Pharmaceutical composition for controlling and/or reducing myopia progression
阅读说明：本技术 用于控制和/或降低近视发展的药物组合物 (Pharmaceutical composition for controlling and/or reducing myopia progression ) 是由 米纳斯·希欧多尔·科罗内奥 莫尼卡·钟 P·R·桑卡里杜尔格 E·L·史密斯三世 阿曼迪普· 于 2018-11-02 设计创作，主要内容包括：用于局部或眼科应用的包含毒蕈碱拮抗剂和腺苷酸拮抗剂的药物组合物,和含有或递送所述药物组合物的眼科装置,及其用于控制和/或降低近视发展的使用方法。(Pharmaceutical compositions for topical or ophthalmic use comprising a muscarinic antagonist and an adenosine antagonist, and ophthalmic devices containing or delivering said pharmaceutical compositions, and methods of use thereof for controlling and/or reducing the progression of myopia.)
1. An ophthalmic composition, comprising:
i) a muscarinic receptor antagonist; and
ii) an adenosine receptor antagonist.
2. The ophthalmic composition of claim 1, wherein the muscarinic receptor antagonist is atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropinic acid, meperidine, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, scopolamine, hyoscyamine (L-hyoscine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropine, sofetamide, solifenacin, darifenacin, benzalkonium, benzethrine, propiverine, aclidinium, trihexyphenidyl/benzhexol, tolterodine, or a pharmaceutically acceptable salt thereof.
3. The ophthalmic composition according to any one of claims 1-2, wherein the muscarinic receptor antagonist is atropine or a pharmaceutically acceptable salt thereof.
4. The ophthalmic composition of any one of claims 1-3, wherein the muscarinic receptor antagonist is present in an amount ranging between about 0.001 wt.% to less than 0.05 wt.% relative to the ophthalmic composition.
5. An ophthalmic composition according to any one of claims 1-4, wherein the adenosine receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
6. The ophthalmic composition according to any one of claims 1 to 5, wherein the adenosine receptor antagonist is caffeine or a pharmaceutically acceptable salt thereof.
7. The ophthalmic composition according to any one of claims 1-6, wherein the adenosine receptor antagonist is present in an amount ranging between about 0.1-5.0 wt.% relative to the ophthalmic composition.
8. The ophthalmic composition according to any one of claims 1-7, wherein the muscarinic receptor antagonist is atropine and is present at a concentration in the range of about 0.01-0.04% relative to the ophthalmic composition, the adenosine receptor antagonist is caffeine and is present at a concentration in the range of about 0.5-3.0% relative to the ophthalmic composition.
9. The ophthalmic composition of any one of claims 1-8, wherein:
i) the ophthalmic composition does not increase the photopic pupil size of the eye by more than 2 mm; and/or
ii) the ophthalmic composition does not reduce the amplitude of accommodation of the eye by more than about 6.0D.
10. The ophthalmic composition of any one of claims 1-9, wherein the ophthalmic composition is a topical ophthalmic composition.
11. The ophthalmic composition of any one of claims 1-10, wherein the ophthalmic composition is contained within an ophthalmic device.
12. The ophthalmic composition of claim 11, wherein the ophthalmic device is a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nano-disc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir.
13. A method of treating myopia in a patient in need thereof, comprising: administering an ophthalmic device according to any one of claims 11-12.
14. A method of treating myopia in a patient in need thereof, comprising: administering an ophthalmic composition according to any one of claims 1-10.
15. The method of treatment according to claim 14, wherein the ophthalmic composition is administered topically to the eye in the form of an eye drop formulation, an eye spray formulation, or an eye gel formulation.
16. The therapeutic method of any one of claims 13-15, wherein the method slows or reduces progression of myopia in the treated patient relative to untreated.
17. The method of treatment according to any one of claims 13-16, wherein the method:
i) increasing choroidal thickness in the eye of the treated patient relative to untreated; and/or
ii) reduces axial (or longitudinal) growth of the eye of the treated patient relative to untreated.
18. The method of treatment according to any one of claims 13-17, wherein the treated patient experiences less severe adverse side effects relative to atropine monotherapy.
19. The treatment method of any one of claims 13-18, wherein the method does not increase the photopic pupil size of the eye by more than about 2 mm.
20. The therapeutic method of any one of claims 13-19, wherein the method does not reduce the amplitude of accommodation of the eye by more than about 6.0D.
Technical Field
The present application relates to pharmaceutical compositions of muscarinic antagonists (muscarinic antagonists) and non-selective adenosine antagonists (non-selective adenosine antagonists) for topical or ocular use, and ophthalmic devices containing or delivering them, for controlling and/or reducing myopia progression, and methods of use thereof.
