The present invention relates to a method for topical administration of ophthalmic compositions in a dropwise manner, preferably for topical administration of ophthalmic compositions comprising semifluorinated alkanes (SFAs). Further, the present invention relates to the use of said methods in the prevention or treatment of ocular diseases or disorders or any symptoms or conditions associated therewith. In a further aspect, the present invention relates to a kit comprising a drop dispenser at least partially filled with a liquid composition for the use in such a method and directions for use of said drop dispenser.
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1. A method for dropwise topical administration of a liquid composition (2), comprising the steps of:
a) providing a drop dispenser (1), comprising:
a container part (1B) with an interior volume partially filled with the liquid composition (2) and a gaseous phase (3) filling the remainder of the interior volume at ambient pressure, the container part (1B) having a displaceable section (1C) and optionally a substantially stationary section, and
a dropper part (1A) in physical connection and in fluid communication with the interior volume of the container part (1B), comprising an outflow channel (5), connecting the interior volume of the container part (1B) to the environment;
b) exerting a first force to the displaceable section (1C) of the container part (1B) of the drop dispenser (1) while holding the drop dispenser (1) in an upright position in which the outflow channel (5) is not in contact with the liquid composition (2), thereby reducing the interior volume of the container part (1B) and forcing the gaseous phase (3) of the interior volume at least partially out of the drop dispenser (1) into the environment;
c) inverting the drop dispenser (1) to an inverted position in which the liquid composition (2) is in contact with the outflow channel (5);
d) releasing said first force from the displaceable section (1C) of the container part (1B) at least partly, thereby reducing the pressure inside the container part (1B) below ambient pressure; and
e) exerting a second force to the displaceable section (1C) of the container part (1B), while still holding the drop dispenser in the inverted position in which the liquid composition (2) is in contact with the outflow channel (5), thereby raising the pressure inside the interior volume of the container part (1B) above ambient pressure and releasing the liquid composition (2) dropwise from the dropper part (1A) of the drop dispenser (1).
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f) dropwise administering the liquid composition (2) to the eye, eye lid, eye sac or an ophthalmic tissue of a subject in need thereof.
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This application is a reissue of application Ser. No. 16/312,855, filed as application No. PCT/EP2017/065163 on Jun. 21, 2017, now U.S. Pat. No. 10,507,132.
This application is a reissue of Ser. No. 16/312,855, filed on Dec. 21, 2018, now U.S. Pat. No. 10,507,132, which is a U.S. national stage application filed under 35 U.S.C. § 371 of International Application No. PCT/EP2017/065163, filed on Jun. 21, 2017, which claims priority to, and the benefit of, European Application No. 16176074.9, filed Jun. 23, 2016, and European Application No. 16180202.0 filed Jul. 19, 2016, and European Application No. 17169837.6, filed May 6, 2017, the contents of each of which are incorporated herein by reference in their entireties.
The present invention relates to a method for topical administration of ophthalmic compositions in a dropwise manner, preferably for topical administration of ophthalmic compositions comprising semifluorinated alkanes (SFAs). Further, the present invention relates to the use of said methods in the prevention or treatment of ocular diseases or disorders or any symptoms or conditions associated therewith. In a further aspect, the present invention relates to specific designs of a drop dispenser and to a kit comprising a drop dispenser at least partially filled with a liquid composition for the use in such a method and directions for use of said drop dispenser.
Semifluorinated alkanes (SFAs) are linear or branched compounds composed of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. Semi-fluorinated alkanes have been described for various applications, for example commercially for unfolding and reapplying a retina, for long-term tamponade as vitreous humour substitute (H. Meinert et al., European Journal of Ophthalmology, Vol. 10(3), pp. 189-197, 2000), and as wash-out solutions for residual silicon oil after vitreo-retinal surgery.
WO2011/073134 discloses solutions of cyclosporine in semifluorinated alkanes of the formula CF3(CF2)n(CH2)mCH3, optionally in the presence of a co-solvent such as ethanol, wherein the semifluorinated alkane functions as a liquid drug delivery vehicle for cyclosporine for topical treatment of keratoconjunctivitis sicca.
WO2014/041055 describes mixtures of semifluorinated alkanes of the formula CF3(CF2)n(CH2)mCH3. These mixtures are described to be ophthalmically applicable as tear film substitutes or for treating patients with dry eye syndrome and/or meibomian gland dysfunction.
It is known that the volume of drug instilled into the eye is of particular importance as it is one of the sources of drug response variation (German E. J. et. al, Eye 1999, 93-100).
Conventional eye drops are usually water-based compositions. When administering such water-based eye drops to the eye, the patient usually inverts the (eye-)dropper bottle that holds the ophthalmic composition and exerts a pressuring force to the flexible bottle in order to force one or more drops to be released from the (eye-)dropper bottle. This is usually done by simply squeezing the inverted eyedropper bottle resulting in the release of one or more drops (the aforementioned method is referred to as “pressure method” throughout this document).
Said conventional administration method (pressure method) known from water-based ophthalmic compositions is not suitable or not reliably suitable for administering ophthalmic compositions comprising SFAs, since SFA-comprising drops may be released from the eyedropper in a rather uncontrolled manner. Without being bound by theory, this is attributed to the interplay of the special surface properties of the amphiphilic SFAs, namely the interplay of high spreading capabilities, high density and/or low surface tension.
Furthermore, also an administration method that relies only on the inversion of the (eye-) dropper bottle without exerting a pressuring force to the bottle (the aforementioned method is referred to as “inversion method” throughout this document) is not suitable or not reliably suitable for administering ophthalmic compositions comprising SFAs, since SFA-comprising drops are also released from the eyedropper in a highly uncontrolled manner employing said inversion method. Again, this is attributed to the interplay of the special surface properties of the amphiphilic SFAs, namely the interplay of high spreading capabilities, high density and/or low surface tension.
Thus, it is an object of the present invention to establish a reliable method for the controlled administration, preferably for the controlled topical administration of compositions comprising semifluorinated alkanes (SFAs) to the eye in a drop-by-drop manner.
In a first aspect, the invention relates to a method for dropwise topical administration of a liquid composition (2), comprising the steps of:
In a second aspect, the invention relates to the use of a method according to the first aspect of the invention for preventing or treating an ocular disease or disorder or any symptoms or conditions associated therewith.
In a third aspect, the invention relates to a method of treating an ocular disease or disorder or any symptoms or conditions associated therewith, comprising dropwise administration of a liquid ophthalmic composition according to the method according to the first aspect of the invention.
In a fourth aspect, the present invention relates to a drop dispenser (1), comprising
In a fifth further aspect, the invention relates to a kit comprising
Surprisingly, it was found that the administration of drops or droplets of compositions comprising semifluorinated alkanes to the eye is preferably performed utilizing an underpressure in the (eye-)dropper bottle. By generating an underpressure in the interior volume of the dropper bottle, uncontrolled release of said compositions comprising semifluorinated alkanes contained in the dropper bottle is effectively prevented and reliable administration of said compositions in a dropwise manner is safeguarded. This allows for reproducible dosing of compositions comprising SFAs to the eye, including compositions comprising pharmaceutical active ingredients as well as compositions comprising no pharmaceutical active ingredients. The reliable administration is especially important to the administration of therapeutic compositions comprising semifluorinated alkanes since the corresponding drop volumes (approximately in the range of 5 to 15 μl, in many cases in the range of 8 to 15 μl) are much smaller (as compared to aqueous eye drops) and are thus more prone to overdosing or dose variation.
Further, the inventors found that the method of the present invention, employing an underpressure in the dropper bottle, not only works for compositions comprising SFAs, but also for conventional water-based ophthalmic compositions. Thus, the inventors of the present invention surprisingly found a universal administration method for ophthalmic compositions, including water-free (e.g. SFA-based) or water-based compositions. By using the method of the first aspect of the present invention (said method is also referred to as “underpressure method” throughout this document) ophthalmic compositions can be administered to the eye in a highly-controlled fashion, which safeguards the reliably and reproducibly administration of a defined dose of said ophthalmic compositions to the eye.
Even further, the inventors found that the method according to the first aspect of the present invention, employing an underpressure, works reliable also below ambient temperature, namely with ophthalmic compositions that were stored below ambient temperature (e.g. refrigerated compositions), which is problematic when using the pressure method as well as the inversion method, especially in the case of SFA-based compositions. Employing the present invention, said compositions may be directly administered without the need to equilibrate the composition to ambient temperature before use. The method according to the first aspect of the present invention (underpressure method) also works regardless of the volume of the headspace (gaseous volume that fills the remainder of the interior volume of the dropper bottle in addition to the liquid (ophthalmic) composition) in the dropper bottle. During ongoing use of the composition, the volume of the headspace is continuously increasing, as the volume of the liquid ophthalmic composition is decreasing. Such increasing headspace volume hampers reliable administration of ophthalmic compositions utilizing the pressure method or inversion method, especially when SFA-based compositions are employed—which is not the case when the underpressure method according the present invention is employed.
The terms “consist of”, “consists of” and “consisting of” as used herein are so-called closed language meaning that only the mentioned components are present. The terms “comprise”, “comprises” and “comprising” as used herein are so-called open language, meaning that one or more further components may or may not also be present.
The term “active pharmaceutical ingredient” (also referred to as “API” throughout this document) refers to any type of pharmaceutically active compound or derivative that is useful in the prevention, diagnosis, stabilization, treatment, or—generally speaking—management of a condition, disorder or disease.
