Patent Grant
11684589
This application is a U.S. national stage application filed under 35 U.S.C. § 371 of International Application No. PCT/EP2017/073697, filed on Sep. 20, 2017, which claims priority to, and the benefit of, European Application No. 16190138.4, filed Sep. 22, 2016, the contents of each of which are incorporated herein by reference in their entireties.
Blepharitis refers to a family of inflammatory disease processes of the eyelid(s). It usually involves the part of the eyelid where the eyelashes grow and affects both eyelids. A number of diseases and conditions can lead to blepharitis, such as bacterial infection, allergies, clogged oil glands or other conditions. The severity can vary and onset can be acute, resolving without treatment within 2 to 4 weeks, but more generally blepharitis is a long-standing chronic inflammation of varying severity.
Blepharitis can be divided anatomically into two sub-indications: Anterior and posterior blepharitis. Anterior blepharitis refers to inflammation mainly centered around the skin, eyelashes and follicles, while the posterior variant involves the meibomian gland orifices, meibomian glands, and tarsal plate. (Pflugfelder et. al, Ocul. Surf 2014 October; 12(4):273-84) Anterior blepharitis usually is subdivided further into staphylococcal and seborrheic variants. Frequently, a considerable overlap exists in these processes in individual patients. Blepharitis often is associated with systemic diseases, such as rosacea, atopy and seborrheic dermatitis, as well as ocular diseases, such as dry eye syndromes, chalazion, trichiasis, conjunctivitis, and keratitis.
The pathophysiology of blepharitis frequently involves bacterial colonization of the eyelids. This results in direct microbial invasion of tissues, immune system-mediated damage, or damage caused by the production of bacterial toxins, waste products, and enzymes. Colonization of the lid margin is increased in the presence of seborrheic dermatitis or meibomian gland dysfunction. Patients with blepharitis typically present with symptoms of eye irritation, itching, erythema of the lids, and/or changes in the eyelashes.
Blepharitis is often a chronic condition that is difficult to treat. A systematic and long-term commitment to a program of eyelid margin hygiene usually is the basis for the treatment of blepharitis, which is not a cure but a process to be carried out over prolonged periods of time. Useful medications in the treatment of blepharitis may include medications to fight infection (e.g. by topical antibiotics), to control inflammation (e.g. by topical corticosteroids), to affect the immune system (e.g. by immune suppressants) or by treating the underlying condition. Furthermore, conjunctivitis and keratitis can result as a complication of blepharitis and require additional treatment.
J. Nepp et al. provide in Spektrum Augenheilkd (2016) 30:122-136 a workflow-chart for dry eye management from diagnosis to therapy with a compilation of 149 artificial tear medications and application methods. For the treatment of blepharitis and Meibomian gland dysfunction 17 different compound currently available on the market have been compiled under “lubricants—lipids”. Among those the compound EvoTears® (Ursa-Pharm Arzneimittel GmbH, Germany) containing perfluorohexyl-octane has been listed.
Nevertheless, in view of the prevalence of blepharitis and the complex interdependencies with other ophthalmic diseases and conditions such as, for example, dry eye disease, there is still a need for further therapeutic options that allow to directly and efficiently address specific forms or sub-indications of blepharitis with high efficacy. It is therefore an object of the present invention to provide pharmaceutical compositions that allow the treatment of specific forms of blepharitis with high efficacy and a minimized probability of adverse side-effects or interdependencies with other conditions or medications.
In a first aspect, the present invention relates to a pharmaceutical composition comprising or essentially consisting of 1-perfluorohexyl-octane (F6H8) for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith. In a preferred embodiment, the present invention provides a pharmaceutical composition comprising 1-perfluorohexyl-octane (F6H8) for use in the therapy, treatment, prevention or amelioration of posterior blepharitis or symptoms associated therewith. In a particularly preferred embodiment, the present invention provides a pharmaceutical composition consisting of 1-perfluorohexyl-octane (F6H8) for use in the therapy, treatment, prevention or amelioration of posterior blepharitis or symptoms associated therewith.
