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KR-20260065964-A - STORAGE STABLE COMPOSITIONS AND METHODS FOR THE TREATMENT OF REFRACTIVE ERRORS OF THE EYE

KR20260065964AKR 20260065964 AKR20260065964 AKR 20260065964AKR-20260065964-A

Abstract

The present invention provides a composition and a method for achieving a storage-stable aceclidin. The composition preferably comprises aceclidin, an ophthalmic paralyzing agent, a surfactant, a tonic modifier, and optionally a viscosity enhancer and an antioxidant. The present invention provides a method for treating refractive errors of the eye with a storage-stable aceclidin composition.

Inventors

  • 혼, 제랄드
  • 노르단, 리

Assignees

  • 렌즈 테라퓨틱스 인코포레이티드

Dates

Publication Date
20260511
Application Date
20160609
Priority Date
20150618

Claims (20)

  1. Aceclidein at a concentration of about 0.25% to about 2.0% w/v; An ophthalmoplegic agent at a concentration of about 0.025% to about 0.1% w/v; Surfactant; Tension regulators; and Optionally including a viscosity enhancer; An ophthalmic composition for treating presbyopia, wherein the pH of the composition is about 4.75 to about 5.0 and the viscosity of the composition is about 1 to about 5,000 centipoise (cps) at about 2 to about 8°C, where w/v means weight per volume.
  2. In paragraph 1, The ophthalmoplegic agent is selected from the group consisting of pyrenzepine, tropamide, cyclopentolate hydrochloride, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin, tolterodine, oxybutinin, ipratropium, oxytropium, tiotropium, ottensepard, and combinations thereof; The surfactant is selected from the group consisting of polyoxyl 40 stearate, gamma cyclodextrin, sulfobutyl ether β-cyclodextrin, 2-hydroxypropyl cyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, poloxamer, polysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, polyoxyl alkyl, cyclodextrin, and combinations thereof; The tension modifier is selected from the group consisting of mannitol, sodium chloride, potassium chloride, glycerin, and combinations thereof; An ophthalmic composition for treating presbyopia in which any viscosity enhancer is not a polysaccharide.
  3. In paragraph 2, The ophthalmoplegic agent is Tropicamide; The surfactant is polyoxyl 40 stearate; An ophthalmic composition for treating presbyopia, in which the tonic modifier is mannitol.
  4. In paragraph 1, An ophthalmic composition for treating presbyopia, comprising a viscosity enhancer selected from the group consisting of guar gum, hydroxypropyl-guar, xanthan gum, alginate, chitosan, gelite, hyaluronic acid, dextran, and carbomer, and one or more excipients selected from antioxidants selected from citrate, citric acid monohydrate, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dicalcium diethylenetriamine pentaacetic acid, and combinations thereof, wherein the viscosity is about 1 to about 5,000 centipoises (cps) before topical administration and about 1 to about 50 cps upon topical administration.
  5. In paragraph 4, An ophthalmic composition for treating presbyopia, wherein one or more excipients are viscosity enhancers selected from carbomer 934 and carbomer 940, and the viscosity is about 1 to about 5,000 centipoise (cps) at about 2 to about 8°C.
  6. In paragraph 4, An ophthalmic composition for treating presbyopia, wherein one or more excipients are antioxidants, and said antioxidant is citric acid monohydrate.
  7. Aceclidein at a concentration of about 0.25% to about 2.0% w/v; Tropicamide at a concentration of about 0.025% to about 0.1% w/v; Polyoxyl 40 stearate at a concentration of about 2.0% to about 10.0% w/v; Mannitol at a concentration of about 0.5% to about 6.0% w/v; A buffer selected from acetate buffer, citrate buffer, phosphate buffer, and citrophosphate buffer at a concentration of about 3 millimolar; Optionally, citric acid monohydrate at a concentration of about 0.1% to about 0.2% w/v; A viscosity enhancer selected from Carbomer 934 and Carbomer 940 at a concentration of about 0.01% to about 1.0% w/v, optionally; and Optionally containing benzalkonium chloride (BAK) at a concentration of about 0.02% w/v; and An ophthalmic composition for treating presbyopia, wherein the pH of the composition is about 4.75 to about 5.0 and the viscosity of the composition is about 1 to about 5,000 centipoise (cps) at about 2 to about 8°C, where w/v means weight per volume.
  8. In Paragraph 7, An ophthalmic composition for treating presbyopia, wherein the concentration of aceclidin is about 1.45% to about 1.75% w/v, the concentration of tropamide is about 0.042% w/v, the concentration of polyoxyl 40 stearate is about 4.5% to about 5.5% w/v, the concentration of mannitol is about 2.5% to about 4.0% w/v, the concentration of any citric acid monohydrate is about 0.1% w/v, the viscosity enhancer is carbomer 940 at a concentration of about 0.09% to about 1.0% w/v, and the pH is about 4.75.
