Classifications

• • 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
  • 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
  • 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
  • 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
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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 medium chain triglycerides (MCTs) or light liquid paraffin oil as liquid vehicle, wherein, the formulation of atropine is used for treating myopia.
• MCTs medium chain triglycerides
• 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 to 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 shelf life 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.
• Atropine solution was used for causing cycloplegic refraction in the eye of the subject, for causing mydriasis in the eye of the subject, for treating amblyopia or lazy eye in children, for relieving vitreous floater symptoms, for treating or preventing painful ciliary muscle spasm or for treating myopia progression in pediatric subjects.
• the present invention provides a topical ophthalmological composition that includes: a muscarinic receptor antagonist as an active pharmaceutical ingredient (API); and a liquid vehicle selected from the group consisting of a medium chain triglyceride (MCT) and a light liquid paraffin oil.
• a muscarinic receptor antagonist as an active pharmaceutical ingredient (API)
• a liquid vehicle selected from the group consisting of a medium chain triglyceride (MCT) and a light liquid paraffin oil.
• MCT medium chain triglyceride
• 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.
• a concentration of the atropine in the free base form is from about 0.001% to about 0.1% (w/w).
• the atropine free base is formulated in the MCT or formulated in the light liquid paraffin.
• the MCT is a triglyceride of fatty acids, and the fatty acids selected from the group consisting of hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.
• the topical ophthalmological composition further includes a semi-fluorinated alkane compound.
• the semi-fluorinated alkane compound has a formula of RFRH or a formula of RFRHRF; RF is a perfluorinated hydrocarbon with 1 to 15 carbon atoms, and RH is a non-fluorinated hydrocarbon with 1 to 15 carbon atoms.
• a weight ratio of the MCT or the light liquid paraffin oil to the semi-fluorinated alkane is from 99 to 1.
• the semifluorinated alkane is selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10), preferably, the semifluorinated alkane is F6H8 (perfluorohexyl octane) .
• the topical ophthalmological composition further includes an organic cosolvent.
• the organic cosolvent is selected from the group consisting of phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol, preferably, the organic cosolvent is phenethyl alcohol.
• a concentration of phenethyl alcohol is about 0.01% to about 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 an eye drop 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; the topical ophthalmological composition treats amblyopia or lazy eye in children; the topical ophthalmological composition relieves vitreous floater symptoms; or the topical ophthalmological composition treats or prevents painful ciliary muscle spasm.
• Figure 1 shows the chromatogram of Atropine (tR: 12.947) standard solution.
• Figure 2 shows the pupil size measurement at day 7 post dosing of Example 5.
• Figure 3 shows the pupil size measurement at day 22 post dosing of Example 5.
• 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.
• MCTs Medium-chain triglycerides
• the fatty acids have an aliphatic chain of 6-12 carbon atoms, and can be, for example, hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.
• the MCTs can be a single triglyceride or a mixture of triglycerides. Representative chemical structures of the MCTs are shown below.
• Light liquid paraffin oil (paraffinum liquidum) is a refined mineral oil used in cosmetics and medicine. It contains a mixture of liquid saturated hydrocarbons.
• Semifluorinated alkane is an amphiphilic liquid with two mutually immiscible moieties (hydrocarbon segment and perfluorinated segment) bound covalently.
• Examples of Semifluorinated alkanes include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10); preferably, perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyloctane (F6H8).
• Atropine solution (water) formulations had been previously proven effective in treating myopia, specially reducing myopia progression.
• 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.
• the term “about” means in the range of +20% to -20% of a value, +10% to -10% of the value, or +5% to -5% of the value.
• the disclosure is based on the studies described in the examples that show atropine can be dissolve in MCTs or light liquid paraffin oil at sufficient concentration to have biological efficacy.
• a cosolvent and/or a semifluorinated alkane is added to the formulation.
• the cosolvent can be, for example, phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, or polyethylene glycol.
• the cosolvent and semifluorinated alkane increase the solubility of atropine and the stability of the formulation over a long period of time.
• Example 1 Dissolution of atropine in MCTs or light liquid paraffin oil.
• Atropine free base was determined to be soluble in light liquid paraffin oil at 75 pg/ml (0.0075% w/w). The addition of 0.1% ethanol to light liquid paraffin oil increased the solubility to 82 pg/ml and the addition of 0.25% phenethyl alcohol to light liquid paraffin oil increased the solubility to above 100 pg/ml.
• Atropine free base was determined to be soluble in MCT at 3100 pg/ml (0.31% w/w). In this particular study, 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 solubility we observed in MCT is well above that needed for efficacy and the concentration in light liquid paraffin is also in the range of efficacy.
• a concentration of the atropine in the free base form can be from about 0.001% to about 0.5% (w/w), or from about 0.001% to about 0.1% (w/w), for example, about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5% or any range thereof.
• Example 2 Miscibility of semi-fluorinated alkane with MCT or light liquid paraffin oil.
• F6H8, a semi-fluorinated alkane was tested for miscibility with MCT with the ratio of F6H8 to MCT from 1 :99 to 99: 1. The results showed that F6H8 was miscible with MCT at all ratios.
