Semifluorinated compounds and compositions thereof
阅读说明：本技术 半氟化化合物和其组合物 (Semifluorinated compounds and compositions thereof ) 是由 拉尔夫·格里伦恩伯杰 弗兰克·洛施尔 迪特尔·谢勒 哈特穆特·沃斯 于 2016-09-29 设计创作，主要内容包括：本发明涉及包含半氟化化合物的组合物,以及其作为药物局部施用于眼的用途。(The present invention relates to compositions comprising semifluorinated compounds and their use as medicaments for topical administration to the eye.)
1. Composition comprising CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
2. The composition of claim 1 comprising at least about 80% CF by weight3(CF2)5(CH2)7CH3。
3. The composition of claim 1 comprising up to about 25% by weight CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
4. The composition of any of the preceding claims comprising about 97% CF by weight3(CF2)5(CH2)7CH3And up to about 3 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
5. The composition of any one of the preceding claims, formulated as a clear liquid solution.
6. The composition of any one of the preceding claims, which is substantially free of:
(a) a polymer,
(b) perfluorinated compounds, and/or
(c) A dissolved pharmacologically active ingredient.
7. Composition according to any one of the preceding claims, having a dynamic viscosity at ambient temperature and pressure not exceeding 10 mPa-s, and preferably not exceeding 4 mPa-s.
8. A composition according to any one of the preceding claims for use as a medicament.
9. The composition of claim 8, wherein the composition is topically applied to the lacrimal sac, within the lower eyelid, to the surface of the eye, or to ocular tissue.
10. The composition of claim 9, comprising administering the composition up to 4 times per day.
11. The composition according to any one of claims 8 to 10 for use in the treatment of keratoconjunctivitis sicca and/or meibomian gland dysfunction or a symptom or condition associated therewith.
12. The composition according to any one of claims 8 to 11 for use in the treatment of corneal injury.
13. The composition according to any one of claims 8 to 11 for use as a lubricant for the surface of the eye.
14. A kit comprising a composition according to any preceding claim and a container for holding the composition, wherein the container comprises a dispensing device suitable for topical application of the composition to the lacrimal sac, into the lower eyelid, to the surface of the eye, or to ocular tissue.
15. The kit of claim 14, wherein the dispensing device comprises a dropper size to dispense droplets having a volume of 8 to 15 μ L.
Technical Field
The present invention is in the field of compositions comprising semifluorinated compounds and their use in ocular administration.
Background
Semifluorinated alkanes are compounds comprising at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. Described of the general formula CF3(CF2)n(CH2)mCH3Wherein n and m are integers representing the number of carbon atoms in each segment, for use in various applications, such as commercially for spreading and recoating the retina, as long-term tamponades for vitreous humor replacement (h.meiert et al, European Journal of opthalmology, vol.10(3), pp.189-197, 2000), and as eluates of residual silicone oils after vitreoretinal surgery.
Formula CF3(CF2)n(CH2)mCH3The semifluorinated alkanes of (a) are described in other applications.
WO2011/073134 discloses at formula CF3(CF2)n(CH2)mCH3Optionally in the presence of a co-solvent such as ethanol, wherein the semifluorinated alkane serves as a liquid drug delivery vehicle for the cyclosporin for the topical treatment of keratoconjunctivitis sicca.
WO2014/041055 describes the formula CF3(CF2)n(CH2)mCH3(which may optionally be denoted as F (CF)2)n(CH2)mH) Mixtures of semifluorinated alkanes of (a). These mixtures are described as being ophthalmically useful as tear film substitutes or for treating patients with dry eye and/or meibomian gland dysfunction.
The nomenclature commonly used for semifluorinated compounds having linear and unbranched segments is FnHm, where F represents the perfluorinated hydrocarbon segment, H represents the non-fluorinated segment, and n and m define the number of carbon atoms of the corresponding segment. For example, F3H3 is used for perfluoropropylpropane CF3(CF2)2(CH2)2CH3I.e., 1-perfluoropropylpropane.
However, formula CF3-(CF2)5-CH(CH3)-(CH2)5-CH3And comprises CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Have not been described, particularly for ophthalmic applications. It is therefore an object of the present invention to provide compositions comprising such compounds, particularly in terms of their use in compositions for ophthalmic use.
