Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

• the present invention relates to topical ophthalmological compositions of a muscarinic receptor antagonist dissolved in semifluorinated alkane as a liquid vehicle, wherein, the formulation of atropine is used for treating myopia.
• Atropine is an anti-muscarinic compound and is a competitive antagonist of muscarinic receptors. It has anti-parasympathetic functions. It is used for several indications such as anticholinergic poisoning and bradycardia. In the eye, it is traditionally used for dilating pupil. Recently, low dose of atropine is shown be able to attenuate the progression of myopia in young adults (Li 2019). For the myopia indication, atropine is approved in only a few countries as of now.
• Myopia or nearsightedness, is a condition in which people can see close objects clearly, but objects farther away appear blurred. Myopia occurs if the eyeball is too long or the cornea (the clear front cover of the eye) is too curved so that distant objects can’t be focused correctly on retina. Myopia is the most common eye disorder worldwide. About 30 percent of the U.S. population has myopia. The etiology of myopia is unknown. Genetics is believed to have a role in myopia. Myopia development may be affected by how a person uses the eyes. It may occur in school-age children and progresses until about age 20. However, myopia may also develop in adults due to visual stress or health conditions such as diabetes. Myopia may increase the risk of other ocular diseases (Wu 2019).
• Atropine solution (water-based) formulations have been tested in multiple clinical trials and is proven to be able to slow down the progression of myopia (Cooper 2018, Li 2019, Yam 2020).
• atropine is prone to degradation at neutral pH solution once the container is open to the air, therefore, the shelflife of the product at neutral pH is often less than 1 year.
• Low pH of 3-6 in the formulation is used to increase the stability of atropine in solution (Berton 2020; Saito 2019). However, low pH is also known to cause irritation and discomfort in the eye.
• This invention uses an organic liquid carrier to create a more stable and less irritating formulation of atropine for ocular, in particular myopia, indications.
• a topical ophthalmological composition includes: a therapeutically effective amount of a muscarinic receptor antagonist as an active pharmaceutical ingredient; and a semifluorinated alkane, as a liquid vehicle.
• the topical ophthalmological composition treats an ocular disease.
• the muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine.
• the muscarinic receptor antagonist is atropine.
• the atropine is in a free base form or a salt form.
• the concentration of the atropine in a free base form is from about 0.0001% to about 1.0% (w/w), preferably, from about 0.001% to about 0.1% (w/w), more preferably, from about 0.01% to about 0.1% (w/w).
• the semifluorinated alkane is a compound of formula RFRH or of formula RFRHRF, wherein RF is a perfluorinated hydrocarbon with 15 or less carbon atoms, and wherein RH is a non-fluorinated hydrocarbon with 15 or less carbon atoms.
• the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8 and F6H10.
• the semifluorinated alkane is F6H8 (perfluorohexyl octane) .
• the topical ophthalmological composition further includes an organic cosolvent selected from the group consisting of phenylethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol.
• the organic cosolvent is ethanol or phenylethyl alcohol.
• the concentration of ethanol is about 1% (w/w) or less, for example, 0.001% to 1% (w/w); or the concentration of phenylethyl alcohol is about 1% (w/w) or less, for example, 0.001% to 1% (w/w).
• the topical ophthalmological composition is a nonaqueous solution, a suspension, or an emulsion.
• the atropine in the topical ophthalmological composition is chemically stable for at least 0.5 year, for at least 1 year, or for at least 2 years.
• the topical ophthalmological composition is adapted for topically administering as eye drops to an eye of a patient.
• the topical ophthalmological composition causes minimal irritation in the eye.
• the ocular disease is myopia.
• the topical ophthalmological composition slows a myopia progression.
• Figure 1 shows the chromatogram of Atropine (tR: 12.947) standard solution.
• a muscarinic receptor antagonist is an anticholinergic agent that blocks the activities of a muscarinic acetylcholine receptor.
• the muscarinic receptor antagonist may be atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, or tolterodine.
• the muscarinic receptor antagonist is atropine or pirenzepine. More preferably, the muscarinic receptor antagonist is atropine.
• the topical ophthalmological composition of the present invention includes a therapeutically effective amount of the muscarinic receptor antagonist, e.g., atropine.
• a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
• Atropine solution (water) formulations had been previously proven effective in treating myopia, specially reducing myopia progression (Li 2019, Wu 2019).
• the atropine sulfate monohydrate aqueous formulation had been tested in the clinic at concentrations ranging from 0.01% to 1% and all these doses have demonstrated efficacy in myopia treatment.
• the solution formulation had two drawbacks. The first is that once the container opens to air, the atropine at neutral pH in the solution is prone to degradation, therefore, the shelf life of the product at neutral pH is often less than 1 year. Furthermore, this instability of the atropine in the solution requires that the formulation is used within about a month.
• the second shortcoming is that the low pH, such as in the pH range of 3.5 to 6.0, used to reduce atropine degradation to increase product shelf life, can cause irritation or discomfort to the human eye as reported of adverse events in the patients.
• F6H8 is an amphiphilic liquid with two mutually immiscible moieties (hydrocarbon segment as RH and perfluorinated segment as RF) bound covalently.
