RU2816363C2 - Eye disease treatment - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to ophthalmology. Disclosed is use of composition containing 0.05 to 1 wt./wt.% pimecrolimus, for the treatment of subjects with a clinical diagnosis of moderate to severe blepharitis, where the subjects to be treated have moderate to severe blepharitis signs and symptoms, characterized by the presence of eyelid oedema, debris and eye discomfort.

EFFECT: invention provides creating an ophthalmic composition well tolerated by patients and used in therapy of moderate to severe blepharitis.

30 cl, 10 dwg, 11 tbl, 8 ex

Description

The present invention relates to the field of therapy of eye diseases. In particular, the present invention relates to a composition containing pimecrolimus for use in the topical topical treatment of moderate to severe blepharitis, particularly in a patient population comprising subjects clinically diagnosed with moderate to severe blepharitis, wherein Subjects to be treated have signs and symptoms of moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris, and discomfort in the eye area. In particular, the present invention relates to an ophthalmic composition that is well tolerated by patients and produces clinically significant improvement in signs and symptoms in treated patients.

PREREQUISITES FOR CREATION OF THE INVENTION

Blepharitis is a chronic inflammatory disease that affects the eyelids and eyelid margins, which can subsequently affect the surface of the eye. This is a form of dermatitis affecting the skin, associated hair, sebaceous glands, mucocutaneous border and meibomian glands.

Blepharitis often results in unsightly redness and crusting of the eyelid margin, which is distressing for patients. In addition, it causes discomfort with a wide range of ocular symptoms ranging from mild transient irritation to persistent burning, itching, pain, contact lens intolerance, photophobia, eye fatigue and visual disturbances. Symptoms usually worsen in the morning, and the patient may experience multiple flare-ups.

In the most severe cases, ulceration and perforation of the cornea may occur. Although blepharitis does not typically cause vision loss, it is burdensome for both patients and health care providers responsible for caring for patients with blepharitis.

Typically, subclassification based on the anatomical location of the affected tissues is divided into anterior and posterior blepharitis. The etiology and pathophysiology of blepharitis varies somewhat depending on the type. Anterior blepharitis causes inflammation primarily at the base of the eyelashes. Posterior blepharitis affects the posterior margin of the eyelid (the area of the eyelid that is in contact with the cornea and bulbar conjunctiva), while marginal blepharitis includes both anterior and posterior blepharitis. There is considerable overlap between these categories and are often seen together, and the treatments used today are largely the same.

Blepharitis and dry eye often coexist and may have similar symptoms, but they are considered separate diseases with different pathogenesis, requiring specific treatment approaches. The International Dry Eye Syndrome Workshop (DEWS) Committee, composed of the world's leading experts in the field of ocular surface diseases, published a report in 2017 [14] that provided a current definition of dry eye syndrome that clearly describes pathology other than blepharitis;

“Dry eye syndrome is a multifactorial disease of the ocular surface characterized by loss of tear film homeostasis and accompanied by ocular symptoms in which tear film instability and hyperosmolarity, inflammation and damage to the ocular surface, and neurosensory impairment play an etiological role.”

Blepharitis is a widespread disease. A survey conducted in the USA among ophthalmologists and optometrists showed that, respectively, 37% and 47% of the patients of these specialists suffer from this disease [15], which is difficult to treat.

There are currently no approved pharmacological treatments for any form of blepharitis in Europe or the United States. In the absence of a recognized standard of care, the most widely prescribed treatments are antibiotics and topical steroids used “off-label”.

There are no randomized, controlled clinical trials demonstrating improvement in the signs and symptoms of blepharitis with topical antibiotics. A review by Lindsley and others reported that for anterior blepharitis, topical antibiotics provided some symptomatic relief and were effective in clearing bacteria from the eyelid margin [1]. However, it is unclear how bacterial elimination is associated with clinical improvement in this pathology. Indeed, the role of bacteria in the etiology of the disease is poorly understood, and clinical evidence to support the use of antibacterial treatment is inconclusive [2, 3]. Even among patients diagnosed with so-called staphylococcal blepharitis, only half test positive for Staphylococcus aureus [2].

Long-term and/or overuse of topical antibiotics is known to be a key driver of antimicrobial resistance (AMR), and there is evidence that topical use of ocular antibiotics may promote the development of resistance in bacteria in other areas of the eye [10]. The public health threat posed by rising AMR has received widespread press coverage and has already led to numerous antimicrobial stewardship programs. In the absence of clearly defined clinical benefit, the widespread use of long courses of topical antibiotics for the treatment of blepharitis is contrary to the principles of judicious use of antimicrobials and may contribute to the problem of growing antimicrobial resistance.

Topical steroids may provide some relief of symptoms. Eyelid hygiene, including warm compresses and eyelid scrubs, demonstrated a definite reduction in symptoms in both anterior and posterior blepharitis. However, overall, no convincing evidence was observed for any of the therapies in terms of effective treatment of blepharitis.

Although the use of topical ocular steroids for this type of chronic disease is of concern to many ophthalmologists, it is the most commonly used treatment option after topical antibiotics. Only short courses of treatment are acceptable because long-term use exposes patients to the risk of documented and sight-threatening side effects, including increased intraocular pressure, cataracts, and infections caused by opportunistic organisms. Surprisingly, there is only a small amount of published evidence demonstrating the clinical benefit of topical steroids, even in acute treatment of signs and symptoms, and they are contraindicated for long-term treatment. However, it is likely that some patients are at risk of developing potentially serious side effects due to inappropriate long-term use of topical steroids without convincing evidence of clinical benefit.

A new treatment modality that meets stringent regulatory requirements for efficacy and safety would likely become the accepted standard of care in the field and, as a result, reduce the potentially inappropriate use of topical antibiotics and topical steroids.

The active ingredient in the compositions and methods of the present invention is pimecrolimus. Pimecrolimus is an immunomodulatory drug of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream marketed by Novartis under the brand name Elidel®. The preparation of pimecrolimus and pharmaceutical compositions containing pimecrolimus are discussed in international publications WO 01/60345 A2, WO 97/03654, WO 99/01458 and WO 01/90110 A1, in US patents No. 6,197,781 and No. 6,004,973 and in European patents 1754482 Al, 1482936 B1 and 0427680 B1, which are hereby incorporated herein by reference in their entirety and in all respects.

Pimecrolimus, a derivative of ascomycin macrolactam, is a reliable anti-inflammatory agent that blocks the transcription of early cytokines. The rationale for the use of pimecrolimus in patients with blepharitis is to treat the disease by targeting the associated inflammation. Pimecrolimus has been demonstrated to be highly effective in vitro and highly effective in animal studies for the treatment of skin inflammation [4]. In vivo data indicate that when applied topically, pimecrolimus has greater anti-inflammatory activity in the skin layer than cyclosporine A, but has a lower potential for systemic immunosuppression compared with cyclosporine A and tacrolimus [5, 6, 7]. Unlike steroids, pimecrolimus does not cause skin atrophy [4], and there is no evidence that the use of pimecrolimus in the eye area is associated with the development of cataracts or increased intraocular pressure.

For use in the treatment of blepharitis, topical ophthalmic compositions containing ascomycin have been proposed (see, for example, EP 1482936 and EP 1765482). However, there are no clinical results demonstrating the benefit of these ophthalmic compositions containing ascomycin, in general, or pimecrolimus, in particular, in the treatment of blepharitis.

For example, EP 2319493 discusses a variety of drug formulations that may contain various active ingredients, including, but not limited to, pimecrolimus. It is further stated that such medicinal compositions can be used in the treatment of blepharitis. However, EP 2319493 does not provide experimental or clinical data regarding the treatment of blepharitis with a drug containing pimecrolimus.

and Reinhard reported that a clinical study of the treatment of chronic blepharitis using an ointment containing 0.3% pimecrolimus found no significant differences in signs and symptoms compared with the placebo group [11]. However, any detailed information about the ointment ingredients, study design, and signs and symptoms analyzed is not available.

A retrospective case review by Kiiski and others found that pimecrolimus cream 1% (Elidel®) was poorly tolerated, causing ocular discomfort, and had little clinical effect when used to treat atopic blepharoconjunctivitis [8]. Additionally, another paper reported that off-label use of 1% pimecrolimus cream (Elidel®) for the treatment of blepharitis resulted in ocular pain [9], primarily due to the fact that Elidel® Not intended for ophthalmic use and is poorly tolerated in the eye area. The fact that ophthalmologists are willing to expose patients to discomfort resulting from the use of these improperly formulated drugs speaks volumes about the desperation of the profession.

There are reports that pimecrolimus may be used to treat dry eyes. For example, according to Ousler and others, an ophthalmic suspension containing 0.3% pimecrolimus reduces corneal staining in patients with dry eye syndrome [12]. Rynerson and Perry suggested that blepharitis and dry eye are not two different diseases and should instead be combined under the name “dry eye blepharitis syndrome” (DEBS) [13]. WO 2017/152027 (with Rynerson as sole inventor) discusses the use of compounds that inhibit or disrupt biofilm for the treatment of DEBS, but the use of pimecrolimus is not disclosed therein. Although blepharitis and dry eye can present with similar symptoms and may even occur simultaneously in the same patient, they are two different conditions. Blepharitis is inflammation of the eyelid and/or lid margin, while dry eye syndrome is defined as “a multifactorial disease of the ocular surface characterized by loss of tear film homeostasis and accompanied by ocular symptoms in which tear film instability and hyperosmolarity, inflammation and damage to the ocular surface play an etiological role.” as well as neurosensory disorders" [14]. In addition, dry eye is now treated with liquid medications that are dropped directly into the eye.

Accordingly, there is a recognized need to provide an ophthalmic composition that is well tolerated by patients and demonstrates clinically significant improvements in a defined population of patients with moderate to severe blepharitis.