In a second aspect, the present invention relates to a method of treating a patient suffering from anterior or posterior blepharitis or symptoms associated therewith, comprising topically administering a pharmaceutical composition comprising or essentially consisting of 1-perfluorohexyl-octane to the eye of that patient.
In a third aspect, the present invention relates to the use of a pharmaceutical composition comprising or essentially consisting of 1-perfluorohexyl-octane for the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith.
In a fourth aspect, the present invention provides a pharmaceutical kit for the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith, comprising
In a first aspect, the present invention relates to a pharmaceutical composition comprising 1-perfluorohexyl-octane (F6H8) for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith. In a particularly preferred embodiment, the present invention provides a pharmaceutical composition consisting of 1-perfluorohexyl-octane (F6H8) for use in the therapy, treatment, prevention or amelioration of posterior blepharitis or symptoms associated therewith. According to the present invention, the clinical condition to be treated in a patient diagnosed therewith or to be prevented by therapy may be either anterior or posterior blepharitis, which are specific sub-indications of blepharitis as the more general indication. The anterior or posterior blepharitis to be treated according to the present invention may be acute or chronic and may or may not yet be manifested in the case of the prevention of a suspected anterior or posterior blepharitis.
The term therapy, treatment, prevention or amelioration as used herein, may be summarized by the term “treatment” and means, as used herein, in a broad sense any act performed on a patient useful in the management or prevention of a medical condition or disease of such patient.
The term anterior blepharitis as used herein refers to an inflammation mainly centered around the skin, eyelashes, and follicles of an eye or both eyes of a patient mainly affecting the outside front of the eyelid where eyelashes are attached. Anterior blepharitis as used herein further may be subdivided into staphylococcal and seborrheic variants. However, a considerable overlap may exist with respect to the named variants and processes in individual patients frequently.
The term posterior blepharitis as used herein refers to a variant or sub-indication of blepharitis that involves the meibomian gland orifices, the meibomian glands, and the tarsal plate. Posterior blepharitis affects the inner edge of the eyelid that touches the eyeball. Frequently, it is linked to dysfunction of meibomian glands within the eyelids that secrete oils to help lubricate the eye, which creates a favorable environment for bacterial growth. Posterior blepharitis can also develop as a result of other skin conditions, such as acne rosacea and scalp dandruff.
Both variants of blepharitis as referred to herein may or may not be associated with systemic diseases, such as, for example, rosacea, atopy, and seborrheic dermatitis, as well as ocular diseases, such as, for example, dry eye syndromes, chalazion, trichiasis, conjunctivitis, and keratitis.
Furthermore, anterior or posterior blepharitis as referred to herein may or may not involve bacterial colonization of the eyelids and, as a result thereof, may involve direct microbial invasion of tissues, immune system-mediated damage, or damage caused by the production of bacterial toxins, waste products, and enzymes. Furthermore, colonization of the lid margin associated with anterior or posterior blepharitis as referred to herein may or may not be increased in the presence of seborrheic dermatitis or meibomian gland dysfunction. Furthermore, anterior or posterior blepharitis as referred to herein may typically occur together with symptoms of eye irritation, such as, for example, itching, erythema of the lids, and/or changes in the eyelashes.
In a preferred embodiment, however, the present invention relates to a pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith, wherein the anterior or posterior blepharitis is a posterior blepharitis. Accordingly, the present invention relates to a pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of posterior blepharitis or symptoms associated therewith.
In a further embodiment, the present invention relates to a pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith, preferably posterior blepharitis, which may occur at certain levels of intensity. For example, the anterior or posterior blepharitis according to the present invention may occur with weak or light intensity or with an average intensity or with a severe intensity (i.e. an intensity above the average intensity) when compared with the distribution of intensities occurring in a group with a representative number of cases of blepharitis.