• F4H5 perfluorobutylpentane
• F4H6 perfluorobutylhexane
• F6H4 perfluorohexylbutane
• F6H6 perfluorohexylhexane
• F6H10 perfluorohexyldecane
• the disclosure is based on the studies described in the examples that show atropine can be dissolve in F6H8 at sufficient concentration to have biological efficacy.
• the formulation of atropine in F6H8 is stable for prolonged times at room temperature and can be made into a product with sufficient self-life for regulatory approval. This formulation is not irritating in the eye in animal model studies when dosed at a concentration higher than what is needed for some indications.
• Examples 1 and 2 demonstrated that stable atropine formulations ranging from about 0.0001 to 0.15% can be achieved in F6H8 with the addition of three co-solvents.
• Example 7 showed that equivalent doses of the atropine free base F6H8 organic formulation achieved similar efficacy to that of the atropine sulfate monohydrate aqueous formulation in a rabbit model.
• Example 1 Dissolution of atropine in F6H8.
• the solubility of atropine was determined to be 129 pg/ml (0.0129% w/w) in F6H8 alone. When 0.1% ethanol was added, the solubility was 171.5 ug/ml (0.0173% w/w).
• the free base form of atropine was used, while the mono sulfate salt was previously used in the solution formulation approved for myopia usage.
• the MW of the free base is 83% equivalent to the mono sulfate salt form of atropine solution formulation.
• the 0.01% atropine mono sulfate salt solution was previously shown effective for myopia treatment in the clinic and was approved in several countries. This 0.01% atropine salt concentration was equivalent to 0.0083% of the free base concentration.
• the F6H8 formulation can deliver sufficient amount of atropine for the treatment of myopia.
• the 0.0129% concentration we observed was about 55% higher than the 0.0083% needed for efficacy.
• the concentration of atropine can be increased further by adding ethanol to the formulation The addition of just 0.1% ethanol increased the solubility by 33%. Higher levels of ethanol would likely further increase the solubility of atropine in F6H8.
• the concentrations of atropine in the F6H8 formulations are show in Table 1.
• compositions with phenylethyl alcohol as co-solvent Compositions with phenylethyl alcohol as co-solvent
• compositions with ethanol as co-solvent Compositions with ethanol as co-solvent
• Example 2 The atropine F6H8 formulation is stable over time
• Atropine is dissolved in F6H8 as described in Example 1.
• the level of atropine is measure by the HPLC method at 25°C at 1, 3, 6, 9 and 12 months.
• the atropine in the formulation is defined as stable if the level is maintained between 90-110% of the original level.
• Example 3 The atropine F6H8 formulation is tolerable in a rabbit study
• the atropine F6H8 formulation is evaluated in rabbits for ocular tolerability.
• the atropine formulation is well tolerated in rabbits with no significant irritation and discomfort issues.
• 0.0125% atropine was prepared by dissolving appropriate amount of atropine free base in 100% F6H8.
• the stability of atropine formulation over time was assessed at 25°C.
• Table 6 below showed that atropine levels remained stable at least for 3 months with minimum change from the target concentration. This example, disclosed for the first time, demonstrated that the atropine formulation in the invention was stable for at room temperature.
• Table 6 Stability of 0.0125% atropine free base in 100% F6H8
• Example 5 In vivo ocular tolerability in rabbits
• Example 6 In vivo ocular tolerability in dogs
• Example 7 In vivo pharmacological potency in a rabbit model
• the pharmacological potency of the atropine formulation in F6H8 and 0.25% phenylethyl alcohol was tested in a rabbit model. The potency was measured as pupil dilation in normal naive rabbits. Three concentrations of the F6H8 formulation of atropine (0.012%, 0.01%, 0.08%) were compared to that of an aqueous formulation of 0.01% atropine which was known to have good pupil dilation effects. One drop of each formulation was dosed into the eye and pupil size was measured during the following 8 hours.
• each animal was given 40 pL of testing article (see Table 12 below) to both eyes.
• First day of dosing was designated as Day 1.
• the pupil size of both eyes of all animals were measured at baseline (30 minutes before dosing), 0.5h, Ih, 2h, 3h, 4h, 6h, 8h after dosing on day 1 .
• the pupil size measurement data were analyzed for efficacy to determine which doses of atropine free base in Vehicle was equivalent to the dose of the control group of 0.01% atropine sulfate monohydrate in normal saline. Animals were allowed 2 days for wash-out period.
• phase 2 each animal was given 40 pL of testing article (see Table 13 below) to both eyes for 14 days. First day of dosing in Phase 2 was designated as Day 4. The pupil size of both eyes of all animals were measured at baseline (30 minutes before dosing), 0.5h, Ih, 2h, 3h, 4h, 6h, 8h after dosing on Day 4 and Day 17.
• Table 12 The study design of phase 1 included in the study report.
• Table 13 The study design of phase 2 included in the study report. bEquivalent dose is determined from Phase 1 efficacy data. The optimized concentrations of atropine free base in Vehicle that gives equivalent efficacy as 0.01% atropine sulfate monohydrate in normal saline.

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