Background
Myopia (sometimes referred to as near-sightedness (nearsightedness) or short-sightedness) is a condition in which there is a mismatch between the length of the eye and the optical properties of the eye, resulting in imaging in front of the retina of the eye. This refractive error results in blurred vision for distant objects, while near or nearby objects appear normal. Most often, the mismatch is due to the longer eyeball length (sometimes referred to as axial length) than the optical system of the eye. Longer eye length is typically due to excessive axial (or longitudinal) growth of the eye. Although heterogeneous, myopic conditions are common worldwide. For example, although The incidence of myopia in The United states and Europe is about 30-40% of The population, it has reached epidemic proportions in many other countries, particularly in east Asia, over 90% of teenagers and young adults (Dolgin E., "The myopia bou. short-sight diagnosis disease waist," Nature (2015) 519: 276-. By comparison, the incidence of east asia was about 10-30% about 50 to 60 years ago. In addition, during the same period, it has been noted that in many east asian countries, the incidence of high Myopia (more severe Myopia than-5.00 diopter (D)) has increased from a few percent to about 20% (Morgan IG, He m., "An infectious Step Forward in Myopia prediction: Low-doseaatropine," Ophthalmology (2016) 123: 232-3). In addition to The inconvenience and expense associated with correcting distance blurred vision, for The long-term health of myopic eyes in older individuals, there are consequences of developing increased incidence of other vision impairments, including myopic maculopathy, retinal detachment, glaucoma, and cataracts (cutoff bj., The Myopias: basic science and Clinical management. harper & Row, philidophia, PA, 1985). Thus, there is a need to prevent the eye from developing to higher myopia levels. In recent years, some early preventive measures and interventions including the use of drugs, optical and environmental interventions have been proposed and evaluated for their slowing of myopia progression. Among them, pharmaceutical intervention is generally more effective in reducing myopia.
For pharmaceutical intervention, one compound observed to slow myopia progression is Atropine (Atropine), a muscarinic antagonist (more specifically, a non-selective muscarinic acetylcholine antagonist) (Chua et al Atropine for the treatment of childhood myopia, Ophthalmol, 2285-. Initially, atropine was used at a concentration of about 1% to reduce myopia. However, a problem associated with the use of atropine is that the concentration of the dose observed to be effective in reducing myopia also causes side effects. The use of atropine at concentrations of 1% and 0.5% resulted in the following significant short-term side effects: mydriatic pupillary dilation, photophobia (discomfort or sensitivity to light), glare and inability to read or fixate at close distances are also believed to result in long-term side effects such as damage to ocular structures (e.g., due to increased light lens and retina). In addition, certain side effects, such as allergies, have also been reported. More significantly, myopia rebound occurs upon termination of atropine dose administration. Furthermore, while atropine is in use, individuals need to wear bifocal glasses so that they can clearly see far and near. Due to the problems associated with the side effects associated with the use of high concentrations of Atropine, low concentrations of Atropine (Chia, "Atropine for the treatment of bacterial of the children: safety and efficacy of 0.5%, 0.1% and 0.01% doses," Ophthalmology (2012)119(2), 347) 354; Chia A, Lu QS, Tan D., "Five-clinical trial Atropine for the treatment of the fungal of the mydia 2: myodia control with the treatment of 0.01% eyedrops," Ophthalmology (2016) 123: 391-9) were tested. According to these tests, low concentrations of topical atropine (0.01 wt.%) are believed not to cause the side effects observed with high concentrations of atropine of 1 wt.%, 0.5 wt.%, and even 0.1 wt.%. With 0.01 wt.% atropine, a significantly reduced rebound effect after high dose was also observed during elution and less side effects resulted due to minimal increase in pupil size and insignificant effect on the amplitude of modulation. However, by closer examination, low doses of Atropine (0.01 wt.%), while effective in reducing side effects, are not effective in reducing shaft length elongation (Yam et al LowConcentration Atropine for Myopia Progress (LAMP) study: A randomised, double-cored, plate-controlled tertiary of 0.05 wt.%, 0.025 wt.% and 0.01 wt.% Atropineeye drop in Myopia control, Ophthalmology, pub ahead of print, 2018; Chia et al Atropine for the Treatment of cardiac muscle: safety and effectiveness of 0.2012 wt.%, 0.1 wt.% and 0.01 wt.% of Myoplasia (Atropine for treeing) 2.347: 2.54). Thus, there is a need for therapeutically effective doses that reduce axial elongation of the eye without significant adverse/side effects.
