Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
  • A61J1/14—Details; Accessories therefor
  • A61J1/1468—Containers characterised by specific material properties
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/02—Local antiseptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• Uveitis is an inflammation of the uvea, the middle layer of the eye. Located between the sclera, the eye’s white outer coat, and the inner layer of the eye, called the retina, the uvea consists of the iris, ciliary body and choroid.
• uveitis is classified in: uveitis at the front of the eye (anterior uveitis), which can cause redness and pain; uveitis in the middle of the eye (intermediate uveitis), which can cause floaters and blurred vision; uveitis at the back of the eye (posterior uveitis), which can cause vision problems.
• Uveitis can sometimes affect both the front and the back of the eye and this is known as panuveitis.
• Uveitis at the front of the eye is the most common type of uveitis, accounting for about three out of four cases.
• anterior uveitis includes ulceris (inflammation in the anterior chamber alone) and iridocyclitis (inflammation in the anterior chamber and anterior vitreous).
• Posterior uveitis generally refers to chorioretinitis.
• the inflammatory products i.e. cells, fibrin, excess proteins
• these inflammations are commonly found in the fluid spaces of the eye, i.e. anterior chamber, posterior chamber and vitreous space as well as infiltrating the tissue imminently involved in the inflammatory response.
• Uveitis can also be described according to how long it lasts: acute uveitis, in case it develops quickly and improves within three months; recurrent uveitis, where there are repeated episodes of inflammation separated by gaps of several months; chronic uveitis, where the inflammation lasts longer and returns within three months of stopping treatment.
• Uveitis is further classified according to etiological criteria in three main categories: infectious (e.g. bacterial, viral, fungal); non-infectious (e.g. known systemic associations, no known systemic association); masquerade (e.g. neoplastic).
• Corticosteroids and immunosuppressive agents are described as treatment options for uveitis.
• Topical administration of steroids is accompanied by side effects like increase of the intraocular pressure, susceptibility to infections, impaired corneal and scleral wound healing, corneal epithelial toxicity and crystalline keratopathy. It is important that patients on topical corticosteroids be regularly monitored to assess the response to therapy as well as development of side effects.
• the commonly available topical corticosteroids preparations are reported in the table below.
• Immunosuppressive drugs can be classified as antimetabolites, T cell inhibitors, and alkylating agents.
• the antimetabolites include methotrexate, azathioprine, and mycophenolate mofetil.
• the T cell inhibitors include cyclosporine, tacrolimus, voclosporin, and sirolimus.
• the alkylating agents include cyclophosphamide and chlorambucil.
• Systemic administration of cyclosporine (Sandimmune ® , Neoral) at a dose of 2.5-5 mg/kg/day is associated with renal dysfunction, tremor, hirsutism, hypertension, gum hyperplasia.
• immunosuppressive drugs may take many weeks to have an effect, so initial therapy of ocular inflammation typically include high dose of systemic steroids. Immunosuppressive therapy can be started simultaneously with corticosteroids in severe cases or during the tapering of oral corticosteroids 4-8 weeks later in cases of chronic uveitis (K. Babu et al., Indian J. Ophthalmol.; 2013 Jun; 61(6):277-283). Cyclosporins have been used to treat inflammatory conditions. Cyclosporine is available, at least in the US as an approved medicine in the form of an ophthalmic (o/w) emulsion (Restasis®). This product is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivis sicca.
• ophthalmic ophthalmic
• Restasis® ophthalmic emulsion
• US4649047 describes a study in which cyclosporine in olive oil is administered to rabbits’ eyes. The levels of cyclosporine found in the different ocular tissues is described.
• W02011/073134 Al describes pharmaceutical compositions in the form of solutions comprising cyclosporine and a semifluorinated alkane as a liquid vehicle which may be administered to the eye of a patient, such as for the treatment of keratoconjunctivitis sicca, for instance compositions comprising cyclosporine in semifluorinated alkane 1-perfluorobutyl-pentane (F4H5) in the presence of ethanol as a co-solvent.
• W02011/073134 Al however does not describe treatement of uveitis.
• the invention relates to a pharmaceutical composition for use in the treatment of uveitis, wherein the composition comprises cyclosporine in 1- perfluorobutyl-pentane.
• the invention provides for a kit comprising a pharmaceutical composition for such uses, wherein the kit comprises a container for holding the pharmaceutical composition and a drop dispenser adapted for administering about 8 to 12 m ⁇ volume of the composition per drop.