The term “therapeutically effective amount” as used herein refers to a dose, concentration or strength which is useful for producing a desired pharmacological effect.
According to the first aspect the present invention provides a method for dropwise topical administration of a liquid composition (2), comprising the steps a) to e) which will be described in further detail below.
The term “dropwise” as used herein means that a liquid, more specifically the liquid composition of the present invention is provided in a drop-by-drop fashion, which means that one discrete drop, irrespective of its size or volume, is provided or administered at a time and/or that a plurality of drops or droplets, preferably of the liquid composition, is provided in a consecutive manner, one at a time.
Further, according to the present invention, dropwise administration of the liquid composition is performed topically, meaning on the surface, e.g. to the skin or other outer boundary of a human or animal body or any part thereof. Preferably, the liquid composition is topically administered to the eye surface or an eye tissue.
The term “liquid composition” according to the present invention means any water-containing or water-free liquid, solution, emulsion or dispersion, preferably a liquid solution that may be applied to the human or animal body and that may optionally contain one or more active pharmaceutical ingredient (API) as defined above or further compounds like excipients, may optionally contain one or more active pharmaceutical ingredient (API) as defined above or further compounds like excipients, such as organic solvents, lipids, oils, lipophilic vitamins, lubricants, viscosity agents, acids, bases, antioxidants, stabilizers, synergists, coloring agents, thickening agents,—and if required in a particular cases—a preservative or a surfactant and mixtures thereof.
Potentially useful organic solvents include, but are not limited to, glycerol, propylene glycol, polyethylene glycol, ethanol, acetone, ethyl acetate, isopropyl alcohol, pentylene glycol, liquid paraffin, triglyceride oils and hydrofluorocarbons.
Potentially useful lipids or oily excipients include, but are not limited to, triglyceride oils (e.g. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), mineral oil (e.g. petrolatum and liquid paraffin), medium chain triglycerides (MCT), oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, oily cholesterol esters, oily wax esters, glycerophospholipids, sphingolipids, or any oily substance which is physiologically tolerated by the eye.
Potentially useful antioxidants include, but are not limited to, vitamin E or vitamin E derivatives, ascorbic acid, sulphites, hydrogen sulphites, gallic acid esters, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT) or acetylcysteine.
According to step a) of the administration method according to the first aspect of the present invention a drop dispenser (1) is provided. A “drop dispenser” as used herein may be a container, dispenser, applicator or bottle of any suitable kind for handheld use which can hold at least a single dose, preferably multiple doses of the liquid composition and which may be designed of a single piece or multiple pieces or parts and which may typically be made of a material which is essentially inert against the liquid composition to be administered and which may be rigid such as glass (especially when used in a combination with a flexible material) or preferably flexible, such as, for example polyethylene or polypropylene. In a preferred embodiment of the present invention the container part (1B) of the drop dispenser (1) is at least partially made of a flexible polymer, preferably of a flexible thermoplastic polymer.
The drop dispenser provided in step a) of the present invention comprises a container part (1B) and a dropper part (1A). The “container part” is the portion of the drop dispenser which holds the liquid composition to be administered dropwise in the amount of a single dose, preferably however in an amount of multiple doses or drops, typically in an amount of 0.1 to 15 ml, more typically in an amount of 0.1 to 10 ml, even more typically in an amount of 0.1 to 5 ml. The container part holds an interior space or volume which is at least partially filled with the liquid composition to be administered. The container part (1B) also holds a gaseous phase (3) which fills the remainder of the interior volume which is not filled with the liquid composition (2). The gaseous phase typically consists of air or a protective gas or a mixture of air and a protective gas or a mixture of different protective gases and evaporated portions or traces of the components of the liquid composition (2). According to step a) of the present method the gaseous phase (3) as well as the liquid composition (2) is held under ambient pressure, which means that it is under the same pressure as the surrounding atmospheric pressure, at least after the container has been opened.
The container part (1B) of the drop dispenser according to step a) has a displaceable section (1C) and optionally a substantially stationary section. The term “displaceable section” as used herein may be any portion or area of the container part (1B) that may be displaced out of its original position relative to a fixed portion of the drop dispenser, e.g. relative to dropper part of the drop dispenser by an external force applied, for example by pressing, pushing, shifting, tilting or bending out of its original position to a displaced position without affecting the physical integrity of the container part (1B). Preferably the displacement of the displaceable section (1C) of the container part (1B) induces a deformation, preferable a reversible deformation of the container part, in which the inner volume of the container part is reduced. Optionally the container part (1B) may also comprise a stationary or substantially stationary section which is not or substantially not displaced together with the displaceable section when an external force is applied. The stationary section may or may not be present and may be a separate part connected to the displaceable section or may be a portion of the displaceable section which may not be displace relative to fixed portion of the drop dispenser.
The drop dispenser provided in step a) of the present invention also has a dropper part (1A). The “dropper part” is the portion of the drop dispenser through which the liquid composition (2) is discharged from the container part (1B) and subsequently administered. It is physically connected to the container part (1B) and connects the interior volume of the container part (1B) to the environment through an outflow channel (5) through which the liquid composition (2) to be administered is discharged. The outflow channel may optionally comprise a drop brake channel (6) which elongates the outflow channel further into the interior volume of the container part (1B).
According to step b) of the administration method of the present invention a first force is exerted to the displaceable section (1C) of the container part (1B) of the drop dispenser (1) while the drop dispenser is held in an upright position. The term “upright position” means that the drop dispenser is oriented such that the outflow channel (5) or the optional drop brake channel (6) is not in contact with the liquid composition (2) held in the container part. This is usually the case when the dropper part comprising the outflow channel is oriented upwards and the liquid composition, by the force of gravity, is held in the lowermost part, i.e. the bottom end of the drop dispenser. In this orientation, the outflow channel only contacts the gaseous phase (3) and not the liquid composition (2). Accordingly, the term “upright position” also encompasses orientations of the drop dispenser which are not completely perpendicular. It also encompasses inclined orientations of the dispenser with an inclination angle of up to 90°, often with an inclination angle of approximately 0° to 45°, more often with an inclination angle of approximately 0° to 30° between the normal axis of the drop dispenser (1) and a perpendicular reference line, as long as the liquid composition does not contact the outflow channel (5) or the optional drop brake channel (6).
Preferably, the first force is a pressuring force exerted to the displaceable section of the container part (1B), for example a pressuring force applied by the fingers of a user of the drop dispenser to a flexible wall of the container part (1B). Thereby the interior volume of the container part of the drop dispenser is reduced and the gaseous phase is at least partly or in whole, preferably partly, forced out of the drop dispenser (1) into the environment.
According to step c) of the method of the present invention the drop dispenser is then inverted to an inverted position in which the liquid composition is in contact with the outflow channel (5) or, if present, the optional drop brake channel (6). The term “inverted position” as used herein means that the drop dispenser is oriented such that the outflow channel (5) or the optional drop brake channel (6) is in contact with liquid composition (2) held in the container part. This is usually the case when the dropper part comprising the outflow channel is oriented downwards and the liquid composition, by the force of gravity, is held in the lowermost end of the drop dispenser. In this orientation, the outflow channel only contacts the liquid composition (2) and not the gaseous phase (3). Accordingly, the term “inverted position” also encompasses orientations of the drop dispenser (1) which are not completely perpendicular. It also encompasses inclined orientations of the dispenser with an inclination angle of up to 90°, often with an inclination angle of approximately 0° to 45°, more often with an inclination angle of approximately 0° to 30° between the normal axis of the drop dispenser (1) and a perpendicular reference line, as long as the liquid composition is in contact with the outflow channel (5) or the optional drop brake channel (6) of the dropper part.
According to step d) of the method of the present invention said first force exerted to the displaceable section (1C) of the container part (1B) in step b) is at least partly released while still holding the drop dispenser in the inverted position. Thereby, the inner volume of the container part (1B) is enlarged or allowed to enlarge and the pressure inside the container part (1B) is at least temporarily reduced below ambient pressure (also termed as “underpressure” in this document). This allows air from the environment to enter in the outflow channel (5) of the dropper part and prevents any liquid composition (2) from leaking unintentionally or uncontrolled from the outflow channel (5).
According to step e) of the method of the present invention a second force is exerted to the displaceable section (1C) of the container part (1B), while still holding the drop dispenser in the inverted position in which the liquid composition (2) is in contact with the outflow channel (5). In a preferred embodiment, the second force is the same kind of force as applied according to step b), preferably also a pressuring force applied by the fingers of a user of the drop dispenser to a flexible wall of the container part (1B). By exerting the second force to the displaceable part (1C) of the drop dispenser (1) the pressure inside the interior volume of the container part (1B) is raised at least temporarily above ambient pressure and the liquid composition (2) is released dropwise from the dropper part (1A) of the drop dispenser (1).
In a further embodiment, the administration method according to the present invention optionally comprises the additional step
In a preferred embodiment of the present invention the drop dispenser (1) as described above is a dropper bottle (1) with a dropper part (1A) and a container part (1B), the container part (1B) comprising the displaceable section (1C).
The term “dropper bottle” (1) as used in connection with this preferred embodiment of the invention refers to a medical device that is/may be used as an eye drop delivery system (eyedropper), but which may also be helpful in administering certain compositions in a drop-by-drop manner to other parts of the body that are accessible to topical administration, such as ear, skin, nose, head, finger or other limbs. A dropper bottle may comprise a bottle part (1B) and a dropper part (1A) (see
The term “bottle part” (1B) of the dropper bottle, as used herein refers to part of the dropper bottle (1) that holds the liquid (ophthalmic) composition (2) to be administered in its interior volume. Besides the liquid (ophthalmic) composition (2) the remaining part of the interior volume is filled by a gaseous phase (3). As described above, said gaseous phase (3) may comprise air or another gas, such as an inert gas (e.g. argon, nitrogen). It is understood that, as the volume of the liquid composition (2) is decreasing upon repeated use/release of drops, the volume of the gaseous phase (3) is correspondingly increasing.
