WO2013074625A1 - Suspensions of cyclosporin a form 2 - Google Patents
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- WO2013074625A1 WO2013074625A1 PCT/US2012/065011 US2012065011W WO2013074625A1 WO 2013074625 A1 WO2013074625 A1 WO 2013074625A1 US 2012065011 W US2012065011 W US 2012065011W WO 2013074625 A1 WO2013074625 A1 WO 2013074625A1
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- 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
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- 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
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- 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
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- 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
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- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
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- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- 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
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- 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
- A61P27/14—Decongestants or antiallergics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
- C07K7/645—Cyclosporins; Related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- This invention relates to the fields of nanotechnology and drug formulation technology.
- Cyclosporine A is the active ingredient in Restasis®, a drug that is used to treat dry eye disease. Cyclosporin A is poorly soluble in water, and so is currently formulated either by dissolving the drug in oil to form an emulsion, or by mixing the drug with high levels of surfactants and/or solubilizers to form an aqueous solution.
- the inventors have discovered a formulation of cyclosporin A using a new crystalline polymorph of cyclosporin A, to create nanosuspensions comprising particles of cyclosporin A having an average size of around 1 micrometer or less (to put that number in perspective, the average thickness of a human hair is around 100 micrometers).
- a nanosuspension of cyclosporin A when delivered topically to the eye, may have one or more advantages, including the following:
- Figure 1 shows the particle size distribution of cyclosporin A Form 2 nanosuspensions prepared using a high pressure homogenizer compared to suspensions prior to milling.
- Figure 2 compares the particle size distribution of cyclosporin A Form 2 nanosuspensions prepared using different surfactants and stabilizers.
- Figure 3 shows the particle size distribution of Formulation diluted in vehicle containing Na CMC.
- Figure 4 shows average particle size of a nanosuspension using
- Form 3 cyclosporin A Form 3 compared to a nanosuspensions using Form 2 after milling using a microfluidizer.
- Form 2 Forms a nanosuspension (particle size ⁇ 1 ⁇ ) while Form 3 does not.
- Figures 5-13 show the results when four different formulations according to the invention (summarized in Table 2) and Restasis® are administered to NZW female rabbits (two rabbits total, one formulation per eye) in a single topical dose:
- Figure 5 shows concentrations in the cornea.
- Figure 7 shows concentrations in the bulbar conjunctiva.
- Figure 8 shows concentrations in the palpebral conjunctiva.
- Figure 9 summarizes pharmacokinetic data for the bulbar conjunctiva and palpebral conjunctiva.
- Figure 10 shows concentrations in the bulbar conjunctiva.
- Figure 1 1 shows concentrations in the palpebral conjunctiva.
- Figure 12 shows concentrations in the lacrimal gland.
- Figure 13 summarizes pharmacokinetic data for lacrimal gland.
- Figure 14 depicts characteristic X-ray powder diffraction (XRPD) patterns of CsA in a new crystalline form (designated as Form 2 herein), tetragonal form (designated as Form 1 herein), and orthorhombic form (designated as Form 3 herein).
- XRPD X-ray powder diffraction
- Figure 15 depicts the XRPD diffractogram of CsA crystalline Form 2.
- Figure 16 depicts the water sorption/desorption profile of CsA Form 2.
- Figure 17 depicts MDSC analysis of CsA Form 2 recovered from 0.04% formulation with 1 % PS80.
- Figure 18 shows the simulated XRPD pattern of cyclosporine A forms.
- Cyclosporin A is a cyclic peptide having the following chemical structure:
- ciclosporin A It is the active ingredient in Restasis® (Allergan, Inc., Irvine, California), an emulsion comprising 0.05% (w/v) cyclosporin. Restasis® is approved in the United States to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Cyclosporin A form 2
- Cyclosporin A is known to exist in an amorphous form, liquid crystal form, tetragonal crystalline form (form 1 ), and an orthorhombic form (form 3).
- a new crystalline form, cyclosporin A Form 2 has recently been discovered.
- the XRPD pattern of CsA Form 2 differs significantly from the tetragonal form and orthorhombic form (FIG. 14).
- These major peaks are defined as those being unique to Form 2 relative to the orthorhombic or tetragonal forms; as well as, peaks having an intensity greater than 5 times the background.