SUMMARY OF THE INVENTION

This technical problem is solved by the embodiments presented herein and described in the claims.

Accordingly, in one aspect, the invention provides a composition containing 0.05% to 0.6% pimecrolimus for use in the treatment of subjects clinically diagnosed with moderate to severe blepharitis.

That is, the present invention provides a pharmaceutical composition that is effective in the treatment of moderate to severe blepharitis. Example 7 shows that treatment of patients suffering from moderate to severe blepharitis, which is characterized by swelling of the eyelid margin, debris and discomfort in the eye area, using a composition containing 0.3% pimecrolimus, leads to at least a decrease eyelid margin swelling and ocular discomfort compared with control patients receiving placebo/vehicle without pimecrolimus. In contrast, it has been demonstrated that patients who do not fit the strict definition of moderate to severe blepharitis, characterized by the presence of eyelid margin swelling, debris, and discomfort in the eye area, show no or only slight improvement in signs and symptoms after treatment using the composition of the present invention compared to control patients receiving placebo/vehicle without pimecrolimus (Example 8). Thus, it has surprisingly been found that a composition containing 0.3% pimecrolimus is effective for the treatment of moderate to severe blepharitis, namely blepharitis characterized by swelling of the eyelid margin, debris and discomfort in the eye area.

In previous studies, the main disadvantages of treating blepharitis with pimecrolimus were the high rate of intolerance in the eye area, high rates of treatment discontinuation, and low efficacy. The efficacy and safety of pimecrolimus in the treatment of blepharitis was tested in a randomized, double-blind, placebo/vehicle controlled study (CASM981 G2201) conducted by Novartis using 1% skin cream (Elidel®). This study was stopped early due to intolerance to the composition of the cream when applied to the eye area. The conclusion of the clinical trial report states: "The efficacy results of this final analysis support the interim results which suggested that pimecrolimus cream 1% (dermatological formulation) when applied to the outer eyelid would not be effective in treating blepharitis."

In a study by Kiiski et al, 56% of all patients treated for atopic blepharoconjunctivitis with pimecrolimus 1% cream (Elidel®) discontinued treatment due to lack of therapeutic effect or due to the presence of adverse events [8]. In contrast, in the present invention, only 20% of all patients treated with the composition of the present invention discontinued treatment for similar reasons, and a clear and clinically significant treatment effect was observed.

Thus, it was unexpectedly found that treatment using a composition of the present invention containing 0.3% pimecrolimus resulted in an improvement in the signs and symptoms associated with moderate to severe blepharitis and was well tolerated by patients compared to previous studies.

Bacteria are thought to play a role in the etiology of blepharitis, and most treatments prescribed for the disease involve the use of an antibiotic. It is therefore surprising that antibiotic-free therapy was able to demonstrate consistent and sustained improvement in both signs and symptoms of the disease compared with placebo/vehicle.

This is the first trial ever conducted to show clinically significant improvement in both signs and symptoms in a randomized, double-blind, placebo/vehicle controlled clinical trial in patients with moderate to severe blepharitis.

From Example 5, 67% of patients using the composition of the present invention reported at least one adverse event compared to 68% of patients who received placebo/vehicle without pimecrolimus (Table 5). The most common adverse event in this case was eye irritation, which was reported by 40% of patients using the composition of the present invention and 32% of patients receiving placebo/vehicle (Table 6). According to Example 6, in the patient groups participating in the study, at least one adverse event was reported by 60% of patients using the composition of the present invention and 55% of patients receiving placebo/vehicle, with eye irritation reported by 29% patients using the composition of the present invention, compared to 24% of patients receiving placebo/vehicle (Tables 10 and 11). Accordingly, the use of pimecrolimus, when contained in the composition of the present invention, does not lead to a significant increase in the number of side effects compared to control (placebo/vehicle) when applied to the human eyelid. Thus, the composition of the present invention unexpectedly has improved tolerability in the ocular region compared to previously proposed compositions containing pimecrolimus when used in the treatment of blepharitis, and in this aspect is comparable to vehicle/placebo.

For the purposes of the present invention, blepharitis is classified as mild blepharitis or moderate to severe blepharitis. A subject is considered to have moderate to severe blepharitis if all of the following signs and symptoms are present:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4, which corresponds to diffuse lid margin swelling, severe lid margin swelling with changes in the eyelid creases, and swelling that clearly reduces the lid gap (sign ).

(ii) A score of at least 2 (moderate) for amount of debris on a scale of 0 to 4, representing few fragments (6-20 collars), multiple fragments (21-40 collars), or clumps/strands (more than 40 “collars”) at the edge of the eyelid (sign).

(iii) A symptom score of at least 40 mm (moderate) for the degree of ocular discomfort as assessed by the patient using a 100 mm visual analogue scale (symptom).

It should be understood that a subject whose eyelid edge swelling and debris score is at least 2, and eye discomfort score is at least 40 mm is defined as having moderate to severe blepharitis. Thus, the terms “moderate to severe blepharitis” and “moderate to severe blepharitis characterized by eyelid margin swelling, debris, and eye discomfort” are used interchangeably in the context of the present invention.

In particular, it should be understood that a very severe form of blepharitis is not defined within the scope of the present invention. That is, a subject with very severe symptoms (score 4) in terms of degree of eyelid margin swelling and amount of debris and with an ocular discomfort score of at least 40 mm would, for the purposes of the present invention, still be classified as having moderate blepharitis. to a severe degree.

In some cases, a subject diagnosed with moderate to severe blepharitis may also experience redness of the eyelid margin. Swelling of the eyelid margin and redness of the eyelid margin often coexist. Thus, in some embodiments, a subject is determined to have moderate to severe blepharitis if the following signs and/or symptoms are present:

(i) A score of at least 2 for degree of eyelid margin swelling AND eyelid margin redness on a scale of 0 to 4; And

(ii) A score of at least 2 for the amount of debris on a scale of 0 to 4; And

(iii) A symptom rating score of at least 40 mm for ocular discomfort on a 100 mm visual analogue scale.

On the other hand, a subject is considered to have no or mild blepharitis if the subject has an eyelid margin swelling and/or debris score of less than 2 and/or an ocular discomfort score of less than 40 mm. In particular, Example 8 shows that subjects who have no or only a small amount of debris do not benefit from the composition of the present invention. Thus, it should be understood that subjects who have no or only a small amount of debris do not fall within the definition of moderate to severe blepharitis used in the present invention.

In the context of the present invention, it has surprisingly been found that the composition of the present invention is very effective in treating patients with moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris and discomfort in the eye area and, optionally, redness of the eyelid margin.

Accordingly, in one aspect, the present invention provides a composition containing from 0.05% (w/w) to 0.6% (w/w) pimecrolimus, for use in the treatment of subjects with a clinical diagnosis of moderate to severe blepharitis. degree, with subjects being treated having signs and symptoms of moderate to severe blepharitis, characterized by eyelid margin swelling, debris and discomfort in the eye area.

In a specific aspect, the invention relates to a composition containing from 0.05% (wt/wt) to 0.6% (wt/wt) pimecrolimus, for use in the treatment of subjects with a clinical diagnosis of moderate to severe blepharitis, wherein A subject is defined as having moderate to severe blepharitis if the following signs and/or symptoms are present:

(i) A score of at least 2 for the degree of eyelid margin swelling on a scale of 0 to 4; And

(ii) A score of at least 2 for the amount of debris on a scale of 0 to 4; And

(iii) A symptom rating score of at least 40 mm for ocular discomfort on a 100 mm visual analogue scale.

Thus, in certain embodiments, the present invention provides a composition for use in accordance with the present invention, wherein the subjects to be treated have:

(i) A score of at least 2 for the degree of eyelid margin swelling on a scale of 0 to 4; And

(ii) A score of at least 2 for the amount of debris on a scale of 0 to 4; And

(iii) A symptom rating score of at least 40 mm for ocular discomfort on a 100 mm visual analogue scale.

In an alternative embodiment, the invention provides a composition containing from 0.05% (wt/wt) to 1% (wt/wt) pimecrolimus, for use in the treatment of subjects with a clinical diagnosis of moderate to severe blepharitis, subject to Treatment subjects have signs and symptoms of moderate to severe blepharitis, characterized by eyelid margin swelling, debris, and discomfort in the eye area.

One skilled in the art will be well aware of ways to determine the above signs and symptoms without undue experimental stress and inventive skill. Example 4 explains how to assess these signs and symptoms. To provide an objective and comparable assessment of signs of moderate to severe blepharitis, the severity of these signs can be interpreted from photographs.

It was previously reported that pimecrolimus 0.3% ointment did not significantly improve the signs and symptoms of chronic blepharitis compared with placebo [11]. However, it was demonstrated that the composition of the present invention significantly improved several signs and symptoms related to moderate to severe blepharitis.

Accordingly, it has been unexpectedly discovered herein that compositions containing low concentrations of pimecrolimus, for example 0.3%, are effective in treating subjects suffering from moderate to severe blepharitis, wherein the subjects being treated have the following signs and symptoms:

(i) A score of at least 2 for the degree of eyelid margin swelling on a scale of 0 to 4; And

(ii) A score of at least 2 for the amount of debris on a scale of 0 to 4; And

(iii) A symptom rating score of at least 40 mm for ocular discomfort on a 100 mm visual analogue scale.

That is, the present patent application identifies a group of patients that respond to treatment with a composition containing from 0.05% (wt/wt) to 0.6% (wt/wt) pimecrolimus, preferably from 0.1% ( w/w) to 0.4% (w/w) pimecrolimus, more preferably 0.3% (w/w) pimecrolimus. In other embodiments, a patient population of the present invention may be treated with a composition containing from 0.05% (w/w) to 1% (w/w) pimecrolimus.

