New uses and methods of treatment

Abstract

The present invention provides a pharmaceutical composition comprising a reverse thermoreversible hydrogel as an active ingredient, the pharmaceutical composition being for administration to the eye of a mammalian subject. In particular, the present invention relates to a pharmaceutical composition for use in the ophthalmic treatment of dry eye disease and a method for the ophthalmic treatment of dry eye disease.

Description

Technical Field

[0001] The present invention is in the field of pharmaceutical compositions for administration in the eye of a mammalian subject. In particular, the present invention relates to pharmaceutical compositions for use in the ophthalmic treatment of dry eye disease and methods for the ophthalmic treatment of dry eye disease. Background Art

[0002] According to the nonprofit Tear Film & Ocular Surface Society, dry eye disease (DED) (interchangeably referred to as "dry eye syndrome") is a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis and associated ocular symptoms, with tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities playing an etiological role (Craig et al. (2017), The Ocular Surface 15:802-812).

[0003] DED is common in populations worldwide, but prevalence varies between countries, primarily due to differences in definitions and patient inclusion criteria (Stapleton et al. (2017), The Ocular Surface 15:334-365).

[0004] Available treatments for dry eye disease are reviewed in Gomes and Santo (2019), The Ocular Surface 17:9-19 (see Table 1).

[0005] Sustained-release formulations of reverse thermosensitive reversible gels based on block copolymers and associative gelling agents are disclosed, for example, in US Pat. No. 9,592,295. While many different applications and uses of the disclosed hydrogels are given in US Pat. No. 9,592,295, all of these applications and uses rely on the use of the hydrogel as a carrier or vehicle for delivering and releasing active ingredients that are disclosed outside of the actual hydrogel. US Pat. No. 9,592,295 discloses any use of the gel itself as an active ingredient, nor does it suggest that it can itself have a therapeutic effect.

[0006] A Phase II clinical trial, identified as NCT03821415, investigated the use of the hydrogel disclosed in US Pat. No. 9,592,295 as a drug delivery vehicle or carrier for the active ingredient 17β-estradiol-3-phosphate in the treatment of dry eye disease. In the setting of this clinical trial, a hydrogel without the active ingredient was used as a placebo, based on the understanding that the hydrogel formulation itself would not have any therapeutic effect. The results of the clinical trial in question have not yet been reported.

[0007] There is a need in the art for convenient and effective formulations for treating dry eye in mammalian subjects in need thereof, as well as novel methods of treating such conditions. Summary of the Invention

[0008] The object of the present invention is to satisfy this need. Other objects will be clear to those skilled in the art from this disclosure.

[0009] Therefore, in a first aspect, the present disclosure provides a pharmaceutical composition comprising as an active ingredient a reverse thermoreversible hydrogel, wherein the hydrogel comprises, by weight percentage of the total composition:

[0010] - about 5% to 25% of a water-soluble block copolymer comprising at least two polyethylene oxide blocks and at least one polypropylene oxide block; and

[0011] - about 0.05% to 10% of at least one associative gelling agent having a water solubility of less than 0.5 g / 100 ml at 20° C. and capable of forming a water-soluble intermolecular complex with the water-soluble block copolymer in water;

[0012] wherein the composition does not contain any additional active ingredients,

[0013] The pharmaceutical composition is used for treating dry eye disease in an eye of a mammalian subject in need thereof by topical administration.

[0014] By using a reverse thermoreversible hydrogel as defined herein, it is possible to provide a pharmaceutical composition that is liquid at normal room temperature but forms a gel at the elevated temperatures of the mammalian body (e.g., 32° C. and above). The beneficial gelling properties of the pharmaceutical composition facilitate its application to the desired ocular environment of a subject. In particular, these properties allow for convenient storage, handling, and administration of the composition in liquid form at room temperature, while upon encountering the elevated temperatures associated with the eye, the composition forms a hydrogel with beneficial properties.

[0015] Evidence of the effects of such hydrogels on dry eye symptoms and objective endpoints is provided by the following examples. In the context of a clinical trial designed to test the hydrogel as a carrier for an added active ingredient, the hydrogel was unexpectedly shown to be effective, even in the absence of the additional active ingredient. Furthermore, the effects observed in this study using a hydrogel placebo were rapid, with an onset of only 30 days. While the onset of action was not as rapid as with the study product with added active ingredient, the benefits were still significant. The trials also demonstrated that the hydrogel was safe to use.

