WO2012161655A1 - Composition et/ou procédé pour réduire et/ou prévenir la progression de la myopie comprenant de l'atropine - Google Patents

Composition et/ou procédé pour réduire et/ou prévenir la progression de la myopie comprenant de l'atropine Download PDF

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WO2012161655A1
WO2012161655A1 PCT/SG2012/000174 SG2012000174W WO2012161655A1 WO 2012161655 A1 WO2012161655 A1 WO 2012161655A1 SG 2012000174 W SG2012000174 W SG 2012000174W WO 2012161655 A1 WO2012161655 A1 WO 2012161655A1
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atropine
composition
myopia
progression
groups
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PCT/SG2012/000174
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English (en)
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Donald Tan
Wei Han CHUA
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Singapore Health Services Pte Ltd
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    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the present invention relates to a composition and/or method for reducing and/or preventing myopia progression.
  • the invention relates to an ultra-low concentration atropine solution for reducing and/or preventing myopia progression.
  • Myopia is a type of refractive error of the eye, in which the visual image is focused in front of the retina, typically resulting in blurred vision of distant objects. Myopia is especially prevalent among Asians and has been reported to be as high as 70-90% in Asian countries. Myopia may be corrected by prescription lenses (for example, spectacles or contact lenses) or refractive surgery (for example, LASIK or phakic intraocular lens implantation).
  • prescription lenses for example, spectacles or contact lenses
  • refractive surgery for example, LASIK or phakic intraocular lens implantation
  • Atropine is a non-specific muscarinic antagonist. Atropine at 1 .0% and 0.5% has been demonstrated through randomised trials to be effective in slowing myopia progression (Shih et al., 1999).
  • the safety profile, and associated side- local and systemic effects of atropine i.e. its effect on pupil size and accommodation
  • Every unit increase in pupil size results in an exponential increase in the amount of light entering the eye, and this may cause glare and photophobia.
  • Atropine also decreases accommodation amplitude (ability to focus on near objects), thus reducing near vision so that children may require bifocal or progressive glasses to read or see close objects.
  • Atropine in the treatment of myopia study 1 (ATOM1 ), 1 % atropine was reported to be effective in slowing the progression of myopia (Chua et al., 2006). Side effects were recognised with 1 % atropine treated eyes, including blurring of near vision in the atropine-treated eye (likely due to cycloplegia) and anisocoria or uneven pupil size, (likely due to mydriasis).
  • the present composition provides an ultra-low concentration atropine composition for reducing and/or preventing myopia progression.
  • the present invention provides a composition for reducing and/or preventing myopia progression comprising less than 0.025% atropine.
  • the invention relates to the use of atropine in the preparation of a composition for reducing and/or preventing myopia progression, wherein the composition comprises less than 0.025% atropine.
  • the invention also provides a method for reducing and/or preventing myopia progression comprising administering to a subject a composition comprising less than 0.025% atropine.
  • Figure 1 is a flow chart illustrating the study design of ATOM1 .
  • Figure 2 is a graph showing mean spherical equivalent change from baseline from ATOM1 .
  • Figure 3 is a graph showing mean axial length change from baseline from ATOM1 .
  • Figure 4 is a flow chart illustrating the study design of ATOM2.
  • Figure 5 is a graph showing the mean change in spherical equivalent for groups from baseline 2 to 24 months with 0.01 %, 0.1 % and 0.5% atropine from ATOM2 and 1 % atropine and placebo from ATOM1 .
  • Figure 6 is a graph illustrating progression of myopia according to severity (pooled eyes) with 0.01 %, 0.1% and 0.5% atropine from ATOM2 and 1% atropine and placebo from ATOM1. Myopia progression from baseline 2 is classified as severe (if > 1 D), moderate (0.5-0.99 D) and mild (if ⁇ 0.5 D).
  • Figure 7 is a graph illustrating the main change in axial lengths from baseline 2 to 24 months from ATOM2.
  • Figure 8 is a graph illustrating the changes in spherical equivalent in groups from ATOM2 after stopping atropine for 1 year.
  • Figure 9 is a graph illustrating the changes in axial length in groups from ATOM2 after stopping atropine for 1 year. Definitions
  • Amblyopia (also known as “lazy eye”) refers to a decrease of vision, either unilaterally or bilaterally, with no apparent structural abnormality in the eye. In amblyopia, visual stimulation either fails to transmit or is poorly transmitted through the optic nerve to the brain.
  • Angecoria refers to a condition where the pupils of the eyes are uneven in size.
  • Cycloplegia refers to paralysis of the ciliary muscle of the eye, resulting in a loss of accommodation.
  • Mydriasis refers to a condition where the pupil of the eye is dilated due to disease, trauma or the use of drugs. Mydriasis may be associated with glare intolerance and photophobia.