Another pharmaceutical intervention that has been observed to have some efficacy in slowing myopia progression is the compound 7-methylxanthine (sometimes referred to as 7-MX; a metabolite of caffeine and theobromine) which is a adenosine receptor antagonist (more specifically, a non-selective adenosine antagonist). This compound is described in U.S. patent No.6,710,051, which is incorporated herein by reference in its entirety. Myopic children have been shown to slow myopia progression and delay ocular axial growth by oral systemic doses of 7-methylxanthine for one year without significant side effects (Trier K, Munk rib-Madsen S, Cui D,
Notably, while it has been observed that haloperidol-induced catalepsy has been inhibited by potentiating the effect of muscarinic receptor antagonists through low doses of Caffeine (Moo-Puc RE, G Lo of the gora-Alfaro JL, Alvarez-Cervera FJ, Pineda JC, Arankowsky-Sandoval G, Heredia-L pez F., "Caffeine and muconic agglomerated act in synergy to inhibit muscarinic receptor-induced metabolism," Neuropharmacology (2003) 45: 493 503), it has not been known whether the use of Caffeine (or related agents or other adenylic acid antagonists) as an adjuvant ophthalmic therapy can reduce the dose of muscarinic receptor antagonists required to slow down progression of myopia and/or whether it can reduce adverse ophthalmic side effects associated with monotherapy. Caffeine is a non-selective adenosine receptor antagonist and increased regulation of Caffeine uptake throughout the body is observed (Osei et al, Caffeine inter is associated with pulse division and enhanced dacccommodation. eye, 31(4), 615-. Caffeine has been safely applied topically to the human eye at a concentration of 1 wt.% (Chandra P, Gaur A, Varma S., "Effect of coffee on the intracellular compression tissues with primary open angle glaucoma," Clin Ophthalmol. (2011) 5: 1623-9). Interestingly, 7-methylxanthines (sometimes called7-MX), metabolites of caffeine, have been used in animal models and in human trials to treat myopia by oral systemic administration (Nie HH, Huo LJ, Yang X, Gao ZY, Zeng JW, Trier K, Cui DM., "Effects of 7-methylxanthine on form-depletion myia in pimenta consumption," int.j.ophthalmol. (2012) 5: 133-7; cui D, Trier K, Zena J, Wu K, Yu M, Hu J, Chen X, Ge J., "Effects of 7-methyxanthine on the scribe in form of deprivationalia in guineea pigs," Acta Ophthalmol. (2011) 89: 328-34; and Trier K, Olsen EB, Kobayashi T, Ribel-Madsen SM., "Biochemical and ultrastructural change in rubber mill after treatment with 7-methylxanthine, theobromamine, acetazolamide, or L-ornithine," Br J Ophthalmol "(1999) 83: 1370-5). In addition, given the potential role of 7-methylxanthines as adenosine antagonists for neurotransmitter release, including GABA, it has been observed to delay myopia progression and axial eye growth without significant side effects (Trier K, Munk rib-Madsen S, Cui D,Christensen S.，“Systemic 7-methylxanthine in retarding axial eyegrowth and myopia progression：a 36-month pilot study，”J Ocul Biol Dis Infor.(2008)1：85-93)。
accordingly, there is a need for pharmaceutical compositions, and ophthalmic devices containing or delivering the same, and methods of their use, that are effective in controlling and/or reducing myopia progression while avoiding or minimizing adverse side effects associated with pupil size or accommodation.
Definition of
Unless otherwise defined, as is commonly used in the art, the following terms are used herein:
the term "myopic eye" is understood to mean an eye that is already myopic, pre-myopic or has a refractive condition that progresses towards myopia.
The term "ophthalmic device" is understood to mean an object placed on or present in the eye. The device may provide optical correction. Ophthalmic devices include, but are not limited to, contact lenses, ocular inserts, corneal onlays (corneal inlays), nanoplatelets (nano wafers), liposomes, nanoparticles, punctal plugs (punctal plugs), or hydrogel matrices with microfluidic reservoirs (microfluidics).
Unless otherwise indicated, the term "treating" includes a generally accepted meaning that encompasses preventing, controlling, slowing, reducing, delaying and/or alleviating symptoms associated with a disease (e.g., myopia), progression of a disease (e.g., myopia, such as the progression of myopia in a patient's eye), and/or a disease (e.g., myopia). Treatment may include therapeutic and/or prophylactic administration (e.g., as disclosed herein, pharmaceutical compositions or ophthalmic devices). For example, treatment of an eye that is already myopic (or at risk of developing myopia) in a patient diagnosed with myopia (high, moderate, or low) or pre-myopia (at risk of developing myopia) may include, but is not limited to, preventing, controlling, slowing, reducing, delaying, or reducing the progression of myopia in a patient diagnosed with myopia or at risk of developing myopia, increasing the choroidal thickness of the patient's eye (e.g., myopic eye, pre-myopic eye, or eye at risk of developing myopia), and/or decreasing the axial (or longitudinal) growth of the patient's eye (e.g., myopic eye, pre-myopic eye, or eye at risk of developing myopia).
The term "muscarinic antagonist" or "muscarinic receptor antagonist" refers to an agent which acts on or blocks muscarinic receptors to prevent or antagonize the action of cholinergic agents or muscarinic agonists or muscarinic receptor agonists.
The term "adenosine antagonist" or "adenosine receptor antagonist" refers to an agent that acts on or blocks an adenosine receptor to prevent or antagonize the action of an adenosine agonist or an adenosine receptor agonist.
The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human.
In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child.
Disclosure of Invention
Some embodiments described herein may provide pharmaceutical compositions, ophthalmic devices, and therapeutic methods to prevent, control, slow, reduce, delay, and/or reduce myopia progression.
In one aspect, provided herein are pharmaceutical compositions comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist.
In another aspect, provided herein is an ophthalmic device containing a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist, wherein the ophthalmic device delivers the pharmaceutical composition in a sustained release manner.
In another aspect, provided herein is a method of treating myopia in a patient in need thereof, comprising administering a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist.
In another aspect, provided herein is a method of treating myopia to prevent, slow, delay, control and/or reduce myopia progression in the eye of a patient in need thereof, comprising administering a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist.
In another aspect, provided herein is a method of treating myopia in a patient in need thereof, comprising administering a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist, and administering a pharmaceutical composition comprising an adenosine antagonist.