[0016] Suitable hydrogel compositions are those described in US 9592295, which is hereby incorporated by reference. In one embodiment, the water-soluble block copolymer of the hydrogel is a block copolymer having the general formula HO-(EO) a -(PO) b -(EO) a -H triblock copolymer, wherein (EO) a It is polyethylene oxide block, (PO) b is a polypropylene oxide block, a is in the range of 50 to 150, and b is in the range of 35 to 70. In a specific embodiment, in such a triblock copolymer, a is about 101 and b is about 56. Such copolymers as disclosed herein and in US 9592295 are generally referred to as "poloxamers", and a specific embodiment in which a is about 101 and b is about 56 is referred to as poloxamer 407.

[0017] The hydrogel composition further comprises at least one associative gelling agent. In one embodiment, the at least one associative gelling agent is selected from the group consisting of oxyalkylated fatty alcohols, esters of oxyalkylated fatty alcohols, oxyalkylated alkyl alcohols, esters of oxyalkylated alkyl alcohols, oxyalkylated alkylaryl alcohols, aliphatic hydroxycarboxylic acids, esters of aliphatic hydroxycarboxylic acids, aromatic hydroxycarboxylic acids, esters of aromatic hydroxycarboxylic acids, poly(hydroxycarboxylic acids), oxyalkylated sorbitol esters, oxyalkylated triglycerides, oxyalkylated glycerides, esters of oxyalkylated sorbitol, polyol esters, sorbitol esters, and mixtures thereof. In a more particular embodiment, the at least one associative gelling agent is an ester of an oxyalkylated fatty alcohol. Contemplated embodiments of such oxyalkylated fatty alcohols are, for example, selected from the group consisting of di-PPG-2 myreth-9 adipate, di-PPG-2 myreth-10 adipate, and di-PPG-2 myreth-11 adipate. In a particular embodiment, the oxyalkylated fatty alcohol is di-PPG-2 myreth-10 adipate.

[0018] Suitable formulations for hydrogels can be determined by those skilled in the art of pharmaceutical formulations. Suitably, the pharmaceutical compositions disclosed herein are formulated in a manner that is easily topically applied to the eyes of mammalian subjects. Therefore, in one embodiment, the composition is administered in the form of eye drops. In one such embodiment, it is provided in a single-drop applicator, dispenser, or bottle. In another such embodiment, it is provided in a multi-drop applicator, dispenser, or bottle. In another embodiment, the composition is provided as a spray. In yet another embodiment, the composition is provided as an eyewash or in any other manner suitable for application to the ocular environment. In one embodiment, the composition is formulated as eye drops and administered as eye drops. As explained above, the reverse thermoreversible property of the composition ensures that it is in liquid form when refrigerated or at room temperature. This allows, for example, a drop of liquid to be administered into the eye. After administration in this manner, the composition will gel when the higher temperature in the eye is reached.

[0019] In the clinical trials reported in the examples that follow, the effects of the hydrogel itself were observed when administered twice daily. In one embodiment of the uses and methods of the present disclosure, the composition is administered twice daily or less frequently (e.g., once daily or less frequently). In a particular embodiment, the composition is administered twice daily. In another particular embodiment, the composition is administered once daily.

[0020] Throughout this disclosure, the use of the term dry eye is intended to broadly encompass any form of condition that exhibits dry eye pathology, whether or not caused by reduced tear flow, and regardless of the underlying cause. For an overview of all the various conditions and underlying causes contemplated within the scope of this disclosure, see Craig et al. (2017, supra). Figure 1 . In the most general sense of the present disclosure, the mammalian subject to be treated is not limited to any particular species, sex, age group, or other classification. Thus, in one embodiment, the mammalian subject is male. In another embodiment, the mammalian subject is female. In one embodiment, the subject is human. In a particular such embodiment, the subject is male. In another particular such embodiment, the subject is female. In a preferred embodiment, dry eye is a result of hormonal changes associated with menopause in women. Thus, in one such embodiment, the mammalian subject to be treated is a woman in menopause. In another such embodiment, the mammalian subject to be treated is a postmenopausal woman. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1is a graph showing the evolution of the Schirmer Type II test score ("Schirmer FAS") for study groups 1-4 during the course of the clinical trial described in Example 2. Group 1: solid line. Group 2: dotted line. Group 3: short dash line. Group 4: long dash line.

[0022] Figure 2 is a graph showing the evolution of TFBUT ("tBUT") for study groups 1-4 during the course of the clinical trial described in Example 2. Group 1: solid line. Group 2: dotted line. Group 3: short dash line. Group 4: long dash line. Example

[0023] Example 1

[0024] Preparation of reverse thermoreversible hydrogels

[0025] Reverse thermoreversible hydrogels were prepared using the ingredients listed below in the weight percentages.The thermogelling formulation was based on Poloxamer 407 and Di-PPG-2 Myreth-10 Adipate as thermogelling agents.