Accordingly, in one embodiment the present invention relates to a pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith, wherein the anterior or posterior blepharitis is a severe anterior or posterior blepharitis. In a preferred embodiment, however, the present invention relates to a pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of severe posterior blepharitis, that means posterior blepharitis with severe intensity, or symptoms associated therewith. Surprisingly, it has been found, that the use of the pharmaceutical compositions according to this first aspect of the invention is especially beneficial for the treatment of severe forms of blepharitis as shown by experimental data outlined further below.
The pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis, preferably posterior blepharitis, or symptoms associated therewith comprises 1-perfluorohexyl-octane. 1-perfluorohexyl-octane is also known as F6H8, according to the nomenclature FnHm, wherein n is an integer representing the number of carbon atoms of the linear, unbranched perfluorinated segment and m is an integer representing the number of carbon atoms of the linear, unbranched hydrocarbon segment.
The pharmaceutical composition for use according to the present invention usually comprises 1-perfluorohexyl-octane in an amount of at least 90 wt.-%, preferably in an amount of from 95 to 100 wt.-%, more preferably in an amount of 97 to 99.95 wt.-% and even more preferred in an amount of from 98.5 to 99.9 wt.-% based on the final dosage form. Accordingly, in a preferred embodiment of the present invention the pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis, preferably posterior blepharitis essentially consists of 1-perfluorohexyl-octane. In a specific embodiment, of the present invention the pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis, preferably posterior blepharitis consists of 1-perfluorohexyl-octane. In this particular case the pharmaceutical compositions for use according to the present invention may, as an alternative, be referred to as “pharmaceutical preparation” or “medicinal product”. The pharmaceutical composition for use according to the present invention is usually provided as a clear solution, preferably in sterilized form.
In a further preferred embodiment, the pharmaceutical compositions for use according to the present invention are substantially free of a dissolved pharmacological active ingredient which is not 1-perfluorohexyl-octane. As used herein, the term “pharmacological active ingredient” refers to any type of pharmaceutically active compound or drug, i.e. one that produces a pharmacological effect and that may accordingly be useful in the prevention, diagnosis, stabilization, treatment, or generally speaking, the management of a condition or disease. Although free of (other) pharmacologically active ingredients the pharmaceutical compounds for use according to the present invention, however have beneficial therapeutic effects in the treatment or prevention of anterior or posterior blepharitis.
Furthermore, the pharmaceutical composition for use according to the present invention, however may or may not comprise small amounts of 2-perfluorohexyl-octane, which, depending on the source or preparation method may or may not be present in an amount of usually up to 3 wt.-%, preferably in an amount from 0.1 to 2.0 wt.-%, more preferably in an amount of 0.1 to 1 wt.-% of the final dosage form.
In one preferred embodiment, the pharmaceutical compositions for use according to the present invention are substantially free of water and/or substantially free of a preservative. As understood herein, the term ‘substantially free’ in reference to a composition constituent refers to the presence of said constituent in no more than trace amounts and that if present in trace amounts the constituent provides no technical contribution to the composition.
The pharmaceutical compositions for use according to the present invention are commercially available and may be purchased under the tradename NovaTears® (Novaliq GmbH, Germany) or EvoTears® (URSAPHARM Arzneimittel GmbH, Germany).
The pharmaceutical composition for use according to the present invention may be topically administered to a surface of the eye, into a lower eyelid, to the lacrimal sac or to an ophthalmic tissue of a patient in need thereof. Usually, single droplets of the pharmaceutical composition, preferably single droplets of NovaTears®, are administered directly to the surface of the eye. Preferably, the droplets may be administered into a pocket of the eyelid that may be formed by gently pulling down the lower eyelid of an eye.