• F6H8, a semi-fluorinated alkane was tested for miscibility with light liquid paraffin oil with the ratio of F6H8 to light liquid paraffin oil from 1 :99 to 99: 1. The results showed that F6H8 was miscible with light liquid paraffin oil at all ratios.
• Example 3 Solubility of Atropine in Formulations of MCT and F6H8 with or without Co-solvent
• Example 4 Stability of Atropine in Formulations of MCT and F6H8 with or without Co-solvent
• Table 6 Stability of Atropine (expressed as Percentage Relative to the Target Dose) in Formulation of 0.25% phenethyl alcohol, 10% MCT, 89.75% F6H8
• Table 7 Stability of Atropine (expressed as Percentage Relative to the Target Dose) in Formulation of 0.5% phenethyl alcohol, 10% MCT, 89.5% F6H8
• Example 5 In vivo Pharmacological and Ocular Toxicity Study in a Rabbit Model
• the purpose of this study was to determine the pharmacological potency and the potential ocular toxicity of the atropine formulation in 0.25% phenylethyl alcohol, 10% MCT and 89.75%F6H8.
• Test articles were administered by topical ocular instillation to New Zealand White rabbits twice daily for 28 days.
• the pharmacological potency was measured as pupil dilation in normal naive rabbits.
• Three concentrations of atropine (0.01%, 0.025%, 0.05%) in the formulation above were compared to that of an aqueous formulation of 0.03% atropine sulphate salt, which was known to have good pupil dilation effects.
• the formulation without atropine served as the vehicle control in the study.
• the study design is shown in Table 8. Forty eight rabbits (24 per sex) were randomly assigned to 5 groups to determine the toxicity of atropine when administered twice daily for 28 days by topical instillation. The control group was administered with vehicle. Animals were randomly assigned to groups based on body weight. The control and high dose group were 6/sex/group, the low, mid dose and comparator group were 4/sex/group. The last surviving animals in the control and high dose groups were allocated for recovery. Table 8: The Study Design
• dose level and “dosage” are used interchangeably, “concentration” and “strength” are used interchangeably.
• a Doses represent active ingredient, left eye will be treated and right eye will be remained untreated
• Replacement animals if any, will be numbered per Testing Facility SOP and will be included in the study report.
• c Estimated daily dose levels are calculated by the present dosing concentration, volume and frequency.
• the comparator is 0.03% atropine sulfate monohydrate in saline containing 100 ppm benzalkonium chloride (BAK).
• Atropine in vehicle or control article or comparator alone were administered to left eye of animals twice daily with approximately 12 hours apart by topical instillation for 28 days. The right eye remained the untreated control eye. Animals were dosed via topical ocular instillation to the left eyes at a volume of 40 pL/eye.
• Pupil size were measured in both eyes of all animals on 3 separate days during acclimation prior to dosing initiation to establish the baseline and acclimation of animals to the procedure. The results are shown in Figure 2 (pupil size measurement at day 7 post dosing) and Figure 3 (pupil size measurement at day 22 post dosing). The pupil size of both eyes of all animals were measured at baseline (30 minutes before dosing), 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr and 12 hr after 1 st dose on 7 th day and 22 nd day. CBT-009 represented atropine.
• Ocular Toxicity 0.01%, 0.025% and 0.05% atropine in F6H8f-based formulation, the control vehicle or a comparator of 0.03% atropine sulfate in aqueous solution were administered to the left eyes of male and female New Zealand White rabbits by twice daily topical instillation and the right eyes were untreated. Following the end of the dosing period, terminal-interval animals were euthanized and recovery-interval animals were maintained for a 14-day recovery period and then euthanized. All animals were maintained for a 14-day recovery period and then euthanized. All animals from the terminal and recovery intervals survived to their scheduled euthanasia.
• Example 6 In vivo Ocular Tolerability Study in a Rabbit Model
• Study Design Three (3) female Dutch belted rabbits were given 40 pL of 0.012% atropine free base in 100% MCT to the right eyes and 40 pL of 0.012% atropine free base in 100% light liquid paraffin (LLP) to the left eyes, 1 drop/eye, twice per day, 12 hrs apart for 14 consecutive days. Ocular discomfort observation and ocular irritation observation were performed for all animals at predose (twice, on different days) and daily during the dosing phase after the last daily dose. Cornea examination was performed for all animals at predose (once) phase and once after the last daily dose on Day 1 and Day 14. The first dosing day were designated as DI and the last dosing day was designated as D14.
• the atropine formulation was well tolerated in all rabbits. No significant ocular irritation or ophthalmic findings were observed in any animals. There were no test article-related effects on body weights and food consumption during the study. There were no other test article-related ophthalmologic findings during the scheduled examinations for all animals. No or mild (+1) conjunctiva swelling or conjunctiva congestion was observed during the study. This Example demonstrated the safety of the claimed novel formulation of atropine for ocular use.
• Example 7 In vivo Ocular Tolerability Study in a Dog Model
• the atropine formulation was well tolerated in all dogs. No significant ocular irritation or ophthalmic findings were observed in any animals. There were no test article- related effects on body weights and food consumption during the study. There were no other test article-related ophthalmologic findings during the scheduled examinations for all animals. No or mild (+1) conjunctiva swelling or conjunctiva congestion was observed during the study. This Example demonstrated the safety of the claimed novel formulation of atropine for ocular use.

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