In another aspect, provided herein is a method of preventing, slowing, delaying, controlling and/or reducing the progression of myopia in the eye of a patient in need thereof, comprising administering a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist, and administering a pharmaceutical composition comprising an adenosine antagonist.
In another aspect, provided herein is a method of treating myopia in a patient in need thereof, comprising administering an ophthalmic device comprising a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist.
In another aspect, provided herein is a method of preventing, slowing, delaying, controlling and/or reducing the progression of myopia in the eye of a patient in need thereof, comprising administering an ophthalmic device comprising a pharmaceutical composition comprising a muscarinic antagonist, e.g., a low concentration of a muscarinic antagonist and an adenosine antagonist.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is a non-selective muscarinic acetylcholine energy antagonist.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is an M1 selective antagonist.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is tropine (tropine) or a pharmaceutically acceptable salt thereof.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is tropinic acid (tropic acid).
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is used at low concentrations. In certain embodiments, the muscarinic antagonist is used at a low concentration, e.g., it is atropine and is used at a concentration of less than 0.05 wt.% relative to the pharmaceutical composition. In certain embodiments, the muscarinic antagonist is atropine used at a concentration of between less than about 0.05 wt.% to not less than 0.001 wt.% relative to the pharmaceutical composition. In certain embodiments, the muscarinic antagonist is atropine used at a concentration of about 0.045 wt.% or less relative to the pharmaceutical composition. In certain embodiments, the muscarinic antagonist is atropine and is used at a concentration of about 0.04 wt.% or less relative to the pharmaceutical composition. In certain embodiments, the muscarinic antagonist is atropine and is used at a concentration of about 0.035 wt.% or less relative to the pharmaceutical composition. In certain embodiments, the muscarinic antagonist is atropine and is used at a concentration of about 0.03 wt.% or less relative to the pharmaceutical composition. In certain embodiments, the concentration of atropine is within the following ranges relative to the pharmaceutical composition: less than between 0.05 wt.% and 0.001 wt.%, such as between about 0.045 wt.% and 0.001 wt.%, between about 0.04 wt.% and 0.001 wt.%, between about 0.035 wt.% and 0.001 wt.%, between about 0.03 wt.% and 0.001 wt.%, between about 0.025 wt.% and 0.001 wt.%, between about 0.02 wt.% and 0.001 wt.%, between about 0.015 wt.% and 0.001 wt.%, between about 0.01 wt.% and 0.001 wt.%, between <0.01 wt.% and 0.001 wt.%, between about 0.045 wt.% and 0.01 wt.%, between about 0.04 wt.% and 0.02 wt.%, between about 0.03 wt.% and 0.02 wt.%, or between about 0.03 wt.% and 0.01 wt.%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist is present in an amount relative to the pharmaceutical composition within the following ranges: between about 0.001 and less than 0.05 wt.%, such as between about 0.001-0.045 wt.%, between about 0.001-0.04 wt.%, between about 0.001-0.035 wt.%, between about 0.001-0.03 wt.%, between about 0.001-0.025 wt.%, between about 0.001-0.02 wt.%, between about 0.001-0.015 wt.%, between about 0.001-0.01 wt.%, between about 0.001-0.005 wt.%, between about 0.005-0.03 wt.%, between about 0.005-0.04 wt.%, between about 0.01-0.03 wt.%, between about 0.01-0.045 wt.%, between about 0.01-0.04 wt.%, between about 0.02-0.03 wt.%, between about 0.015-0.025 wt.%, between about 0.015-0.015 wt.%, between about 0.015-0.03 wt.%, or between about 0.015 wt.%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the adenosine antagonist is a non-selective adenosine antagonist.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the non-selective adenosine antagonist is a xanthine derivative (xanthine derivative) or a pharmaceutically acceptable salt thereof.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the non-selective adenosine antagonist is caffeine or a pharmaceutically acceptable salt thereof.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the non-selective adenosine antagonist is caffeine citrate.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the non-selective adenosine antagonist is 7-methylxanthine or a pharmaceutically acceptable salt thereof.
In certain embodiments of the pharmaceutical composition, ophthalmic device or method of treatment disclosed herein, the adenosine antagonist is present in an amount relative to the pharmaceutical composition within the following ranges: between about 0.1-5.0 wt.%, between about 0.1-4.0 wt.%, between about 0.1-3.0 wt.%, between about 0.1-2.0 wt.%, between about 0.1-1.0 wt.%, between about 0.5-5.0 wt.%, between about 1.0-2.0 wt.%, between about 2.0-5.0 wt.%, between about 3.0-5.0 wt.%, or between about 4.0-5.0 wt.%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is an aqueous composition, an ophthalmic formulation, an ophthalmic aqueous formulation, an eye drop formulation, an eye spray formulation, an ophthalmic pharmaceutical composition contained within a contact lens blister package, a topical formulation, a topical ophthalmic composition, an ophthalmic gel formulation, an ophthalmic emulsion, an ophthalmic liposome, a nano-disc, a nano-particle suspension, or an ophthalmic ointment.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions further comprise one or more other ophthalmically acceptable excipients and additives, including carriers, stabilizers, tonicity adjusting agents, preservatives, buffers, tonicity adjusting agents, thickening agents, or other excipients.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is a sustained release formulation or subconjunctival depot (depot).