- the new crystalline form (Form 2) of CsA is a nonstoichiometric hydrate of Cyclosporin A.
- the crystalline Form 2 is represented by the formula:
- X H 2 O wherein X is the number of molecules of water and varies from 0 to 3. In one embodiment, X in the above formula is 2.
- Form 2 appears to be a kinetically stable form of CsA in aqueous
- Suspensions containing Form 2 show no conversion to other known polymorphic or pseudomorphic forms upon storage. It has been found that Form 1 and the amorphous form convert to Form 2 in the presence of water. The single crystal structure of the hydrate form of CsA Form 2 has been determined and the crystal structure parameters are listed in Table 2. These results indicate that Form 2 is unique compared to other known crystalline forms of cyclosporine A.
- Table 1 Crystal data and data collection parameters of crystal
- the asymmetric unit of this CsA Form 2 contains one cyclosporine A molecule and two water molecules. It is possible that any small molecule that can hydrogen bond to water could play the role of space filler, which would give a range of potential structures running from the orthorhombic dihydrate to distorted monoclinic dihydrate
- the XRPD pattern calculated from the single-crystal structure is shown in Figure 8 and it matches the experimental pattern shown in Figure 2. These matching patterns further corroborate that Form 2 is a unique and pure crystalline form of cyclosporine A.
- thermogravimetric analysis combined with KF titration and vapor sorption desorption analysis suggest that CsA Form 2 is a non-stoichiometric hydrate of CsA.
- the vapor sorption analysis of Cyclosporine Form 2 indicates that water content in the new crystal form reversibly varies with relative humidity as shown in Fig. 16. Similar to the tetragonal form, the new CsA form undergoes a phase transition to a liquid crystal or amorphous form at 124.4 °C prior to melting as indicated by the modulated differential calorimetric (MDSC) analysis ( Figure 17).
- MDSC modulated differential calorimetric
- Cyclosporin A Form 2 may be obtained by suspending amorphous 0.05 % cyclosporin A (w/v) in 1 % Polysorbate 80, heating the solution to 65 °C, holding it at that temperature for 24 hours, and then recovering the precipitate by vacuum filtration. One can then use the cyclosporin A Form 2 thus obtained to generate additional amounts, using Cyclosporin A Form 2 as a seed crystal; in this method, one suspends about 30 g cyclosporin A in a solution of 900 ml water containing 1 % (w/v) Polysorbate 80, heats the solution to 65 °C, and then seeds it with 0.2 g of cyclosporin A Form 2 at a temperature of 52 °C. The solution is then stirred for about 22 hours at a temperature of between about 61 °C and 65 °C, and then recovers the precipitate that results.
- compositions of the invention are ophthalmically acceptable suspensions of Cyclosporin A form 2.
- ophthalmically acceptable the inventors mean that the suspensions are formulated in such a way as to be non-irritating when
- compositions are suspensions; that is, they comprise particles of cyclosporin A form 2, having an average particle size greater than about 1 ⁇ , dispersed throughout a liquid vehicle.
- compositions are nanosuspensions; that is, they comprise particles of cyclosporin A form 2, having an average particle size of less than about 1 ⁇ , that are dispersed throughout a liquid vehicle.
- the suspension comprises cyclosporin A form 2 at a concentration of about 0.001 % to about 10% (w/v). In one embodiment, the suspension comprises cyclosporin A form 2 at a concentration of about 0.001 % (w/v) to about 0.01 %, about 0.001 % (w/v) to about 0.04% (w/v), about 0.001 % (w/v) to about 0.03% (w/v), about 0.001 % (w/v) to about 0.02% (w/v), or about 0.001 % (w/v) to about 0.01 % (w/v).
- the suspension comprises cyclosporin A form 2 at a concentration of about 0.01 % (w/v) to about 0.05%, about 0.01 % (w/v) to about 0.04% (w/v), about 0.01 % (w/v) to about 0.03% (w/v), about 0.01 % (w/v) to about 0.02% (w/v), or about 0.01 % (w/v) to about 0.01 % (w/v).
- the suspension comprises cyclosporin A form 2 at a concentration of about 0.01 % (w/v) to about 0.1 %, about 0.1 % (w/v) to about 0.5% (w/v), about 0.01 % (w/v) to about 1 % (w/v), or about 1 % (w/v) to about 10%.