The droplets of the pharmaceutical composition, especially the droplets of the pharmaceutical composition consisting essentially of 1-perfluorohexyl-octane usually have a volume of about 8 to 15 μL, often a volume of about 10 μl per droplet. In most cases the present pharmaceutical compositions are administered in an amount of 1 to 6 droplets, preferably 3 to 4 droplets to each eye per day corresponding to a daily overall volume of the pharmaceutical composition of 30 to 40 μl per eye. Usually, the pharmaceutical is administered at a dose of 1 droplet per eye per administration with 3 to 4 administrations per day. Depending on the intensity as well as other factors, such as, for example, associated other diseases as described above, however, modes and volumes of administration as well as the duration of the treatment can vary significantly.
In yet another embodiment of the pharmaceutical composition for use according to the present invention, the anterior or posterior blepharitis may be associated with an underlying clinical condition selected from the group consisting of bacterial infections, seborrheic dermatitis, clogged or malfunctioning oil glands in the eyelids, rosacea, allergic reactions and infestation with eyelash mites and/or lice. Allergic reactions may be caused by or attributed to for example, eye medications, to contact lens solutions or to certain eye makeup.
In yet another embodiment, the pharmaceutical composition for use according to the present invention, the anterior or posterior blepharitis, preferably the posterior blepharitis to be treated, prevented or ameliorated is associated with mybomian gland dysfunction and/or dry eye disease (DED).
In a further embodiment, the pharmaceutical composition for use according to the present invention is not administered to patients wearing contact lenses.
In a further embodiment, it has been found advantageous that the pharmaceutical composition for use in the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis, preferably posterior blepharitis, or symptoms associated therewith, the pharmaceutical composition is administered to a patient having a Tear Film Break-Up Time (TFBUT; Shapiro A., et. al. Am J Ophthalmol. 1979 October; 88(4):752-7) of up to 10 s, preferably of up to 6 s. (Shapiro A., et. al. Am J Ophthalmol. 1979 October; 88(4):752-7).
Furthermore, it has been found advantageous that the pharmaceutical composition for use according to the present invention is administered to a patient having an Ocular Surface Disease Index in the range of from 16 to 55 (Schiffman, R. M., et. al, Arch. Ophthalmol. 118:615-621, 2000).
In yet another embodiment, it has been found advantageous that the pharmaceutical composition for use according to the present invention is administered to a patient having a Schirmer I Test value (Shapiro A., et. al. Am J Ophthalmol. 1979 October; 88(4):752-7) of at least 2 mm (2 mm and above), preferably 5 mm and above as recorded during a 5 min test period.
Furthermore, it has been found advantageous that the pharmaceutical composition for use according to the present invention is administered to a patient having an added peripheral corneal and conjunctival Oxford staining grade of up to 10. (Bron, A. J., et. al., Cornea. 22:640-650, 2003.)
Preferably, in yet another embodiment, it has been found advantageous that the pharmaceutical composition for use according to the present invention is administered to a patient having a Tear Film Break-Up Time of up to 10 s, an Ocular Surface Disease Index in the range of from 16 to 55, a Schirmer I Test value of at least 2 mm, and an added peripheral corneal and conjunctival Oxford staining grade of up to 10.
In a further aspect, the present invention as described in detail above relates to a method of treating a patient suffering from anterior or posterior blepharitis or symptoms associated therewith, comprising topically administering a pharmaceutical composition comprising or essentially consisting of 1-perfluorohexyl-octane to the eye of that patient. In a specific embodiment, the method comprises topically administering a pharmaceutical composition consisting of 1-perfluorohexyl-octane to the eye of that patient. In this aspect also, the treatment of posterior blepharitis is preferred according to all embodiments outlined above for the first aspect of the invention.
In yet another aspect, the present invention relates to the use of a pharmaceutical composition as described in detail above comprising or essentially consisting of 1-perfluorohexyl-octane for the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith. In specific embodiment, the present invention relates to the use of a pharmaceutical composition consisting of 1-perfluorohexyl-octane for the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith. Likewise, in this aspect of the invention the treatment of posterior blepharitis is preferred in accordance with all embodiment outlined above for the first aspect of the invention.