The “dropper part” (1A) as used herein refers to the part of the dropper bottle (1) from which the liquid (ophthalmic) composition is physically released in a dropwise, i.e. in a drop-by-drop manner. The dropper part (1A) is or may be mounted onto the bottle part (1B), connecting the interior volume of the bottle part to the environment. This connection (fluid communication) of the interior volume to the environment is effected in sequential order (from the distal to the proximal end) by the optional drop brake channel (6) (see
The term “deformable wall part (1C)” as used herein in connection with the dropper bottle of this embodiment of the invention refers to the wall part of the bottle part (1B) of the dropper bottle (1), which is fabricated in such that is allows to be deformed by a pressuring force exerted to it. The deformation of the wall part (1C) effects the interior volume to be compressed, resulting in the release of the gaseous phase (3) and/or the liquid (ophthalmic) composition (2) from the interior volume to the environment, as well as the intake of a gaseous phase (e.g. air) into the interior volume. The deformable wall part is preferably manufactured from a at least partially deformable material, preferably from an at least partially deformable plastic material, such as polypropylene or polyethylene. More preferably the deformable wall part is preferably manufactured from a at least partially manually deformable plastic material.
Preferably, the deformable wall part is manufactured from an at least partially manually deformable plastic material with a preferred thickness in the range of from 0.4 to 1.6 mm, preferably with a thickness in the range of from 0.5 to 1.0 mm, more preferably with a thickness in the range of from 0.6 to 0.8 mm.
The term “dropper brake channel” (6) of the dropper bottle according to this preferred embodiment of the invention as used herein refers to an optional channel-like device that extends from the duct opening (4) of the outflow channel (5) into the interior volume of the bottle part. When present, the dropper brake channel (6) is in fluid communication with the interior volume of the bottle part (1B) and with the outflow channel (5). The dropper brake channel may act as a means to limit or reduce the flow of the ophthalmic composition upon inversion of the dropper bottle (1).
The term “duct opening (4)” of the dropper bottle as used herein refers to the most distal end of the outflow channel (5). The duct opening (4) is preferably circular and/or has a preferred diameter in the range of from 0.15 to 1.2 mm, preferably its diameter is in the range of from 0.18 to 0.5 mm, more preferably its diameter is in the range of from 0.2 to 0.3 mm.
The term “outflow channel (5)” as used in connection with this embodiment of the invention refers to a channel-like device that connects the interior volume of the dropper bottle (1) to the environment, safeguarding the fluid (or gaseous) communication between interior volume and the environment. Herein, the outflow channel (5) is delimited at its distal end by the duct opening (4) located inside the interior volume of the dropper bottle and by the dropper mouth (7) at its very proximal end located outside the interior volume of the dropper bottle.
Upon administration, the liquid, preferably the liquid ophthalmic composition is delivered from interior volume through the outflow channel (5) to the dropper mouth (7), where the composition is released in a drop-by-drop manner. The outflow channel (5) is preferably a circular channel. Preferably, the outflow channel (5) has different diameters at its distal end (duct opening (4)) and at its proximal end (dropper mouth (7)). In one embodiment, the diameter at the distal end (duct opening (4)) is smaller than the diameter at the proximal end (dropper mouth (7)). In this embodiment, the outflow channel is narrowing from the proximal dropper mouth (7) to the distal duct opening (4). In still a further embodiment, the diameter at the distal end (duct opening (4)) is larger than the diameter at the proximal end (dropper mouth (7)).
The term “dropper mouth” (7) as used in this embodiment refers to the most proximal end of the outflow channel (5), where the drops to be released are formed. The diameter of the dropper mouth (7) is preferably circular and/or its diameter is preferably in the range of 1 to 5 mm, preferably its diameter is in the range of 2 to 3 mm, more preferably its diameter is in the range of 2.0 to 2.6 mm, even more preferably its diameter is in the range of about 2.0 to 2.4 mm.
The term “pressuring force” as used in this preferred embodiment refers to a force that is applied to the deformable wall part (1C) to effect the interior volume of the bottle part (1B) to be compressed. Preferably, said force is by manually pressuring the deformable wall part (1C), e.g. by manually squeezing.
In a further preferred embodiment, the administration method according to the present invention, the inversion of the drop dispenser (1) to the inverted position according to step (c) and the release of the first force according to step (d) is performed at least partly simultaneously. This means that the release of the first force, preferably the first pressuring force exerted to the displaceable part (1C) of the drop dispenser may or may not be performed in whole or in part during the inversion of the drop dispenser according to step c). Preferably, however, the release of the first force does not start, before the contact between the liquid composition and the outflow channel (5) is established. Irrespective of whether or not steps c) and d) are performed simultaneously in whole or in part the administration method according to the present invention it is beneficial and preferred when upon release of the first force in step d) air is at least partially sucked into the outflow channel (5) forming a barrier to prevent uncontrolled release of the liquid composition (2) from the dropper dispenser (1). Therefore, according to this beneficial embodiment of the present invention the reduced pressure generated inside the interior volume of the container part (1B) prevents the unintended, in many cases non-dropwise and therefore non-reproducible release of the liquid composition (2) from the drop dispenser (1).
In a further embodiment of the first aspect of the invention, the method optionally further comprises the steps:
The liquid composition utilized in the method of the present invention may be a water-containing or alternatively a water-free composition. Examples of composition successfully utilized in practicing the method of the present invention are listed in Table 2.
In a further preferred embodiment of the present invention the liquid composition (2) to be administered in a dropwise fashion is an ophthalmic composition, whereas the term “ophthalmic” as used herein means that the liquid composition can be topically administered to the eye, to the eye surface or to an eye tissue of a human or an animal.
The liquid composition may comprise water, dissolved salts, buffer solutions and solvents known to those of skill in the art to be compatible with the above-described ophthalmic administration.
Accordingly, a broad diversity of commercially available, water-based ophthalmic compositions, such as e.g. Systane®, Arteleac®, Refresh (see Table 2) and the like are suited as liquid compositions (2) to be administered according to the method of the present invention.
Further, the liquid composition (2) may comprise one or more excipients, such as an organic cosolvent, such as an oil selected from glyceride oils, liquid waxes, and liquid paraffin or mineral oil, or said liquid composition may comprise an organic solvent exhibiting a high degree of biocompatibility, such as glycerol, propylene glycol, polyethylene glycol or ethanol.
The liquid composition (2) to be administered may be used in form of a solution or a suspension or an emulsion. Further, it may generally be used at different temperatures, such as different room or ambient temperatures. Furthermore, it may be used in a cooled state, for example after storage in a cooler or freezer. Typically, the liquid composition (2) to be administered may be used at a temperature (of the liquid, not necessarily of the surroundings) of approximately from −15 to 40° C., more typically of from −10° C. to 37° C. In a preferred embodiment of the present invention the liquid composition has a temperature in the range from −7° C. to 30° C., preferably in the range from 20° C. to 30° C.
The liquid composition (2) optionally comprises one or more pharmaceutical active ingredients (APIs) such as for example: prostaglandin analogs (e.g. latanoprost, unoprostone, travoprost, bimatoprost, tafluprost), g-blockers, (e.g. timolol, brimonidine), cabonic anhydrase inhibitors (e.g. acetazolamide, dorzolamide, methazolamide, brinzolamide), antihistamines (e.g. olopatadine, levocabastine), corticosteroids (e.g. loteprednol, prednisolone, dexamethasone), fluorquinolone antibiotics (e.g. moxifloxacin, gatifloxacin, ofloxacin, levofloxacin), aminoglycoside antibiotics (e.g. tobramycin), macrolide antibiotics (e.g. azithromycin), VEGF-inhibitors (e.g. ranibizumab, bevacizumab, aflibercept), macrolide immunsuppressants (e.g. cyclosporine, tacrolimus, sirolimus), NSAIDs (e.g. bromfenac, nepafenac, diclofenac, ketorolac).
In a preferred embodiment, the liquid composition (2) to be topically administered according to present invention comprises a liquid semifluorinated alkane or a mixture of two or more different semifluorinated alkanes.
The term “semifluorinated alkane” (also referred to as “SFA” throughout this document) refers to a linear or branched compound composed of at least one perfluorinated segment (F-segment) and at least one non-fluorinated hydrocarbon segment (H-segment). More preferably, the semifluorinated alkane is a linear or branched compound composed of one perfluorinated segment (F-segment) and one non-fluorinated hydrocarbon segment (H-segment). Preferably, said semifluorinated alkane is a compound that exists in a liquid state at least at one temperature within the temperature range of 4° to 40° C., with the perfluorinated segment and/or the hydrocarbon segment of the said SFA optionally comprising or consisting of a cyclic hydrocarbon segment, or optionally said SFA within the hydrocarbon segment comprising an unsaturated moiety.
Preferably, the F-segment of a linear or branched SFA comprises between 3 to 10 carbon atoms. It is also preferred that the H-segment comprises between 3 to 10 carbon atoms. It is particularly preferred that the F- and the H-segment comprise, but independently from one another, 3 to 10 carbon atoms. Preferably, each segment independently from another is having carbon atoms selected from the range of 3 to 10.