Within the scope of the present invention, it is preferred that the composition of the present invention be applied to the affected area of a subject suffering from moderate to severe blepharitis. Accordingly, the composition of the present invention is preferably applied to the eyelid and/or the eyelid margin of the subject. During application of the composition of the present invention to the affected area or eyelid of a subject suffering from moderate to severe blepharitis, a portion of the composition may come into contact with tissues on the surface of the eye, such as the cornea, conjunctiva, etc. Therefore, the compatibility of the composition of the present invention with ocular tissue is a preferred aspect. According to the Examples set forth herein, the stated compatibility of the composition of the present invention is surprisingly higher than that of other semi-solid compositions containing pimecrolimus known in the art.

The ingredients of a pharmaceutical composition are critical to the method of administration. The preferred method of administration of the composition of the present invention is topical external application. Appropriate compositions are typically applied topically to the skin, preferably to the skin around the eyelid and, in particular, to the eyelid, preferably to the skin of the eyelid and/or the edge of the eyelid.

The term “composition” as used herein means a composition containing at least one pharmaceutically active ingredient and one or more pharmaceutically acceptable excipients. As used herein, the pharmaceutically active ingredient, which is pimecrolimus, provides a therapeutic effect for treating a disease in a subject or group of subjects.

As used herein, the term "treatment" (and its grammatical variations such as "treat" or "treating") means a clinical intervention in an attempt to alter the natural course of disease in a subject receiving treatment, which may be either prophylactic or therapeutic. for the treatment of symptoms and signs of moderate to severe blepharitis. Desirable effects of treatment include, but are not limited to, prevention of onset or recurrence of the disease, alleviation of signs and symptoms, reduction of any direct or indirect pathological consequences of the disease, reduction in the rate of disease progression, improvement or alleviation of the disease, and remission or improvement of prognosis. Within the scope of the present invention, the composition is preferably used for the treatment of moderate to severe blepharitis, as defined above.

The term "subject" or the plural form "subjects" as used herein means any animal, preferably a mammal, and more preferably a human. Examples of subjects include humans, primates, rodents, guinea pigs, rabbits, sheep, pigs, goats, cattle, cows, horses, dogs and cats. For purposes of the present invention, the terms "subject" and "patient" are used interchangeably. It should be understood that a composition for use in accordance with the present invention or a method of the present invention can be used to treat a single subject suffering from moderate to severe blepharitis, as well as to treat groups of subjects suffering from moderate to severe blepharitis.

The term "clinical diagnosis" means a diagnosis based on knowledge obtained through medical history and physical examination, alone or in combination with testing that provides additional data to make the diagnosis. Within the scope of the present invention, the clinical diagnosis may be based on the signs and symptoms that are typically associated with moderate to severe blepharitis.

For purposes of the present invention, a composition for use in the treatment of subjects clinically diagnosed with moderate to severe blepharitis comprises pimecrolimus in an amount of 0.05% to 0.6% by weight (w/w). In a preferred embodiment, the invention relates to a composition for use in accordance with the present invention containing from 0.1% to 0.4% (wt/wt) pimecrolimus. In a more preferred embodiment, the invention relates to a composition for use in accordance with the present invention containing 0.3% (w/w) pimecrolimus. In a particular embodiment, the invention relates to a composition for use in accordance with the present invention containing 0.1% (w/w) pimecrolimus. In an alternative embodiment, the composition for use in the treatment of subjects with a clinical diagnosis of moderate to severe blepharitis comprises pimecrolimus in an amount of 0.05% to 1% by weight (w/w).

In one embodiment, the invention provides a composition for use according to the present invention, further comprising a medium chain triglyceride and a microcrystalline wax.

That is, the composition for use in accordance with the present invention may contain any combination of medium chain triglyceride and microcrystalline wax in any amount.

The term "triglyceride" as used herein means an ester derived from glycerol and three fatty acids. Medium chain triglycerides are triglycerides containing C6-C12 fatty acids, for example the fatty acids known and commercially available under the trade names Acomed®, Myritol®, Captex®, Neobee®M5F, Miglyol®810, Miglyol®812, Mazol®, Sefsol ®860 and Sefsol®870. Such medium chain triglycerides are typically obtained from oil extracted from the solid dried endosperm fraction of Cocos nucifera or from the dried endosperm of Elaeisguineensis. They consist of a mixture of triglycerides of saturated fatty acids. Mainly from caprylic acid and capric acid, and contain at least 95 percent saturated fatty acids with 8-10 carbon atoms.

Microcrystalline wax is characterized by a fine crystalline structure in contrast to the larger crystalline structure of paraffin wax. Microcrystalline waxes contain long, branched hydrocarbon chains. Microcrystalline waxes are more flexible, less oily, have higher tensile strength, greater adhesion and higher melting points than paraffin wax, and have excellent gelling properties. The composition of the present invention may contain any microcrystalline wax known in the art. Preferably, the microcrystalline wax contained in the composition of the present invention complies with the requirements of the United States Pharmacopoeia (USP 43-NF38).

The composition of the present invention may contain any medium chain triglyceride in any amount suitable to obtain the claimed technical effect. In a preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the medium chain triglyceride content is from 30% (w/w) to 60% (w/w). In a more preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the medium chain triglyceride content is 50% (w/w)

The composition of the present invention may contain any microcrystalline wax in any amount suitable to obtain the claimed technical effect. In a preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the microcrystalline wax content is from 3% (w/w) to 10% (w/w). In a more preferred embodiment, the invention provides a composition of the present invention wherein the microcrystalline wax content is 6% (w/w).

In a particular embodiment, the invention relates to a composition for use according to the present invention containing 0.3% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax.

In another embodiment, the invention provides a composition for use according to the present invention containing 0.1% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax.

In another embodiment, the invention provides a composition for use according to the present invention containing 1% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax.

The composition of the present invention may contain any medium chain triglyceride in the above amounts, provided that it is suitable to obtain the claimed technical effect. Preferably, the composition of the present invention contains medium chain triglycerides, including decanoglycerides and/or octanoglycerides. Accordingly, in a preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the medium chain triglyceride comprises caprylic acid and/or capric acid.

That is, the medium chain triglyceride contained in the composition of the present invention may include one, two or three caprylic acid fatty acid units and/or one, two or three capric acid fatty acid units. The medium chain triglyceride contained in the composition of the present invention may also be a mixture of triglycerides in which at least 95% of the triglycerides contain one, two or three caprylic acid fatty acid units and/or one, two or three capric acid fatty acid units, respectively.

Caprylic acid is the common name for an eight-carbon saturated fatty acid known systematically as octanoic acid. Capric acid is a saturated medium-chain fatty acid with a ten-carbon backbone.

The commercially available medium chain triglyceride Miglyol®812 contains caprylic acid and capric acid. Thus, in a more preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the medium chain triglyceride is Miglyol®812. In a particular embodiment, the invention relates to a composition for use according to the present invention, wherein the medium chain triglyceride is a mixture of triglycerides with 50-64% eight-carbon and 30-45% ten-carbon saturated fatty acids.

The composition of the present invention can be used to treat subjects who exhibit moderate to severe signs and symptoms of blepharitis. Accordingly, in another embodiment, the invention provides a composition for use according to the present invention in a patient population comprising subjects with signs and symptoms of moderate to severe blepharitis, wherein the subjects to be treated are characterized by the presence of eyelid margin swelling, debris and discomfort in the area eye.

In a particular embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the subjects to be treated have:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4;

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of 0 to 4;

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

That is, a subject is considered to have moderate to severe blepharitis if all of the following signs and symptoms are present:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4, which corresponds to diffuse lid margin swelling, severe lid margin swelling with changes in the eyelid creases, and swelling that clearly reduces the lid gap (sign ).

(ii) A score of at least 2 (moderate) for amount of debris on a scale of 0 to 4, representing few fragments (6-20 collars), multiple fragments (21-40 collars), or clumps/strands (more than 40 “collars”) at the edge of the eyelid (sign).

(iii) A symptom score of at least 40 mm (moderate) for the degree of ocular discomfort as assessed by the patient using a 100 mm visual analogue scale (symptom).

One skilled in the art will be knowledgeable about ways to determine the severity of the above signs and symptoms without undue experimental stress and inventive skill. Example 4 explains how to assess these signs and symptoms. To provide an objective and comparable assessment of signs of moderate to severe blepharitis, the severity of these signs can be interpreted from photographs.

In another embodiment, the present invention provides a composition for use in the treatment of moderate to severe blepharitis, comprising 0.3% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax, in a patient population comprising subjects with signs and symptoms of moderate blepharitis to a severe degree, with the subjects being treated characterized by the presence of swelling of the eyelid margin, debris and discomfort in the eye area.

In a particular embodiment, the invention relates to a composition for use in the treatment of moderate to severe blepharitis, containing 0.3% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax, in subjects having:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4;

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of 0 to 4;

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

In another embodiment, the invention provides a composition for use in the treatment of moderate to severe blepharitis, comprising 0.1% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax, in a patient population comprising subjects with signs and symptoms of moderate to severe blepharitis severe, with the subjects being treated characterized by the presence of swelling of the eyelid margin, debris and discomfort in the eye area.

In a particular embodiment, the invention relates to a composition for use in the treatment of moderate to severe blepharitis, comprising 0.1% pimecrolimus, 50% medium chain triglyceride and 6% microcrystalline wax, in subjects having:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4;

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of 0 to 4;

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

The term “patient population” as used herein refers to the subgroup of individuals who have been found to exhibit the signs and symptoms of moderate to severe blepharitis described above.

Example 7 includes subjects diagnosed with moderate to severe blepharitis, characterized by eyelid margin swelling, debris, and eye discomfort for at least three months. Accordingly, in another embodiment, the invention provides a composition for use in accordance with the present invention, wherein the subjects have been diagnosed with moderate to severe blepharitis, characterized by the presence of eyelid margin swelling, debris, and discomfort in the eye area for at least , three months. That is, the subject was diagnosed with moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris, and discomfort in the eye area, three months ago or earlier.

