New uses and methods of treatment

Abstract

The present invention relates to pharmaceutical compositions comprising a reversible thermoreversible hydrogel as an active ingredient for administration to the eye of a mammalian subject, and in particular to pharmaceutical compositions and methods for use in the ophthalmic treatment of dry eye disease.

Description

[Technical Field]

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

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

[0003] DED is widespread in human populations worldwide, but prevalence varies between countries, primarily due to differences in definitions and 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] Slow-release formulations based on reversible thermoreversible gels of block copolymers and associative gelators are disclosed, for example, in U.S. Patent No. 9,592,295. While many different applications and uses for the disclosed hydrogels are given in U.S. Patent No. 9,592,295, all of these applications and uses rely on the use of the hydrogel as a carrier or vehicle for the delivery and release of active ingredients, which are disclosed external to the actual hydrogel. There is no disclosure in U.S. Patent No. 9,592,295 of any use of the gel itself as an active ingredient, and there is no indication that it may have a therapeutic effect in itself.

[0006] A Phase II clinical trial identified as NCT03821415 investigated the use of a hydrogel disclosed in US9592295 as a drug delivery vehicle or carrier for the active ingredient 17β-estradiol-3-phosphate in the treatment of dry eye disease. In the context of this clinical trial, a hydrogel without the active ingredient was used as a placebo, i.e., with the understanding that the hydrogel formulation itself would not have any therapeutic effect. The results of the clinical trial in question were not reported.

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

[0008] Meeting this need is an object of the present invention. Other objects will be apparent to those skilled in the art from this disclosure.

[0009] In a first aspect, the present disclosure provides a pharmaceutical composition, the pharmaceutical composition comprising a reversible thermoreversible hydrogel as an active ingredient, the hydrogel comprising, in weight percent of the total composition:

[0010] - about 5-25% of a water-soluble block copolymer containing at least two blocks of polyethylene oxide and at least one block of polypropylene oxide; 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 in water with said water-soluble block copolymer; Including,

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

[0013] For use in treating dry eye disease by topical administration to the eye of a mammalian subject in need of treatment.

[0014] The use of the reversible thermoreversible hydrogels defined herein can provide pharmaceutical compositions that are liquid at normal room temperature but form gels at higher temperatures in a mammalian body, such as 32°C or higher. The beneficial gelling properties of the pharmaceutical compositions facilitate application in the desired ocular environment of a subject. In particular, these properties allow for convenient storage, handling, and administration of the compositions in liquid form at room temperature, but form hydrogels with beneficial properties when exposed to higher temperatures relative to the eye.

[0015] Evidence of the effectiveness of the hydrogel itself on symptoms and objective endpoints in dry eye disease is provided by the following examples: In the context of a clinical trial designed to test the hydrogel as a carrier for added active ingredients, the hydrogel itself was unexpectedly shown to be effective, even in the absence of additional active ingredients.

[0016] Furthermore, the effects observed with the hydrogel placebo in this study had a rapid onset of effect in just 30 days. This provides a significant benefit, although the onset was not as rapid as with the active ingredient-added investigational drug. The study also demonstrated that the hydrogel is safe for use.

[0017] Suitable hydrogel compositions are those described in US9592295, incorporated herein by reference. In one embodiment, the water-soluble block copolymer of the hydrogel is a triblock copolymer having the general formula HO-(EO)a-(PO)b-(EO)aH, where (EO)a is a 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, a is about 101 and b is about 56 in the triblock copolymer. Copolymers such as those disclosed herein and in US9592295 are commonly known as "poloxamers," and a specific embodiment in which a is about 101 and b is about 56 is known as Poloxamer 407.