• the present invention relates to, in a first aspect, a pharmaceutical composition for use in a method of treating uveitis or a disease or condition associated thereto, wherein the composition comprises cyclosporine at a concentration of from about 0.05% (w/v) to 0.5% (w/v) and 1-perfluorobutyl-pentane.
• Uveitis is the inflammation of the uvea.
• the inflammatory products of this inflammation are commonly found in the fluid spaces of the eye, like for example the anterior chamber, the posterior chamber and the vitreous space.
• Uveitis disrupts vision by primarily causing problems with the lens, retina, optic nerve, and vitreous.
• Uveitis can affect one or both eyes. Symptoms may develop rapidly and can include: blurred vision, dark, floating spots in the vision (floaters), eye pain, redness of the eye, sensitivity to light (photophobia).
• Posterior uveitis primarily occurs in the back of the eye, often involving both the retina and the choroid. It is often called choroditis or chorioretinitis.
• Anterior uveitis means an inflammation of the iris (iritis) or the iris and the ciliar body (iridocyclitis).
• the term “intermediate uveitis” is used for that subset of uveitis where the vitreous is the major site of the inflammation and if there is an associated infection (for example, Lyme disease) or systemic disease (for example, sarcoidosis)
• uveitis is one selected from anterior uveitis and posterior uveitis. In a more preferred embodiment, uveitis is anterior uveitis.
• Cyclosporine (synonyms include cyclosporin A, CsA, or ciclosporin) is a cyclic nonribosomal peptide comprising 11 amino acids with the empirical formula C 62 H 111 N 11 O 12 and molecular weight of 1202.61. It is an immunosuppressant drug that is widely used in post-allergenic organ transplant, to reduce the activity of the patient’s immune system and thereby, the risk of organ rejection. Cyclosporine is typically provided as a colourless or white powder.
• Cyclosporine is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes.
• cyclophilin immunocompetent lymphocytes
• This complex of cyclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells.
• Cyclosporine is a pharmacological treatment option for dry eye disease, which is available as a prescription medication, for example in the US in the form of an 0.05 % ophthalmic (o/w) emulsion (Restasis ® ). This product is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivis sicca. Restasis ® is administered twice a day in each eye approximately 12 hours apart. It is packaged in single-vials. (Prescribing Information, Restasis ® ).
• the pharmaceutical composition for the use of the present invention is formulated as a solution, even more preferred as a clear solution.
• a “clear solution”, as mentioned above and understood herein, refers to a liquid solution in which all solutes are fully dissolvable or dissolved under room temperature conditions i.e. between 15 and 25 °C.
• the clear solution does not comprise of any particulate or solid phase components and preferably has a refractive index approximate to that of water (i.e. 1.333) at room temperature.
• the pharmaceutical composition comprises 1- perfluorobutyl-pentane, with the chemical formula F(CF2)4(CH2)sH. It is an inert, water-insoluble liquid, with a density of 1.284 g/cm 3 at 25 °C and refractive index of 1.3204 at 20 °C.
• Alternative nomenclature for this compound includes F4H5, wherein F denotes a linear perfluorinated alkane segment comprising 4 carbon atoms and wherein H denotes a linear and non-fluorinated alkane segment of 5 carbon atoms.
• the 1-perfluorobutyl-pentane is substantially free of water.
• the pharmaceutical composition for the use of the present invention may comprise from about 95 to about 99% wt.-%, more preferably from about 98 to about 99% wt.-%, of 1-perfluorobutyl-pentane as described above, based on the total weight of the composition.
• the pharmaceutical composition for use according to the present invention may comprise at least about 97 % (w/w), preferably at least about 98 % (w/w), more preferably at least about 99 % (w/w) of 1-perfluorobutyl-pentane, based on the total weight of the pharmaceutical composition.
• the pharmaceutical composition according to the present invention may optionally further comprise 2-perfluorobutyl-pentane.
• the composition in addition to 1-perfluorobutyl-pentane, may optionally comprise minor amounts of 2-perfluorobutyl-pentane of up to 2 % (w/w), preferably up to 1 % (w/w), more preferably of up to 0.5 % (w/w).
• the concentration of cyclosporine in the pharmaceutical composition for use according to the invention is in the range of from 0.05% (w/v) to about 0.5 % (w/v) with respect to the total volume of the composition, preferably in the range of from about 0.05% to 0.3% (w/v), more preferably in the range of from 0.05% to 0.2 % (w/v).