It is further preferred, that the F-segment of a linear or branched SFA comprises between 4 to 10 carbon atoms and/or that the H-segment comprises between 4 to 10 carbon atoms. It is particularly further preferred that the F- and the H-segment comprise, but independently from one another, 4 to 10 carbon atoms. Preferably, each segment is independently from another having carbon atoms selected from the range of 4 to 10.
Optionally, the linear or branched SFA may comprise a branched non-fluorinated hydrocarbon segment comprising one or more alkyl groups selected from the group consisting of —CH3, C2H5, C3H7 and C4H9 and/or the linear or branched SFA may comprise a branched perfluorinated hydrocarbon segment, comprising one or more perfluorinated alkyl groups selected from the group consisting of —CF3, C2F5, C3F7 and C4F9.
It is further preferred that the ratio of the carbon atoms of the F-segment and the H-segment (said ratio obtained by dividing the number of carbon atoms in the F-segment by the numbers of carbon atoms in the H-segment; e.g. said ratio is 0.75 for 1-perfluorohexyloctane (F6H8)) of a linear or branched SFA is 0.5, more preferably said ratio is 0.6. It is further preferred that the ratio of the carbon atoms of the F-segment and the H-segment is in the range between 0.6 and 3.0, more preferably said ratio is between 0.6 and 1.0.
In a preferred embodiment of the present invention the semifluorinated alkane refers to a linear compound composed of at least one perfluorinated segment (F-segment) and at least one hydrocarbon segment (H-segment). More preferably, said semifluorinated alkane is a linear compound composed of one perfluorinated segment (F-segment) and one hydrocarbon segment (H-segment).
According to another nomenclature, the linear semifluorinated alkanes may be referred to as FnHm, wherein F means the perfluorinated hydrocarbon segment, H means the non-fluorinated hydrocarbon segment and n, m is the number of carbon atoms of the respective segment. For example, F4H5 is used for 1-perfluorobutylpentane.
Preferably, the F-segment of a linear SFA comprises between 3 to 10 carbon atoms. It is also preferred that the H-segment comprises between 3 to 10 carbon atoms. It is particularly preferred that the F- and the H-segment comprise, but independently from one another, 3 to 10 carbon atoms. Preferably, each segment independently from another is having carbon atoms selected from the range of 3 to 10.
It is further preferred, that the F-segment of a linear SFA comprises between 4 to 10 carbon atoms and/or that the H-segment comprises between 4 to 10 carbon atoms. It is particularly further preferred that the F- and the H-segment comprise, but independently from one another, 4 to 10 carbon atoms. Preferably, each segment is independently from another having carbon atoms selected from the range of 4 to 10.
Optionally, the linear SFA may comprise a branched non-fluorinated hydrocarbon segment comprising one or more alkyl groups selected from the group consisting of —CH3, C2H5, C3H7 and C4H9 and/or the linear SFA may comprise a branched perfluorinated hydrocarbon segment, comprising one or more perfluorinated alkyl groups selected from the group consisting of —CF3, C2F5, C3F7 and C4F9. It is further preferred that the ratio of the carbon atoms of the F-segment and the H-segment (said ratio obtained by dividing the number of carbon atoms in the F-segment by the numbers of carbon atoms in the H-segment; e.g. said ratio is 0.75 for 1-perfluorohexyloctane (F6H8)) of a linear SFA is 0.5, more preferably said ratio is ≥0.6. It is further preferred that the ratio of the carbon atoms of the F-segment and the H-segment is in the range from 0.6 to 3.0, more preferably said ratio is in the range from 0.6 to 1.0.
Preferably, the semifluorinated alkane is a linear compound of the formula F(CF2)n(CH2)mH wherein n and m are integers independently selected from the range of 3 to 10, more preferably the semifluorinated alkane is a linear compound of the formula F(CF2)n(CH2)mH wherein n and m are integers independently selected from the range of 4 to 10. Even more preferred the semifluorinated alkane is a liquid of the formula F(CF2)n(CH2)mH wherein n and m are integers independently selected from the range of 4 to 10.
Preferably, the linear SFA is selected from the group consisting of F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, more preferably said linear SFA is selected from the group consisting of F4H4, F4H5, F4H6, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10, even more preferably the linear SFA is selected from the group consisting of F4H4, F4H5, F4H6, F5H4, F5H5, F5H6, F5H7, F5H8, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10, most preferably the linear SFA is selected from the group consisting of F4H4, F4H5, F4H6, F5H5, F5H6, F5H7, F5H8, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10. In a further preferred embodiment, the linear SFA is selected from the group consisting of F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8. In an even further preferred embodiment the linear SFA is selected from F4H5 and F6H8.
The liquid composition (2) to be administered by the method of the present invention may optionally comprise water. In a preferred embodiment, however, the liquid composition is water-free or at least substantially water-free. When comprising water the liquid composition may be a aqueous composition, typically comprising water up to approximately 99% by weight of the final composition or alternatively the liquid composition may be an emulsion, typically comprising up to approximately 90% by weight of the final composition, more typically approximately 0.01 to 80%, even more typically approximately 0.01 to 50%.
The liquid composition (2), preferably the substantially water-free solution comprising a liquid semifluorinated alkane or a mixture of two or more different semifluorinated alkanes to be administered usually has a density measured at 25° C. in the range of 0.7 to 1.9 g/cm3, preferably in the range of 1.0 and 1.7 g/cm3, more preferably in the range of 1.2 to 1.4 g/cm3. The viscosity of the liquid composition (2) measured at 25° C. versus air usually may be in the range of 0.3 to 5.2 mPa s, preferably in the range of 0.9 to 4.0 mPa s, more preferably in the range of 1.0 to 3.5 mPa s.
The surface tension of the liquid composition (2) versus air measured at 25° C. usually is in the range of 15 to 75 mN/m, preferably in the range of 15 to 30 mN/m, more preferably in the range of 15 to 23 mN/m.
Further, the composition utilized in the method of the present invention may comprise one or more active pharmaceutical ingredient (APIs) or alternatively may not comprise does or does not comprise an active pharmaceutical ingredient. Examples of liquid ophthalmic compositions are listed in Table 2.
According to the present invention a broad range of dropper configurations can be utilized when practicing the administration method according to the present invention (underpressure method). Examples of such droppers are listed in Table 1, with its dropper bottle configurations listed in Table 2. The dropper bottle (1) may comprise configurations of the dropper part (1A) and the bottle part (1B) as defined above.
In still a further embodiment of the first aspect of the invention, the administration method optionally further comprises the steps:
In a second aspect, the invention relates to the use of the method according to the first aspect of the invention for preventing or treating an ocular disease or any symptoms or conditions associated therewith.
The term “ocular disease” as used herein refers to a disease or a disorder of the eye, including disorders or diseases of the eyelid, lacrimal system, orbit, conjunctiva, sclera, cornea, iris, ciliary body, lens, choroid or retina, including disorders classified by WHO according to ICD codes H00-H06, H10-H13, H15-H22, H25-H28, H30-H36, H40-H42, H43-H45, H46-H48, H49-H52, H53-H54, H55-H59.
Generally, the administration of the ophthalmic composition (2) according to the method of the present invention may be carried out regularly, such as up to once per week, or up to once per day or up to 8, 7, 6, 5, 4, 3 or up to 2 times per day.
In a third aspect, the invention relates to a method of treating an ocular disease or any symptoms or conditions associated therewith comprising dropwise administration a liquid ophthalmic composition according to the method of the first aspect of the present invention.
In a fourth aspect, the present invention relates to a drop dispenser (1), comprising
The drop dispenser (1) according to this aspect of the invention is particularly suitable and can preferably be adapted to be used in the administration method according to the first aspect of the invention. However, it should be understood the drop dispenser according to this aspect of the invention can also be used independently of the administration method according to the first aspect of the invention. Accordingly, as the drop dispenser provided in step a) of the present invention, it comprises a container part (1B) and a dropper part (1A) which are as described in connection with the first aspect of the invention.
The container part (1B) preferably also has a displaceable section (1C) and also holds a gaseous phase (3) which fills the remainder of the interior volume which is not filled with the liquid composition (2), whereas the terms displaceable section (1C), gaseous phase and liquid composition are also as defined in connection with the drop dispenser provided in the first aspect of the invention.
Furthermore, the drop dispenser of the present aspect of the invention has a dropper part (1A) as the one provided for in step a) of the present administration method. The “dropper part” is the portion of the drop dispenser through which the liquid composition (2) is discharged from the container part (1B) and subsequently administered. It is physically connected to the container part (1B) and connects the interior volume of the container part (1B) to the environment through an outflow channel (5) through which the liquid composition (2) to be administered is discharged. In this embodiment also, the outflow channel may optionally comprise a drop brake channel (6) which elongates the outflow channel further into the interior volume of the container part (1B).
The term “outflow channel (5)” as used in connection with this embodiment of the invention refers to a channel-like device that connects the interior volume of the dropper bottle (1) to the environment, safeguarding the fluid (or gaseous) communication between interior volume and the environment. Herein, the outflow channel (5) is delimited at its distal end by the duct opening (4) located inside the interior volume of the dropper bottle and by the dropper mouth (7) at its very proximal end located outside the interior volume of the dropper bottle. Upon administration, the liquid, preferably the liquid ophthalmic composition is delivered from interior volume through the outflow channel (5) to the dropper mouth (7), where the composition is released in a drop-by-drop manner.