[0018] The hydrogel composition also includes at least one associative gellant. In one embodiment, the at least one associative gellant 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 sorbitan esters, oxyalkylated triglycerides, oxyalkylated glyceryl esters, esters of oxyalkylated sorbitol, polyol esters, sorbitan esters, and mixtures thereof. In a more specific embodiment, the at least one associative gellant is an ester of an oxyalkylated fatty alcohol. Contemplated embodiments of the oxyalkylated fatty alcohol are selected from the group consisting of, for example, di-PPG-2 myreth-9 adipate, di-PPG-2 myreth-10 adipate, and di-PPG-2 myreth-11 adipate. In certain embodiments, the oxyalkylated fatty alcohol is di-PPG-2 myreth-10 adipate.

[0019] Suitable formulations of hydrogels can be ascertained by those skilled in the art of pharmaceutical formulation. Suitably, the pharmaceutical compositions disclosed herein are formulated to facilitate topical administration to the eye of a mammalian subject. In one embodiment, the composition is administered in the form of eye drops. In one such embodiment, the eye drops are provided in a single-drop applicator, dispenser, or bottle. In another such embodiment, the eye drops are 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 eye wash or any other suitable means of administration to the ocular environment. In one embodiment, the composition is formulated and administered as eye drops. As explained above, the reversible thermoreversible properties of the composition ensure that it remains in liquid form during refrigeration or at room temperature. This allows, for example, for administration of drops to the eye. After administration in this manner, the composition gels upon reaching the higher temperature within the eye.

[0020] In the clinical trials reported in the following examples, the efficacy of the hydrogel itself was observed when administered twice daily. In one embodiment of the use and method aspects of the present disclosure, the composition is rarely administered more than twice daily, for example, rarely administered more than once daily. In one specific embodiment, the composition is administered twice daily. In another specific embodiment, the composition is administered once daily.

[0021] Throughout this disclosure, the use of the term dry eye disease is intended to broadly encompass any form of condition exhibiting dry eye pathology, whether or not caused by reduced tear flow, and regardless of the underlying cause. For an overview of all possible conditions and underlying causes within the scope of this disclosure, see Figure 1 in Craig et al. (2017, supra). In the most general sense of this disclosure, the mammalian subject to be treated is not limited to any particular species, sex, age group, or other category. In one embodiment, the mammalian subject is male. In another embodiment, the mammalian subject is female. In one embodiment, the subject is human. In certain such embodiments, the subject is male. In another particular such embodiment, the subject is female. In a preferred aspect, dry eye disease is the result of hormonal changes associated with menopause in women. Thus, in one such embodiment, the mammalian subject to be treated is a female who is undergoing menopause. In another such embodiment, the mammalian subject to be treated is a postmenopausal female. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 shows the evolution of Schirmer Type II test scores ("Schirmer FAS") for study groups 1-4 over the course of the clinical trial described in Example 2. Group 1: solid line. Group 2: dotted line. Group 3: short dashes. Group 4: long dashes. [Figure 2] Figure 2 shows the progression of TFBUT ("tBUT") test scores for study groups 1-4 over the course of the clinical trial described in Example 2. Group 1: solid line. Group 2: dotted line. Group 3: short dashes. Group 4: long dashes. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0023] Example 1

[0024] Preparation of reversible thermoreversible hydrogels

[0025] A reversible thermoreversible hydrogel was prepared using the following ingredients in the weight percentages indicated: This thermogelling formulation was based on poloxamer 407 and di-PPG-2 myreth-10 adipate as the thermogelling agent.

[0026] Ingredients: % (w / w) Poloxamer 407 12.9 Di-PPG-2 Mireth-10 Adipate 3.61 Sodium phosphate monobasic dihydrate 0.008 Sodium phosphate dibasic dihydrate 0.140 HCl, 1M Qs pH 7.4 NaOH, 1M Qs pH 7.4 Water for injection...Qs 100%

[0027] Poloxamer 407 was dissolved in phosphate buffer under low temperature conditions, and after warming to room temperature, di-PPG-2 myreth-10 adipate was added to prepare a 78.1:21.9 weight ratio. The pH was then adjusted to within the range of 7.2-7.6 by adding 1M HCl and / or 1M NaOH. The resulting formulation is a mucoadhesive hydrogel suitable for the treatment of dry eye disease via topical administration to the eye. The hydrogel prepared above is referred to as "Intelligel" in the following examples and was used as a carrier or vehicle for additional ingredients intended as active ingredients.