In another embodiment, the invention relates to a composition for use in accordance with the present invention, further comprising a preservative.

A preservative is a substance or chemical that is added to products such as food, beverages, pharmaceuticals, paints, biological specimens, cosmetics, wood, and many other products to prevent decomposition by microorganisms or unwanted chemical changes.

The composition of the present invention may further include any preservative in any amount, provided that the composition retains the claimed technical effect in the presence of the preservative. The amount of preservative in the composition of the present invention depends mainly on the type and mode of action of the preservative. In a preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the preservative content is from 0.5% (w/w) to 2% (w/w). In a more preferred embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the preservative content is 1.0%.

The preservative may be any preservative, preferably an ophthalmologically acceptable preservative. Suitable preservatives include:

(a) a quaternary ammonium compound, e.g. benzalkonium chloride (N-benzyl-N-(C8-C18-alkyl)-N,N-dimethylammonium chloride), benzoxonium chloride, benzethonium chloride, cetrimide (hexadecyl-trimethylammonium bromide), sepazonium chloride , cetylpyridinium chloride, domiphen bromide (Bradosol®), etc.,

(b) alkylmercuric salts of thiosalicylic acid, for example thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate,

(c) parabens, such as for example methylparaben or propylparaben,

(d) alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenylethyl alcohol,

(e) biguanide derivatives, such as, for example, chlorhexidine or polyhexamethylene biguanide,

(f) sodium perborate,

(g) imidazolidinyl urea, known and commercially available under the trade name Germal®II,

(h) sorbic acid,

(i) stabilized oxychloro complexes, for example those known and commercially available under the trade name Purite®,

(j) polyglycol-polyamine condensation resins, for example those known and commercially available under the trademark Polyquart® from Henkel KGaA,

(1) stabilized hydrogen peroxide obtained from a source of hydrogen peroxide to provide an effective trace amount of hydrogen peroxide formed, for example, sodium perborate tetrahydrate, and/or

(m) a mixture of any of the components (a) - (1).

Preferably, the preservative contained in the composition of the present invention is phenylethyl alcohol. Thus, in a preferred embodiment, the invention relates to the composition of the present invention in which the preservative is phenylethyl alcohol.

Phenylethyl alcohol, also known as phenethyl alcohol, 2-phenyl-ethan-1-ol or 2-phenylethanol, is an organic compound consisting of a phenethyl (C ₆ H ₅ CH ₂ CH ₂ ) group attached to an OH. It is a colorless liquid that is slightly soluble in water (2 ml/100 ml H ₂ O), but miscible with most organic solvents.

Figures 7 and 8 show that a reduction in ocular swelling and discomfort in patients with moderate to severe blepharitis who were treated with the composition of the present invention was observed as early as two weeks after the start of treatment. Accordingly, in some embodiments, the invention provides a composition for use according to the present invention, wherein the treatment period is at least two weeks.

The beneficial effects of therapy using the composition of the present invention on the signs and symptoms associated with moderate to severe blepharitis persist over six and twelve weeks of treatment. Thus, in another embodiment, the invention relates to a composition for use in accordance with the present invention, wherein the treatment period is from 6 to 12 weeks, preferably where the treatment period is 6 weeks or 12 weeks.

Tables 3, 4, 8 and 9 summarize the effects of the compositions of the present invention on the signs and symptoms associated with moderate to severe blepharitis after treatment for 12 weeks. Accordingly, in a preferred embodiment, the invention relates to a composition for use according to the present invention, wherein the treatment period is 12 weeks.

In a particular embodiment, the invention relates to a composition for use according to the present invention, where the treatment period is 6 weeks.

"Treatment period" as used herein means the duration and/or frequency of application of the composition to the target surface, in particular the eyelid and/or eyelid margin.

In another embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a clinically significant difference in mean improvement from baseline for at least one sign and/or symptom, particularly for at least one sign and one symptom.

That is, treating a patient suffering from moderate to severe blepharitis with a composition of the present invention may result in improvement in any sign or symptom associated with moderate to severe blepharitis. The preferred signs and symptoms to evaluate moderate to severe blepharitis are: debris, swollen meibomian glands, redness of the eyelid margin, swelling of the eyelid margin, and eye discomfort.

A symptom is a deviation from normal function or sensation that is obvious to the subject, reflecting the presence of an unusual condition or disease. A sign can be objectively observed by someone other than the subject, while a symptom cannot. There is a correlation between this difference and the difference between the medical history and the physical examination. Some signs are only relevant to physical examination because identifying them requires medical knowledge.

In the context of the present invention, the severity of moderate to severe symptoms of blepharitis can be quantified using scores ranging from 0 (no symptom) to 4 (very severe symptom). Moderate to severe symptom severity of blepharitis can be quantified as a visual analogue scale score of ocular discomfort ranging from 0 mm (no symptom) to 100 mm (severe symptom).

Debris is a sign defined as the formation of discharge in the eye and can be quantified by counting the number of “collars,” which are scales of scab around the base of the eyelashes. The severity of debris can be determined based on the number of collars in the eye. To ensure objective and comparable results, the severity of debris can be interpreted from photographs.

Meibomian gland swelling is a sign that is described as an enlarged internal plug of hardened secretions that may protrude from the opening of the meibomian gland when pressure is applied. The degree of meibomian gland swelling can be quantified by determining the proportion of meibomian gland openings that contain cloudy or oily secretions. To ensure objective and comparable results, the degree of meibomian gland swelling can be interpreted from photographs.

Eyelid margin redness is a symptom defined as painless or painful redness of the eyelid margin. To ensure objective and comparable results, the degree of redness of the eyelid margin can be interpreted from photographs.

Eyelid margin swelling is a symptom defined as a painless or painful abnormal protrusion or enlargement of the eyelid margin. To ensure objective and comparable results, the degree of swelling of the eyelid margin can be interpreted from photographs.

It should be understood that swelling of the eyelid margin is often accompanied by redness of the eyelid margin. Thus, a subject suffering from moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris and discomfort in the eye area, is often diagnosed with redness of the eyelid margin.

Eye discomfort is a general term that describes the lack of usual comfort in/around the eyes. Since discomfort in the eye area can only be felt by the subject suffering from such discomfort, it is classified as a symptom. Accordingly, the severity of the discomfort in the eye area should be determined by the subject. Subjects suffering from eye discomfort may describe at least one of the following symptoms: eyelid itching, foreign body/gritty sensation in the eyes, dry eyes, burning/pain in the eyes, heavy eyelids, sensitivity to light and /or blurred vision. A visual analogue scale can be used to quantify the severity of ocular discomfort.

Scores may be reported as average scores for a population of subjects. The average score for a particular attribute can be calculated by adding up the scores of all subjects in the population for that attribute and then dividing the resulting sum of scores by the number of subjects in the population. The average ocular discomfort score (symptom) can be calculated by adding up the scores of all subjects in the population for a given symptom and then dividing the resulting sum by the number of subjects in the population.

Baseline is defined as the score obtained at the start of treatment. The baseline may be the score obtained for a single subject at the start of treatment, or the average score obtained for a population of subjects at the start of treatment. Preferably, the baseline is expressed as a mean score for the population. An improvement in score or mean score from baseline is defined as a decrease in score or mean score at the end of treatment compared with the score or mean score for the same symptom or for ocular discomfort at the beginning of treatment.

For purposes of the present invention, a difference in scores for a trait is considered clinically significant if the score or mean score obtained at the end of treatment is at least 1 unit lower than the score or mean score obtained at the beginning of treatment (baseline). The difference in eye discomfort scores (symptom) is considered clinically significant if the eye discomfort score or mean score obtained at the end of treatment is at least 30 mm less than the ocular discomfort score or mean score obtained at the end of treatment. obtained at the beginning of treatment (baseline).

Therefore, in a preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a mean score improvement of at least 1 point relative to baseline for eyelid margin swelling and/or debris (sign ), and an improvement in the mean score of at least 30 mm from baseline for ocular discomfort (symptom).

In the context of the present invention, the degree of swelling of the eyelid margin is expressed as a score ranging from 0 (no swelling) to 4 (very severe swelling). Figures 3, 5 and 7 and Tables 3 and 8 demonstrate that treatment of subjects with the composition of the present invention reduced the subjects' mean scores by at least 1 unit from baseline, which is considered a clinically significant result. Accordingly, in another embodiment, the invention provides a composition of the present invention when, at the end of treatment, the subject or subjects demonstrate a decrease in the eyelid margin puffiness score or mean score of at least 1 point relative to baseline.

The severity of discomfort in the eye area was displayed on a visual analogue scale ranging from 0 mm (no discomfort) to 100 mm (severe discomfort). Figures 4, 6 and 8 and Tables 4 and 9 show that treatment of subjects with the composition of the present invention resulted in a reduction in the average ocular discomfort score (on a visual analogue scale) of at least by 30 mm relative to the original level. Thus, for purposes of the present invention, a subject is considered to have experienced a clinically significant improvement in ocular discomfort if, at the end of treatment, the subject demonstrates a decrease of at least 30 mm from baseline on a visual analogue scale with a range from 0 mm to 100 mm.

Alternatively and preferably, the mean score is considered to be improved from baseline compared to placebo/vehicle if the improvement in mean score from baseline for a sign or symptom at the end of treatment with a composition of the present invention exceeds the improvement in mean score from baseline for placebo/vehicle. carrier medium.

Thus, in an alternative embodiment, the invention provides a composition for use in accordance with the present invention wherein, at the end of treatment, subjects demonstrate a clinically significant difference in mean score improvement from baseline compared to placebo/vehicle in terms of at least , one sign and/or symptom, in particular with respect to at least one sign and one symptom.

In a preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle results for at least one trait and/ or symptom, in particular in relation to at least one sign and one symptom, the treatment period being from 6 to 12 weeks.