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is a sustained release formulation contained within an ophthalmic device.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic device is a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nano-disc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic devices deliver the pharmaceutical compositions in a sustained release manner.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions, e.g., as ophthalmic compositions for the treatment of ophthalmic disorders or conditions.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of anterior myopia, or myopia progression.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of high myopia, moderate myopia, or low myopia.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are formulated as ophthalmic compositions for the treatment of patients diagnosed with (or at risk of developing) pre-myopia.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is substantially uniformly distributed throughout the ophthalmic device.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the ophthalmic devices are contained within contact lens blister packages.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions submerge the ophthalmic devices within contact lens blister packages.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the muscarinic antagonist and the adenosine antagonist are co-administered simultaneously, either sequentially with the administration of the muscarinic antagonist first and then the adenosine antagonist, or sequentially with the administration of the adenosine antagonist first and then the administration of the muscarinic antagonist.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods prevent the development of myopia in the treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods control the progression of myopia in a treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods reduce the progression of myopia in the treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods slow or reduce the progression of myopia in the treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods control, slow, reduce, delay, and/or alleviate myopia progression in a treated patient in the following ranges relative to untreated: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90%.
In certain embodiments, as disclosed herein, a method of treating myopia in a patient in need thereof can increase the choroidal thickness of the eye of the treated patient, e.g., by about 5-100% relative to untreated, such as by increasing the choroidal thickness of the eye of the treated patient relative to untreated in the following range: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 25-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, use of the pharmaceutical compositions, ophthalmic devices, or methods of treatment limits the increase in the size of the photopic pupil (photopic pupil) of the user's eye to about 1-2mm, about 1mm, about 2mm, less than 1 mm.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, use of the pharmaceutical compositions, ophthalmic devices, or methods of treatment limits the reduction in the accommodative amplitude of the eye of the user to about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D, and less than 1.0D.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods reverse the progression of myopia in the treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the patient has high, moderate, or low myopia.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the patient is pre-myopia (or is at risk of developing myopia).
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods increase the choroidal thickness of the eye of the treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods increase the choroidal thickness of the eye of the treated patient relative to untreated by the following ranges: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 25-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods prevent, control, slow, reduce, delay, and/or reduce axial (or longitudinal) growth of the eye of a treated patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods control, slow, reduce, delay, and/or reduce the progression of myopia in a patient diagnosed with or at risk of developing myopia, increase the choroidal thickness of the patient's eye (e.g., myopic eye, anterior myopic eye, or eye at risk of developing myopia), and/or reduce axial (or longitudinal) growth of the patient's eye (e.g., myopic eye, anterior myopic eye, or eye at risk of developing myopia).
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the method controls, slows, reduces, retards, and/or reduces axial (or longitudinal) growth of the eye of the treated patient by between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90%, or between about 75-90% relative to untreated.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the patient is treated for a period of time between about 1 month and 10 years, such as a period of time of at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 7 years, or at least 9 years.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods result in less severe adverse side effects relative to atropine monotherapy.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods result in a smaller increase in pupil size relative to atropine monotherapy.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the methods result in a smaller reduction in modulation amplitude relative to atropine monotherapy.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered to the eye of the patient.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered topically.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical compositions are administered to the eye in the form of an eye drop formulation, an eye spray formulation, or an eye gel formulation.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered to the eye in the form of an ophthalmic emulsion, an ophthalmic liposome, a nano-disc, a nano-particle suspension, or an ophthalmic ointment.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered to the eye of the patient ophthalmically by an ophthalmic device.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the pharmaceutical composition is administered 1, 2, 3, 4, or 5 times per day.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the patient is about 4-18 years of age, or about 16-26 years of age.
Other features and advantages of the subject matter described herein will be apparent from the description and drawings, and from the claims.
Drawings
The various aspects of the embodiments described herein are best understood from the following detailed description when read with the accompanying drawing figures.
Fig. 1 is a flowchart showing a procedure for evaluating changes in vascular membrane thickness in primates due to administration of an atropine or caffeine monotherapy eye drop formulation or a combination therapy eye drop formulation containing atropine and caffeine.
Figure 2 is a graph showing choroidal thickness measurements resulting from administration of an atropine or caffeine monotherapy eye drop formulation or a combination therapy eye drop formulation containing atropine and caffeine to a primate.
Fig. 3 is a flowchart showing a procedure for evaluating changes in vascular membrane thickness in primates due to administration of an atropine or caffeine monotherapy eye drop formulation or a combination therapy eye drop formulation containing atropine and caffeine.
Fig. 4 is a graph showing choroidal thickness measurements resulting from administration of an atropine or caffeine monotherapy eye drop formulation or a combination therapy eye drop formulation containing atropine and caffeine to a primate.
Figures 5A-5D are graphs showing refractive error and axial length change due to administration of atropine eye drops alone or eye drop formulations containing atropine and caffeine to primates.
Detailed Description
The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter. Specific examples of components and arrangements are described below to simplify the present disclosure. Of course, these are merely examples and are not intended to be limiting. Additionally, the present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.