  • Photophobia refers to a condition of sensitivity to light. In ordinary medical terms, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure.
  • Strabismus also known as “crossed eyes” refers to a condition in which the two eyes do not line up in the same direction, and therefore do not look at the same object at the same time.
  • the composition of the present invention comprises an ultra-low concentration of atropine, i.e. less than 0.025% atropine.
  • concentration of atropine in the composition may be any value less than 0.025%, for example, the composition may comprise 0.001 to 0.0249% atropine; 0.005% to 0.0249% atropine, 0.01 to 0.0249% atropine, 0.005 to 0.02% atropine, 0.05 to 0.015% atropine or 008 to 0.012% atropine.
  • the composition may comprise 0.001 %, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01 %, 0.01 1 %, 0.012%, 0.013%, 0.0 4%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.021 %, 0.022%, 0.023%, 0.024%, 0.0245% or 0.0249% atropine.
  • the composition comprises about 0.01 % atropine. More in particular, the composition comprises 0.01 %.
  • the composition may further comprise at least one pharmaceutically acceptable excipient.
  • the composition according to any aspect of the invention may be for use in reducing and/or preventing myopia progression and/or treating myopia.
  • the invention includes a method of reducing and/or preventing myopia progression comprising administering to a subject a composition according to any aspect of the invention.
  • the composition is for administration to the eye.
  • the composition is for topical administration to the eye.
  • the composition is an eye-drop composition After onset, myopia typically progresses during childhood and may only stabilise in adulthood. Accordingly, the composition is suitable for reducing and/or preventing myopia progression in subjects where myopia is still progressing and/or has not stabilised, even in late adulthood.
  • the composition is suitable for reducing and/or preventing myopia progression in subjects from 3 to 30 years old, where myopia is still progressing and/or has not stabilised.
  • the composition is suitable for reducing and/or preventing myopia in children from 6 to 12 years old.
  • the invention also provides a method for reducing and/or preventing myopia progression comprising administering to a subject a composition according to any aspect of the invention.
  • a study (Example 2), 400 children were administered either 0.01 %, 0.05% or 0.1 % atropine nightly to both eyes and myopia progression was monitored over a period of 2 years.
  • the results of this study showed that 0.01 % atropine was found to induce negligible side-effects (for example: loss of accommodation, mydriasis, allergic conjunctivitis, dermatitis) compared to atropine at 0.1% and 0.05% and retains comparable efficacy in controlling myopia progression.
  • ATOM1 400 children aged 6-12 years with spherical equivalents of -1 .00 D and - 6.00 D were randomly assigned to having 1 % atropine or placebo medication in one eye (Chua et a/., 2006).
  • the design of the study is illustrated in Figure 1 and summarised below.
  • the results from ATOM1 are compared and also used in Example 2.
  • Subjects 400 children aged 6 to 12 years with refractive error of spherical equivalent - 1 .00 to -6.00 D and astigmatism of -1 .50 D or less. Intervention: Subjects (the children) were assigned with equal probability to receive either 1 % atropine or vehicle eye-drops once nightly for 2 years. Only 1 eye of each subject was chosen through randomization for treatment.
  • Main Outcome Measures The main efficacy outcome measures were change in spherical equivalent refraction as measured by cycloplegic autorefraction and change in ocular axial length as measured by ultrasonography.
  • the primary safety outcome measure was the occurrence of adverse events.
  • Subjects 400 children aged 6-12 years with myopia of at least -2.0 D and astigmatism of -1.50 D or less. intervention: Subjects (the children) were randomly assigned in a 2:2:1 ratio to 0.5%, 0.1 % and 0.01 % atropine, to be administered once nightly to both eyes for 2 years. Cycloplegic refraction, axial length, accommodation amplitude, pupil diameter and visual acuity were noted at baseline, 2 weeks and then every 4 months for 2 years. Main outcome measure: Myopia progression at 2 years. Changes were noted and differences between groups were compared using the Huber-White robust standard error to allow for data clustering of two eyes per subject.
  • myopia progression in ATOM1 was -1 .20 ⁇ 0.69 D in the placebo group and -0.28 ⁇ 0.92 in the 1 % atropine group.
  • the mean increase in axial length was 0.27 ⁇ 0.25 mm, 0.28 ⁇ 0.28 mm and 0.41 ⁇ 0.32 mm in the 0.5%, 0.1 % and 0.01 % groups (p ⁇ 0.01 between the 0.01 % and 0.1 % groups and between the 0.01 % and 0.5% groups). Differences in myopia progression (0.19 D) and axial length change (0.14 mm) between groups, however, were small and may be considered clinically insignificant. 0.01 % atropine had negligible effect on accommodation and pupil size and no effect on near visual acuity. Allergic conjunctivitis and dermatitis were the most common adverse effect noted; with 16 cases in 0.1 % and 0.5% atropine groups, none in the 0.01 % group.