Disclosure of Invention
In a first aspect, the present invention relates to a composition comprising CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3The composition of (1). In particular, the present invention relates to compositions comprising at least about 80 weight percent CF3(CF2)5(CH2)7CH3And, in another aspect, to a composition comprising up to about 25 wt% CF3-(CF2)5-CH(CH3)-(CH2)5-CH3The composition of (1).
In another aspect, the invention relates to a composition comprising said compound in the form of a transparent liquid solution.
In yet another aspect, the present invention provides compositions comprising CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3For the treatment of dry eye and/or meibomian gland dysfunction and any symptoms or conditions associated with these conditions.
In another aspect, the invention provides a method of treating dry eye and/or any symptom or condition associated with meibomian gland dysfunction comprising topically applying the composition to the lacrimal sac, into the lower eyelid, to the surface of the eye, or to ocular tissue.
In yet another aspect, the invention provides a kit comprising a composition of the invention in a container comprising a dispensing device suitable for topical administration of the composition to the eye or eye tissue.
Drawings
FIG. 1 is a drawing depicting a reaction from a compound CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Evaporation time of the constituent composition and Compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Graph of percentage as a function of composition.
FIG. 2 is a drawing depicting a reaction from a compound CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Measured refractive index of the constituent composition and Compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Graph of percentage as a function of composition.
FIG. 3 is a representation of a slave CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Schematic representation of the results obtained comparing Ex vivo (Ex vivo) eye irritation test (EVEIT) of the composition of (a), hyaluronic acid standard reference and 0.01% BAC positive control.
Detailed Description
In a first aspect, the present invention relates to a composition comprising CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3The composition of (1).
Based on hydrocarbon alkanes as roots, compounds CF3-(CF2)5-CH(CH3)-(CH2)5-CH3Also can be called as2-perfluorohexyloctane. The compounds have a stereogenic center at the 2-alkyl position. As understood herein, a general formula includes both enantiomers, enriched mixtures of both enantiomers, and racemic mixtures. Compound CF3(CF2)5(CH2)7CH3Or 1-perfluorohexyloctane, or FnHm according to the name F6H8, 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.
Particularly preferred compositions of the invention are those comprising at least about 80% by weight CF3(CF2)5(CH2)7CH3Those of (a). In other embodiments, the composition comprises at least about 90% or at least about 95% or at least 97% by weight CF3(CF2)5(CH2)7CH3. In another preferred embodiment of the invention, the composition comprises up to about 25% by weight CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. In other embodiments, the composition comprises up to about 10 wt.%, or up to about 5 wt.%, or up to about 3 wt.% of the compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
As used herein, the term wt% refers to the weight of a component as a percentage of the weight of the composition as a whole. The term preceding a parameter such as wt% includes about the exact value as well as any value that falls within the degree of variability typically observed in the measurement and determination of the parameter, including those determined using standard techniques and equipment known in the art and in the field.
In a further preferred embodiment, the composition of the present invention comprises about 97% by weight CF3(CF2)5(CH2)7CH3And up to about 3 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. In yet another embodimentThe composition may comprise about 98 wt% CF3(CF2)5(CH2)7CH3And up to about 1 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
The compositions comprising these semifluorinated alkanes as defined above are preferably in liquid form and are preferably formulated as transparent liquid solutions. Transparent in this case means that there are no dispersed solid or liquid particles that cause turbidity. In other words, the clear solution is a pure single phase liquid system, with only small and technically irrelevant amounts of particulate impurities that may be present.
In optional embodiments, the composition may be formulated for administration as a gel, suspension, microemulsion, or spray. Preferably, the composition is provided in sterile form.
Furthermore, the composition is preferably formulated as a liquid solution that exhibits a refractive index close to that of water of 1.333 at Room Temperature (RT). In a particularly preferred embodiment, the liquid solution has a refractive index in the range of about 1.30 to about 1.35 at 20 ℃, as measured by a refractometer.
The compositions as defined above may also contain other excipients as required or available, for example one or more acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers and, if desired, preservatives. In a preferred embodiment, the composition as described herein is substantially free of water and/or substantially free of preservatives, such as benzalkonium chloride (benzalkonium chloride).