• the concentration of cyclosporine in the pharmaceutical composition for use according to the invention is in the range of about 0.05 to 0.1 % (w/v), more preferably about 0.05% (w/v) or about 0.1 % (w/v).
• % (w/v) denotes the amount of a component of a composition as a weight percentage in relation to the total volume of the composition (with ‘w’ denoting the weight and V denoting volume).
• 0.05 % (w/v) may be understood as relating to 0.5 mg of a component in 1 mL of the composition, and 0.1 % (w/v) would correspond to 1.0 mg of a component in 1 mL of the composition.
• % (w/w) refers to the amount of a component of a composition as a weight percentage in relation to the total weight of the composition (with ‘w’ denoting weight).
• a single dose of the pharmaceutical composition for the use of the present invention may be administered in a volume of about 8-12 m ⁇ , preferably in a volume of about 10-12 m ⁇ , more preferably 11-12 m ⁇ , most preferably about 11 m ⁇ .
• a dose of a composition for use according to the present invention and as described in any one of the embodiments herein is preferably topically administered in the form of a (i.e. one) single drop to an eye of a subject.
• the drop may be administered to the surface of the eye, preferably to any surface region or tissue of the eye that is accessible to topical administration or instillation, for example to the cornea or conjunctiva.
• the single drop of the composition may be instilled directly onto a surface of the eye, such as the corneal surface of the eye, or alternatively into a space i.e. sac or pocket formed by gently pulling down of the lower eyelid of an eye.
• the term 'administration to an eye’ or 'per eye’ refers to the administration of a given dose, e.g. a single dose, of a pharmaceutical composition according to the invention to an individual eye of a subject.
• the therapy of the uveitis and diseases or associated conditions as described herein however, should be understood as being not limited to the treatment of a single eye in a subject, but as being also inclusive of a therapy involving the administration of composition according to the present invention to each i.e. both eyes of a subject which are affected by uveitis.
• the pharmaceutical composition may also comprise one or more further excipients as an optional and additional component.
• excipients refers to any pharmaceutically acceptable natural or synthetic substance that may be added to the pharmaceutical composition to enhance or otherwise modify its physical or chemical constitution or stability or therapeutic properties.
• the present pharmaceutical composition may optionally comprise one or more excipients such as, for example, an antioxidant, a preservative, a lipid or oily excipient, a surfactant or a lubricant or a combination of at least 2 excipients thereof.
• Suitable antioxidants for use in the present pharmaceutical composition comprise, for example: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), vitamin E, vitamin E derivatives (i.e. alpha- tocopherol acetate) or ascorbic acid.
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• TBHQ tertiary butylhydroquinone
• vitamin E i.e. alpha- tocopherol acetate
• ascorbic acid i.e. alpha- tocopherol acetate
• Suitable lipid or oily excipients for use in the pharmaceutical composition of the present invention comprise, for example, triglyceride oils (i.e. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), triglycerides, mineral oil (i.e. 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, or any other oily substance which is physiologically tolerated by the eye.
• triglyceride oils i.e. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil
• mineral oil i.e. petrolatum and liquid paraffin
• MCT medium chain triglycerides
• oily fatty acids isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids
• Suitable lubricants for use in the pharmaceutical composition of the present invention comprise, for example, carboxymethylcellulose and its sodium salt (CMC, carmellose), polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC, hypromellose), hyaluronic acid and its sodium salt, or hydroxypropyl guar gum.
• CMC carboxymethylcellulose and its sodium salt
• HPMC hydroxypropyl methylcellulose
• hyaluronic acid and its sodium salt or hydroxypropyl guar gum.
• the pharmaceutical composition according to the present invention may or may not comprise pharmaceutically suitable natural or synthetic preservatives, such as, for example, benzalkonium chloride and chlorhexidine. In a preferred embodiment, however, the pharmaceutical composition according to the present invention does not comprise a pharmaceutically acceptable preservative.
• the present pharmaceutical composition may also comprise one or more further solvents.
• further solvents refers to a solvent or mixture of two or more different solvents other than 1-perfluorobutyl-pentane.
• Suitable further solvents may be chosen from, for example, alcohols, such as ethanol, isopropanol or other further solvent which is physiologically tolerated by the eye.
