Patent Application
20230131227
The present invention is in the field of pharmaceutical compositions for administration in 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.
According to the non-profit organization Tear Film & Ocular Surface Society, dry eye disease (DED), interchangeably denoted “dry eye syndrome”, is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles (Craig et al (2017), The Ocular Surface 15:802-812).
DED is widespread in the human population worldwide, but rates of prevalence differ between countries mainly as a result of differing definitions and patient inclusion criteria (Stapleton et al (2017), The Ocular Surface 15:334-365).
Available treatments for dry eye disease are reviewed in Gomes and Santo (2019), The Ocular Surface 17:9-19 (see Table 1).
Slow-release formulations based on a reversibly thermo-reversible gel of a block copolymer and an associative gelling agent are disclosed in e.g. U.S. Pat. No. 9,592,295. While many different applications and uses for the disclosed hydrogels are given in U.S. Pat. No. 9,592,295, all of these applications and uses rely on the use of the hydrogel as carrier or vehicle for delivery and release of active ingredients, which are disclosed as external to the actual hydrogel. There is no disclosure in U.S. Pat. No. 9,592,295 of any use of the gel itself as active ingredient, and no indication that it may have a therapeutic effect in its own right.
A phase II clinical trial identified as NCT03821415 investigated the use of a hydrogel as disclosed in U.S. 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 setup of this clinical trial, the hydrogel without active ingredient was used as placebo, i.e. a use based on the understanding that the hydrogel formulation per se does not have any therapeutic effect. The results of the clinical trial in question have not been reported.
There is a need in the art for a convenient and effective formulation for treatment of dry eye disease in mammalian subjects in need thereof, and for novel methods to treat such a condition.
It is an object of the present invention to meet this need. Other objects are apparent to the skilled person from the disclosure.
Thus, in a first aspect, the disclosure provides a pharmaceutical composition, which comprises a reversely thermo-reversible hydrogel as active ingredient, said hydrogel comprising, by weight percent of the total composition:
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.
By the use of a reversely thermo-reversible hydrogel as defined herein, it is possible to provide a pharmaceutical composition which is liquid at normal room temperature, but which forms a gel at the higher temperatures of a mammalian body, e.g. from 32° C. and upwards. The beneficial gelling properties of the pharmaceutical composition make for ease of application in the desired ocular environment of the subject. In particular, these properties allow for convenient storage, handling and administration of the composition in liquid form at room temperature, whereas it forms a hydrogel with beneficial properties once it encounters the higher temperatures associated with the eye.
Evidence of the effect of the hydrogel as such on symptoms and objective endpoints in dry eye disease is provided by the Examples that follow. In the context of a clinical trial designed to test the hydrogel as carrier for an added active ingredient, it was unexpectedly shown that the hydrogel as such is efficacious, even in the absence of an additional active ingredient. Furthermore, the effects observed with the hydrogel placebo in this study had a rapid onset of only 30 days. This is of significant benefit, in spite of the fact that the onset was not quite as rapid as the investigational product with an added active ingredient. The trial also showed that the hydrogel is safe for use.
Suitable hydrogel compositions are those described in U.S. Pat. No. 9,592,295, hereby incorporated by reference. In one embodiment, the water soluble block copolymer of the hydrogel is a tri-block copolymer having the general formula HO-(EO)a—(PO)b-(EO)a—H, where (EO)a is a polyethylene oxide block, (PO)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. In a particular embodiment, a is about 101 and b is about 56 in such a tri-block copolymer. Such copolymers as those disclosed herein and in U.S. Pat. No. 9,592,295 are commonly known as “poloxamers”, and the specific embodiment of a being about 101 and b being about 56 is known as Poloxamer 407.
The hydrogel composition also 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 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. In a more specific embodiment, the at least one associative gelling agent is an ester of 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, said oxyalkylated fatty alcohol is di-PPG-2 myreth-10 adipate.
A suitable formulation of the hydrogel can be ascertained by a person of skill in the art of pharmaceutical formulations. Suitably, the pharmaceutical composition disclosed herein is formulated in such a way that local administration into the eye of a mammalian subject is facilitated. Thus, in one embodiment, the composition is administered in the form of an eye drop. In one such embodiment, it is provided in a single drop applicator, dispenser or bottle. In another such embodiment, it is provided in a multiple 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 any other suitable means of administration into the ocular environment. In one embodiment, the composition is formulated and administered as an eye drop. As explained above, the reversely thermo-reversible properties of the composition ensure that it is in liquid form while refrigerated or at room temperature. This allows e.g. the administration of a drop of liquid into the eye. After administration in this way, the composition will gel when reaching the higher temperature in the eye.
In the clinical trial reported in the Examples to follow, the effect of the hydrogel per se was observed when it was administered twice daily. In one embodiment of the use and method aspects of the present disclosure, the composition is administered twice daily or more seldom, for example once daily or more seldom. In one specific embodiment, the composition is administered twice daily. In another specific embodiment, the composition is administered once daily.
Throughout this disclosure, the use of the term dry eye disease is intended to broadly encompass any form of condition that exhibits a dry eye pathology, whether caused by reduced tear flow or not, and regardless of underlying cause. For an overview of various conditions and underlying causes that are all contemplated within the ambit of the disclosure, see
Therefore, in one such embodiment, the mammalian subject to be treated is a woman undergoing menopause. In another such embodiment, the mammalian subject to be treated is a post-menopausal woman.
Preparation of a Reversely Thermo-Reversible Hydrogel
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.
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.
Design of a Clinical Trial of Active Ingredient 17β-Estradiol-3-Phosphate in IntelliGel as Carrier
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.
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.
The study population consisted of 104 participants meeting a list of inclusion criteria that included:
The products tested in the trial were:
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.
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.
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).
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:
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.
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.
Unexpected Efficacy Shown in Placebo Group
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.
The result of the Schirmer test for all four study groups is shown in
The result of the TFBUT test for all four study groups is shown in
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20162821.1 | Mar 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/056314 | 3/12/2021 | WO |