[0028] Example 2

[0029] Design of clinical trials of the active ingredient 17β-estradiol-3-phosphate in Intelligel as a carrier

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

[0031] Briefly, this study was a multicenter, randomized, double-masked, parallel-group, placebo-controlled phase II study in which the ophthalmic formulation RP101 was tested only against Intelgel as placebo.

[0032] Study population

[0033] The study population consisted of 104 participants who met a list of inclusion criteria, including: - Gender and menopausal status: Postmenopausal women; postmenopausal status was defined as the last menstrual period at least 3 years prior to screening. - Dry eye disease: Patients with moderate to severe dry eye syndrome, - Schirmer test with anesthesia of 7 mm or less in 5 minutes in the worse eye (test eye), - Tear film break-up time: TFBUT of 10 seconds or less in the worse eye (test eye), - Visual acuity: 20 / 200 or better corrected visual acuity in each eye; Symptoms: At least two typical dry eye disease symptoms from at least three months prior to screening: foreign body sensation, burning / stinging, redness, tearing, pain, itching, blurred vision, photophobia, eyelid swelling, wetness, and mucus discharge.

[0034] Of the 104 participants enrolled, 77 completed the entire study.

[0035] investigational drug

[0036] The products tested in the study were:

[0037] Test 1 (T1): RP101 0.05% 0.05% w / w E3P in Intelligel

[0038] Test 2 (T2): RP101 0.1% 0.1% w / w E3P in Intelligel

[0039] Placebo (P): Intelligel as described in Example 1, without E3P

[0040] Treatment group

[0041] Subjects were randomly assigned in four equal increments to the following treatment groups and received one of the treatments shown in Table 1 below for 90 consecutive days:

[0042] [Table 1]

[0043] the purpose

[0044] The primary objective of this study was to establish an effective dose / dosage regimen of RP101 in postmenopausal women with moderate to severe dry eye disease applying RP101 ophthalmic sterile solution or matching placebo (vehicle) once daily (qd) or twice daily (bid) for 3 months.

[0045] Secondary objectives of the study were to evaluate the safety and tolerability of treatment, to evaluate tear film osmolality and corneal thickness as exploratory variables in specific substudies; and to evaluate the pharmacokinetics (PK) of serum 17-β-estradiol after the first and last doses (PK substudy).

[0046] endpoint

[0047] The primary endpoint was to assess clinical efficacy based on measurements from the Schirmer Type II test (with anesthesia) during and at the end of treatment with RP101 or matching placebo. Secondary endpoint parameters for assessing efficacy included: - Visual analogue scale (VAS) for ocular tolerance (foreign body sensation, burning / stinging, itching, pain, stickiness, blurred vision, redness, tearing, eyelid swelling, photophobia) - Dry Eye Symptom Assessment (SANDE) - Visual acuity (Early Treatment Diabetic Retinopathy Trial [ETDRS] chart) - Slit lamp examination (SLE) - Tear film osmolality (specific substudies only) - Tear film breakup time (TFBUT) - Fundus ophthalmology examination - Corneal fluorescein staining - Corneal pachymetry (certain substudies only) - Frequency of artificial tear (rescue) instillation during the treatment phase (i.e., number of drops instilled daily)

[0048] Schirmer test type II

[0049] This test was performed to measure basal aqueous tear production after instillation of preservative-free anesthetic eye drops. Both eyes may be tested simultaneously. Schirmer's Plus® strips were used. The test was performed in a dimly lit room. The lower lid was gently and briefly pulled downward while the patient looked up. The rounded, bent end of the sterile strip was inserted into the inferior conjunctival sac over the temporal third of the lower eyelid margin. The test was performed without directly touching the Schirmer's test strip with the fingers to avoid contamination with skin oils. The patient was instructed to gently close their eyes. After 5 minutes, the test strip was removed, and the length of tear absorption on the strip was measured (mm / 5 minutes). The wetted distance after 5 minutes was recorded for each eye.