Myopia, axial elongation of the eye, affects most people. Myopia onset is usually during the age of primary school and progresses until eye growth is complete. Despite the use of corrective lenses, the development of myopia can lead to increased visual deficits. The present disclosure recognizes the importance of compositions and therapies for treating, preventing, controlling, slowing, reducing, delaying and/or mitigating the onset and progression of myopia, particularly pharmaceutical compositions that reduce potential side effects and provide therapeutic benefits or combinations thereof, by convenient administration or implementation, ophthalmic devices containing or delivering the pharmaceutical compositions, and methods of their use.
Pharmaceutical composition therapy is a widely used and powerful strategy in medicine with the aim of achieving synergistic therapeutic effects, reducing dose and toxicity, and minimizing or delaying the induction of drug resistance (Chou TC., "drug combination therapies and the third synergy using the Chou-Talalaymethod," Cancer Res. (2010) 70: 440-6). The present disclosure identifies certain compounds, such as atropine, that provide synergistic effects with muscarinic receptor antagonists to enhance myopia reduction or myopia-slowing effects while avoiding or minimizing adverse side effects, such as those observed by atropine monotherapy.
The present application provides pharmaceutical compositions of non-selective muscarinic receptor antagonists and non-selective adenosine antagonists for topical or ocular applications, and ophthalmic devices containing or delivering the same, and methods of their use for controlling and/or reducing myopia progression.
In certain embodiments, the pharmaceutical composition may comprise or consist of a muscarinic receptor antagonist and an adenosine receptor antagonist. In certain embodiments, the muscarinic antagonist may be a non-selective muscarinic acetylcholine receptor antagonist, or may be an M1 selective antagonist. In certain embodiments, the muscarinic antagonist may be a non-selective muscarinic receptor antagonist, such as a low concentration of the non-selective muscarinic receptor antagonist. In certain embodiments, the adenosine antagonist is a non-selective adenosine antagonist.
In certain embodiments, the muscarinic antagonist provided with the pharmaceutical compositions disclosed herein may be atropine (atropine), atropine sulfate (atropine sulfate), noratropine (noratropine), atropine-N-oxide (atropine-N-oxide), tropine (tropine), tropine acid (tropic acid), atropine (atropine methonitrate), diphenhydramine (diphenhydramine), dimenhydrinate (dimehydramine), dicyclomine (dicyclomine), flavoxate (flavodoxoate), oxybutynin (oxybutynin), tiotropium salt (tiotropium), scopolamine (hyoscine), hyoscyamine (L-scopolamine), hydroxyzine (hydroxyzinamine), ipratropium (ipratropium), piroctone (pyridoxine), pyrimethanine (octopiroctone), pyrimethanamine (neofenamate), pyrimethanamine (octopiroctone), pyrimethanamine (octopine (octopiroctone), pyrimethanine (octopine (metane), pyrimethanamide (metane (metazone), pyrimethanamide (octopiroctone), pyrimethanamide (metane), pyrimethanamide (metane), pyrimethanamide (metazone), pyrimethanamide (metane), pyrimethanamide (propine), pyrimethanamide (metane), pyrimethanamide (propine (propi, Mebeverine (mebeverine), propiconazole (procyclidine), aclidinium bromide (aclidinium bromide), trihexyphenidyl/benzhexol, tolterodine (tolterodine), or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the muscarinic receptor antagonist is atropine or a pharmaceutically acceptable salt thereof. In certain embodiments, the muscarinic receptor antagonist is a tropine or a pharmaceutically acceptable salt thereof. In certain embodiments, the muscarinic receptor antagonist is tropine. In certain embodiments, the muscarinic receptor antagonist provided with the pharmaceutical composition disclosed herein may be present at low concentrations, e.g., in an amount of less than 0.05 wt.% relative to the pharmaceutical composition, such as 0.045 wt.% or less, 0.04 wt.% or less, 0.035 wt.% or less, or 0.03 wt.% or less. For example, in certain embodiments, the muscarinic receptor antagonist provided with the pharmaceutical composition disclosed herein may be present at low concentrations, e.g., in the following ranges relative to the pharmaceutical composition: about 0.001 to less than 0.05 wt.%, such as between about 0.001 to 0.045 wt.%, between about 0.001 to 0.04 wt.%, between about 0.001 to 0.035 wt.%, between about 0.001 to 0.03 wt.%, between about 0.001 to 0.025 wt.%, between about 0.001 to 0.02 wt.%, between about 0.001 to 0.015 wt.%, between about 0.001 to 0.01 wt.%, between about 0.001 to 0.005 wt.%, between about 0.005 to 0.03 wt.%, between about 0.005 to 0.04 wt.%, between about 0.01 to 0.03 wt.%, between about 0.01 to 0.045 wt.%, between about 0.01 to 0.04 wt.%, between about 0.02 to 0.03 wt.%, between about 0.015 to 0.025 wt.%, between about 0.015 to 0.015 wt.%, or between about 0.015 to 0.015 wt.%.
In certain embodiments, the muscarinic antagonist may be present in the pharmaceutical composition disclosed herein in an amount of less than 0.05 wt.%, such as in an amount of about 0.001 wt.%, about 0.002 wt.%, about 0.005 wt.%, about 0.01 wt.%, about 0.015 wt.%, about 0.02 wt.%, about 0.025 wt.%, about 0.03 wt.%, about 0.035 wt.%, about 0.04 wt.%, or about 0.045 wt.%, relative to the pharmaceutical composition.