In another embodiment of the present invention, the above composition is substantially free of the following: (a) a polymer, (b) a perfluorinated compound, and/or (c) a dissolved pharmacologically active ingredient that is not a semifluorinated alkane. Such compositions are also preferably formulated as clear liquid solutions. In another embodiment, the composition as described in any of the embodiments herein may be substantially free of any form of pharmacologically active ingredient and which is not a semifluorinated alkane.
As understood herein, the term "substantially free" with respect to a component of a composition means that the component is present in an amount not exceeding trace amounts, and if present in trace amounts, the component does not contribute technically to the composition.
Examples of polymers that are preferably not present in the compositions of the present invention include silicone polymers (polymerized siloxanes), polyether polymers and fluorinated or perfluorinated derivatives thereof.
Examples of perfluorinated compounds (i.e., compounds in which all hydrogen atoms are substituted with fluorine and which are preferably absent in the compositions of the present invention) include perfluoroalkanes, such as perfluorodecalin, and halogenated perfluoroalkanes, such as perfluorooctylbromide.
The compositions of the present invention are also substantially free of dissolved pharmacologically active ingredients (which are not semifluorinated alkanes). As used herein, the term "pharmacologically active ingredient" refers to any type of pharmaceutically active compound or drug, i.e., a pharmaceutically active compound or drug that produces a pharmacological effect and is therefore useful for prophylaxis, diagnosis, stabilization, treatment, or, in general, for management of a condition or disease.
In a preferred embodiment, the composition according to the invention consists essentially of CF3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3And (4) forming. Preferably, the composition consists essentially of about 97 weight percent CF3(CF2)5(CH2)7CH3And up to about 3 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3And (4) forming.
As used herein, the term "consisting essentially of is a so-called closed language meaning that only the components mentioned are present. Rather, the terms "comprising," "including," and "containing" are used herein as so-called open language, which means that other ingredients may also be present.
However, the compounds of the present invention and compositions containing them have beneficial therapeutic effects at the site of administration even if they do not contain other pharmacologically active ingredients.
The composition as defined above is preferably formulated to have a dynamic viscosity, measured at standard ambient temperature and pressure (25 ℃, 1 atm), of not more than 10 mPa-s, and preferably not more than 4 mPa-s. Preferably, the composition has a dynamic viscosity of 1 to 4 mPa-s. The viscosity of the composition can be determined using any standard viscometer apparatus known in the art, for example using a glass tube or capillary viscometer.
The compositions described herein are useful for medical applications, particularly for ophthalmology, particularly for topical administration to the eye, e.g., to the lacrimal sac, within the lower eyelid, to the surface of the eye, or to any ocular tissue or anatomical structure associated with the eyeball that may be used for topical administration.
It has been found that the compositions of the present invention are beneficial for use in the treatment of diseases and conditions that would benefit from the stabilization of the tear film and tear film lipid layer and the lubrication of the ocular surface. Thus, the compositions of the present invention are particularly useful in the treatment of dry eye disease (keratoconjunctivitis sicca) and/or Meibomian Gland Dysfunction (MGD) and any symptom thereof or any symptom associated therewith.
Dry eye, also known as keratoconjunctivitis sicca, can be divided into two categories, namely water-deficient dry eye and evaporative dry eye. These conditions are not necessarily mutually exclusive. Water-deficient dry eye is commonly observed in patients with sjogren's syndrome or patients with lacrimal insufficiency, lacrimal obstruction, or reflex hyposecretion. Evaporative dry eye, on the other hand, has a different root cause and is associated with increased/abnormal evaporative loss of the tear film, for example due to meibomian gland disease, eyelid aperture disease, blinking disease or ocular surface disease.
Symptoms of dry eye include dry eyes, itching, gritty or foreign body sensation; pain, soreness, stinging or burning; itching, increased demand for blinking eyes, eye fatigue, photophobia, blurred vision, redness and inflammation of eye tissues, excessive mucus discharge and crusting/coagulation, contact lens intolerance, and excessive reflex tearing.