In another aspect, the present invention relates to a pharmaceutical kit for the therapy, treatment, prevention or amelioration of anterior or posterior blepharitis or symptoms associated therewith, comprising
According to item a) of this aspect of the invention the pharmaceutical kit comprises a pharmaceutical composition for use as described above for the first aspect of the present invention. In a specific embodiment, in item a) the pharmaceutical composition is a pharmaceutical composition for use according to the first aspect of the invention consisting of 1-perfluorohexyl-octane.
A container as used in connection with item b) of this aspect of the invention can be provided in any suitable form as a container for single use holding a single dose of the pharmaceutical composition or as a container for multiple uses holding a plurality of single doses. Preferably, the container comprises a dispensing means which allows for dropwise topical administration of the pharmaceutical composition to a surface of the eye of a patient. In one embodiment, the container comprising a dispensing means may be a conventional dropper bottle such as a bottle made of glass or a thermoplastic elastomer with a suitable dispensing means or single-use droppers.
In a further preferred embodiment of this aspect of the invention, the dispensing means comprises a dropper of dimensions such as to dispense droplets having a volume of about 8 to 15 μL, preferably of about 10 μl. With a small droplet volume, precise dosing to the eye can be achieved and an excess amount of discharge of a substantial fraction of the composition from the eye subsequent to administration can be avoided.
Directions for use of the pharmaceutical composition according to item c) of this aspect of the invention can be provided in any suitable form such as, for example, as an enclosed label or instruction leaflet in printed or other readable form.
Alternatively, the directions for use can be provided in electronic or computer readable form, such as a barcode or a QR-code.
The following examples serve to illustrate the invention however these are not to be understood as restricting the scope of the invention.
A prospective, uncontrolled, open-label, multi-center observational study was conducted with a total of 72 (53 female, 19 male) patients included, with 1 to 20 patients per site. Two patients were lost for follow-up during the study. Patients to be included had to fulfill following criteria:
Among those, patients fulfilling the following criteria were not included in the study:
Patients selected as described above were administered 1-perfluorohexyloctane (F6H8) eye drops, manufactured under the tradename “NovaTears®” (Novaliq GmbH, Heidelberg, Germany) for a period of 7 weeks. Said formulation consists essentially of 1-perfluorohexyloctane (F6H8), it is water-free and contains no additional preservatives or ingredients. A dose of 3 to 4 droplets (corresponding to to 40 μl, 10 μl per drop) per eye and day were administered topically to the eye, with 1 droplet being administered as a single dose. NovaTears® single droplets were administered directly to the surface of the eye into a pocket that was formed by gently pulling down the lower eyelid. Assessment of the eyes treated was performed once before the start of NovaTears® administration (baseline) and once after 7 weeks of treatment (follow-up).
Assessment of Blepharitis
Anterior blepharitis involves inflammation of the lid margin anterior to the gray line and is usually concentrated around the eyelashes and follicles. Posterior blepharitis involves inflammation of the posterior lid margin. The severity of anterior and posterior blepharitis was rated separately for each eye by selecting one of the following ratings: “none”, “+”, “++”, “+++” (with “+++” indicating most severe blepharitis anterior or posterior).
Assessment of Anterior Blepharitis
Table I summarizes the assessment of 122 eyes from 61 patients, with the results of right and left eyes combined. Herein, the evaluation of anterior blepharitis showed that patients clearly profit from the treatment with 1-perfluorohexyloctane (F6H8). The severity of blepharitis was observed to be decreased for all patients, including patients with blepharitis severity scores indicated as “++” and “+”.
Assessment of Posterior Blepharitis
Table II summarizes the assessment of 122 eyes from 61 patients, with the results of right and left eyes combined. Herein, the assessment of posterior blepharitis showed that the severity of blepharitis was observed to be decreased for all patients after treatment with 1-perfluorohexyloctane, including patients with blepharitis severity scores rated as “++” and “+”. The most significant reduction in the severity of posterior blepharitis after treatment with 1-perfluoro-hexyloctane (F6H8), however, was found in patients with the most severe posterior blepharitis rated as “+++”.