- the suspensions may comprise about 0.001 % (w/v), about 0.002% (w/v), about 0.003% (w/v), about 0.004% (w/v), about 0.005% (w/v), about 0.006% (w/v), about 0.007% (w/v), about 0.008% (w/v), about 0.009% (w/v), about 0.01 % (w/v), about 0.015% (w/v), about 0.02% (w/v), about 0.025% (w/v), about 0.03% (w/v), about 0.035% (w/v), about 0.04% (w/v), about 0.045% (w/v), about 0.05% (w/v), about 0.055% (w/v), about 0.06% (w/v), about 0.065% (w/v), about 0.07% (w/v), about 0.075% (w/v), about 0.08% (w/v), about 0.085% (w/v), about 0.09% (w/v), about 0.095% (w/v), about 0.00
- the suspension comprises a surfactant.
- the surfactant is selected from polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), polyethylene glycol 660 hydroxystearate (Solutol), polyoxyethylene (40) stearate Myrj 52 (POE-40-Stearate), pluronic F68
- the vehicle may contain all of these surfactants, or one, two, three, four, or five of them.
- the suspensions contain about 0.001 % (w/v) to about 1 % (w/v), about 0.001 % (w/v) to about 0.1 % (w/v), about 0.01 % (w/v) to about 0.1 % (w/v), or about 0.1 % (w/v) to about 1 % (w/v) of the surfactant.
- the suspensions may contain about 0.001 % (w/v), about 0.002% (w/v), about 0.003% (w/v), about 0.004% (w/v), about 0.005% (w/v), about 0.006% (w/v), about 0.007% (w/v), about 0.008% (w/v), about 0.009% (w/v), about 0.01 % (w/v), about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), about 0.1 % (w/v), about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v), about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v), about 0.9% (w/v), about 1 % (w/v), about
- the suspension may contain the same or different amounts of each.
- the suspensions may comprise a stabilizer.
- the stabilizer is selected from hydroxy propyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose, polyvinyl pyrolidone, carboxymethylcellulose, Pemulen®, and Pemulen® TR-2.
- Pemulen® is the trade name for high molecular weight, crosslinked copolymers of acrylic acid and C10- C30 alkyl acrylate produced by Lubrizol Corp.
- Pemulen® TR-2 is a C10-30 alkyl acrylate crosspolymer containing a higher level of hydrophobic groups than other Pemulen® polymers.
- the vehicle may contain all of these stabilizers, or none of them, or it may contain one, two, three, four, or five of them.
- the suspensions contain about 0.01 % (w/v) to about 1 % (w/v), or about 0.01 % (w/v) to about 0.1 % (w/v), or about 0.1 % (w/v) to about 1 % (w/v) of the stabilizer.
- the suspensions may contain about about 0.01 % (w/v), about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), about 0.1 % (w/v), about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v), about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v), about 0.9% (w/v), about 1 % (w/v), about 2% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), or about 10% of the stablizer.
- the suspension may contain the same or different amounts of each.
- the vehicle may also comprise a tonicity adjustor selected from glycerin, mannitol, sodium citrate dihydrate, potassium chloride, boric acid, and sodium borate decahydrate.
- the tonicity adjustor is added as needed to achieve the desired tonicity; the vehicle may contain all of these tonicity adjusters, or none of them, or it may contain one, two, three, four, or five of them.
- the tonicity adjustors are present in an amount of between about 0.1 % (w/v) and about 10% (w/v).
- the suspension may contain the same or different amounts of each.
- the suspension usually contains water, in an amount sufficient to provide a desired pH, tonicity, and other characteristics that would make the suspension appropriate for administration to the eye.
- the formulations of the invention may be made by mixing cyclosporin A form 2 with the appropriate surfactants, stabilizers, and tonicity adjustors, as described above, to form a suspension If fine particles of cyclosporin A are desired, the suspension is then milled using a high pressure homogenizer, such as those commercially available from Microfluidics Int'l Corp. of Newton,
- cyclosporin form A 2 A unique and surprising property of cyclosporin form A 2 is that it may be milled, if desired, to obtain a suspension with an average particle size (d90) of less than 1 ⁇ .