The drop dispenser according to this aspect of the invention is characterized in that at least a portion of the outflow channel (5) has an inner diameter in the range of 0.09 to 0.19 mm, preferably in the range of from about 0.10 to about 0.18 mm, more preferably from about 0.11 to about 0.17 mm, even more preferably from about 0.12 to about 0.16 mm, yet more preferably from about 0.13 to about 0.16 mm or even from about 0.14 to about 0.16 mm and most preferably of about 0.15 mm. The term “at least a portion of” the outflow channel means that either the whole channel over its entire length has an inner diameter in the described range or that only a portion, part or fraction of the outflow channel has an inner diameter in the defined range or ranges. For example, about 75% or less, 60% or less, 50% or less or even 40%, 30% or even only 25% or less of the total length of the outflow channel (5) may have an inner diameter in the range as defined above. In other embodiments, only a small portion, such as only 20% or less or even only 10% or less of the total length of the outflow channel may have an inner diameter in the range as defined above.
In a preferred embodiment, the duct opening (4) of the outflow channel has an inner diameter in the range of 0.09 to 0.19 mm, preferably in the range of from about 0.10 to about 0.18 mm, more preferably from about 0.11 to about 0.17 mm, even more preferably from about 0.12 to about 0.16 mm, yet more preferably from about 0.13 to about 0.16 mm or even from about 0.14 to about 0.16 mm and most preferably of about 0.15 mm. In yet further embodiments, the duct opening (4) and a portion of the outflow channel (5) beginning at the duct opening have an inner diameter in the range of 0.09 to 0.19 mm.
In this aspect of the invention also, the outflow channel (5) may have different cross-sectional shapes, such as circular, elliptic, rectangular or quadratic or the like, however, it is preferably a circular channel. In cases in which the duct channel does not have a circular cross-sectional shape the term “inner diameter” is to be understood as the largest diameter of such particular shape. Preferably, the outflow channel (5) has different diameters at its distal end (duct opening (4)) and at its proximal end (dropper mouth (7)). In one embodiment, the diameter at the distal end (duct opening (4)) is smaller than the diameter at the proximal end (dropper mouth (7)). In this embodiment, the outflow channel is narrowing from the proximal dropper mouth (7) to the distal duct opening (4). In still a further embodiment, the diameter at the distal end (duct opening (4)) is larger than the diameter at the proximal end (dropper mouth (7)).
The term “duct opening (4)” of the dropper bottle as used herein refers to the most distal end of the outflow channel (5). Accordingly, the duct opening (4) is preferably circular and/or has a preferred diameter which may also be in the range of from 0.09 to 0.19 mm or, in cases in which the portion of the outflow channel (5) having an inner diameter of 0.09 to 0.19 mm does not comprise the duct opening (4), preferably the inner diameter of the duct opening (4) is in the range of from 0.2 to 0.5 mm, more preferably its diameter is in the range of from 0.2 to 0.3 mm.
The term “dropper mouth” (7) as used in this embodiment refers to the most proximal end of the outflow channel (5), where the drops to be released are formed. The diameter of the dropper mouth (7) is preferably circular and/or its diameter is preferably in the range of 1 to 5 mm, preferably its diameter is in the range of 2 to 3 mm, more preferably its diameter is in the range of 2.0 to 2.6 mm, even more preferably its diameter is in the range of about 2.0 to 2.4 mm.
In a particularly preferred embodiment, the duct opening (4) of the outflow channel has an inner diameter of about 0.15 mm and the diameter of the dropper mouth (7) is about 2.0 to 2.4 mm, preferably about 2.4 mm. In yet a further particularly preferred embodiment the duct opening (4) of the outflow channel has an inner diameter of about 0.15 mm and the inner diameter of the rest of the outflow channel including the dropper mouth (7) is about 2.0 to 2.4 mm, preferably about 2.4 mm. In both embodiments, the duct opening (4), the outflow channel (5) and/or the dropper mouth (7) preferably has a circular cross-sectional shape.
According to this aspect of the invention also, it is to be understood that the optional drop brake channel (6), if present, does not form part of the outflow channel (5) which extends from the duct opening (4) and therefore does not contribute to the total length of the outflow channel (5).
One advantage of the reduced diameter of at least a portion of the outflow channel of the drop dispenser according to the present aspect of the invention is that the undesired spontaneous outflow or drop-formation of the liquid composition, preferably the liquid ophthalmic composition can be reduced significantly for aqueous as well as non-aqueous compositions. Especially in cases of non-aqueous compositions, especially for SFA-containing compositions this has been found to be particularly beneficial.
It has been found that for practical purposes a range of 0.09 to 0.19 mm of at least a portion of the outflow channel is preferable as it combines significantly reduced spontaneous outflow with acceptable forces necessary to press the liquid composition through the outflow channel (5). Particularly in view of a possible use of the disclosed drop dispenser (1) characterized by least a portion of the outflow channel (5) having an inner diameter in the range of 0.09 to 0.19 mm in an administration method according to the first aspect of the invention this has been shown of considerable importance for e.g. elderly or disabled users.
Furthermore, it has been found that the drop dispenser according to the present aspect of the invention offers higher precision and reproducibility of the drop sizes and volumes to be dispensed, independent of the temperature of the drop dispenser, liquid composition and/or the environment as well as the actual filling level of the drop dispenser or “headspace” above the liquid composition in the drop dispenser.
The outflow channel (5) with at least a portion having an inner diameter in the range of 0.09 to 0.19 mm according to this aspect of the invention can be produced by standard techniques, such as laser drilling or welding.
In a fifth aspect, the present invention relates to a kit comprising
The directions or instructions for use comprised by the kit according to this aspect of the invention may be in in any form suited to instruct the user how to perform the topical administration method according to first aspect of the invention (underpressure method). It may be in any readable or tangible form, preferably in printed form or in any machine- or computer-readable form preferably in form of a machine-readable optical label such as, for example, a barcode or a QR-code. In a particularly preferred embodiment the directions for use are provided in form of an instruction leaflet, product or package insert or as an enclosed label. Preferably the directions or instructions for use are provided in printed form, for example in form of a printed label, which may be provided together with the drop dispenser (1) or dropper bottle (1) to be used according to the method of the first aspect of the invention. For example, such a label may be packaged together with the said drop dispenser (1) or dropper bottle (1).
In summary, the present invention comprises the following numbered items:
F8H12, F10H10, more preferably said linear SFA is selected from the group consisting of F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8 most preferably the semifluorinated alkane is selected from F4H5 and F6H8.
In
In
In
In
In
It is understood that according to the present invention the release of the liquid ophthalmic composition in a dropwise manner may be performed not only at said 2 exemplary positions depicted in
In
The following examples serve to illustrate the present invention without, however, limiting it in any respect:
The liquid NovaTears® (Novaliq GmbH, Germany) ophthalmic composition for treating dry eye disease, comprises 1-Perfluorohexyloctane (F6H8) and is provided in a dropper bottle (1) with a polyethylene dropper part (1A) mounted to a polypropylene bottle part (1B) for holding 3 ml of NovaTears®. The dropper part (1A) comprises an outflow channel (5) with a dropper mouth (7) (diameter 2.4 mm) at its proximal end and a duct opening (4) (0.3 mm diameter) at its distal end. The dropper part (1A) further comprises a dropper brake channel (6) which extends the outflow-channel (5) from the duct opening (4) into the interior volume of the bottle part (1B). The outflow channel (5) and the dropper brake channel (6) are in fluid communication with the interior volume of the bottle part (1B), allowing—upon inverting of the dropper bottle (1)—the liquid ophthalmic composition to flow from the interior volume to the proximal end of the outflow channel (5). Herein, the liquid first fills the optional drop brake channel (6), before it enters into the outflow channel (5) at the duct opening (4) and continues to the dropper mouth (7), where it is released as a drop.
After opening the dropper bottle (1), the subjects head is slightly tilted back, while looking upward. The lower eyelid is gently pulled downward, before the dropper bottle (1) is positioned with the dropper part (1A) above the lower eyelid. The dropper bottle is then inverted with the dropper mouth (7) facing to the eye of the subject. By doing so, drops are instantly released in an uncontrolled manner from the dropper mouth (7). Dropping starts unintentionally with drops being released in medium frequency. Dropping of the bottle can only be stopped by reverting the bottle back to the starting position.
After opening the dropper bottle (1), the subjects head is slightly tilted back, while looking upward. The lower eyelid is gently pulled downward, before the dropper bottle (1) is positioned with the dropper part (1A) above the lower eyelid. The dropper bottle (1) is then inverted with the dropper mouth (7) facing to the eye of the subject and then the deformable wall part (1C) of the bottle part (1B) is slightly squeezed by hand. By doing so, drops are instantly released in an uncontrolled manner from the dropper mouth (7). Dropping starts unintentionally with drops being released in high frequency. Dropping of the bottle can only be stopped by releasing the pressure force and reverting the bottle back to the starting position.