• Ethanol may be present in the pharmaceutical composition for use according to the present invention in an amount of up to about 1.0 wt.-%, such as, for example from 0.2 to 1.0 wt.-% (corresponding to 0.2% to 1.0% (w/w)) or 0.5 to 1.0 wt.-% (corresponding to 0.5 to 1.0% (w/w)), based on the total weight of the composition (final dosage form).
• the pharmaceutical composition for use according to the present invention comprises about 0.5 to 1.0 wt.-% ethanol, more preferably about 1.0 wt.-% ethanol with respect to the total weight of the pharmaceutical composition.
• the pharmaceutical composition for the use of the present invention is essentially free of water, whereas the residual water may be attributed to the potential residual water content of cyclosporin.
• the term ‘essentially’ as used herein means if present then in trace or residual amounts such as to confer no technical advantage or relevance in respect of the object of the invention.
• the term “up to about” or “up to” used in context of a parameter refers to any value of the parameter greater than zero and up to, and inclusive of, the defined parameter.
• an amount of “up to about 1.0 % (w/w) of ethanol” should be understood as including any value greater than zero ranging up to and including the value of 1.0 % (w/w) of ethanol, and would include, for example, values such as 0.01%, 0.05%, 0.1 %, 0.2 %, 0.3 %, 0.4 %, 0.5 % 0.6 %, 0.7, 0.8, 0.9, 0.95 %, 0.99 % (w/w) of ethanol, taking into account any degree of variability usually observed in measuring or determining this parameter, using the standard techniques and equipment known in the relevant field.
• the pharmaceutical composition for the use of the present invention is (essentially) water-free and/or preservative free.
• the composition for the use according to the invention may comprise about 0.05 % to 0.1 % (w/v) cyclosporine dissolved in 1- perfluorobutyl-pentane, and about 1.0 % (w/w) of ethanol based on the total weight of the composition.
• the pharmaceutical composition for the use of the present invention consists essentially of about 0.05% to 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane. In another embodiment, the pharmaceutical composition for the use of the present invention consists essentially of about 0.05% to 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) ethanol based on the total weight of the composition.
• composition for use as described herein may preferably comprise, or consist of:
• the pharmaceutical composition for the use of the present invention is a clear solution comprising cyclosporin at a concentration of from about 0.05 % (w/v) to 0.5% (w/v), preferably from about 0.05% (w/v) to 0.3% (w/v), more preferably from about 0.05% (w/v) to 0.2 % (w/v), most preferably from 0.05% (w/v) to 0.1% (w/v) dissolved in 1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol (at room temperature conditions i.e. between 15 to 25 °C).
• the pharmaceutical composition for the use of the present invention is provided in sterile form.
• the pharmaceutical composition for use according to the present invention are substantially free of water, substantially free of a preservative and are effective in inhibiting microbal growth.
• the pharmaceutical composition for use according to the present invention form small droplets (drops), in the range of about 8-12 pi, more preferably about 10-12 pi, even more preferably about 11-12 pi, most preferably about 11 pi, when administered from a drop dispenser.
• droplets small droplets
• the composition for use is topically administered to a subject suffering from uveitis, such anterior uveitis or posterior uveitis, as single droplets having a volume of about 8-12 pi, more preferably of about 10-12 pi, even more preferably of about 11-12 pi, most preferably as droplets having a volume of about 11 pi.
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 4 to 240 mg cyclosporine per eye, preferably as a daily dose of 4 to 60 mg cyclosporine per eye, more preferably as a daily dose of 16 to 240 mg cyclosporine per eye, most preferably as a daily dose of 8 to 120 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 4 to 48 mg cyclosporine per eye, preferably as a daily dose of 4 to 12 mg cyclosporine per eye, more preferably as a daily dose of 16 to 48 mg cyclosporine per eye, most preferably as a daily dose of 8 to 24 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 4 to 32 mg cyclosporine per eye, preferably as a daily dose of 4 to 6 mg cyclosporine per eye, more preferably as a daily dose of 16 to 32 mg cyclosporine per eye, most preferably as a daily dose of 8 to 16 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 8 to 48 mg cyclosporine per eye, preferably as a daily dose of 8 to 12 mg cyclosporine per eye, more preferably as a daily dose of 32 to 48 mg cyclosporine per eye, most preferably as a daily dose of 16 to 24 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 5 to 24 mg cyclosporine per eye, preferably as a daily dose of 5 to 6 mg cyclosporine per eye, more preferably as a daily dose of 20 to 24 mg cyclosporine per eye, most preferably as a daily dose of 10 to 12 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a daily dose of 10 to 48 mg cyclosporine per eye, preferably as a daily dose of 10 to 12 mg cyclosporine per eye, more preferably as a daily dose of 40 to 48 mg cyclosporine per eye, most preferably as a daily dose of 20 to 24 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the parmaceutical composition for use is topically administered to the eye of a subject suffering form uveitis, such as anterior uveitis or posterior uveitis, up to four times per day, preferable the composition is administered three times per day, even more preferred the composition is topically administered twice per day or the composition is topically administered once per day.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, as a single dose of 4 to 60 mg cyclosporine per eye, preferably as a single dose of 4 to 12 mg cyclosporine per eye, more preferably as a single dose of 4 to 6 mg cyclosporine per eye, even more preferably as a single dose of 8 to 12 mg cyclosporine per eye, most preferably as a single dose of 5 to 6 mg, or as a single dose of 10 to 12 mg.