- the cyclosporin A in such a nanosuspension has higher bioavailability compared to other (macro) suspensions of cyclosporin A, due to the higher surface area available for dissolution; bioavailability is further enhanced because the smaller particles enable the Cyclosporin A to be retained on the eye longer.
- the smaller particles of the nanosuspensions result in a formulation with a lower potential to produce a foreign body sensation or other irritation that a subject perceives when the formulation is instilled in the eye. Also, because the particles are smaller, they associate more readily with surfactants and stabilizers, thereby permitting one to use lower concentrations of them.
- compositions of the invention may be used to treat any condition of the eye which is known to be amenable to topical treatment with cyclosporin A (such as with Restasis®) at the concentrations stated here.
- compositions of the invention may be used to treat patients suffering from dry eye, to treat blepharitis and meibomian gland disease, to restore corneal sensitivity that has been impaired due to refractive surgery on the eye, to treat allergic conjunctivitis and atopic and vernal keratoconjunctivitis, and to treat ptyregia, conjunctival and corneal inflammation, keratoconjuntivitis, graft versus host disease, post- transplant glaucoma, corneal transplants, mycotic keratitis, Thygeson's superficial punctate keratitis, uveitis, and Theodore's superior limbic keratoconjunctivitis, among other conditions.
- the International Dry Eye Workshop defines dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.” It includes those conditions, such as keratoconjunctivitis sicca, that are caused by tear deficiency or excessive evaporation of tears.
- Blepharitis is a chronic disorder producing inflammation of the anterior and posterior lid margin, with involvement of skin and its related structures (hairs and sebaceous glands), the mucocutaneous junction, and the meibomian glands. It can also affect the conjunctiva, tear film, and the corneal surface in advanced stages and may be associated with dry eye. Blepharitis is commonly classified into anterior or posterior blepharitis, with anterior affecting the lash bearing region of the lids, and posterior primarily affecting the meibomian gland orifices.
- Meibomian gland disease most often occurs as one of three forms: primary meibomitis, secondary meibomitis, and meibomian seborrhea.
- Meibomian seborrhea is characterized by excessive meibomian secretion in the absence of inflammation (hypersecretory meibomian gland disease).
- Primary meibomitis by contrast, is distinguished by stagnant and inspissated meibomian secretions (obstructive hypersecretory meibomian gland disease).
- Secondary meibomitis represents a localized inflammatory response in which the meibomian glands are secondarily inflamed in a spotty fashion from an anterior lid margin blepharitis.
- LASEK LASEK
- EPI-LASEK customized transepithelial non-contact ablation, or other procedures in which the corneal nerves are severed.
- Impaired corneal sensitivity may also occur after viral infection, such as by HSV-1 , HSV-2, and VZV viruses.
- Patients with impaired corneal sensitivity often complain that their eyes feel dry, even though tear production and evaporation may be normal, suggesting that "dryness" in such patients is actually a form of corneal neuropathy that results when corneal nerves are severed by surgery or inflamed after viral infection.
- Allergic conjunctivitis is an inflammation of the conjunctiva resulting from hypersensitivity to one or more allergens. It may be acute, intermittent, or chronic. It occurs seasonally, that is, at only certain time of the year, or it occurs
- Symptoms of seasonal and perennial allergic conjunctivitis include, in addition to inflammation of the conjunctiva, lacrimation, tearing, conjunctival vascular dilation, itching, papillary hyperlasia, chemosis, eyelid edema, and discharge from the eye.
- the discharge may form a crust over the eyes after a night's sleep.
- Atopic keratoconjunctivitis is a chronic, severe form of allergic conjunctivitis that often leads to visual impairment. Symptoms include itching, burning, pain, redness, foreign body sensation, light sensitivity and blurry vision. There is often a discharge, especially on awakening from a night's sleep; the discharge may be stringy, ropy, and mucoid. The lower conjunctiva is often more prominently affected than the upper conjunctiva. The conjunctiva may range from pale, edematous, and featureless to having the characteristics of advanced disease, including papillary hypertrophy, subepithelial fibrosis, formix foreshortening, trichiasis, entropion, and madurosis.
- the disease progresses to punctate epithelial erosions, corneal neovascularization, and other features of keratopathy which may impair vision.