Meibomian Gland Dysfunction (MGD) refers to a condition in which the meibomian glands are unable to secrete sufficient oil, or the oil secretion is of poor or abnormal quality. Typically, the oil gland opening may be blocked or obstructed, resulting in less oil being secreted by the gland. The oil secreted from the glands may be granular (hard-skinned) or otherwise abnormal, and may irritate the eyes or ocular tissues. In the early stages, patients are often asymptomatic, but MGD can cause or exacerbate dry eye symptoms and blepharitis if not treated promptly. The oil glands become clogged due to thickening of the secretions. The chronically obstructed glands eventually become unable to secrete oil, which may lead to permanent changes in the tear film and dry eyes.
Symptoms of meibomian gland dysfunction include dryness, burning pain, itching, sliminess/crusting, tearing (watering), light sensitivity, red eye, foreign body sensation, shot/hordeolum or intermittent blurred vision.
In a preferred embodiment, the compositions of the present invention as described above are used for topical ocular treatment of evaporative dry eye and/or Meibomian Gland Dysfunction (MGD), and for the treatment or prevention of any one of the symptoms or conditions associated therewith. In another embodiment, a composition as described herein can be used as a lubricant on the surface of the eye to ameliorate one or more symptoms associated with dry eye and moisturize the surface of the eye.
In another preferred embodiment of the invention, the compounds and compositions thereof as described above are used for the topical ocular treatment of corneal lesions. Thus, the compounds and compositions are actively supporting the corneal healing process of corneal injury (e.g., corneal erosion).
In a further embodiment, treatment of conditions (e.g., corneal damage) and diseases and their associated symptoms as described above is also preferably performed by a method of administering to a patient in need thereof an effective amount of a composition as described above, including CF, as also described above3(CF2)5(CH2)7CH3And CF3-(CF2)5-CH(CH3)-(CH2)5-CH3For example, wherein the composition comprises up to about 25% by weight CF3-(CF2)5-CH(CH3)-(CH2)5-CH3。
The advantages of the above compounds and compositions in the context of use according to the present invention are believed to be related to their properties which are particularly suitable for ophthalmic applications. The refractive index of the compounds of the present invention is very close to that of water, meaning that there is no or minimal effect on the vision of the patient after administration, unlike ophthalmic compositions based on oily vehicles which may cause blurred vision upon administration. The generally low viscosity and low surface tension of these compounds and in particular their high wetting and spreading ability also ensure that they are quickly contained and adapted for administration on the surface of the eye.
As will be more clearly shown in the examples below, the compositions of the invention were found to be biocompatible and did not show significant cytotoxic effects. Furthermore, these compositions have been shown not only to have good tolerability in the eye and no impact on vision, but also to provide beneficial effects in terms of ocular lubrication and tear film stabilization in the form of relief of symptoms in patients with mild to moderate symptoms associated with dry eye. Patients with dry eye and/or dysfunctional meibomian glands often express opaque and thicker meibum, which may result in an abnormal lipid layer in the tear film. Without wishing to be bound by theory, it is believed that the physicochemical properties of the compounds comprised in the compositions of the invention may play a role in stabilizing the lipid layer of the tear film, for example by solubilizing certain lipid components or improving the fluidity of the lipid layer, and may provide a lubricating effect to the eye.
In another aspect, the present invention provides a method of treating dry eye and any symptoms or conditions associated therewith, comprising topically applying a composition of the present invention to the lacrimal sac, into the lower eyelid, to the surface of the eye, or to ocular tissue. Preferably, the composition may be administered to the eye or eye tissue up to four times per day.
Furthermore, the present invention provides a kit comprising any one of the compositions as described above and a container for containing the composition. The container preferably comprises a dispensing means, such as an eye dropper, suitable for topical application of the composition to the eye capsule, lower eyelid to the eye or eye tissue.
In a further preferred embodiment, the dispensing means comprises a dropper of such a size as to dispense droplets of a volume of from 8. mu.L to 15. mu.L, preferably from about 8. mu.L to 12. mu.L, more preferably of a volume of about 10. mu.L. With small droplet volumes, precise dosing to the eye can be achieved and excessive expulsion of a substantial portion of the composition from the eye after administration can be avoided.
In addition, the compositions of the present invention may be administered to the eye or eye tissue up to four times per day; preferably one drop per dose (about 8 to 15 μ L in volume) is administered per eye. Treatment may last for at least six weeks. In one embodiment of the invention, the composition is administered to each eye 1 drop of a dose in a volume of about 8 to 15 μ L, preferably about 10 μ L, 3 to 4 times per day.
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