In certain embodiments, the adenosine receptor antagonist provided with the pharmaceutical compositions disclosed herein can be a non-selective adenosine antagonist. For example, in certain embodiments, the non-selective adenosine antagonist can be a xanthine derivative, such as a substituted xanthine derivative or a pharmaceutically acceptable salt thereof, such as caffeine; 7-methylxanthine; 1, 7-dimethylxanthine (para-xanthine), 3, 7-dimethylxanthine (theobromine); 7-methylxanthine (heteroxanthine), 3-methylxanthine; 1-methylxanthine, Isobutylmethylxanthine (IBMX); l-hexyl-3, 7-dimethylxanthine (pentiteine); 1, 7-dimethylxanthine; or substituted xanthines as described in detail in U.S. patent No.6,710,051; or mixtures thereof. In a preferred embodiment, the adenosine receptor antagonist is caffeine or 7-methylxanthine or a pharmaceutically acceptable salt thereof, for example, caffeine or a pharmaceutically acceptable salt thereof, such as caffeine citrate. In certain embodiments, the adenosine antagonist provided with the pharmaceutical composition disclosed herein may be present in an amount in the range of about 0.1-5.0 wt.% relative to the pharmaceutical composition, such as in the following ranges relative to the pharmaceutical composition: between about 0.1-4.0 wt.%, between about 0.1-3.0 wt.%, between about 0.1-2.0 wt.%, between about 0.1-1.0 wt.%, between about 0.5-5.0 wt.%, between about 1.0-2.0 wt.%, between about 2.0-5.0 wt.%, between about 3.0-5.0 wt.%, or between about 4.0-5.0 wt.%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the use of the pharmaceutical composition, the use of the ophthalmic device, or the method of treatment will control, slow, reduce, delay, and/or alleviate myopia progression in the treated patient in the following ranges relative to untreated: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.
In certain embodiments of the pharmaceutical compositions, ophthalmic devices, or methods of treatment disclosed herein, the use of the pharmaceutical composition, the use of the ophthalmic device, or the method of treatment increases the photopic pupil size of a user's eye to about 1mm to 2mm, about 1mm, about 2mm, less than 2mm, or less than 1 mm.
In certain embodiments of the pharmaceutical composition, ophthalmic device, or method of treatment disclosed herein, the reduction in modulation amplitude by the pharmaceutical composition, ophthalmic device, or method of treatment is about 1.0-6.0D, 1.0-5.0D, 1.0-4.0D, 1.0-3.0D, 1.0-2.0D, less than 6.0D, less than 5.0D, less than 4.0D, less than 3.0D, less than 2.0D, and less than 1.0D.
In certain embodiments, the pharmaceutical composition may comprise a "hybrid molecule" (sometimes referred to herein as a "conjugate molecule") or a "conjugate compound") synthesized from a muscarinic receptor antagonist and an adenosine receptor antagonist. In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule synthesized from atropine and caffeine. In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule comprising one atropine molecule conjugated to one caffeine molecule, a conjugate compound represented by formula (I) (having one atropine molecule conjugated to caffeine N1), a conjugate compound represented by formula (II) (having one atropine molecule conjugated to caffeine N3), or a conjugate compound represented by formula (III) (having one atropine molecule conjugated to caffeine N7):
wherein R is1Is an atropine moiety, and wherein L is a divalent linker, whereby said divalent linker group covalently conjugates the atropine molecule to the caffeine molecule. In certain embodiments, suitable divalent linkers may include hydrocarbon linkers comprising a stable bond, such as hydrophobic hydrocarbon linkers. Suitable hydrocarbon linkers may include polyalkyl linkers, e.g., C5-C20An alkyl linker; c5-C6Cycloalkyl linkers, such as a 1, 4-cyclohexyl linker, a 1, 3-cyclohexyl linker, a 1, 2-cyclohexyl linker, a 1, 3-cyclopentyl or a 1, 2-cyclopentyl group; c5-C6A cycloalkenyl linker. In certain embodiments, suitable divalent linkers may include a hydrophilic stabilizing bond, such as a polyethylene glycol linker, e.g., - (OCH)2CH2)n-, where n is 5 to 20. In certain embodiments, suitable divalent linkers may include ester linkages susceptible to hydrolysis by esterases, such as acetyl linkers, e.g., - (o (co) CH2) -. For example, by way of illustration, the hybrid molecule can be a conjugate compound having formula (I) with divalent linkers each via L (the L two)The valency linker is a polyalkyl linker, wherein N is 5-20), one atropine molecule conjugated from the N-methyl group to caffeine N1 position by an L bivalent linker (said L bivalent linker is a polyethylene glycol linker, wherein N is 5-20) or by an L bivalent linker (said L bivalent linker is an acetyl linker):
in certain embodiments, the hybrid molecule is a conjugate compound having formula (II) or (III) having one atropine molecule conjugated from an N-methyl group to the N3 or N7 position of caffeine, respectively, through an L divalent linker (the L divalent linker is a polyalkyl linker, wherein N is 5-20), through an L divalent linker (the L divalent linker is a polyethylene glycol linker, wherein N is 5-20), or through an L divalent linker (the L divalent linker is an acetyl linker).