- CD25+T lymphocytes, macrophages, and dendritic cells are significantly elevated in the substantia intestinal.
- vernal keratoconjunctivitis is a severe form of allergic conjunctivitis, but it tends to affect the upper conjunctiva more prominently than the lower. It occurs in two forms. In the palpebral form, square, hard, flattened, closely packed papillae are present; in the bulbar (limbal) form, the circumcorneal conjunctiva becomes hypertrophied and grayish. Both forms are often accompanied by a mucoid discharge. Corneal epithelium loss may occur, accompanied by pain and photophobia, as may central corneal plaques and Trantas' dots.
- the inventors prepared the following compositions:
- Cyclosporin A was mixed with an appropriate vehicle to form a suspension.
- concentration of Cyclosporin A in this suspension is in the range of 1 -10%.
- the cyclosporin A suspension was milled using a high pressure homogenizer (a Microfluidizer®, manufactured by Microfluidics, Newton, MA) or a ball mill to get nanosuspensions such that d90 ⁇ 1 Urn.
- a high pressure homogenizer a Microfluidizer®, manufactured by Microfluidics, Newton, MA
- a ball mill to get nanosuspensions such that d90 ⁇ 1 Urn.
- Step-2 Preparation of final product a.
- the concentrated nanosuspensions prepared in Step-1 were diluted in vehicles suitable for ophthalmic dosing to obtain final product at required dose strength of cyclosporin A.
- Vehicles suitable for dilution may contain buffers, stabilizers, gelling agents and/or dilution to obtain final formulations with desired concentration of CsA.
- compositions of nanosuspension formulations prepared after dilution of the nanosuspension concentrates are listed in Table 2,
- Figure 1 shows the particle size distribution of cyclosporin A Form 2 nanosuspensions prepared using a high pressure homogenizer compared to suspensions prior to milling.
- Figure 2 compares the particle size distribution of cyclosporin A Form 2 nanosuspensions prepared using different surfactants and stabilizers.
- Figure 3 shows the particle size distribution of Formulation diluted in vehicle containing Na CMC (Table-2, vehicle A). Note that no change in particle size is seen in the diluted Formulations over 2 weeks as compared to the
- Cyclosporin A Form 2 Forms a nanosuspensions (particle size ⁇ 1 ⁇ ) while Form 3 does not.
- Form 2 nanosuspensions with lower particle size than any other crystalline form of CsA.
- the smaller particle size of Form 2 nanosuspensions is an advantage over other forms; among other reasons, it is expected to show higher bioavailability due to larger surface area for dissolution and longer retention in the eye, as well as improved physical stability.
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Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK12794830.5T DK2779994T3 (en) | 2011-11-15 | 2012-11-14 | SUSPENSIONS OF CYCLOSPORIN A FORM 2 |
KR1020147016157A KR102015152B1 (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin a form 2 |
EP12794830.5A EP2779994B1 (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin a form 2 |
CN201280066573.3A CN104080442B (en) | 2011-11-15 | 2012-11-14 | The suspension of cyclosporin A form 2 |
RU2014123470A RU2641963C2 (en) | 2011-11-15 | 2012-11-14 | Cyclosporine suspensions a of form 2 |
EP20156348.3A EP3701939A1 (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin a form 2 |
CA2856057A CA2856057C (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin a form 2 |
BR112014011770-5A BR112014011770B1 (en) | 2011-11-15 | 2012-11-14 | CYCLOSPORIN A FORM 2 SUSPENSIONS |
AU2012339632A AU2012339632A1 (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin A Form 2 |