  9. In paragraph 8, An ophthalmic composition for treating presbyopia comprising citric acid monohydrate at a concentration of about 0.1% w/v and BAK at a concentration of about 0.02% w/v, wherein aceclidin is at a concentration of about 1.75% w/v, polyoxyl 40 stearate is at a concentration of about 4.5% w/v, mannitol is at a concentration of about 2.5% w/v, and the buffer is acetate buffer.
  10. In paragraph 8, An ophthalmic composition for treating presbyopia comprising citric acid monohydrate at a concentration of about 0.10% w/v and carbomer 940 at a concentration of about 0.09% w/v, wherein aceclidin is at a concentration of about 1.55% w/v, polyoxyl 40 stearate is at a concentration of about 5.5% w/v, mannitol is at a concentration of about 4.0% w/v, and the buffer is acetate buffer.
  11. In paragraph 8, An ophthalmic composition for treating presbyopia comprising carbomer 940 at a concentration of about 0.25% w/v and BAK at a concentration of about 0.02% w/v, wherein aceclidin is at a concentration of about 1.50% w/v, polyoxyl 40 stearate is at a concentration of about 5.5% w/v, mannitol is at a concentration of about 2.5% w/v, and the buffer is phosphate buffer.
  12. In paragraph 8, An ophthalmic composition for treating presbyopia comprising citric acid monohydrate at a concentration of about 0.10% w/v and carbomer 940 at a concentration of about 0.75% w/v, wherein aceclidin is at a concentration of about 1.45% w/v, polyoxyl 40 stearate is at a concentration of about 5.5% w/v, mannitol is at a concentration of about 4.0% w/v, and the buffer is acetate buffer.
  13. In paragraph 8, An ophthalmic composition for treating presbyopia comprising citric acid monohydrate at a concentration of about 0.10% w/v and carbomer 940 at a concentration of about 1.0% w/v, wherein aceclidin is at a concentration of about 1.45% w/v, polyoxyl 40 stearate is at a concentration of about 5.5% w/v, mannitol is at a concentration of about 4.0% w/v, and the buffer is phosphate buffer.
  14. A method for stabilizing a composition according to claim 1, comprising maintaining the composition according to claim 1 at about 2 to about 8°C.
  15. a) adding to the composition a surfactant selected from the group consisting of polyoxyl 40 stearate, gamma cyclodextrin, sulfobutyl ether β-cyclodextrin, 2-hydroxypropyl cyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, poloxamer, polysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, polyoxyl alkyl, cyclodextrin, and combinations thereof; b) Adding a tension modifier selected from mannitol, sodium chloride, potassium chloride, glycerin, and combinations thereof; b) Optionally adding to the composition a viscosity enhancer selected from the group consisting of guar gum, hydroxypropyl-guar, xanthan gum, alginate, chitosan, gelite, hyaluronic acid, dextran, carbomer, and combinations thereof; c) buffering the pH of the composition to about 4.0 to about 6.0; and d) maintaining the composition at about 2 to about 8°C; A method for stabilizing an aqueous aceclidin composition comprising
  16. In paragraph 15, Includes adding a viscosity enhancer, The surfactant is polyoxyl 40 stearate; The tension regulator is mannitol; The viscosity enhancer is Carbomer 940; A method for stabilizing an aqueous aceclidin composition having a pH of about 4.75.
  17. A method for treating refractive errors of the eye comprising administering the composition of claim 1 in a pharmaceutically acceptable amount to a patient who requires it, A method for treating refractive errors of the eye, wherein the above refractive error is selected from presbyopia, hyperopia, myopia, astigmatism, and combinations thereof.
  18. In Paragraph 17, A method for treating refractive errors of the eye, such as presbyopia.
  19. A method for treating refractive errors of the eye comprising administering the composition of claim 1 in a pharmaceutically acceptable amount to a patient who requires it, A method for treating refractive errors of the eye, wherein the pupil size is reduced to about 1.5 to about 2.5 millimeters, and the refractive error is selected from the group consisting of corneal irregular astigmatism, corneal non-uniformity due to ectasia, corneal non-uniformity due to clara, higher-order aberrations, and higher-order aberrations induced by refractive surgery.
  20. In Paragraph 19, A method for treating refractive errors of the eye in which the pupil size is reduced to about 1.7 to about 2.0 millimeters.

