NEW USE AND METHOD OF TREATMENT

Abstract

The present invention provides a pharmaceutical composition comprising a reversely thermo-reversible hydrogel as active ingredient, for administration to the eye of mammalian subjects. In particular, it relates to a pharmaceutical composition for use in, and a method for, the ophthalmic treatment of dry eye disease.

Claims

1. Pharmaceutical composition, which comprises a reversely thermo-reversible hydrogel as active ingredient, said hydrogel comprising, by weight percent of the total composition: about 5-25% of a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide; and about 0.05-10% of at least one associative gelling agent having a water solubility of less than 0.5 g/100 ml at 20° C. and being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; wherein said composition does not comprise any additional active ingredient, for use in the treatment of dry eye disease by local administration in the eye of a mammalian subject in need thereof.

2. Pharmaceutical composition for use according to claim 1, wherein said water soluble block copolymer is a tri-block copolymer having the general formula HO-(EO).sub.a—(PO).sub.b-(EO).sub.a—H, where (EO).sub.a is a polyethylene oxide block, (PO).sub.b is a polypropylene oxide block, a is in the range from 50 to 150, and b is in the range from 35 to 70.

3. Pharmaceutical composition for use according to claim 2, where a is about 101, and b is about 56.

4. Pharmaceutical composition for use according to claim 1, wherein said at least one associative gelling agent is selected from the group consisting of oxyalkylated fatty alcohol, esters of oxyalkylated fatty alcohol, oxyalkylated alkyl alcohol, esters of oxyalkylated alkyl alcohol, oxyalkylated alkylaryl alcohol, aliphatic hydroxy carboxylic acid, esters of aliphatic hydroxy carboxylic acid, aromatic hydroxy carboxylic acid, esters of aromatic hydroxy carboxylic acid, poly(hydroxy carboxylic acid), oxyalkylated sorbitan ester, oxyalkylated triglyceride, oxyalkylated glyceryl ester, esters of oxyalkylated sorbitol, polyol ester, sorbitan ester, and mixtures thereof.

5. Pharmaceutical composition for use according to claim 4, wherein said at least one associative gelling agent is an ester of oxyalkylated fatty alcohol.

6. Pharmaceutical composition for use according to claim 5, wherein said oxyalkylated fatty alcohol is 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.

7. Pharmaceutical composition for use according to claim 6, wherein said oxyalkylated fatty alcohol is di-PPG-2 myreth-10 adipate.

8. Pharmaceutical composition for use according to claim 1, in which said mammalian subject is a human patient.

9. Pharmaceutical composition for use according to claim 8, wherein said patient is a woman.

10. Pharmaceutical composition for use according to claim 9, wherein said woman is selected from the group consisting of a woman undergoing menopause and a post-menopausal woman.

11. Method of treatment of dry eye disease, comprising the step of local administration in the eye of a mammalian subject in need thereof, of a pharmaceutical composition, which comprises a reversely thermo-reversible hydrogel as active ingredient, said hydrogel comprising, by weight percent of the total composition: about 5-25% of a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide; and about 0.05-10% of at least one associative gelling agent having a water solubility of less than 0.5 g/100 ml at 20° C. and being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; wherein said composition does not comprise any additional active ingredient.

12. Method according to claim 11, wherein said water soluble block copolymer is a tri-block copolymer having the general formula HO-(EO).sub.a—(PO).sub.b-(EO).sub.a—H, where (EO).sub.a is a polyethylene oxide block, (PO).sub.b is a polypropylene oxide block, a is in the range from 50 to 150, and b is in the range from 35 to 70.

13. Method according to claim 12, where a is about 101, and b is about 56.

14. Method according to claim 11, wherein said at least one associative gelling agent is selected from the group consisting of oxyalkylated fatty alcohol, esters of oxyalkylated fatty alcohol, oxyalkylated alkyl alcohol, esters of oxyalkylated alkyl alcohol, oxyalkylated alkylaryl alcohol, aliphatic hydroxy carboxylic acid, esters of aliphatic hydroxy carboxylic acid, aromatic hydroxy carboxylic acid, esters of aromatic hydroxy carboxylic acid, poly(hydroxy carboxylic acid), oxyalkylated sorbitan ester, oxyalkylated triglyceride, oxyalkylated glyceryl ester, esters of oxyalkylated sorbitol, polyol ester, sorbitan ester, and mixtures thereof.