  • Atropine has negligible side-effects compared to atropine at 0.1 & and 0.5% and retains comparable efficacy in controlling myopia progression.
  • Subjects were randomized to receive 0.5%, 0.1 % or 0.01 % atropine once nightly in both eyes at an allocation ratio of 2:2:1 in six strata defined by gender and age-groups of 6-7, 8-10 and 1 1 -12 years to ensure gender and age balance across the three treatment arms.
  • Trial medications were pre-packaged so that bottles were pre- labelled with subject number and of similar appearance.
  • Trial medication consisted of the appropriate dose of atropine sulfate with 0.02% of 50% benzaikonium chloride as preservative (Ashwood Laboratories Ltd, Macau).
  • Accommodation amplitude was calculated as the inverse of NPA.
  • Mesopic pupil size was measured with the Procyon 3000 pupillometer (Lion House, Red Lion Street, London, UK), using the Meso-Hi (4 lux) setting.
  • Photopic pupil size was measured using the Neuroptics pupillometer (Neuroptics Inc, Irvine, CA, USA) while the subjects were viewing a target placed at 3m, after at least l Osecond of exposure to lamps providing 300 lux of luminance. In both cases, at least 5 pupil size readings (with range ⁇ 0.5 mm) were recorded and averaged.
  • Cycloplegic autorefraction was determined 30 minutes after 3 drops of cyclopentolate 1% (Cyclogyl, Alcon-Convreur) were administered at 5 minutes apart using a Canon RK-F1 autorefractor (Canon Inc. Ltd, Tochigiken, Japan). Five readings, all of which had to be less than 0.25 D apart, were obtained and averaged. Spherical equivalent was calculated as sphere plus half cylinder power.
  • the Zeiss IOL Master Carl Zeiss Meditec Inc, CA, USA
  • a non-contact partial coherence interferometry was used to measure the ocular axial length. Five readings, with a maximum-minimum deviation of 0.05 mm or less, were taken and averaged.
  • the primary end-point was myopia progression over 2 years. Since a hyperopic shift may occur after commencing atropine, myopic progression was calculated from the second baseline, when the subjects had been on trial medication for 2 weeks. Level of myopia progression in each eye was further categorized as being mild ( ⁇ 0.5 D), moderate (0.5 to 0.99 D) or severe (>1 .0 D). i
  • Secondary end-points included myopia progression at one year, change in axial length at one and two years, and side-effect parameters such as changes in accommodation amplitude, mesopic and photopic pupil size and best-corrected distance and near visual acuity.
  • Myopia and axial changes were noted from second baseline, while accommodation, pupil size and visual acuity were monitored from first baseline. Any adverse events, regardless of whether they appeared relevant to atropine use, were documented.
  • Table 1 Characteristics at baseline and second baseline (ie. 2 weeks after starting trial medication) '
  • BCVA best-corrected visual acuity
  • Myopia progression and axial length change from second baseline; other parameters: change from initial baseline
  • Pairwise comparison P-values are represented by A: significant (P ⁇ 0.05) difference between 0.01% and 0.5% atropine, B: significant difference between 0.01% and 0.1% atropine, and C: significant difference between 0.1% and 0.5% atropine.
  • Pupil size, under both photopic and mesopic conditions, in the 0.01% group increased by only 1 mm, while pupils in the 0.1 % and 0.5% groups were about 3 mm larger (Table 2). While the atropine effect on pupil diameter remained unchanged over time, the accommodation appeared to improve in the 0.1% and 0.5% groups over time (Table 2).
  • the mean accommodation amplitude in the 0.5% group fell from 15.8 D at baseline to 2.2 D at the second baseline visit but rose to 3.6 D and 4.1 D by the end of the first and second years. Changes in 0.01% group were less, varying from 16.2 D to 1 1.3 D, 11.7 D and 1 1.8 D over the same time-period.
  • Adverse events Majority of the adverse events were deemed to be unrelated to study treatment (eg. flulike illness) (Table 3).
  • Adverse reactions directly attributable to atropine included allergic conjunctivitis, which occurred in 13 subjects (4.1 %) in 0.1 % atropine and 0.5% atropine groups, in 3 (1.2%) subjects, symptoms were severe enough to warrant ceasing trial medication.
  • Four subjects in the 0.1 % and 0.5% groups (1 .3%) had allergy related dermatitis of the eyelids.
  • Six subjects had other eye symptoms, 5 of which could be attributed to atropine including 1 case of irritation and another of blur in the 0.01 % atropine group, and 2 cases of ocular irritation and 1 with intolerable glare in the 0.5% atropine group.