After opening the dropper bottle (1), the subjects head is slightly tilted back, while looking upward your head back and look upward. The lower eyelid is gently pulled downward, before the dropper bottle (1) is positioned with the dropper part (1A) above the lower eyelid. While still in the upright position the deformable wall part (1C) of the bottle part (1B) of the dropper bottle (1) is slightly squeezed to force some of the gaseous volume in the headspace of the bottle part (1B) out of the dropper bottle (1). Then, the dropper bottle (1) is inverted (with the dropper mouth (7) facing down to the eye) and simultaneously the pressure is released from the deformable wall part (1C), thereby generating an underpressure inside the interior volume of the dropper bottle (1). Concomitantly, air from the environment is sucked through the outflow channel (5) into the interior volume. The underpressure generated prevents unintentional or uncontrolled release of drops from the dropper bottle (1). The controlled release of the composition in a drop-by-drop manner is initiated only when a second pressuring force is applied to the deformable wall part (1C). Hereby, the number of drops to be released is easily controlled by the second pressuring force. The dropping can be easily stopped by release of said second pressuring force and re-initiated by re-applying one or more further pressuring forces to the deformable wall part (1B) of the dropper bottle (1). Following the steps above, the NovaTears® ophthalmic composition is administered reliably to patients suffering from dry eye disease (keratoconjunctivitis sicca).
The liquid ophthalmic composition for treating dry eye disease, comprising 1 mg/ml Ciclosporine A, dissolved in 1 wt-% ethanol in 1-Perfluorobutyl-pentane (F4H5) is provided in a dropper bottle (1) with a polyethylene dropper part (1A) mounted to a polypropylene bottle part (1B).
Said cyclosporine-containing ophthalmic SFA-based-composition (3) is administered as described in Example 4. Herein, the underpressure generated prevents unintentional or uncontrolled release of drops of the pharmaceutical composition from the dropper bottle (1). The controlled release of the composition in a drop-by-drop manner is initiated only when a second pressuring force is applied to the deformable wall part (1C). Hereby, the number of drops to be released is easily controlled by said second pressuring force. The dropping of the pharmaceutical composition can be easily stopped by release of said second pressuring force and re-initiated by re-applying one or more further pressuring forces to the deformable wall part (1B) of the dropper bottle (1). Following the steps above, the ciclosporine-containing ophthalmic composition is administered reliably to patients suffering from dry eye disease (keratoconjunctivitis sicca).
In the following, the administration method of the present invention (underpressure method) is compared to the inversion method. Herein, different liquid ophthalmic compositions and different dropper bottle configurations were tested when using either the underpressure method or the inversion method
Experimental Procedure for the Underpressure Method (According to the Present Invention):
A dropper bottle (1) as listed in Table 1 below was provided and filled with a liquid ophthalmic composition as identified in Table 2. Then the sidewalls as the deformable wall part (1C)) of the dropper bottle (1) were slightly squeezed to force the gaseous phase (3) partially out of the dropper bottle (1). Afterwards, the bottles were inverted manually to an inverted position. During or after inversion of the dropper bottles the squeezing was stopped and the pressuring force was released, concomitantly generating underpressure in the inner volume of the dropper bottle (1). Finally, the inverted drop bottles were mounted on a suitable bottle holder at a fixed inclination versus the perpendicular axis. During a period of 30 seconds it was observed if drops are unintentionally released in an uncontrolled fashion without applying a second pressuring force to the deformable wall part of the bottle and the number of drops released were recorded.
Experimental Procedure for the Inversion Method (not According to the Present Invention):
A dropper bottle (1) as listed in Table 1 below was provided and filled with a liquid ophthalmic composition as identified in Table 2. Then the dropper bottles were inverted manually to an inverted position. Finally, the inverted drop bottles were mounted on a suitable bottle holder at a fixed inclination versus the perpendicular axis. During a period of 30 seconds it was observed if drops are unintentionally released in an uncontrolled fashion without applying a second pressuring force to the deformable wall part of the bottle and the number of drops released were recorded. Table 1: Dropper bottle configurations as employed in Example 6:
diameter
dropper
diameter
dropper
dropper,
dropper
mouth
duct
brake
dropper
manu-
bottle part
part
opening
opening
channel
type
facturer
(1B)
(1A)
(7)/mm
(4)/mm
(6)
1
Packsys
polypro-
polyeth-
2.4
0.3
yes
GmbH
pylene
ylene
2
Packsys
polyeth-
polyeth-
2.4
0.3
yes
GmbH
ylene
ylene
3
Packsys
polypro-
polyeth-
2.4
0.8
no
GmbH
pylene
ylene
4
Packsys
polypro-
polyeth-
2.4
1.2
no
GmbH
pylene
ylene
5
Packsys
polypro-
polyeth-
2.4
0.2
yes
GmbH
pylene
ylene
6
Systane ®
n.d.
n.d.
n.d.
n.d.
yes
dropper
7
Artelac ®
n.d.
n.d.
n.d.
n.d.
yes
dropper
(Bausch +
Lomb)
8
Refresh ® by
n.d.
n.d.
n.d.
n.d.
yes
Artelac ®
dropper
9
Thealoz ®
n.d
n.d.
n.d.
n.d.
n.d.
Abak*
10
Nemera
n.d
n.d.
n.d.
n.d.
n.d.
Novelia ®**
TABLE 2
Formulation
API,
dropper
duct opening
release of first
dropping
inversion method
underpressure
Solvent
type
excipients
type
diameter/mm
pressuring force
angle
successful
method successful
F6H8
solution
n.a.
1
0.3
after
0°
no
yes
inversion
F6H8
solution
n.a.
1
0.3
after
tilted
no
yes
inversion
(45°)
F4H5
solution
n.a.
1
0.3
after
0°
no
yes
inverting
F4H5
solution
n.a.
1
0.3
after
tilted
no
yes
inversion
(45°)
F4H5
solution
cyclosporin
1
0.3
after
0°
no
yes
(0.1% w/v),
inversion
ethanol (1%
w/w)
F4H5
solution
cyclosporin
1
0.3
after
tilted
no
yes
(0.1% w/v),
inversion
(45°)
ethanol (1%
w/w)
F6H8
solution
n.a.
1
0.3
during
0°
no
yes
inversion
F6H8
solution
n.a.
1
0.3
during
tilted
no
yes
inversion
(45°)
F6H8
solution
n.a.
2
0.3
during
0°
no
yes
inversion
F6H8
solution
n.a.
2
0.3
during
tilted
no
yes
inversion
(45°)
F6H8
solution
n.a.
2
0.3
during
tilted
no
yes
inversion
(45°)
F4H5
solution
n.a.
3
0.8
during
0°
no
yes
inversion
F4H5
solution
n.a.
4
1.2
during
0°
no
yes
inversion
water
solution
n.a.
4
1.2
during
0°
(yes)
yes
inversion
F4H5
suspension
sucrose
1
0.3
during
0°
n.a.
yes
(0.025%
inversion
w/w)
ethanol
solution
n.a.
5
0.2
during
0°
(yes)
yes
inversion
F4H5
solution
cyclosporin
5
0.2
during
0°
no
yes
(0.1 % w/v),
ethanol (1%
inversion
w/w)
water
solution
Systane ®
6
n.a.
during
0°
(yes)
yes
(commercial
inversion
eye drops)
water
solution
Artelac ®
7
n.a.
during
0°
no
yes
(commercial
inversion
eye drops)
F4H5
solution
n.a.
6
n.a.
during
0°
no
yes
inversion
F4H5
solution
n.a.
7
n.a.
during
0°
no
yes
inversion
Propyl-
solution
5
0.2
during
0°
no
no
ethylen-
inversion
glycol
water
solution
Refresh ®
8
n.a.
during
0°
no
yes
(commercial
inversion
eye drops)
F6H8
solution
n.a.
8
n.a.
during
0°
no
yes
inversion
water
solution
Thealoz ®
9
n.a.
during
0°
yes
yes
Duo
inversion
(commercial
eye drops)
water
solution
Thealoz ®
9
n.a.
after
0°
yes
yes
Duo
inversion
(commercial
eye drops)
F4H5
solution
n.a.
10
n.a.
during
0°
yes
yes
inversion
F4H5
solution
n.a.
10
n.a.
after
0°
yes
yes
inversion
F4H5
solution
n.a.
1
0.3
during
0°
no
yes
inversion
F4H5
solution
n.a.
1
0.3
during
90°
no
yes
inversion
F4H5
solution
n.a.
1
0.3
after
0°
no
yes
inversion
F4H5
solution
n.a.
1
0.3
after
90°
no
yes
inversion
Herein, the inversion method or the underpressure method were considered successful (“yes”) when no drops within 30 seconds were unintentionally released from the dropper mouth (7) of the dropper bottle in an uncontrolled fashion without any pressure applied to the deformable wall part (1C) of the dropper bottle (1). Further, “(yes)” in brackets refers to only one drop unintentionally released within said 30 second observation period.
According to the protocols as described under example 6 above for the inversion method and the underpressure method, respectively, further measurements were carried out at 21° C. and 5° C. with increasing gaseous phase (3) (headspace volume) in the interior volume of the dropper bottle (1). The results are listed in Table 3:
TABLE 3
compo-
inversion
under-
sition
method
pressure
Formula-
dropper
tempera-
volume/
success-
method
Solvent
tion type
type
ture/° C.
ml
ful
successful
F6H8
solution
1
21
5
no
yes
F6H8
solution
1
21
4
no
yes
F6H8
solution
1
21
3
no
yes
F6H8
solution
1
21
2
no
yes
F6H8
solution
1
21
1
no
yes
F6H8
solution
2
21
5
no
yes
F6H8
solution
2
21
4
no
yes
F6H8
solution
2
21
3
no
yes
F6H8
solution
2
21
2
no
yes
F6H8
solution
2
21
1
no
yes
F6H8
solution
1
5
5
no
yes
F6H8
solution
1
5
4
no
yes
F6H8
solution
1
5
3
no
yes
F6H8
solution
1
5
2
no
yes
F6H8
solution
1
5
1
no
yes
F6H8
solution
2
5
5
no
yes
F6H8
solution
2
5
4
no
yes
F6H8
solution
2
5
3
no
yes
F6H8
solution
2
5
2
no
yes
F6H8
solution
2
5
1
no
yes
Herein, the inversion method or the underpressure method were considered successful (“yes”) when no drops within 30 seconds were unintentionally released from the dropper mouth (7) of the dropper bottle in an uncontrolled fashion without any pressure applied to the deformable wall part (1C) of the dropper bottle (1). Further, “(yes)” in brackets refers to only one drop unintentionally released within said 30 second observation period.