15. Method according to claim 14, wherein said at least one associative gelling agent is an ester of oxyalkylated fatty alcohol.

16. Method according to claim 15, wherein said oxyalkylated fatty alcohol is 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.

17. Method according to claim 16, wherein said oxyalkylated fatty alcohol is di-PPG-2 myreth-10 adipate.

18. Method according to claim 11, in which said mammalian subject is a human patient.

19. Method according to claim 18, wherein said patient is a woman.

20. Method according to claim 19, wherein said woman is selected from the group consisting of a woman undergoing menopause and a post-menopausal woman.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 is a diagram showing 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.

[0023] FIG. 2 is a diagram showing the evolution 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.

EXAMPLES

Example 1

[0024] Preparation of a Reversely Thermo-Reversible Hydrogel

[0025] A reversely thermo-reversible hydrogel was prepared using the below ingredients in the listed weight percentages. The thermogelling formulation was based on Poloxamer 407 and di-PPG-2 myreth-10 adipate as thermogelling agents.

TABLE-US-00001 Component % (w/w) Poloxamer 407 12.9 Di-PPG-2 myreth-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%

[0026] Poloxamer 407 was dissolved in phosphate buffer at cold conditions, after which the temperature was raised to room temperature and di-PPG-2 myreth-10 adipate was added, creating a weight ratio of 78.1:21.9. Then, pH was adjusted to within the range from 7.2 to 7.6 by addition of 1 M HCl and/or 1 M NaOH. The resulting formulation was a mucoadhesive hydrogel, suitable for the treatment of dry eye disease by local administration in the eye. The hydrogel prepared above is denoted “IntelliGel” in the following Example and used as carrier or vehicle for an additional agent intended as active ingredient.

Example 2

[0027] Design of a Clinical Trial of Active Ingredient 17β-Estradiol-3-Phosphate in IntelliGel as Carrier

[0028] A clinical trial was carried out with the purpose of testing the effect of 0.05% and 0.1% 17β-estradiol-3-phosphate (“E3P”) on dry eye disease, when delivered via slow release from the IntelliGel hydrogel prepared in Example 1 as carrier. The tested drug product, comprising E3P in IntelliGel, was denoted RP101, and the clinical trial design is described on clinicaltrials.gov with the identifier NCT03821415.

[0029] In brief, the trial was a multicentre, randomized, double-masked, parallel-group, placebo-controlled Phase II study, in which the ophthalmic formulation RP101 was tested against IntelliGel only, as placebo.

Study Population

[0030] The study population consisted of 104 participants meeting a list of inclusion criteria that included: [0031] Sex and menopause: postmenopausal women; postmenopausal condition defined as final menstrual period at least 3 years before the screening [0032] Dry eye disease: patients with moderate to severe dry eye syndrome [0033] Schirmer's test with anesthesia ≤7 mm/5 min in the worse eye (study eye) [0034] Tear film breakup time: TFBUT 10 s in the worse eye (study eye) [0035] Visual acuity: corrected visual acuity ≥20/200 in each eye [0036] Symptoms: at least 2 of the typical dry eye disease symptoms since at least 3 months before the screening: foreign body sensation, burning/stinging, redness, tearing, pain, itching, blurred vision, photophobia, eyelid swelling, moisture and mucous discharge [0037] Of the 104 enrolled participants, 77 completed the entire trial.

Investigational Product

[0038] The products tested in the trial were:

TEST 1 (T1): RP101 0.05%

[0039] 0.05% w/w of E3P in IntelliGel

TEST 2 (T2): RP101 0.1

[0040] 0.1% w/w of E3P in IntelliGel
PLACEBO (P): IntelliGel according to Example 1, without E3P

Treatment Groups

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

TABLE-US-00002 TABLE 1 Dose regimen Morning Evening Group 1 T1 T1 Group 2 T2 P Group 3 T2 T2 Group 4 P P

Objectives

[0042] The primary objective of the study was to establish the effective dose/dose regimen of RP101 in post-menopausal women with moderate to severe dry eye disease applying RP101 ophthalmic sterile solution or matching placebo (vehicle) once (q.d.) or twice a day (b.i.d.) for 3 months.