• uveitis such as anterior uveitis or posterior uveitis
• the parmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, once per day as a single dose of 4 to 60 mg cyclosporine per eye, preferably once per day as a single dose of 4 to 12 mg cyclosporine per eye, more preferably once per day as a single dose of 4 to 6 mg cyclosporine per eye, even more preferably once per day as a single dose of 8 to 12 mg cyclosporine per eye, most preferably once per day as a single dose of 5 to 6 mg, or once per day as a single dose of 10 to 12 mg.
• uveitis such as anterior uveitis or posterior uveitis
• the parmaceutical composition for use is topically administered to to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 4 to 60 mg cyclosporine per eye, preferably twice per day as a single dose of 4 to 12 mg cyclosporine per eye, more preferably twice per day as a single dose of 4 to 6 mg cyclosporine per eye, even more preferably twice per day as a single dose of 8 to 12 mg cyclosporine per eye, most preferably twice per day as a single dose of 5 to 6 mg, or twice per day as a single dose of 10 to 12 mg.
• uveitis such as anterior uveitis or posterior uveitis
• the parmaceutical composition for use is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, four times per day as a single dose of 4 to 60 mg cyclosporine per eye, preferably four times per day as a single dose of 4 to 12 mg cyclosporine per eye, more preferably four times per day as a single dose of 4 to 6 mg cyclosporine per eye, even more preferably four times per day as a single dose of 8 to 12 mg cyclosporine per eye, most preferably four times per day as a single dose of 5 to 6 mg, or four times per day as a single dose of 10 to 12 mg.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use comprising 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 8 to 12 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use comprising 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 10 to 12 mg cyclosporine per eye.
• the pharmaceutical composition for use comprising 0.05 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 4 to 6 mg cyclosporine per eye.
• the pharmaceutical composition for use comprising 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 5 to 6 mg cyclosporine per eye.
• the pharmaceutical composition for use comprising or essentially consisting of 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutyl- pentane, and optionally about 1.0 % (w/w) of ethanol, is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 8 to 12 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use comprising or essentially consisting of 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane, and optionally about 1.0 % (w/w) of ethanol, is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 10 to 12 mg cyclosporine per eye.
• the pharmaceutical composition for use comprising or essentially consisting of 0.05 % (w/v) cyclosporine dissolved in 1-perfluorobutyl- pentane, and optionally about 1.0 % (w/w) of ethanol, is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 4 to 6 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• the pharmaceutical composition for use comprising or essentially consisting of 0.1 % (w/v) cyclosporine dissolved in 1-perfluorobutylpentane, and optionally about 1.0 % (w/w) of ethanol, is topically administered to the eye of a subject suffering from uveitis, such as anterior uveitis or posterior uveitis, twice per day as a single dose of 5 to 6 mg cyclosporine per eye.
• uveitis such as anterior uveitis or posterior uveitis
• compositions if any other constituent or component is present in the composition other than those prefaced by such term, then it is present only in trace or residual amounts such as to confer no technical advantage or relevance in respect of the object of the invention, such as may be further understood by the term 'essentially” or “substantially” used in conjunction with these terms (e.g. 'essentially consisting of”).
• the methods may comprise the topical administration, such as by direct topical instillation to the eye, of any one of the defined compositions, preferably in any one of the described doses or amounts, and/or over any one of the defined periods for therapy.
• Said treatment methods and compositions for therapeutic use are moreover preferably targeted towards human subjects diagnosed and/or suffering from uveitis.