Three polypropylene droppers (Packsys®) with a duct opening diameter of 0.3 mm and a mouth diameter of 2.4 mm (“Dropper 14182”) were filled with 1 ml, 3 ml and 5 ml of F6H8. Prior to testing the bottles were closed with dropper and cap. The cap was removed and sample fluid F6H8 was dispensed dropwise. 5 drops of F6H8 were collected from the start, middle and end of each sample (5 ml; 3 ml; 1 ml respectively) were weighed and the corresponding drop sizes calculated on the basis of the density of F6H8 (1.331 gcm−3). Table 4 shows the resulting average drop weights and volumes:
TABLE 4
F6H8
Dropper 14182
5 mL
3 mL
1 mL
Average
Average Drop Weight (mg)
14.967
15.458
15.035
15.153
% RSD of Drop Weight
0.940
0.873
1.061
0.964
Average Drop Volume (μL)
11.245
11.614
11.296
11.385
% RSD of Drop Size
0.706
0.656
0.797
0.725
The experiment was repeated using three polypropylene droppers (Packsys®) with a duct opening diameter of 0.15 mm and a mouth diameter of 2.4 mm (“Dropper 14014”). Table 5 shows the resulting average drop weights and volumes:
TABLE 5
F6H8
Dropper 14014
5 mL
3 mL
1 mL
Through-Life
Average Drop Weight (mg)
14.509
14.540
14.498
14.516
% RSD of Drop Weight
0.646
0.760
0.699
0.687
Average Drop Volume (μL)
10.901
10.924
10.893
10.906
% RSD of Drop Size
0.486
0.571
0.525
0.516
Table 6 shows the drop weights in mg as measured for the three droppers, each having a duct opening diameter of 0.3 mm and a mouth diameter of 2.4 mm (Dropper 14182).
TABLE 6
14182
Fill
F6H8 Drop Weight (mg)
Volume
1
2
3
5 mL
15.260
16.089
14.115
13.397
15.257
13.251
15.168
15.620
16.119
14.873
14.525
16.155
14.105
14.813
15.753
3 mL
15.693
14.928
17.034
15.739
15.120
16.204
14.668
14.648
16.424
15.949
14.665
16.584
15.058
13.855
15.295
1 mL
14.637
15.426
16.599
14.877
13.054
16.255
13.947
14.200
13.827
15.543
14.526
16.084
16.526
14.572
15.451
Table 7 shows the comparison of the drop sizes generated with droppers having a duct opening of either 0.3 mm or 0.15 mm. As can be seen, a smaller diameter of the duct opening helps to adjust the drop volume to a target drop volume of 10111. Furthermore, a smaller duct opening allows to realize more constant drop volumes, independent from the fill level of the dropper bottle used.
TABLE 7
Material: F6H8
5 mL
3 mL
1 mL
Average
14182 Average Drop Volume (μL)
11.245
11.614
11.296
11.385
14182 % RSD of Drop Size
0.706
0.656
0.797
0.725
14014 Average Drop Volume (μL)
10.901
10.924
10.893
10.906
14014 % RSD of Drop Size
0.486
0.571
0.525
0.516
A drop dispenser (Packsys GmbH) with a volume of 5 ml, a duct opening with a diameter of 0.15 mm and a dropper mouth with a diameter of 2.4 mm was tested at 5° C. with F4H5 and F6H8 at different volumes.
Three of the above-described polypropylene dropper bottles were filled with different volumes of F4H5 and F6H8 (5 ml; 3 ml; 1 ml). Prior to testing, the bottles were closed with dropper and cap; then stored over night at 5° C. This was repeated with the three bottles containing each material.
Without pressing the bottle was automatically inverted by 180° for 30 seconds. Drop formation of F4H5 or F6H8 and release was observed on blue paper and counted. For data analysis purposes any droplet that failed to drop but was observed was counted as a drop. Table 8 shows the number of drops observed.
TABLE 8
Fill
F4H5
F6H8
Volume
1
2
3
1
2
3
5 mL
0
0
0
0
0
0
3 mL
2
3
2
0
1
1
1 mL
2
2
1
1
2
2
Furthermore, 5 drops of each SFA was collected from each of the 3 parallel drop dispensers from the start, middle and end of each sample (5 ml; 3 ml; 1 ml respectively), weighed and the drop size calculated on the basis of the respective density (F4H5, 1.29 g/cm3; F6H8, 1.331 g/cm3). Table 9 shows the drop sizes observed for each of the 3 drop dispensers tested in parallel.
TABLE 9
Fill
F4H5 Drop Weight (mg)
F6H8 Drop Weight (mg)
Volume
1
2
3
1
2
3
5 mL
14.209
13.560
13.998
15.391
15.448
15.265
15.132
13.543
13.160
15.078
15.406
16.189
14.408
12.940
15.184
14.308
15.406
16.092
13.724
12.989
13.177
15.714
16.137
15.987
12.268
13.932
13.449
14.587
15.864
15.310
3 mL
12.881
14.085
13.914
15.749
15.819
15.696
15.184
12.648
14.611
12.865
15.067
15.597
13.935
13.912
14.462
15.587
14.946
16.227
13.287
12.881
13.411
14.672
15.383
15.440
13.176
13.687
14.569
15.909
15.022
15.446
1 mL
14.651
13.984
14.068
15.845
13.675
13.202
13.519
13.997
13.428
15.345
15.501
15.472
13.473
14.600
13.841
15.019
15.541
15.680
13.211
10.317
13.176
15.501
13.537
14.010
12.102
13.885
12.675
14.160
14.996
14.869
Table 10 shows the average weights as well as the average volumes of the observed drops.
TABLE 10
F4H5
F6H8
Aver-
Aver-
Summary
5 ml
3 ml
1 ml
age
5 ml
3 ml
1 ml
age
Average
13.712
13.776
13.395
13.628
15.479
15.295
14.824
15.199
Drop
Weight
(mg)
% RSD
0.800
0.734
1.082
0.881
0.547
0.786
0.873
0.783
of Drop
Weight
Average
10.629
10.679
10.384
10.564
11.629
11.491
11.137
11.419
Drop
volume
(μl)
% RSD
0.620
0.569
0.839
0.683
0.411
0.591
0.656
0.588
of Drop
size
In this experiment 3 series of 5 polypropylene droppers with a duct opening diameter of 0.15 mm and a mouth diameter of 2.4 mm (“Dropper 14014”) and a total volume of 5 ml were filled with F6H8 at different filling volumes: 5 droppers (droppers 1 to 5) were filled with 0.2 ml F6H8 each (filling level “nearly empty”); 5 droppers were filled with 3 ml F6H8 each (filling level “half full”) and 5 droppers were filled with 5 ml F6H8 each (filling level “full”) at room temperature. The dropper bottles were opened and inverted by 180° to a vertical orientation with the dropper mouth pointing downwards. For a period of 10 s it was observed whether the spontaneous formation of drops occurred. The drops, if formed, were counted. Table 11 summarizes the results of the experiment with “OK” depicting that no drops were formed within 10 s from the inversion of the bottle.