[0043] The secondary objectives of the study were to evaluate the safety and tolerability of the treatment; to evaluate as exploratory variables tear film osmolarity and corneal pachymetry in specific substudies; and to evaluate the pharmacokinetics (PK) of serum 17-β-estradiol after the first and last doses (PK substudy).

Endpoints

[0044] The primary endpoint was to evaluate clinical efficacy during and at the end of the treatment with RP101 or matching placebo on the basis of measurements of Schirmer test type II (with anesthesia). Secondary endpoint parameters for evaluation of efficacy included: [0045] Visual analogue scale (VAS) for ocular tolerability (foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision, redness, tearing, eyelid swelling and photophobia) [0046] Symptom Assessment in Dry Eye (SANDE) [0047] Visual acuity (early treatment diabetic retinopathy study [ETDRS] chart) [0048] Slit lamp examination (SLE) [0049] Tear film osmolarity (only specific substudy) [0050] Tear film break up time (TFBUT) [0051] Fundus ophthalmoscopy [0052] Corneal fluorescein staining [0053] Corneal pachymetry (only specific substudy) [0054] Frequency of instillation (i.e. number of drops instilled daily) of artificial tears (rescue medication) during the treatment phase

Schirmer Test Type 11

[0055] This test was performed to measure basal aqueous tear secretion following the instillation of a preservative-free anesthetic eye drop. Both eyes may be tested at the same time. Schirmer's plus® strips were used. The test was conducted in a dimly lit room. While the patient looked upwards, the lower lid was drawn gently downwards and temporally. The rounded bent end of a sterile strip was inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. The test was done without touching the Schirmer's test strip directly with the fingers, to avoid contamination by skin oils. Patients were instructed to close their eyes gently. After 5 min, the test strip was removed and the length of the tear absorption on the strip was measured (mm/5 min). The wetting distance after 5 min for each eye was recorded.

Tear Film Break Up Time (TFBUT)

[0056] TFBUT was measured by determining the time to tear break-up, and performed after instillation of sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film. In order to achieve maximum fluorescence, the examiner waited approximately 30 s after instillation before evaluating TFBUT. With the aid of a slit lamp at 10× magnification using cobalt blue illumination, the examiner monitored the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is open after the last blink. The TFBUT was measured twice during the first minute after instillation of fluorescein. If the two readings differed by more than 2 s, a third reading was taken. The average of the 2 or 3 measurements was recorded as the TFBUT value.

Example 3

[0057] Unexpected Efficacy Shown in Placebo Group

[0058] The clinical trial described in Example 2 was conducted and the results evaluated. When analyzing the results, it was unexpectedly found that the subjects in group 4, treated with placebo only, exhibited outcomes on objective endpoints that indicate that the placebo as such, i.e. the IntelliGel hydrogel prepared as in Example 1, has a clinical efficacy in its own right, even without E3P added as active ingredient. Furthermore, the efficacy was characterized by a rapid onset, showing clear effects after only 30 days of the study.

Schirmer Test Type II

[0059] The result of the Schirmer test for all four study groups is shown in FIG. 1. As can be seen from this diagram, study group 4, which received IntelliGel placebo only, exhibited a comparable score to the groups that received the investigational product with different concentrations of E3P.

Tear Film Break Up Time (TFBUT)

[0060] The result of the TFBUT test for all four study groups is shown in FIG. 2. As can be seen from this diagram, study group 4, which received IntelliGel placebo only, exhibited a comparable score to the groups that received the investigational product with different concentrations of E3P. In fact, by day 90 of the study, the group receiving placebo exhibited a TFBUT score which was the highest of all study groups.

CONCLUSION

[0061] The outcome of the clinical trial described in Example 2 shows that not only did the investigational product RP101 exhibit consistent and pronounced benefit in objective measures of dry eye disease, but such benefits could also be seen in the placebo group. Also, both the investigational product and the placebo were safe for use. In conclusion, it was shown that the observed benefits are achieved using only a hydrogel per se as “active ingredient” in its own right.