In a more preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle results for at least one trait and /or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks.

In an even more preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle results on at least one attribute and/or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is from 6 to 12 weeks and the composition is applied to the eyelid and/or to the eyelid margin one, two, three or four times in a day.

In an even more preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle results on at least one attribute and/or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks and the composition is applied to the eyelid and/or to the eyelid margin one, two, three or four times per day.

In the most preferred embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle results for at least one trait and /or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks and the composition is applied to the eyelid and/or to the eyelid margin twice a day.

In a particular embodiment, the invention relates to a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle results for at least one trait and/ or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is 2 weeks and the composition is applied to the eyelid and/or to the eyelid margin twice a day.

In certain embodiments, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score relative to baseline (compared to placebo/vehicle) on at least one trait and/ or symptom, wherein said at least one sign and/or symptom is selected from the group consisting of: debris, meibomian gland swelling, eyelid margin redness, eyelid margin swelling, and eye discomfort.

That is, in some embodiments, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline (compared to placebo/vehicle) for debris, meibomian gland swelling, redness of the eyelid margin, swelling of the eyelid margin and discomfort in the eye area.

In a particular embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline (compared to placebo/vehicle) regarding debris and eyelid margin swelling.

In a particular embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline (compared to placebo/vehicle) regarding eyelid margin puffiness and ocular discomfort.

In a particular embodiment, the invention provides a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline (compared to placebo/vehicle) regarding debris and ocular discomfort.

In a particular embodiment, the invention relates to a composition for use in accordance with the present invention, wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline (compared to placebo/vehicle) with respect to debris, eyelid margin swelling, and area discomfort. eye.

An improvement in a trait is considered clinically significant if, at the end of treatment with the composition of the present invention, the improvement in the mean score relative to baseline exceeds at least 0.2 units, preferably at least 0.3; 0.4 units, improvement in mean score from baseline for placebo/vehicle.

Tables 3 and 8 demonstrate that treatment of subjects with the composition of the present invention at the end of treatment reduced the subjects' mean score from baseline compared to placebo/vehicle by at least 0.2 points. Thus, in one embodiment, the invention provides a composition of the present invention where, at the end of treatment, subjects demonstrate an improvement in mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline that exceeds that of placebo/vehicle by at least at least by 0.05; 0.1; 0.15; 0.2; 0.3; 0.4 points.

An improvement in ocular discomfort is considered to be clinically significant if the improvement in mean discomfort score from baseline at the end of treatment with the composition of the present invention exceeds at least 10 mm the improvement in mean discomfort score from baseline for placebo/vehicle. .

Tables 4 and 9 also demonstrate that treatment of subjects with the composition of the present invention at the end of treatment reduced the average visual analogue scale ocular discomfort score compared to placebo/vehicle by at least 10 mm. Thus, in another embodiment, the invention provides a composition of the present invention where, at the end of treatment, subjects demonstrate a reduction in ocular discomfort (symptom) from baseline that is at least 1.2 to 2.0 times greater than placebo/vehicle. 3, 4, 5, 6, 7, 8, 9, preferably 10 mm.

Thus, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline that exceeds that of placebo/vehicle by at least by at least 0.2, preferably by at least 0.3, more preferably by at least 0.4 points; and improvement in mean ocular discomfort (symptom) score from baseline compared with placebo/vehicle.

Thus, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline that exceeds that of placebo/vehicle by at least by at least 0.2, preferably by at least 0.3, more preferably by at least 0.4 points, and when subjects demonstrate a decrease in mean ocular discomfort (symptom) score from baseline greater than that of the placebo/carrier medium by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, preferably 10 mm.

In the context of the present invention, a subject is considered to have moderate to severe blepharitis if the subject has a score of at least 2 for eyelid margin swelling and amount of debris, and an ocular discomfort score of at least 40 mm (symptom ). Entities falling within this definition are discussed in Example 7.

Results regarding the degree of eyelid margin swelling at the end of the 6-week or 12-week treatment period in subjects suffering from moderate to severe blepharitis (baseline >=2) are shown in Figure 7. Accordingly, for subjects suffering from moderate to severe blepharitis to severe, at the end of a 2-week treatment period using the composition of the present invention, the average score relative to baseline decreased by 0.6 points more than for placebo/vehicle, at the end of a 6-week treatment period by 0.7 points more than for placebo/vehicle, and at the end of the 12-week treatment period - 0.4 points more than for placebo/vehicle. Thus, in a more preferred embodiment, the invention provides a composition of the present invention when, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin puffiness score and/or mean score of debris (signs) relative to baseline that is greater than that of placebo/vehicle , by at least 0.2, preferably by at least 0.3, more preferably by at least 0.4 points.

Thus, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or mean score of debris (signs) relative to baseline, greater than that of placebo/vehicle, at least 0.2, preferably at least 0.3, more preferably at least 0.4 points, and a greater improvement in the mean ocular discomfort (symptom) score from baseline compared to placebo/vehicle.

Results regarding the degree of ocular discomfort at the end of the 6-week or 12-week treatment period in subjects suffering from moderate to severe blepharitis (baseline >=40 mm) are shown in Figure 8. Accordingly, for subjects suffering from blepharitis moderate to severe, at the end of a 2-week treatment period with the composition of the present invention, the mean symptom score from baseline decreased by 17 mm more than placebo/vehicle, at the end of a 6-week treatment period by 16 mm more than for placebo/vehicle, and at the end of the 12-week treatment period - 14 mm more than for placebo/vehicle. Thus, in a more preferred embodiment, the invention provides a composition of the present invention where, at the end of treatment, subjects demonstrate an improvement in mean ocular discomfort (symptom) from baseline that exceeds that of placebo/vehicle by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, preferably by 10 mm. In some embodiments, the invention provides a composition of the present invention where, at the end of treatment, subjects demonstrate an improvement in mean ocular discomfort (symptom) from baseline that is at least 12 to 13 times greater than placebo/vehicle. or 14 mm.

Thus, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or mean score of debris (signs) relative to baseline, greater than that of placebo/vehicle, by at least 0.2, preferably by at least 0.3, more preferably by at least 0.4 points, and wherein the subjects demonstrate an improvement in the mean ocular discomfort (symptom) score from baseline level exceeding that of placebo/vehicle by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, preferably at least 10 mm.

Thus, in certain embodiments, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin swelling score and/or mean score of debris (signs) relative to baseline that is greater than that of placebo. / vehicle by at least 0.4 points, and an improvement in the average ocular discomfort (symptom) compared to placebo / vehicle.

In other embodiments, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin swelling score and/or mean score of debris (signs) relative to baseline that is greater than that of placebo/vehicle , by at least 0.4 points, and an improvement in the average ocular discomfort (symptom) score above placebo/vehicle by at least 10 mm, in particular by at least 12, 13, 14 mm.

In a preferred embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or mean score of debris (signs) relative to baseline, greater than that of placebo/vehicle of at least 0.4 points and an improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle over a 6 to 12 week treatment period, or alternatively, a treatment period is 2 weeks.

In a more preferred embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline, greater than that of placebo/vehicle, of at least 0.4 points and an improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle over a 6 or 12 week treatment period, or alternatively a 2 week treatment period weeks.

In an even more preferred embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline that is greater than that of placebo/vehicle of at least 0.4 points and an improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle over a 6 to 12 week treatment period, or alternatively, a treatment period is 2 weeks, and the composition is applied to the eyelid and/or eyelid margin one, two, three or four times a day.

In an even more preferred embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline that is greater than that of placebo/vehicle , by at least 0.4 points, and an improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle, with a treatment period of 6 or 12 weeks, or alternatively, a treatment period of 2 weeks, and the composition is applied to the eyelid and/or eyelid margin one, two, three or four times a day.

In the most preferred embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline, greater than that of placebo/vehicle, of at least 0.4 points and an improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle over a 6 or 12 week treatment period, or alternatively a 2 week treatment period weeks, and the composition is applied to the eyelid and/or eyelid margin twice a day.

In certain embodiments, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline, greater than that of placebo/vehicle, according to at least 0.4 points and an improvement in mean ocular discomfort (symptom) compared to placebo/vehicle over a 2-week treatment period and the composition applied to the eyelid and/or eyelid margin twice daily .

In other embodiments, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline, greater than that of placebo/vehicle, according to by at least 0.4 points, and an improvement in the mean ocular discomfort (symptom) above that of placebo/vehicle by at least 10 mm, in particular by at least 12, 13, 14 mm, with a treatment period of 2 weeks and the composition is applied to the eyelid and/or eyelid margin twice a day.

In a particular embodiment, the invention provides a composition for use in accordance with the present invention when, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (signs) relative to baseline, greater than that of placebo/vehicle, according to by at least 0.4 points, and an improvement in the mean ocular discomfort (symptom) from baseline, greater than placebo/vehicle by at least 10 mm, in particular by at least 12 , 13, 14 mm, in particular when the treatment period is 6 or 12 weeks and the composition is applied to the eyelid and/or eyelid margin twice a day.

The term "placebo/vehicle" as used herein means a composition identical to the composition of the present invention, except that it does not contain the active ingredient of the composition, in this case, pimecrolimus. In another embodiment, the invention relates to a composition for use according to the present invention, which is formulated as an ointment.

The composition of the present invention may have any formulation, provided that the composition retains its inherent claimed technical effect. Preferably, the composition of the present invention may be formulated as an ointment. Suitable ointment bases include, for example, ophthalmologically acceptable oil and fat bases. Suitable ointment bases are:

(a) natural wax, for example white and yellow beeswax, carnauba wax, wool wax (wool fat), purified lanolin, anhydrous lanolin,

(b) petroleum wax, for example paraffin wax, microcrystalline wax,

(c) hydrocarbons, for example liquid paraffin, white and yellow soft paraffin, white petrolatum, yellow petrolatum, or

(d) a combination thereof.