JP2014542400A JP6363506B2 (en) | 2011-11-15 | 2012-11-14 | Cyclosporine A2 suspension |
ES12794830T ES2791751T3 (en) | 2011-11-15 | 2012-11-14 | Suspensions of cyclosporin A form 2 |
HK15102628.9A HK1202066A1 (en) | 2011-11-15 | 2015-03-16 | Suspensions of cyclosporin a form 2 2 a |
AU2017235927A AU2017235927A1 (en) | 2011-11-15 | 2017-09-27 | Suspensions of cyclosporin A Form 2 |
AU2019203051A AU2019203051A1 (en) | 2011-11-15 | 2019-04-30 | Suspensions of cyclosporin A Form 2 |
AU2020270500A AU2020270500B2 (en) | 2011-11-15 | 2020-11-18 | Suspensions of cyclosporin A Form 2 |
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EP (2) | EP2779994B1 (en) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2704810C2 (en) * | 2014-09-17 | 2019-10-31 | Паноптика, Инк. | Ophthalmic compositions for drug delivery and eye anterior segment |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2791751T3 (en) * | 2011-11-15 | 2020-11-05 | Allergan Inc | Suspensions of cyclosporin A form 2 |
US9266927B2 (en) | 2012-06-01 | 2016-02-23 | Allergan, Inc. | Cyclosporin A analogs |
US20150352176A1 (en) * | 2014-06-06 | 2015-12-10 | Newport Research, Inc. | Oil-free and fat-free aqueous suspensions of cyclosporin |
CA2955037A1 (en) * | 2014-07-18 | 2016-01-21 | Allergan, Inc. | Suspension compositions of cyclosporin a for subconjunctival and periocular injection |
CN104511012B (en) * | 2015-01-07 | 2017-01-18 | 鲁南厚普制药有限公司 | Ciclosporin oral solution |
US9914755B2 (en) | 2015-01-08 | 2018-03-13 | Allergan, Inc. | Cyclosporin derivatives wherein the MeBmt sidechain has been cyclized |
US11583496B2 (en) * | 2016-10-12 | 2023-02-21 | PS Therapy Inc. | Drug vehicle compositions and methods of use thereof |
CN113559059B (en) * | 2021-07-21 | 2023-04-28 | 上海应用技术大学 | Cationic nano suspension and preparation method and application thereof |
KR102640323B1 (en) | 2021-11-30 | 2024-02-27 | 대우제약 주식회사 | Stable nanosuspension of cyclosporine |
TW202408579A (en) * | 2022-07-20 | 2024-03-01 | 日商旭化成股份有限公司 | Hyaluronic acid derivative drug composition and drug composition |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989001772A1 (en) * | 1987-09-03 | 1989-03-09 | University Of Georgia Research Foundation, Inc. | Ocular cyclosporin composition |
US20060205639A1 (en) * | 1999-12-30 | 2006-09-14 | Domb Abraham J | Pro-nanodispersion for the delivery of cyclosporin |
US20080299206A1 (en) * | 2006-03-07 | 2008-12-04 | Novavax, Inc. | Ophthalmic preparations |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU203564B (en) * | 1987-12-21 | 1991-08-28 | Sandoz Ag | Process for producing new orthorombos cyclosporin without solvatation |
US5474979A (en) | 1994-05-17 | 1995-12-12 | Allergan, Inc. | Nonirritating emulsions for sensitive tissue |
PT789580E (en) * | 1994-11-03 | 2002-09-30 | Novartis Ag | CYCLOSPORINE FORMULATIONS FOR ORAL ADMINISTRATION WITH SIMPLE COMPOSITION AND HIGH BIODISPONIBILITY AND PROCESS FOR ITS PRODUCTION |
DE19819273A1 (en) * | 1998-04-30 | 1999-11-11 | Pharmatec International S Giul | Pharmaceutical ciclosporin formulation with improved biopharmaceutical properties, increased physical quality and stability as well as processes for its manufacture |
US6254860B1 (en) | 1999-04-13 | 2001-07-03 | Allergan Sales, Inc. | Ocular treatment using cyclosporin-A derivatives |
EP1387676A2 (en) * | 2001-05-01 | 2004-02-11 | Angiotech Pharmaceuticals, Inc. | Compositions comprising an anti-microtubule agent and a polypeptide or a polysaccharide and the use thereof for the preparation of a medicament for the treatment of inflammatory conditions |
GB2391472B (en) * | 2002-08-02 | 2004-12-08 | Satishchandra Punambhai Patel | Pharmaceutical compositions |