• the invention provides also a kit comprising a pharmaceutical composition for use according to the invention and any of the embodiments described above, wherein the kit comprises a container for holding the pharmaceutical composition and a drop dispenser adapted for administering about 8 to 12 m ⁇ volume of the composition per drop.
• the drop dispenser may be adapted for administering about 10-12 m ⁇ of the composition per drop, preferably 11-12 m ⁇ of the composition per drop, more preferably 11 m ⁇ of the composition per drop.
• the drop dispenser may be a dispenser or applicator means which may be mounted, fixed or connected to the container for holding the pharmaceutical composition.
• the drop dispenser is adapted for dispensing a single dose in the form of a single drop of the composition. More preferably, the drop dispenser is adapted for dispensing a single dose of 8- to 12-m1 volume, preferably 10 to 12 m ⁇ , even more preferably 11 to 12 m ⁇ , most preferably a single dose of about ll-ml volume.
• the container for holding the pharmaceutical composition as understood herein is preferably of a volume which may hold a single dose, but more preferably of a volume which may hold multiple or a plurality of doses of the composition.
• the container of the kit may hold up to 160 doses of the pharmaceutical composition for use according to the present invention.
• the container and/or the drop dispenser preferably may be manufactured from a thermoplastic material or polymer.
• the container and/or drop dispenser is manufactured from a thermoplastic material selected from polyethylene and polypropylene.
• the drop dispenser is manufactured from a polyethylene material, preferably selected from low density polyethylene and high density polyethylene, and more preferably is manufactured from a high-density polyethylene.
• the container is manufactured from a polypropylene or polyethylene material, and more preferably is manufactured from polypropylene.
• the invention relates to a kit comprising a pharmaceutical composition for use according to the invention, the kit comprising a container for holding the pharmaceutical composition and a drop dispenser adapted for administering about 8 to 12 m ⁇ per drop, preferably 10-12 m ⁇ , more preferably 11- 12 m ⁇ , wherein the container is manufactured from polypropylene and wherein the drop dispenser is manufactured from a polyethylene selected from a low density polyethylene and a high density polyethylene, preferably a high density polyethylene.
• the container has a volume, or an interior space which is at least partially filled with a pharmaceutical compostion for use according to the invention.
• the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 and 0.7.
• the total volume of the container refers to the total interior volume formed by the interior dimensions of the container.
• the volume of the pharmaceutical composition in the container refers to the fill volume, i.e. the volume of the pharmaceutical composition held in the container.
• the container holds a volume of 2.0 mL of a pharmaceutical composition according to the invention.
• the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container would be about 0.7.
• kits comprising a pharmaceutical composition for use in accordance with the present invention, wherein the kit comprises, in addition to a drop dispenser adapted for administering about 8 to 12 m ⁇ per drop, any one of the following: about 2.0 mL of the pharmaceutical composition filled in a 3.0 mL volume container (i.e. a respective ratio of about 0.7); or about 2.0 mL of a pharmaceutical compostion filled in a 5.0 mL volume container (i.e. a respective ratio of about 0.4); or about 2.5 mL of a pharmaceutical compostion filled in a 5.0 mL volume container (i.e. a respective ratio of about 0.5).
• kits comprising a pharmaceutical composition for use in accordance with the present invention, wherein the kit comprises a container for holding the pharmaceutical composition and a drop dispenser adapted for administering about 8 to 12 m ⁇ per drop and wherein the ratio of the volume of head space in the container to the volume of the pharmaceutical composition is between 0.5 to 1.5.
• the volume of head space (or head space volume) in the container refers to the interior volume of the container, formed by the interior dimensions of the container which is not filled or occupied by the liquid pharmaceutical composition but which may contain atmosphere or inert gas.
• a kit comprising a container holding a fill volume of 2.5 mL of a pharmaceutical composition for use according to the present invention
• the head space volume available in the container is about 2.5 mL, wherein the ratio of the head space to pharmaceutical composition fill volume is about 1.0.