[0026]

[0027] Poloxamer 407 is dissolved in phosphate buffer at low temperatures, after which the temperature is raised to room temperature and di-PPG-2 myreth-10 adipate is added, resulting in a weight ratio of 78.1:21.9. The pH is then adjusted to a range of 7.2 to 7.6 by adding 1M HCl and / or 1M NaOH. The resulting formulation is a mucoadhesive hydrogel suitable for treating dry eye disease by topical application to the eye. The hydrogel prepared above is designated "IntelliGel" in the following examples and is used as a carrier or vehicle for additional agents intended as active ingredients.

[0028] Example 2

[0029] Clinical trial design of the active ingredient 17β-estradiol-3-phosphate in IntelliGel as a carrier

[0030] The purpose of the clinical trial was to test the effect of 0.05% and 0.1% 17β-estradiol-3-phosphate ("E3P") on dry eye disease when delivered via slow release of the IntelliGel hydrogel prepared in Example 1 as a vehicle. The drug product tested, comprising E3P in IntelliGel, is designated RP101, and the clinical trial design is described at clinicaltrials.gov under the identifier NCT03821415.

[0031] Briefly, the trial was a multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase II study in which the ophthalmic formulation RP101 was tested versus IntelliGel alone (as placebo).

[0032] Research group

[0033] The study population consisted of 104 participants who met the inclusion criteria list, which included:

[0034] - Gender and menopause: Postmenopausal women; postmenopausal status is defined as the last menstrual period being at least 3 years prior to screening

[0035] - Dry Eye Disease: Patients with moderate to severe dry eye syndrome

[0036] - Anesthesia of the worse eye (study eye) in Schirmer test ≤ 7 mm / 5 min

[0037] - Tear film breakup time: TFBUT ≤ 10 seconds in the worse eye (study eye)

[0038] -Visual acuity: Corrected visual acuity ≥20 / 200 in each eye

[0039] - Symptoms: At least 2 typical dry eye symptoms since at least 3 months prior to screening: foreign body sensation, burning / stinging, redness, tearing, pain, itching, blurred vision, photophobia, eyelid swelling, water and mucus discharge

[0040] Of the 104 enrolled participants, 77 completed the entire trial.

[0041] Research Products

[0042] The products tested in the trial were:

[0043] Test 1 (T1): RP101 0.05%

[0044] 0.05% w / w E3P in IntelliGel

[0045] Test 2 (T2): RP101 0.1%

[0046] 0.1% w / w E3P in IntelliGel

[0047] Placebo (P): IntelliGel according to Example 1 without E3P

[0048] Treatment group

[0049] The subjects were randomly divided into four equal groups and received one of the treatments shown in Table 1 below for 90 consecutive days.

[0050] Table 1

[0051] Dosage regimen Morning night Group 1 T1 T1 Group 2 T2 P Group 3 T2 T2 Group 4 P P

[0052] Purpose

[0053] The primary objective of the study was to establish an effective dose / dosage regimen of RP101 applied once daily (qd) or twice daily (bid) with RP101 ophthalmic sterile solution or matching placebo (vehicle) for 3 months in postmenopausal women with moderate to severe dry eye.

[0054] Secondary objectives of the study were to evaluate the safety and tolerability of treatment; to assess tear film osmolarity and measure corneal thickness as exploratory variables in a specific substudy; and to evaluate the pharmacokinetics (PK) of serum 17-β-estradiol after the first and last doses (PK substudy).

[0055] end

[0056] The primary endpoint was clinical efficacy during and at the end of treatment with RP101 or matching placebo, measured using a Schirmer II test (under anesthesia). Secondary endpoint parameters for efficacy included:

[0057] - Visual Analog Scale (VAS) for ocular intolerance (foreign body sensation, burning / stinging, itching, pain, stickiness, blurred vision, redness, tearing, eyelid swelling, and photophobia)

[0058] -Symptom Assessment of Dry Eyes (SANDE)

[0059] -Visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] chart)

[0060] -Slit lamp examination (SLE)

[0061] -Tear film osmolarity (selected substudies only)

[0062] -Tear film break-up time (TFBUT)

[0063] - Fundus ophthalmoscopy

[0064] -Corneal fluorescein staining

[0065] - Corneal pachymetry (specific substudy only)

[0066] -Frequency of artificial tears (rescue medication) instillation during the treatment phase (ie, number of drops instilled per day)

