latanoprost reduced the efficacy of both THC-VHS-NEC and Rhopressa® when combined. This may be due to changes in excretion profile and / or changes in metabolism. Overall, the combination of THC-VHS-NEC formulation with Rhopressa® was the most effective in terms of both active time and maximum IOP reduction compared to all other single and combined treatment studies. The results are summarized in Table 13 below. [Table 13]

[0165] Overall, the IOP-lowering profile of THC-VHS-NEC in Dutch Belted rabbits was similar to that of the commercially available Rhopressa® in terms of duration of action, and superior to latanoprost in terms of both potency and duration of action. The THC-VHS-NEC formulation, followed by the Rhopressa® formulation, was the most effective of all formulations and combinations tested in terms of IOP-lowering profile.

Claims

1. A pharmaceutical comprising a delta-9-tetrahydrocannabinol amino acid ester or a derivative thereof and a Rho kinase inhibitor for the treatment or prevention of elevated intraocular pressure (IOP).

2. The pharmaceutical composition according to claim 1, wherein the Rho kinase inhibitor is netarsudil or a pharma- ceutical acceptable salt thereof.

3. Delta-9-tetrahydrocannabinol amino acid ester has structure I 【Chemistry 1】 R 1 The pharmaceutical composition of claim 1, wherein comprises valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine, 4(4-aminophenyl)butyric acid, or a salt thereof.

4. The derivatives of delta-9-tetrahydrocannabinol amino acid esters have the structure II 【Chemistry 2】 The pharmaceutical composition according to claim 1, wherein n is an integer of 1 to 9.

5. 2. The method of claim 1, wherein the derivative of delta-9-tetrahydrocannabinol amino acid ester is delta-9-tetrahydrocannabinol-valine-hemisuccinic acid.

6. 2. The pharmaceutical of claim 1, wherein the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof comprises a component of a nanoemulsion.

7. 2. The method of claim 1, wherein the delta-9-tetrahydrocannabinol amino acid ester or derivative thereof and the Rho kinase inhibitor are each administered locally to the eye of the subject.

8. The method of claim 1, which is administered once daily for at least 5 days.

9. 1. A nanoemulsion comprising a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof, an ophthalmically suitable oil, an ophthalmically suitable surfactant, and water.

10. Delta-9-tetrahydrocannabinol amino acid ester has structure I 【Chemistry 3】 R 1 10. The nanoemulsion of claim 9, wherein comprises valine, sarcosine, leucine, glutamine, tryptophan, tyrosine, alanine, 4(4-aminophenyl)butyric acid, or a salt thereof.

11. The derivatives of delta-9-tetrahydrocannabinol amino acid esters have the structure II 【Chemistry 4】 10. The nanoemulsion of claim 9, wherein n is an integer from 1 to 9.

12. 10. The nanoemulsion of claim 9, wherein the derivative of delta-9-tetrahydrocannabinol amino acid ester is delta-9-tetrahydrocannabinol-valine-hemisuccinic acid.

13. 10. The nanoemulsion of claim 9, wherein the nanoemulsion comprises about 0.01% w / v to about 2% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof.

14. 10. The nanoemulsion of claim 9, wherein the ophthalmically suitable oil comprises castor oil, cottonseed oil, soybean oil, sesame oil, or any combination thereof.

15. 10. The nanoemulsion of claim 9, wherein the nanoemulsion comprises about 1% to about 10% w / v of an ophthalmically suitable oil.

16. 10. The nanoemulsion of claim 9, wherein the ophthalmically suitable surfactant comprises a non-ionic surfactant.

17. 10. The nanoemulsion of claim 9, wherein the ophthalmically suitable surfactant comprises a poloxamer, a polysorbate, or any combination thereof.

18. 18. The nanoemulsion of claim 17, wherein the nanoemulsion comprises about 0.01% w / v to about 1% w / v of poloxamer and about 0.5% w / v to about 5% w / v of polysorbate.

19. 10. The nanoemulsion of claim 9, further comprising an ophthalmologically suitable polymer.

20. 20. The nanoemulsion of claim 19, wherein the ophthalmically suitable polymer comprises crosslinked polyacrylic acid.

21. 10. The nanoemulsion of claim 9, further comprising an ophthalmologically suitable polyol.

22. 22. The nanoemulsion of claim 21 , wherein the ophthalmically suitable polyol comprises glycerin.

23. 10. The nanoemulsion of claim 9, further comprising an ophthalmologically suitable ethoxylated tocopherol or tocotrienol.

24. 24. The nanoemulsion of claim 23, wherein the ophthalmically suitable ethoxylated tocopherol or tocotrienol comprises D-alpha-tocopherol polyethylene glycol, vitamin E polyethoxylated succinate, or any combination thereof.

25. 24. The nanoemulsion of claim 23, wherein the nanoemulsion comprises from about 0.0001% w / v to about 0.01% w / v of an ophthalmically suitable ethoxylated tocopherol or tocotrienol.

26. About 0.01% w / v to about 2% w / v of a delta-9-tetrahydrocannabinol amino acid ester or derivative thereof; about 1% to about 10% w / v of an ophthalmically suitable oil; from about 0.51% w / v to about 6% w / v of an ophthalmically suitable surfactant; about 0.1% w / v to about 2% w / v of an ophthalmically suitable polymer; about 1% to about 5% w / v of an ophthalmically suitable polyol; from about 0.0001% w / v to about 0.01% w / v of an ophthalmically suitable ethoxylated tocopherol or tocotrienol, and water, A nanoemulsion comprising:

27. 27. The nanoemulsion of claim 26, further comprising a Rho kinase inhibitor.

28. 28. The nanoemulsion of claim 27, wherein the Rho kinase inhibitor is netarsudil or a pharma- ceutically acceptable salt thereof.

29. 28. The nanoemulsion of claim 27, comprising about 0.005% w / v to about 0.05% w / v of a Rho kinase inhibitor.

30. 30. The nanoemulsion of any one of claims 9 to 29, having an average droplet size of about 200 nm to about 250 nm.

31. 30. The nanoemulsion of any of claims 9 to 29, having a polydispersity index of about 0.15 to about 0.

25.

32. 30. The nanoemulsion of any one of claims 9 to 29, having a zeta potential of about -20 mV to about -60 mV.

33. 30. A medicament for treating or preventing elevated IOP comprising a nanoemulsion according to any one of claims 9 to 29.

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