• kits comprising a pharmaceutical composition for use in accordance with the present invention, wherein the kit comprises, in addition to a drop dispenser adapted for administering about 8 to 12 m ⁇ per drop, preferably about 10-12 m ⁇ per drop, more preferably 11-12 m ⁇ , most preferably 11 m ⁇ , any one of the following: a container holding about 2.0 mL of the pharmaceutical composition, wherein the container has about 1.0 mL volume of head space (i.e. a head space to fill volume ratio of about 0.5); or a container holding about 2.0 mL of the pharmaceutical composition, wherein the container has about 3.0 mL volume of head space (i.e. a head space to fill volume ratio of about 1.5); or a container holding about 2.4 mL of the pharmaceutical composition, wherein the container has about 2.6 mL volume of head space (i.e. a head space to fill volume ratio of about 1.1).
• a drop dispenser adapted for administering about 8 to 12 m ⁇ per drop, preferably about 10-12 m ⁇ per drop,
• kits as provided in accordance with these embodiments may improve storage and dispensability (i.e., ease and consistency in dispensing) of the pharmaceutical compositions.
• the present invention comprises the following items 1 to 10, relating to a method for treating uveitis:
• a method of treating uveitis comprising topically administering to an eye of a human suffering from uveitis or a disease or a condition related thereto a composition comprising about 0.05 to 0.5% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said method is therapeutically effective in treating uveitis or a disease or a condition related thereto in said human.
• uveitis is anterior uveitis or posterior uveitis, preferably anterior uveitis.
• composition comprises ethanol
• composition consists of 0.05% to 0.5 % (w/v) cyclosporine dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1.0% (w/w) ethanol.
• composition consists of 0.05% to 0.5 % (w/v) cyclosporine dissolved in a solution of about at least 99% (w/w) 1-perfluorobutyl-pentane and up to about 1% (w/w) ethanol.
• composition consists of 0.1% to 0.5 % (w/v) cyclosporine dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1.0%
• composition consists of 0.1% to 0.3 % (w/v) cyclosporine dissolved in a solution of about 99% (w/w) 1-perfluorobutyl-pentane and about 1.0% (w/w) ethanol.
• Ikervis® is an oil in water emulsion based on the Novasorb® technology. Tab. 1: Ikervis® emulsion
• test formulation 1 and test formulation 2 were prepared by dissolving Cyclosporine A (CAS 59865-13-3; Euticals GmbH) in F4H5 and F4H5 plus ethanol 1.0% w/w, respectively. Study design
• Dose per eye 50 pL of each formulation was applied by means of a pipette onto the cornea.
• the pig eyes for the ex vivo experiment were received from the slaughterer (Odenwald- Schlachthof). The eyes were used within a few hours. Specifically, less than 3 hours after removal from the animal, the experiment was started. The pigs, from which the eyes were removed, were not treated with hot water, because this could damage the cornea.
• HBSS Hanks' Balanced Salt Solution
• VWR supplier batch S15113L0612; composition with calcium, magnesium, sodium bicarbonate, without phenol red, sterile filtered
• the optic nerve was carefully removed with the scissors to place the porcine eye flat in a cavity of a six-well plate.
• the eyes were moistened with around 4 ml HBSS and covered with a petri dish (35 x 10 mm) to avoid water loss.
• the plate with the eyes was placed in a preheated oven (32°C , deviant from the corneal surface temperature of 34°C, and a bowl of water inside to ensure a constant saturated moisture) for about 5 minutes. After being taken out of the oven, they were moistened with 4 mL HBSS and polycarbonate corneal sleeves were placed on each cornea and fixed with tape to ensure a precise application of the test solution. 50 m ⁇ of the test or reference formulation, respectively, was applied by means of a pipette to the cornea sleeve opening and covered again with the petri dish.
• a dose of 50 m ⁇ of each formulation was applied by means of a pipette to 3.14 cm 2 corneal surface.
• the applied HBSS was distributed very irregularly on the mentioned area and had to be regularly distributed with a pipette.
• Ikervis® in contrast was distributed more regularly on the cornea.
• the first drop of the suspension did not cover the entire area of the cornea, but a large part. After application of the whole volume, the suspension was distributed at the edge of the corneal sleeve. Due to the spreading behaviour of the SFAs, both cyclosporin test formulations were distributed regularly over the entire available area.
• the eyes were rinsed with HBSS buffer to stop the penetration and placed in a new cavity filled with HBSS.
• aqueous humor was collected with a 22.5 gauge needle and placed in a vial. A parallel injection to corneal surface was applied. Maximum 150 m ⁇ sample was withdrawn.
• Cyclosporine A was detected in the vitreous humour and in the retina. In the latter, an amount of cyclosporine A higher than 100 ng/g was found for both test formulations 1 and 2 at each incubation time point.

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