[0067] Schirmer Type II Test

[0068] This test is performed to measure basal aqueous tear production after instillation of preservative-free anesthetic eye drops. Both eyes can be tested simultaneously. Test strips. The test is performed in a dimly lit room. While the patient is looking upward, gently and temporarily pull the lower eyelid downward. Insert the rounded curved end of the sterile test strip into the inferior conjunctival sac, one-third beyond the temporal lower eyelid margin. The test is performed without directly touching the Schirmer test strip with a finger to avoid contamination from skin oils. Instruct the patient to gently close both eyes. After 5 minutes, remove the test strip and measure the tear absorption length on the test strip (mm / 5min). Record the wetting distance of each eye after 5 minutes.

[0069] Tear film breakup time (TFBUT)

[0070] The TFBUT is measured by determining the time it takes for tear breakup to occur and is performed after instilling a sodium fluorescein solution into the inferior conjunctival fornix of each eye. The patient is instructed to blink several times to allow the fluorescein to completely mix with the tear film. To achieve maximum fluorescence, the examiner waits approximately 30 seconds after instillation before evaluating the TFBUT. With the help of a slit lamp with 10x magnification using cobalt blue illumination, the examiner monitors the integrity of the tear film, noting the time it takes from the time the eye is opened after the last blink to the formation of a cavity (a clear space in the tear film). The TFBUT is measured twice during the first minute after the instillation of fluorescein. If the two readings differ by more than 2 seconds, a third reading is taken. The average of the two or three measurements is recorded as the TFBUT value.

[0071] Example 3

[0072] The placebo group showed unexpected efficacy

[0073] The clinical trial described in Example 2 was conducted and the results were evaluated. When the results were analyzed, it was unexpectedly discovered that Group 4, which was treated only with a placebo, demonstrated results on objective endpoints, indicating that even without the addition of E3P as an active ingredient, the placebo (i.e., the IntelliGel hydrogel prepared in Example 1) itself had clinical efficacy. Furthermore, this efficacy was characterized by a rapid onset of action, with clear effects demonstrated after only 30 days of study.

[0074] Schirmer Type II Test

[0075] The Schirmer test results for all four study groups are shown in Figure 1 As can be seen from the figure, Study Group 4, which received only IntelliGel placebo, exhibited scores comparable to the groups that received the investigational product with varying concentrations of E3P.

[0076] Tear film breakup time (TFBUT)

[0077] The TFBUT test results for all four study groups are shown in Figure 2 As can be seen from this figure, Study Group 4, which received only IntelliGel placebo, demonstrated scores comparable to those of the groups that received the study product with varying concentrations of E3P. In fact, by Day 90 of the study, the group receiving placebo demonstrated the highest TFBUT scores of all study groups.

[0078] in conclusion

[0079] The results of the clinical trial described in Example 2 show that not only does the investigational product RP101 demonstrate consistent, significant benefits on objective measures of dry eye, but these benefits are also seen in the placebo group. Furthermore, both the investigational product and the placebo were safe to use. Taken together, these results demonstrate that the observed benefits are achieved independently of the hydrogel itself as the "active ingredient."

Claims

1. A pharmaceutical composition comprising a reverse thermoreversible hydrogel as an active ingredient, wherein the hydrogel comprises, by weight percentage of the total composition: -5%-25% Poloxamer 407; and -0.05%-10% di-PPG-2 myreth-10 adipate; wherein the composition does not contain any additional active ingredients, The pharmaceutical composition is used for treating dry eye disease in an eye of a mammalian subject in need thereof by topical administration.

2. The pharmaceutical composition of claim 1, wherein the mammalian subject is a human patient.

3. The pharmaceutical composition according to claim 2, wherein the patient is a woman.

4. The pharmaceutical composition according to claim 3, wherein the woman is selected from the group consisting of a woman in menopause and a woman in postmenopause.

5. Use of a composition for the preparation of a medicament for treating dry eye disease in a mammalian subject in need thereof by topical administration to the eye of the subject, the composition comprising as an active ingredient a reverse thermoreversible hydrogel, the hydrogel comprising, by weight percentage of the total composition: -5%-25% Poloxamer 407; and -0.05%-10% di-PPG-2 myreth-10 adipate; The composition does not contain any additional active ingredients.

6. The use according to claim 5, wherein the mammalian subject is a human patient.

7. The use according to claim 6, wherein the patient is a woman.

8. The use according to claim 7, wherein the woman is selected from the group consisting of a woman in menopause and a woman in postmenopause.

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