Within the scope of the present invention, the preferred ointment base is white Vaseline.

In certain embodiments, the composition of the present invention is an ointment containing 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and an ointment base, wherein the ointment base is preferably white petrolatum.

In other embodiments, the composition of the present invention is an ointment containing 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax, 1% phenylethyl alcohol and an ointment base, wherein the ointment base is preferably white petrolatum.

In another embodiment, the composition of the present invention is an ointment consisting of 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and an ointment base, wherein the ointment base is preferably white petrolatum.

In another embodiment, the composition of the present invention is an ointment consisting of 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax, 1% phenylethyl alcohol and an ointment base, wherein the ointment base is preferably white Vaseline.

It should be noted that developing a stable ointment-based formulation that is well tolerated by the eye has been a technical challenge. Pimecrolimus is highly hydrophobic and has low solubility (see Figure 2). The solubility of pimecrolimus in excipients that may be used in semi-solid formulations for dermal and, in particular, ophthalmic use is very low and supersaturated solutions should be avoided due to the risk of crystallization and/or separation from solution when subjected to stress (e.g. thermal, shear). Thus, inventive thought was required to obtain a stable ointment of the present invention, in which pimecrolimus remains in solution and does not crystallize. To dissolve pimecrolimus, a large volume of liquid solvent (medium chain triglycerides) is required, which makes it technically difficult to obtain an ointment of appropriate viscosity that is suitable for topical use and adheres well to the eyelid and eyelid margin.

The strong emollient effect of the ointment makes it useful for dry skin, and its occlusive effect enhances the penetration of the active substance of the drug and increases its effectiveness (especially on thickened, crusty skin). The ointment provides a protective film on the skin and has an oily, sticky consistency that traps sweat. Typically, ointments contain little to no water. Example 2 describes the composition of the present invention, which is formulated as an anhydrous ointment based on white petroleum jelly.

In addition to pimecrolimus, which is the active ingredient, the ointment of the present invention may contain one or more excipients. Information on the properties, specifications and characteristics of excipients is given, for example, in standard texts such as Fiedler, N.R.; 1996; Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzen de Gebiete; Editio Cantor Verlag, Aulendorf (Germany), and Kibbe, A.H.; 2000; Handbook of Pharmaceutical Excipients, jointly published by Pharmaceutical Press, London (UK), and American Pharmaceutical Association, Washington (USA), and in manufacturers' brochures. It is preferred that all excipients in the composition of the present invention, in particular in the ointment of the present invention, comply with the requirements of the European Pharmacopoeia and/or the United States Pharmacopoeia.

In another embodiment, the invention provides a composition for use according to the present invention when a single dose of the composition is administered one, two, three, four times a day.

That is, the composition of the present invention can be applied to the affected area, preferably the eyelid and/or eyelid margin, one, two, three or four times a day. In a preferred embodiment, the invention relates to the method of the present invention when a single dose of the composition is administered twice a day.

The term "unit dose" as used herein refers to a physically discrete unit suitable as a single dose for humans and animals. Each unit contains a predetermined amount of the composition of the present invention, calculated so that it is sufficient to obtain the desired effect. The amount of a single dose of the composition of the present invention depends on various factors, for example, on the concentration of the active substance (pimecrolimus) in the composition, on the effect to be achieved, and on the pharmacodynamics associated with the active substance in the body of the subject. Preferably, a single dose is defined as an amount sufficient to cover the eyelid and/or lid margin with a thin layer of the composition of the present invention. Alternatively, a single dose is defined as a 3 mm strip of the composition. A 3 mm strip can be applied to the eyelids up to and including the edge of the eyelid, after the usual morning and evening eyelid hygiene.

In another embodiment, the invention relates to a composition for use according to the present invention where the composition is applied to the eyelid, in particular to the edge of the eyelid, using an applicator.

The eye is a sensitive organ, and self-administration of the composition of the present invention may be difficult for some subjects. Accordingly, application of the composition of the present invention to the eyelid or, in particular, to the edge of the eyelid can be facilitated by the use of an applicator. The applicator may be any applicator known in the art for applying creams or ointments to the skin, in particular to the skin of the eyelid and/or the edge of the eyelid. Preferably, the applicator may be made of a soft or flexible material to prevent damage to ocular tissue. In addition, the applicator may contain an antimicrobial material to prevent infection of the eye or eyelid. The applicator can be designed for multiple or single use.

In another embodiment, the invention relates to a composition for use in accordance with the present invention in human or veterinary therapy.

That is, the composition of the present invention can be used for the treatment of moderate to severe blepharitis in humans and/or animals.

In one aspect, the invention relates to an applicator containing a composition of the present invention.

In another aspect, the invention provides a method for treating subjects clinically diagnosed with moderate to severe blepharitis, the method comprising administering to said subjects a composition containing 0.05% to 0.6% pimecrolimus. Preferably, the method of the present invention includes the use of a composition containing from 0.1% to 0.4% pimecrolimus. Alternatively, the invention provides a method of treating subjects clinically diagnosed with moderate to severe blepharitis, the method comprising administering to said subjects a composition containing 0.05% to 1% pimecrolimus.

In another embodiment, the invention provides a method in accordance with the present invention, wherein the subjects to be treated exhibit signs and symptoms of moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris and discomfort in the eye area. In a particular embodiment, the invention relates to a method in accordance with the present invention, wherein the subjects to be treated exhibit all of the following signs and/or symptoms:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4; and/or

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of O to 4; and/or

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

In one embodiment, the invention relates to a method in accordance with the present invention, wherein the composition is a composition as defined herein.

In one embodiment, the invention relates to a method in accordance with the present invention, wherein the composition contains 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservative.

In a particular embodiment, the invention relates to a method according to the present invention, wherein the composition contains 0.1% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservative.

In certain embodiments, the invention relates to a method in accordance with the present invention, where the composition is an ointment, in particular, where the ointment base is white petroleum jelly.

In certain embodiments, the invention relates to a method in accordance with the present invention, wherein the composition is an ointment containing or including: 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and white petrolatum.

In certain embodiments, the invention relates to a method in accordance with the present invention, wherein the composition is an ointment containing or including: 0.1% or 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax, 1% phenylethyl alcohol and white petrolatum .

In one embodiment, the invention relates to the method of the present invention, where a single dose of the composition is administered one, two, three, four times a day.

In one aspect, the invention provides a method for treating moderate to severe blepharitis, comprising twice daily administration of a composition comprising 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservative to a patient population consisting of subjects with signs and symptoms of moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris, and discomfort in the eye area.

In a particular embodiment, the invention relates to a method of treating moderate to severe blepharitis, comprising twice daily administration of a composition containing 0.3% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservatives in a subject having:

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4;

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of 0 to 4; And

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

In another aspect, the invention provides a method for treating moderate to severe blepharitis comprising twice daily administration of a composition containing 0.1% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservative to a patient population consisting of subjects with signs and symptoms of moderate to severe blepharitis, characterized by swelling of the eyelid margin, debris, and discomfort in the eye area.

In a particular embodiment, the invention relates to a method of treating moderate to severe blepharitis, comprising twice daily administration of a composition containing 1% pimecrolimus, 50% medium chain triglyceride, 6% microcrystalline wax and 1% preservative, to a patient population consisting of subjects having;

(i) A score of at least 2 (moderate) for the degree of eyelid margin swelling on a scale of 0 to 4;

(ii) A score of at least 2 (moderate) for the amount of debris on a scale of O to 4; And

(iii) A symptom score of at least 40 mm (moderate) for ocular discomfort on a 100 mm visual analogue scale.

In one embodiment, the invention relates to the method of the present invention, where the treatment period is from 6 to 12 weeks.

In a preferred embodiment, the invention relates to the method of the present invention, where the treatment period is 6 weeks.

In a particular embodiment, the invention relates to the method of the present invention, where the treatment period is 12 weeks.

In a particular embodiment, the invention relates to the method of the present invention, where the treatment period is at least 2 weeks.

In one embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate a clinically significant difference in mean score improvement from baseline compared to placebo/vehicle for at least one sign and/or symptom, in particularly in relation to at least one sign and one symptom.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle for at least one sign and/or symptom, particularly in relation to at least one sign and one symptom, the treatment period being from 6 to 12 weeks, or, alternatively, the treatment period being 2 weeks.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle for at least one sign and/or symptom, particularly in relation to at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks or, alternatively, the treatment period is 2 weeks.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle for at least one sign and/or symptom, particularly in relation to at least one sign and one symptom, wherein the treatment period is from 6 to 12 weeks, or, alternatively, the treatment period is 2 weeks, and the composition is applied to the eyelid and/or to the edge of the eyelid one, two, three or four times a day.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle for at least one sign and/or symptom, particularly for at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks or, alternatively, the treatment period is 2 weeks and the composition is applied to the eyelid and/or eyelid margin one, two, three or four times a day.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle for at least one sign and/or symptom, particularly for at least one sign and one symptom, wherein the treatment period is 6 or 12 weeks, or alternatively the treatment period is 2 weeks, and the composition is applied to the eyelid and/or eyelid margin twice daily.

In certain embodiments, the invention provides a method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle on at least one sign and/or symptom, wherein said at least one sign and/or symptom is selected from the group consisting of: debris, meibomian gland swelling, eyelid margin redness, eyelid margin swelling, and ocular discomfort.

That is, in certain embodiments, the invention relates to the method of the present invention, where at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle with respect to amount of debris, degree of meibomian gland swelling, degree of eyelid margin erythema , the degree of swelling of the eyelid margin and the degree of discomfort in the eye area.

In a particular embodiment, the invention provides a composition of the present invention wherein, at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle regarding the degree of eyelid margin swelling and amount of debris.

In a particular embodiment, the invention relates to the method of the present invention wherein at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle regarding the degree of eyelid margin puffiness and the degree of ocular discomfort.