The observed changes in severity of anterior and posterior blepharitis between baseline and follow-up for both eyes combined are shown in Table III and Table IV (total sample size=122 eyes (61 patients)). A Wilcoxon Rank Sum test (n=61 each) showed significant changes to the severity score both for anterior blepharitis (right eye: p=0.0040; left eye: p=0.020) and posterior blepharitis (right eye and left eye: p<0.0001).
Lid Margin Assessment
As a further parameter abnormal lid margin features, such as teleangiectasia, plugging and lid swelling were assessed in the study. Assessment was performed for each eye separately. As summarized in Table V lid margin assessment revealed that all abnormal lid margin features such as teleangiectasia, plugging and lid swelling were significantly reduced after treatment with 1-perfluorohexyloctane (F6H8).
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| 16190138 | Sep 2016 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
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| PCT/EP2017/073697 | 9/20/2017 | WO |
| Publishing Document | Publishing Date | Country | Kind |
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| WO2018/054932 | 3/29/2018 | WO | A |
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| 1 152 749 | Nov 2001 | EP |
| 0 939 655 | Jun 2002 | EP |
| 2 110 126 | Oct 2009 | EP |
| 2 332 525 | Jun 2011 | EP |
| 2 335 735 | Jun 2011 | EP |
| 2 462 921 | Jun 2012 | EP |
| S6452722 | Feb 1989 | JP |
| 2000511157 | Aug 2000 | JP |
| 2001158734 | Jun 2001 | JP |
| 2008505177 | Feb 2008 | JP |
| 2011006348 | Jan 2011 | JP |
| WO 1995033447 | Dec 1995 | WO |
| WO 9640052 | Dec 1996 | WO |
| WO 9712852 | Apr 1997 | WO |
| WO 1998005301 | Dec 1998 | WO |
| WO 0010531 | Mar 2000 | WO |
| WO 00024376 | May 2000 | WO |
| WO 00054588 | Sep 2000 | WO |
| WO 200249631 | Jun 2002 | WO |
| WO 2005018530 | Mar 2005 | WO |
| WO 2005099718 | Oct 2005 | WO |
| WO 2005099752 | Oct 2005 | WO |
| WO 2005123035 | Dec 2005 | WO |
| WO 2006007510 | Jan 2006 | WO |
| WO 2006042059 | Apr 2006 | WO |
| WO 2006048242 | May 2006 | WO |
| WO 2007052288 | May 2007 | WO |
| WO 2008060359 | May 2008 | WO |
| WO 2009013435 | Jan 2009 | WO |
| WO 2010062394 | Jun 2010 | WO |
| WO 2010146536 | Dec 2010 | WO |
| WO 2011009436 | Jan 2011 | WO |
| WO 2011073134 | Jun 2011 | WO |
| WO 2011113855 | Sep 2011 | WO |
| WO 2012052418 | Apr 2012 | WO |
| WO 2012062834 | May 2012 | WO |
| WO 2012093113 | Jul 2012 | WO |
| WO 2012121754 | Sep 2012 | WO |
| WO 2012160179 | Nov 2012 | WO |
| WO 2012160180 | Nov 2012 | WO |
| WO 2013110621 | Aug 2013 | WO |
| WO 2014041055 | Mar 2014 | WO |
| WO 2014041071 | Mar 2014 | WO |
| WO 2014154531 | Oct 2014 | WO |
| WO 2015011199 | Jan 2015 | WO |
| WO 2018055101 | Apr 2018 | WO |
| WO 2018115097 | Jun 2018 | WO |
| Entry |
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| Number | Date | Country | |
|---|---|---|---|
| 20190274970 A1 | Sep 2019 | US |