[0050] Tear film breakup time (TFBUT)

[0051] Tear breakup time (TFBUT) was measured by determining the time to tear breakup after instilling fluorescein sodium solution into the inferior conjunctival sac of each eye. Patients were instructed to blink several times to allow the fluorescein to thoroughly mix with the tear film. To achieve maximum fluorescence, the examiner waited approximately 30 seconds after instillation before assessing TFBUT. Using a 10x magnification slit lamp with cobalt blue illumination, the examiner monitored tear film integrity, noting the time it took for an air gap (a clear space within the tear film) to form from the point at which the eyes opened after the last blink. TFBUT was measured twice within the first minute after instillation of fluorescein. If the two readings differed by more than 2 seconds, a third reading was taken. The average of the two or three readings was recorded as the TFBUT value.

[0052] Example 3

[0053] Unexpected efficacy observed in the placebo group

[0054] The clinical trial described in Example 2 was conducted and the results evaluated. Analysis of the results unexpectedly revealed that subjects in Group 4, who were treated with placebo alone, demonstrated objective endpoint results indicating that the placebo itself, i.e., Intelligel hydrogel prepared as in Example 1, possesses clinical efficacy without the addition of E3P as an active ingredient. Furthermore, efficacy was characterized by rapid onset, demonstrating clear efficacy after only 30 days of the study.

[0055] Schirmer test type II

[0056] The results of the Schirmer test for all four study groups are shown in Figure 1. As can be seen, study group 4, which received only the Intelligel placebo, showed comparable scores to the groups receiving the study drug with different concentrations of E3P.

[0057] Tear film breakup time (TFBUT)

[0058] The results of TFBUT testing for all four study groups are shown in Figure 2. As can be seen, study group 4, which received only the Intelligel placebo, demonstrated scores comparable to groups receiving the study drug with different concentrations of E3P. In fact, by day 90 of the study, the group receiving the placebo demonstrated the highest TFBUT scores of all study groups.

[0059] conclusion

[0060] The results of the clinical trial described in Example 2 demonstrate that the investigational drug RP101 not only demonstrated consistent and significant benefits in objective measures of dry eye disease, but also demonstrated such benefits in the placebo group. Furthermore, both the investigational drug and placebo were safe to use. In conclusion, it was demonstrated that the observed benefits were achieved using only the hydrogel itself as the "active ingredient."

Claims

1. A pharmaceutical composition for the treatment of dry eye disease, comprising a reversible thermoreversible hydrogel as the only active ingredient, The hydrogel comprises, in weight percent of the total composition: - approximately 5-25% of poloxamer 407; and - about 0.05 to 10% of di-PPG-2 myreth-10 adipate; Including, The pharmaceutical composition, wherein the treatment comprises administering the pharmaceutical composition to the eye of a mammalian subject by topical administration.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the mammalian subject is a human patient.

3. The pharmaceutical composition for use according to claim 2, wherein the patient is a female.

4. 4. The pharmaceutical composition for use according to claim 3, wherein said woman is selected from the group consisting of menopausal and postmenopausal women.

5. A method for producing a pharmaceutical composition for the treatment of dry eye disease, comprising a reversible thermoreversible hydrogel as the only active ingredient, the method comprising: The hydrogel comprises, in weight percent of the total composition: - approximately 5-25% of poloxamer 407; and - about 0.05 to 10% of di-PPG-2 myreth-10 adipate; Including, The method comprises dissolving poloxamer 407 in a phosphate buffer solution at low temperature, raising the temperature to room temperature, adding di-PPG-2 myreth-10 adipate, and then adjusting the pH to within the range of 7.2 to 7.

6.

6. The method described in claim 5, wherein the adjustment of the pH to within the range of 7.2 to 7.6 is carried out by adding 1 M HCl and / or 1 M NaOH.

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