In a particular embodiment, the invention relates to the method of the present invention where, at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle regarding ocular discomfort and amount of debris.

In a particular embodiment, the invention relates to the method of the present invention where, at the end of treatment, subjects demonstrate a greater improvement in mean scores from baseline compared to placebo/vehicle regarding the degree of eyelid margin puffiness, the degree of ocular discomfort, and the amount of debris.

In a preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness (sign) and/or amount of debris (sign) relative to baseline, greater than that of placebo/vehicle, by at least at least 0.4 points and an improvement in the average ocular discomfort (symptom) compared to placebo/vehicle.

In a more preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin swelling score and/or amount of debris (sign) relative to baseline greater than that of placebo/vehicle by at least by 0.4 points, and a greater improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle, with a treatment period of 6 to 12 weeks, or alternatively, a treatment period of 2 weeks.

In an even more preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or amount of debris (signs) relative to baseline greater than that of placebo/vehicle, at least , by 0.4 points, and a greater improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle, with a treatment period of 6 or 12 weeks, or alternatively a treatment period of 2 weeks.

In an even more preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or amount of debris (signs) relative to baseline greater than that of placebo/vehicle, at least , by 0.4 points, and a greater improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle, with a treatment period of 6 to 12 weeks, or alternatively, a treatment period of 2 weeks, and the composition is applied to the eyelid and/or eyelid margin one, two, three or four times a day.

In an even more preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin puffiness and/or amount of debris (signs) relative to baseline greater than that of placebo/vehicle, at least , by 0.4 points, and a greater improvement in mean ocular discomfort (symptom) score compared with placebo/vehicle, with a treatment period of 6 or 12 weeks, or alternatively a treatment period of 2 weeks, and the composition is applied to the eyelid and/or eyelid margin one, two, three or four times a day.

In the most preferred embodiment, the invention provides a method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin swelling score and/or amount of debris (signs) relative to baseline greater than that of placebo/vehicle by at least by 0.4 points, and a greater improvement in mean ocular discomfort (symptom) score compared to placebo/vehicle, with a treatment period of 6 or 12 weeks, or alternatively a treatment period of 2 weeks , and the composition is applied to the eyelid and/or to the edge of the eyelid twice a day.

In a particular embodiment, the invention relates to the method of the present invention wherein, at the end of treatment, subjects demonstrate an improvement in mean eyelid margin swelling score and/or amount of debris (signs) relative to baseline that exceeds that of placebo/vehicle by at least 0.4 points, and an improvement in the mean ocular discomfort (symptom) from baseline, greater than that of placebo/vehicle by at least 10 mm, in particular by at least 12, 13, 14 mm, in particular when the treatment period is 6 or 12 weeks, or, alternatively, the treatment period is 2 weeks, and the composition is applied to the eyelid and/or to the eyelid margin twice a day.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Structural formula of pimecrolimus

Figure 2: Solubility of pimecrolimus in various solvents. The top table demonstrates the solubility of pimecrolimus in various organic and aqueous solvents. Form B refers to the anhydrous, crystalline polymorph B of pimecrolimus, which is used in the manufacture of the composition of the present invention. The table below contains definitions of terms used to classify solubility.

Figure 3: Effect of ointment containing 0.3% pimecrolimus (solid line) on eyelid margin swelling in subjects throughout the study population. As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 4: Effect of ointment containing 0.3% pimecrolimus (solid line) on ocular discomfort in subjects throughout the study population. As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 5: Effect of ointment containing 0.3% pimecrolimus (solid line) on eyelid margin swelling in a population with blepharitis (characterized by moderate to severe eyelid margin swelling OR redness, debris, and eye discomfort). As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 6: Effect of ointment containing 0.3% pimecrolimus (solid line) on ocular discomfort in a population with blepharitis (characterized by moderate to severe eyelid margin swelling OR redness, debris, and ocular discomfort). As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 7: Effect of an ointment containing 0.3% pimecrolimus (solid line) on eyelid margin swelling in a target population with blepharitis characterized by moderate to severe eyelid margin swelling, debris, and ocular discomfort. As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 8: Effect of ointment containing 0.3% pimecrolimus (solid line) on ocular discomfort in a target population with blepharitis, characterized by moderate to severe eyelid margin swelling, debris and ocular discomfort. As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 9: Effect of ointment containing 0.3% pimecrolimus (solid line) on eyelid margin swelling in a non-target population with blepharitis characterized by eyelid margin swelling OR redness, meibomian gland swelling, moderate to severe ocular discomfort, and moderate to severe absence of debris. As a control, the effect of placebo/vehicle is shown (dashed line).

Figure 10: Effect of ointment containing 0.3% pimecrolimus (solid line) on ocular discomfort in a non-target population with blepharitis characterized by swelling or redness of the eyelid margin, swollen meibomian glands, and moderate to severe ocular discomfort. and a moderate to severe absence of debris. As a control, the effect of placebo/vehicle is shown (dashed line).

EXAMPLES

Example 1: Pimecrolimus Solubility

The active substance is pimecrolimus (Figure 1). Name of pimecrolimus according to IUPAC nomenclature:

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3- methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04, 9]octacos-18-ene-2,3,10,16-tetraone.

The solubility of pimecrolimus in various solvents was determined by HPLC after 24 hours of equilibration (vibration) at 25.0+/-0.5°C. After vibration, the precipitate was separated from the solution, dried and examined by differential scanning calorimetry and X-ray diffraction. The solubility of pimecrolimus in various solvents is presented in Figure 2. The results show that pimecrolimus is insoluble in aqueous solutions and in water.

Example 2: Composition of Dosage Form

Excipients

All excipients used comply with pharmacopoeia standards. Medium chain triglycerides are used as a solubilizer. Microcrystalline wax is added to improve the consistency and physical stability of the ointment. The contents are optimized to prevent or minimize the release of medium chain triglycerides from the ointment base, as well as to maintain an acceptable final consistency for patient comfort. Phenylethyl alcohol is used as a preservative. The phenylethyl alcohol content of 1% was chosen to ensure optimal preservative effectiveness. The final product is tested for sterility in accordance with the requirements of the European Pharmacopoeia.

Example 3: Description of the technological process

1. Heat the medium chain triglycerides.

2. Mix pimecrolimus drug substance until dissolved.

3. Add microcrystalline wax, white petrolatum and, if necessary, phenylethyl alcohol, and dissolve while stirring.

4. Filter the ointment.

5. The filtered ointment mass is mixed and gradually cooled at room temperature, while the temperature, time and mixing speed for this process are documented.

Example 4:

The following examples describe a double-blind, placebo/vehicle-controlled, randomized study of the safety and efficacy of pimecrolimus ophthalmic ointment administered twice daily to treat patients diagnosed with blepharitis.

The purpose of this study was to compare the effectiveness of an ophthalmic ointment containing pimecrolimus 0.3%, administered twice daily, with the effectiveness of placebo/vehicle (MV), also administered twice daily, in the treatment of blepharitis.

A clinical trial was conducted to detect treatment effects of 0.4 points/10 mm in terms of statistical trends (one-sided significance level of 0.1) [i.e., p < 0.2 was preset as the index presence of a trend]. These differences were considered clinically significant (subsequently confirmed by EU regulatory authorities in Denmark and Sweden in 2005).

Study plan

The study was a double-blind, placebo/vehicle-controlled, multicenter, parallel-group, randomized design with an allocation ratio of 1:1, involving 98 patients, with outcome determination at week 12 and a subsequent 6-week follow-up period without use of the drug.

Signs by which effectiveness was assessed

- Change in debris from baseline assessed by slit lamp examination (scale 0-4)

- Change in the degree of swelling of the meibomian glands relative to the initial level (scale 0-4)

- Change in the degree of redness of the eyelid margin relative to the initial level (scale 0-4)

- Change in the degree of swelling of the eyelid margin relative to the initial level (scale 0-4)

- Change in the nature of secretion compared to the initial level (scale 0-3)

- Change in coloration of the cornea and conjunctiva compared to baseline values (Oxford conversion scale 0-5)

- Signs (interpreted from photographs using the central reading center); debris (scale 0-4), redness of the eyelid margin (scale 0-4), swelling of the eyelid margin (scale 0-4), swelling of the meibomian glands (scale 0-4).

Debris (“collar”, scabs/scales, remnants of tear film)

The investigator assessed the severity of the symptoms according to the following classification:

Redness of the edge of the eyelid

The investigator assessed the severity of symptoms according to the following classification:

Swelling of the eyelid edge

The investigator assessed the severity of symptoms according to the following classification:

Meibomian gland swelling

The investigator assessed the severity of symptoms according to the following classification:

Evaluating effectiveness based on symptoms

- Change in the degree of eye discomfort relative to baseline, as assessed by the patient (most severe symptoms at baseline, visual analogue scale)

- Change in severity of ocular symptoms of blepharitis (ie, foreign body sensation, itching, dryness, burning/pain (0-4 points), swollen/heavy eyelids (0-3 points)) from baseline.

Discomfort in the eye area

Discomfort in the eye area was assessed by the patient using a visual analogue scale. At the first visit (week 0), the symptom causing the most ocular discomfort was defined as the “most severe symptom at baseline.”

In week 0:

Which symptom was the most severe for the patient (ie, the symptom that caused the greatest discomfort in the eyes) over the past 2 weeks? Please mark the scale below to indicate how your eyes have felt over the past 2 weeks.

At 2nd, 4th, 6th and 12th weeks:

Your most severe symptom at the start of the study was... (verbal reminder from study center staff).

Please mark the scale below to indicate how your eyes have felt since your last visit.

Scores for all visits are printed on the same form so patients can see what their previous score was. However, staff should not influence the patient's assessment in any way. The level of discomfort is measured by study center staff to the nearest millimeter, starting on the left side of the scale and up to the mark made by the patient.