TABLE 11
Filling volume
0.2 ml
Filling volume
Filling volume
Dropper
(nearly empty)
3 ml (half full)
5 ml (full)
1
OK
OK
OK
2
OK
OK
OK
3
OK
OK
OK
4
OK
OK
OK
5
OK
OK
OK
Kemp, Philip, Graf, Gesche, Ahmed, Yasin, Legner, Stephanie
| Patent | Priority | Assignee | Title |
| Patent | Priority | Assignee | Title |
| 10045996, | Mar 17 2010 | NOVALIQ GMBH | Pharmaceutical composition for treatment of increased intraocular pressure |
| 10058615, | Sep 12 2012 | NOVALIQ GMBH | Semifluorinated alkane compositions |
| 10064944, | Nov 11 2010 | NOVALIQ GMBH | Liquid pharmaceutical composition for the treatment of a posterior eye disease |
| 10130707, | May 25 2011 | DERMALIQ THERAPEUTICS, INC | Topical pharmaceutical composition based on semifluorinated alkanes |
| 10369117, | Sep 12 2012 | NOVALIQ GMBH | Compositions comprising mixtures of semifluorinated alkanes |
| 10449164, | Sep 12 2012 | NOVALIQ GMBH | Methods of treating ocular disorders using semifluorinated alkanes |
| 10525062, | Mar 17 2010 | NOVALIQ GMBH | Pharmaceutical composition for treatment of increased intraocular pressure |
| 10555953, | Mar 17 2010 | NOVALIQ GMBH | Pharmaceutical composition for treatment of increased intraocular pressure |
| 10576154, | Sep 12 2012 | NOVALIQ GMBH | Semifluorinated alkane compositions |
| 10682315, | Sep 30 2015 | NOVALIQ GMBH | Semifluorinated compounds and their compositions |
| 10813976, | Sep 23 2016 | NOVALIQ GMBH | Ophthalmic compositions comprising ciclosporin |
| 10813999, | May 25 2011 | DERMALIQ THERAPEUTICS, INC | Topical pharmaceutical composition based on semifluorinated alkanes |
| 11154513, | Sep 30 2015 | NOVALIQ GMBH | Semifluorinated compounds |
| 11160865, | Oct 20 2010 | NOVALIQ GMBH | Liquid pharmaceutical composition for the delivery of active ingredients |
| 11273174, | Apr 21 2017 | DERMALIQ THERAPEUTICS, INC | Iodine compositions |
| 11278503, | May 12 2017 | NOVALIQ GMBH | Pharmaceutical compositions comprising semifluorinated alkanes for the treatment of contact lense-related conditions |
| 11324757, | Mar 17 2010 | NOVALIQ GMBH | Pharmaceutical composition for treatment of increased intraocular pressure |
| 11413323, | Oct 12 2018 | NOVALIQ GMBH | Ophthalmic composition for treatment of dry eye disease |
| 2616927, | |||
| 5077036, | Jan 14 1986 | PFC THERAPEUTICS, LLC | Biocompatible stable fluorocarbon emulsions for contrast enhancement and oxygen transport comprising 40-125% wt./volume fluorocarbon combined with a phospholipid |
| 5326566, | May 17 1991 | Bristol-Myers Squibb Company | Use of dibutyl adipate and isopropyl myristate in topical and transdermal products |
| 5336175, | Oct 29 1992 | Method for the treatment of retinal detachments | |
| 5370313, | Jan 10 1994 | Bespak PLC | Sterile liquid dispenser |
| 5518731, | Sep 27 1990 | Allergan, Inc | Nonaqueous fluorinated drug delivery vehicle suspensions |
| 5578020, | Sep 01 1995 | Drop dispensing apparatus | |
| 5667809, | Jun 07 1995 | ALLIANCE PHARMACEUTICAL CORP | Continuous fluorochemical microdispersions for the delivery of lipophilic pharmaceutical agents |
| 5874469, | Jan 05 1996 | Alcon Research, Ltd | Fluoroalkyl hydrocarbons for administering water insoluble or unstable drugs |
| 5874481, | Jun 07 1995 | ALLIANCE PHARMACEUTICAL CORP | Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents |
| 5980936, | Aug 07 1997 | ALLIANCE PHARMACEUTICAL CORP | Multiple emulsions comprising a hydrophobic continuous phase |
| 5981607, | Jan 20 1998 | Saint Regis Mohawk Tribe | Emulsion eye drop for alleviation of dry eye related symptoms in dry eye patients and/or contact lens wearers |
| 6042845, | Dec 22 1994 | Johnson & Johnson Consumer Products, Inc. | Anti fungal treatment of nails |
| 6060085, | Sep 11 1996 | Allergan, Inc | Compositions and methods for topical application of therapeutic agents |
| 6113919, | Jul 17 1991 | PFC THERAPEUTICS, LLC | Preparations comprising a fluorocarbon or a highly fluorinated compound and a lipophilic/fluorophilic compound and their uses |
| 6159977, | Nov 16 1998 | Astan, Inc. | Therapeutic anti-fungal nail preparation |
| 6177477, | Mar 24 1999 | FAULDING PHARMACEUTICAL CO | Propofol formulation containing TRIS |
| 6197323, | Mar 10 1997 | Medicinal preparation containing a lipophilic inert gas | |
| 6224887, | Feb 09 1998 | MacroChem Corporation | Antifungal nail lacquer and method using same |
| 6262126, | Sep 29 1995 | Semi-fluorinated alkanes and their use | |
| 6294563, | Oct 27 1994 | Allergan, Inc | Combinations of prostaglandins and brimonidine or derivatives thereof |
| 6372243, | Mar 18 1998 | Bausch & Lomb Incorporated | Low-oxygen fluorocarbon as an agent for ophthalmology |
| 6391879, | Nov 16 1998 | Astan, Inc. | Therapeutic anti-fungal nail preparation |
| 6458376, | Sep 27 1990 | Allergan, Inc | Nonaqueous fluorinated drug delivery suspensions |
| 6486212, | Sep 29 1995 | NOVALIQ GMBH | Semifluorinated alkanes and the use thereof |
| 6489367, | Sep 29 1995 | NOVALIQ GMBH | Semifluorinated alkanes and the use thereof |
| 6730328, | Oct 16 1996 | DURECT CORPORATION | Stable protein and nucleic acid formulations using non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity |
| 7001607, | Aug 14 1999 | Pharm pur GmbH | Artificial tear replacement solution |
| 7026359, | Jun 12 1999 | Bausch & Lomb Incorporated | Utilization of a highly fluorinated oligomeric alkane in ophthalmology |
| 7258869, | Feb 08 1999 | INTARCIA THERAPEUTICS, INC | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle |
| 7740875, | Oct 08 2004 | MQT HOLDINGS, LLC | Organo-gel formulations for therapeutic applications |
| 8029977, | Nov 23 2005 | NOVALIQ GMBH | Method for preserving organs or limbs using a composition containing a siloxane and a semifluorinated alkane and/or hydrofluoroether |
| 8470873, | Feb 01 2006 | LATITUDE PHARMACEUTICALS INC | Vitamin E succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof |
| 8614178, | Dec 14 2009 | NOVALIQ GMBH | Pharmaceutical composition for treatment of dry eye syndrome |
| 8796340, | Nov 23 2009 | NOVALIQ GMBH | Pharmaceutical composition comprising propofol |
| 8916157, | Aug 16 2002 | Abbvie Biotechnology Ltd. | Formulation of human antibodies for treating TNF-α associated disorders |
| 8986738, | Apr 18 2008 | NOVALIQ GMBH | Inhalative and instillative use of semifluorinated alkanes as an active substance carrier in the intrapulmonary area |
| 9241900, | Nov 11 2010 | NOVALIQ GMBH | Liquid pharmaceutical composition for the treatment of a posterior eye disease |
| 9308262, | May 25 2011 | DERMALIQ THERAPEUTICS, INC | Pharmaceutical composition for administration to nails |
| 9757459, | Oct 20 2010 | NOVALIQ GMBH | Liquid pharmaceutical composition for the delivery of active ingredients |
| 9757460, | Jan 23 2012 | NOVALIQ GMBH | Stabilised protein compositions based on semifluorinated alkanes |
| 9770508, | Sep 12 2012 | NOVALIQ GMBH | Semifluorinated alkane compositions |
| 9968678, | Oct 20 2010 | NOVALIQ GMBH | Liquid pharmaceutical composition for the delivery of active ingredients |
| 20020004063, | |||
| 20020128527, | |||
| 20030018044, | |||
| 20030027833, | |||
| 20030170194, | |||
| 20040044045, | |||
| 20040082660, | |||
| 20040265362, | |||
| 20040266702, | |||
| 20050079210, | |||
| 20050175541, | |||
| 20050274744, | |||
| 20050288196, | |||
| 20060153905, | |||
| 20080039807, | |||
| 20080050335, | |||
| 20080153909, | |||
| 20080207537, | |||
| 20080234389, | |||
| 20080260656, | |||
| 20090149546, | |||
| 20100006600, | |||
| 20100008996, | |||
| 20100016814, | |||
| 20100226997, | |||
| 20100274215, | |||
| 20110269704, | |||
| 20120010280, | |||
| 20120095097, | |||
| 20120238639, | |||
| 20130046014, | |||
| 20130084250, | |||
| 20130266652, | |||
| 20130303473, | |||
| 20140004197, | |||
| 20140100180, | |||
| 20140140942, | |||
| 20140369993, | |||
| 20150224064, | |||
| 20150238605, | |||
| 20160159902, | |||
| 20170020726, | |||
| 20170087100, | |||
| 20170087101, | |||
| 20170182060, | |||
| 20180360908, | |||
| 20190274970, | |||
| 20190328717, | |||
| 20190343793, | |||
| 20200268682, | |||
| 20210069014, | |||
| 20210106558, | |||
| 20210346313, | |||
| EP89815, | |||
| EP593552, | |||
| EP670159, | |||
| EP939655, | |||
| EP965329, | |||
| EP965334, | |||
| EP1152749, | |||
| EP2110126, | |||
| EP2332525, | |||
| EP2335735, | |||
| EP2462921, | |||
| JP2000511157, | |||
| JP2001158734, | |||
| JP2008505177, | |||
| JP2011006348, | |||
| JP2011024841, | |||
| JP6452722, | |||
| WO24376, | |||
| WO54588, | |||
| WO10531, | |||
| WO249631, | |||
| WO1995033447, | |||
| WO1998005301, | |||
| WO2004043315, | |||
| WO2005018530, | |||
| WO2005099718, | |||
| WO2005099752, | |||
| WO2005123035, | |||
| WO2006007510, | |||
| WO2006042059, | |||
| WO2006048242, | |||
| WO2007052288, | |||
| WO2008060359, | |||
| WO2009013435, | |||
| WO2010062394, | |||
| WO2010146536, | |||
| WO2011009436, | |||
| WO2011073134, | |||
| WO2011113855, | |||
| WO2012052418, | |||
| WO2012062834, | |||
| WO2012093113, | |||
| WO2012121754, | |||
| WO2012160179, | |||
| WO2012160180, | |||
| WO2013110621, | |||
| WO2014041055, | |||
| WO2014041071, | |||
| WO2014154531, | |||
| WO2015011199, | |||
| WO2016025560, | |||
| WO2018115097, | |||
| WO9640052, | |||
| WO9712852, |
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