KR20050115331A (en) | 2003-04-01 | 2005-12-07 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Inhibitors of phosphodiesterases in infertility |
AU2005209201B2 (en) | 2004-01-20 | 2010-06-03 | Allergan, Inc. | Compositions for localized therapy of the eye, comprising preferably triamcinolone acetonide and hyaluronic acid |
ES2314354T3 (en) * | 2004-11-09 | 2009-03-16 | Novagali Pharma S.A. | EMULSION OF WATER OIL TYPE WITH LOW CONCENTRATION OF CATIONIC AGENT AND POTENTIAL POSITIVE ZETA. |
US7288520B2 (en) * | 2005-07-13 | 2007-10-30 | Allergan, Inc. | Cyclosporin compositions |
CN101484138A (en) * | 2006-03-07 | 2009-07-15 | 诺瓦瓦克斯有限公司 | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
EP2001439A2 (en) | 2006-03-07 | 2008-12-17 | Novavax, Inc. | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
WO2009088570A1 (en) | 2008-01-04 | 2009-07-16 | Sirion Therapeutics, Inc. | Stable aqueous cyclosporin compositions |
US20100303915A1 (en) * | 2009-06-02 | 2010-12-02 | Abbott Medical Optics Inc. | Therapeutic opthalmic emulsions |
EP3508197A1 (en) * | 2009-10-21 | 2019-07-10 | Otonomy, Inc. | Modulation of gel temperature of poloxamer-containing formulations |
UA113627C2 (en) * | 2011-05-27 | 2017-02-27 | CRYSTAL FORM OF CYCLOSPORIN A, PHARMACEUTICAL COMPOSITION AND METHOD OF TREATMENT | |
ES2791751T3 (en) * | 2011-11-15 | 2020-11-05 | Allergan Inc | Suspensions of cyclosporin A form 2 |
US8785394B2 (en) * | 2011-11-15 | 2014-07-22 | Allergan, Inc. | Sustained action formulation of cyclosporin form 2 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989001772A1 (en) * | 1987-09-03 | 1989-03-09 | University Of Georgia Research Foundation, Inc. | Ocular cyclosporin composition |
US20060205639A1 (en) * | 1999-12-30 | 2006-09-14 | Domb Abraham J | Pro-nanodispersion for the delivery of cyclosporin |
US20080299206A1 (en) * | 2006-03-07 | 2008-12-04 | Novavax, Inc. | Ophthalmic preparations |
Non-Patent Citations (1)
Title |
---|
BOWEN P: "Particle Size Distribution Measurement from Millimeters to Nanometers and from Rods to Platelets", JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY, TAYLOR AND FRANCIS GROUP, NEW YORK, NY, US, vol. 23, no. 5, 1 January 2002 (2002-01-01), pages 631 - 662, XP009102859, ISSN: 0193-2691, DOI: 10.1081/DIS-120015368 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2704810C2 (en) * | 2014-09-17 | 2019-10-31 | Паноптика, Инк. | Ophthalmic compositions for drug delivery and eye anterior segment |
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HK1202066A1 (en) | 2015-09-18 |
US8796222B2 (en) | 2014-08-05 |
JP2018162296A (en) | 2018-10-18 |
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EP2779994B1 (en) | 2020-02-19 |
EP3701939A1 (en) | 2020-09-02 |
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BR112014011770B1 (en) | 2022-11-08 |
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AU2020270500A1 (en) | 2020-12-17 |
EP2779994A1 (en) | 2014-09-24 |
AU2019203051A1 (en) | 2019-05-23 |
RU2641963C2 (en) | 2018-01-23 |
JP2020040968A (en) | 2020-03-19 |
US10206971B2 (en) | 2019-02-19 |
JP2014533302A (en) | 2014-12-11 |
CN104080442B (en) | 2018-01-05 |
US9238002B2 (en) | 2016-01-19 |
ES2791751T3 (en) | 2020-11-05 |
US20190343917A1 (en) | 2019-11-14 |
RU2014123470A (en) | 2015-12-27 |
AU2012339632A1 (en) | 2014-06-05 |
CA2856057A1 (en) | 2013-05-23 |
JP6363506B2 (en) | 2018-07-25 |
KR102015152B1 (en) | 2019-08-27 |
CA2856057C (en) | 2017-01-03 |
BR112014011770A2 (en) | 2017-05-09 |
CN104080442A (en) | 2014-10-01 |
AU2017235927A1 (en) | 2017-10-19 |
DK2779994T3 (en) | 2020-05-18 |
US20140322335A1 (en) | 2014-10-30 |
KR20140107254A (en) | 2014-09-04 |
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