Key performance indicators:

- absolute change in the degree of redness of the eyelid margin, from the initial level to the 12th week (scale 0-4).

- absolute change in the degree of swelling of the eyelid margin, from the initial level to the 12th week (scale 0-4).

- absolute change in the degree of discomfort in the eye area, from baseline to week 12 (visual analogue scale 0-100 mm).

Example 5: Population 1 - all patients (who fulfilled the protocol requirements)

Main inclusion criteria

Patients with a clinical diagnosis of blepharitis for at least three months, poor eyelid hygiene, and meeting the following criteria in at least one eye (same eye):

- a score of at least 2 (moderate) for the degree of redness OR swelling (or both) of the eyelid margin

- a score of at least 2 (moderate) for the amount of debris OR the degree of meibomian gland swelling (or both)

- a discomfort score in the eye area of at least 40 mm (moderate severity) (the most severe symptom at baseline) AND a score of at least 2 (moderate severity) for any one symptom

Swelling of the eyelid edge

The effect of Composition 1 on reducing the severity of lid margin swelling is presented in Figure 3 and Table 3. Patients receiving Composition 1 containing 0.3% pimecrolimus experienced a reduction in the severity of lid margin swelling compared to patients receiving placebo/vehicle.

Discomfort in the eye area

The effect of Composition 1 on reducing ocular discomfort is presented in Figure 4 and Table 4. Patients receiving Composition 1 containing 0.3% pimecrolimus experienced a reduction in ocular discomfort compared to patients receiving placebo/vehicle. .

Side effects

From Tables 5 and 6, patients receiving Formulation 1 containing 0.3% pimecrolimus did not report significantly more adverse events compared to patients receiving placebo/vehicle. The most common side effect was eye irritation, which was observed to a similar extent in patients receiving Formulation 1 containing 0.3% pimecrolimus and in patients receiving placebo/vehicle.

Example 6: Population 2 - blepharitis, characterized by swelling and/or redness of the eyelid margin, debris and discomfort in the eye area

Main inclusion criteria

Patients with a clinical diagnosis of blepharitis for at least three months, poor eyelid hygiene, and meeting the following criteria in at least one eye (same eye):

- a score of at least 2 (moderate) for the degree of redness OR swelling (or both) of the eyelid margin

- a score of at least 2 (moderate severity) regarding the amount of debris

- an indicator of the degree of discomfort in the eye area of at least 40 mm (moderate severity) (the most severe symptom at baseline) AND a score of at least 2 (moderate severity) for any one symptom

Swelling of the eyelid edge

The effect of Composition 1 on reducing the severity of eyelid margin swelling is presented in Figure 5 and Table 8. Patients receiving Composition 1 containing 0.3% pimecrolimus experienced a significant reduction in the severity of eyelid margin swelling compared to patients receiving placebo/vehicle. An unexpected result was that patients with moderate to severe blepharitis (baseline >=2) had an improvement in mean score from baseline compared to placebo/vehicle of 0.51.

Discomfort in the eye area

The effect of Composition 1 on reducing ocular discomfort is presented in Figure 9. Patients who received Composition 1 containing 0.3% pimecrolimus had a significant reduction in ocular discomfort compared to patients receiving placebo/vehicle. .

Side effects

From Tables 10 and 11, patients receiving Formulation 1 containing 0.3% pimecrolimus did not report significantly more adverse events compared to patients receiving placebo/vehicle. The most common side effect was eye irritation, which was observed to a similar extent in patients receiving Formulation 1 containing 0.3% pimecrolimus and in patients receiving placebo/vehicle.

Example 7: Population 3 (Target Population) - Moderate to severe blepharitis characterized by eyelid margin swelling, debris, and eye discomfort

Main inclusion criteria

Patients with a clinical diagnosis of blepharitis for at least three months, poor eyelid hygiene, and meeting the following criteria in at least one eye (same eye):

- a score of at least 2 (moderate severity) regarding the degree of swelling of the eyelid margin

- a score of at least 2 (moderate severity) regarding the amount of debris

- a discomfort score in the eye area of at least 40 mm (moderate severity) (the most severe symptom at baseline) AND a score of at least 2 (moderate severity) for any one symptom

Treatment results

Patients receiving Formulation 1 containing 0.3% pimecrolimus experienced a significant reduction in the severity of eyelid margin swelling and a significant reduction in ocular discomfort compared to patients receiving placebo/vehicle (see Figures 7 and 8).

Example 8: Population 4 - Blepharitis characterized by puffiness and/or redness of the eyelid margin, meibomian gland swelling, moderate to severe ocular discomfort, and moderate to severe absence of debris.

Main inclusion criteria

Patients with a clinical diagnosis of blepharitis for at least three months, poor eyelid hygiene, and meeting the following criteria in at least one eye (same eye):

- a score of at least 2 (moderate) for the degree of redness OR swelling (or both) of the eyelid margin

- score<2 (absent/mild) for amount of debris AND at least 2 (moderate) for meibomian gland swelling

- a discomfort score in the eye area of at least 40 mm (moderate) (the most severe symptom at baseline) AND a score of at least 2 (moderate) for any one symptom

Treatment results

Patients in the above-mentioned patient group reported no significant reduction in the degree of eyelid margin puffiness, as well as no apparent improvement in ocular discomfort (see Figures 9 and 10).

BIBLIOGRAPHY

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Claims (33)

1. The use of a composition containing from 0.05 to 1% wt./wt. pimecrolimus, for use in the treatment of subjects clinically diagnosed with moderate to severe blepharitis, wherein the subjects to be treated have signs and symptoms of moderate to severe blepharitis, characterized by the presence of eyelid margin swelling, debris and discomfort in the eye area. 2. Use of the composition according to claim 1, where the composition contains from 0.1 to 0.4% wt./wt. pimecrolimus. 3. Use of a composition according to claim 1 or 2, where the composition contains 0.3% wt./wt. pimecrolimus. 4. Use of a composition according to claim 1 or 2, where the composition contains 0.1% wt./wt. pimecrolimus. 5. Use of the composition according to any one of paragraphs. 1-4, where the composition additionally contains a medium chain triglyceride and microcrystalline wax. 6. Use of the composition according to claim 5, where the content of medium chain triglycerides is from 30 to 60% wt./wt. 7. Use of the composition according to claim 6, where the content of medium chain triglycerides is 50% wt./wt. 8. Application of the composition according to claims. 5-7, where the content of microcrystalline wax is from 3 to 10% wt./wt. 9. Use of the composition according to claim 8, where the content of microcrystalline wax is 6% wt./wt. 10. Application of the composition according to claims. 5-9, where the composition contains 0.3% wt./wt. pimecrolimus, 50% w/w medium chain triglycerides and 6% wt./wt. microcrystalline wax. 11. Application of the composition according to claims. 5-9, where the composition contains 0.1% wt./wt. pimecrolimus, 50% w/w medium chain triglycerides, 6% wt./wt. microcrystalline wax. 12. Application of the composition according to claims. 5-11, where the medium chain triglyceride includes caprylic acid and/or capric acid. 13. Application of the composition according to claims. 1-12, where the composition additionally contains a preservative. 14. Use of the composition according to claim 13, where the preservative content is from 0.5 to 2% wt./wt. 15. Use of the composition according to claim 14, where the preservative content is 1.0% wt./wt. 16. Application of the composition according to claims. 13-15, where the preservative is phenylethyl alcohol. 17. Application of the composition according to claims. 1-16, where the treatment period is from 6 to 12 weeks. 18. Use of the composition according to claim 17, where the treatment period is 12 weeks. 19. Use of the composition according to claim 17, where the treatment period is 6 weeks. 20. Application of the composition according to claims. 1-16, where the treatment period is at least 2 weeks. 21. Use of a composition according to claim 17, wherein at the end of treatment the subjects demonstrate a greater improvement in the mean score from baseline compared to placebo/vehicle in relation to at least one sign and/or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is from 6 to 12 weeks and the composition is applied to the eyelid area and/or eyelid margins twice daily. 22. Use of a composition according to claim 20, wherein at the end of treatment, subjects demonstrate a greater improvement in mean score from baseline compared to placebo/vehicle in relation to at least one sign and/or symptom, in particular in relation to at least one sign and one symptom, wherein the treatment period is 2 weeks and the composition is applied to the eyelid area and/or eyelid margins twice a day. 23. Use of the composition of claim 21 or 22, wherein at the end of treatment, subjects demonstrate at least a 0.4 point improvement in the mean score of eyelid margin swelling and/or amount of debris (sign) from baseline, above that of placebo/carrier. environment, and a greater improvement in mean ocular discomfort (symptom) compared with placebo/vehicle. 24. Use of the composition of claim 21 or 22, wherein at the end of treatment, subjects demonstrate an improvement in the mean score of eyelid margin swelling and/or amount of debris (sign) from baseline that is at least 0.4 above that of placebo/vehicle score, and an improvement in the mean ocular discomfort (symptom) score greater than that of placebo/vehicle by at least 10 mm. 25. Application of the composition according to claims. 1-24, where the composition is formulated as an ointment. 26. Application of the composition according to claims. 1-25, where a single dose of the specified composition is applied one, two, three, four times a day. 27. Application of the composition according to claims. 1-26, wherein a single dose of said composition is administered twice daily. 28. Application of the composition according to claims. 1-27, where the composition is applied to the eyelid, in particular to the edge of the eyelid, using an applicator. 29. Application of the composition according to claims. 1-28, where the composition is used in the treatment of humans or animals. 30. Application of the composition according to claims. 1-29, where the signs and symptoms of moderate to severe blepharitis are: (i) a score of at least 2 for the degree of swelling of the eyelid margin on a scale of 0-4; And (ii) a score of at least 2 for the amount of debris on a scale of 0-4; And (iii) a symptom score of at least 40 mm for ocular discomfort on a 100 mm visual analogue scale.