Description

Methods for treating refractive errors of the eye and storage-stable compositions As a person ages, the minimum distance from the eye at which objects are focused increases, even when provided distance vision is excellent without correction or assistance. For example, a 10-year-old can focus on an object or “focal point” 3 inches (0.072 meters) away from their eyes while maintaining excellent distance vision; a 40-year-old can focus 6 inches (0.15 meters); and a 60-year-old can focus on an object or “focal point” 39 inches (1.0 meter) away with discomfort. The increase in minimum focal length in individuals with excellent unassisted distance vision is called presbyopia, loosely referred to as “older eye.” Excellent distance vision without assistance is also known as emmetropia. The inability to focus on distant objects is known as myopia, and the inability to focus on near objects is known as hyperopia. Specifically, “distance” vision is considered to be a focal point of 1 meter or more from the eye, while near vision is considered to be a focal point of less than 1 meter. The minimum focal distance at which an object can be focused is called the “near point.” The change in focus from the distant point to the near point and any focal point in between is called accommodation. Accommodation is measured in diopters. A diopter is calculated by taking the reciprocal of the focal distance (in meters). For example, the decrease in accommodation from a 10-year-old eye to a 60-year-old eye is approximately 13 diopters (1 ÷ 0.072 meters = 13.89 diopters; 1 ÷ 1 meter = 1 diopter). The highest incidence of presbyopia occurs in people aged 42 to 44. Presbyopia occurs because the eye's ability to adjust focus—utilizing near reflexes, pupil constriction, eye convergence, and specifically the contraction of the ciliary muscle—decreases as a person ages. This decrease in accommodation causes inappropriate changes in the general thickening and increased curvature of the front surface of the lens required for shifting focus from distant to near objects. Important near-focus tasks affected by presbyopia include viewing computer screens (21 inches) and reading printed materials (16 inches). Presbyopia is a common and inevitable effect of aging, and it is the first definite sign for many people in their 40s who are getting older. According to one study, over one billion people worldwide suffered from presbyopia in 2005. The study predicted that this number would nearly double by 2050. If everyone over the age of 45 is considered to have presbyopia, it is estimated that 122 million people in the United States alone had the condition in 2010. As the Baby Boomer generation reaches this critical age, this number is expected to increase. Presbyopia has a drawback stemming from its limitation of the ability to function rapidly in many tasks requiring focus at both near and far points, occurring almost immediately. In patients with presbyopia, these tasks can only be performed after receiving glasses, contact lenses, or invasive surgery. One of these optical modifications, the monovision procedure, can be performed using glasses, contact lenses, or surgery. The monovision procedure corrects one eye for near points and the other eye for far points. However, the monovision procedure entails a loss of depth perception and distance vision, particularly in dim light (e.g., at night). Other surgical procedures to alleviate presbyopia include: (1) implantation of an intraocular lens ( INTRACOR® ; a registered trademark of Technolas Perfect Vision GMBH); (2) corneal reshaping (PresbyLASIK and conductive keratoplasty); and (3) scleral band expansion. and (4) the insertion of a corneal inlay (Flexivue Microlens® ; registered trademark of PresbiBio LLC, Kamra® ; registered trademark of AcuFocus, Inc. and Vue+). The Kamra® corneal inlay manufactured by AcuFocus Works increases the depth of focus by inlaying a pinhole into the cornea. Similar effects can be achieved with common miotic agents such as pilocarpine (a non-selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor). These common miotic agents induce increased ciliary muscle contraction and accommodation of any remaining reserve, improving near vision at the expense of distance vision in individuals who retain some degree of accommodation. These common pupil dilaters improve the depth of focus to allow for a degree of accommodation through the pinhole effect induced by pupil constriction (i.e., contraction), but the pinhole effect only partially offsets the induced accommodative myopia for distance vision. In some cases, such as with pilocarpine or carvacol, the induced accommodation creates induced myopia of 5 diopters or more, causing a shift in focus from distance to near vision and blurred distance vision. These common pupil dilaters induce ciliary muscle spasms