  • the mean myopia and axial length progression in the ATOM1 study was -0.28 ⁇ 0.92 D and -0.02 ⁇ 0.35 mm in the 1 % atropine eyes compared to - 1.20 ⁇ 0.69 D and 0.38 ⁇ 0.38 mm in the placebo eyes.
  • the progression of myopia in the ATOM2 subjects lie in a dose-related manner between these two extremes (Figure 5).
  • ATOM1 The subjects from ATOM1 were slightly younger (mean age: 9.2 versus 9.6 years), had lower spherical equivalents (mean spherical equivalent -3.4 versus -4.7 D) and smaller axial lengths (mean axial length 24.8 versus 25.2 mm) than those in the ATOM2 group. Nevertheless, the reduction in myopia progression with atropine eyedrops observed in both studies with otherwise similar study profiles and methodologies was consistent and should be regarded as definitive outcomes in these studies. Axial lengths were measured differently between the two studies with A-scan ultrasonography used in ATOM1 (Chua et al., 2006) and lOLmaster in ATOM2. Thus, the axial lengths of ATOM1 and ATOM2 have not been compared in Figure 7.
  • the difference in myopia progression at 2 years in the 0.01 % group was statistically significant compared to the 0.5% group and similarly, the difference in axial length increase was statistically larger than both the 0.1 % and 0.5% group.
  • absolute differences between groups were clinically small with differences in myopic progression and axial length increase of only 0.19 D and 0.13 mm over 2 years (Table 2, Figures 5 and 7).
  • the ocular side-effect profile was significantly better with accommodation remaining at 1 1 .8 D, mean pupil size of 5 mm and a mean near logMar vision of 0.01 .
  • Atropine was still clinically effective in reducing myopia progression, but did not cause side-effects normally associated with higher concentrations of atropine.
  • atropine-related adverse effects were uncommon at the 0.01 % dose. Allergic reactions were most frequent; with 3.2% experiencing allergic conjunctivitis and 0.8% experiencing an allergy-associated dermatitis, all of which were in the 0.1 % or 0.5% groups.
  • the benzalkonium preservative in the 0.01 % atropine eyedrop formulation may be at least partly responsible for these allergies.
  • a number of subjects (1 . 1 %) also noted at least 1 line loss in distance best-corrected vision (Table 3).
  • ATOM2 The strength of ATOM2 was its randomised double-blind design and low drop out rate. Instead of a placebo group, the comparison was based on external (historical and population) controls. The non-inclusion of a placebo group was a decision based on findings from the ATOM1 study, which clearly showed the efficacy of atropine treatment compared to placebo, rendering a placebo arm unethical. The more important aspect of this trial remained the comparison of low dose versus high dose not only in terms of efficacy, but also in terms of the visual side effects of atropine. ATOM2 was otherwise designed to have largely similar study parameters so that direct comparison with ATOM1 was deemed appropriate.

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Abstract

Cette invention concerne une composition et/ou un procédé pour réduire et/ou prévenir la progression de la myopie. La composition selon l'invention comprend une ultrabasse concentration d'atropine. La composition comprend moins de 0,025 % d'atropine. Par exemple, la composition comprend environ 0,01 % d'atropine. La composition à ultrabasse concentration d'atropine selon l'invention réduit et/ou prévient la progression de la myopie moyennant des effets secondaires négligeables, tels que la perte d'accommodation, une mydriase, une vision de près floue, la conjonctivite allergique et la dermatite.
PCT/SG2012/000174 2011-05-23 2012-05-18 Composition et/ou procédé pour réduire et/ou prévenir la progression de la myopie comprenant de l'atropine WO2012161655A1 (fr)

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WO2016187426A1 (fr) * 2015-05-19 2016-11-24 Amorphex Therapeutics Llc Dispositif de distribution de faible dose prolongée de médicament de suppression de myopie
WO2017204262A1 (fr) 2016-05-25 2017-11-30 Singapore Health Services Pte Ltd Composition aqueuse contenant de l'atropine
CN107456440A (zh) * 2017-08-07 2017-12-12 杭州赫尔斯科技有限公司 一种低浓度阿托品类药物滴眼液及其制备方法
WO2018154440A1 (fr) * 2017-02-21 2018-08-30 Singapore Health Services Pte Ltd Composition et procédé pour prévenir ou retarder l'apparition de la myopie comprenant de l'atropine
WO2019018749A1 (fr) 2017-07-20 2019-01-24 Alan Laboratories, Inc. Composition et méthodes pour le traitement de la myopie
US10251875B2 (en) 2017-05-11 2019-04-09 Nevakar Inc. Atropine pharmaceutical compositions
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