In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule comprising one atropine molecule conjugated to two caffeine molecules, a conjugate compound represented by formula (IV):
wherein the N-carbamate derivative of atropine is conjugated to two divalent linkers (L) via a trivalent linker, such as a 1, 2, 3-propanetriol moiety, wherein L may independently be a polyethylene glycol linker (wherein N is independently 5-20), a polyalkyl linker, e.g., C5-C20An alkyl linker; c5-C6A cycloalkyl linker; c5-C6A cycloalkenyl linker; or ester linkages, such as acetyl linkers, e.g., - (O (CO) CH2) And wherein each of two independent divalent linkers is further conjugated to R2Group, wherein R2Independently a caffeine moiety independently conjugated at the N1, N3, or N7 positions through an N-methyl group. For example, by way of illustration, the hybrid molecule can be a conjugate compound having formula (IV) with conjugation by 1, 2, 3-propanetriolAn N-carbamate derivative of atropine conjugated to two independent divalent linkers (L) which are polyethylene glycol linkers (wherein N is independently 5-20), and wherein R is2Independently a caffeine moiety independently conjugated at position N1 through an N-methyl group:
in certain embodiments, the hybrid molecule is a conjugate compound having formula (IV) with an N-carbamate derivative of atropine conjugated via 1, 2, 3-propanetriol to two separate divalent linkers (L) which are polyethylene glycol linkers (where N is independently 5-20), and wherein R is2Independently, a caffeine moiety independently conjugated at the N3 or N7 position of caffeine via an N-methyl group.
In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule comprising two atropine molecules conjugated to one caffeine molecule, a conjugate compound represented by formula (V):
wherein the N-carbamate derivative of atropine is conjugated to two separate divalent linkers (L) via a trivalent linker, such as a 1, 2, 3-propanetriol moiety, wherein L may independently be a polyethylene glycol linker (wherein N is independently 5-20), a polyalkyl linker, e.g., C5-C20An alkyl linker; c5-C6A cycloalkyl linker; c5-C6A cycloalkenyl linker; or ester linkages, such as acetyl linkers, e.g., - (O (CO) CH2) -, wherein one of said separate divalent linkers is further conjugated to the atropine moiety through an N-methyl group, and wherein one of said separate divalent linkers is further conjugated to R2Group, wherein R2Is a caffeine moiety conjugated at the N1, N3 or N7 position through an N-methyl group. For example, by way of illustration, the hybrid molecule may be a conjugate having formula (V)A compound having an N-carbamate derivative of atropine conjugated via 1, 2, 3-propanetriol to two separate divalent linkers (L) which are polyethylene glycol linkers (wherein N is independently 5-20), wherein one of the separate divalent linkers is further conjugated to an atropine moiety via an N-methyl group, and wherein one of the separate divalent linkers is further conjugated to R2And wherein R is2Independently a caffeine moiety independently conjugated at position N1 through an N-methyl group:
in certain embodiments, the hybrid molecule is a conjugate compound having the formula (V) with an N-carbamate derivative of atropine conjugated to two separate divalent linkers (L) through 1, 2, 3-propanetriol (the divalent linkers (L) being polyethylene glycol linkers, wherein N is independently 5-20), wherein one of the separate divalent linkers is further conjugated to an atropine moiety through an N-methyl group, and wherein one of the separate divalent linkers is further conjugated to R2And wherein R is2Independently, a caffeine moiety independently conjugated at the N3 or N7 position of caffeine via an N-methyl group.
In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule comprising one tropine molecule conjugated to one caffeine molecule, a conjugated compound represented by formula (VI):
wherein the tropine moiety is conjugated to two separate divalent linkers (L) via a trivalent linker, such as a 1, 2, 3-propanetriol moiety, wherein L may independently be a polyethylene glycol linker (where n is independently 5-20), a polyalkyl linker, e.g., C5-C20An alkyl linker; c5-C6A cycloalkyl linker; c5-C6A cycloalkenyl linker; or an ester linkage, such as an acetyl linker,for example, - (O (CO) CH2) And wherein each of two independent divalent linkers is further conjugated to R2Group, wherein R2Independently a caffeine moiety independently conjugated at the N1, N3, or N7 positions through an N-methyl group. For example, by way of illustration, the hybrid molecule can be a conjugate compound having the formula (VI) with a tropine moiety conjugated through 1, 2, 3-propanetriol to two separate divalent linkers (L) that are polyethylene glycol linkers (where n is independently 5-20), and where R is2Independently a caffeine moiety independently conjugated at position N1 through an N-methyl group:
in certain embodiments, the hybrid molecule is a conjugate compound having formula (V) with a tropine moiety conjugated through 1, 2, 3-propanetriol to two separate divalent linkers (L) that are polyethylene glycol linkers (where n is independently 5-20), and wherein R is2Independently, a caffeine moiety independently conjugated at the N3 or N7 position of caffeine via an N-methyl group.
In certain embodiments, the pharmaceutical composition may comprise a hybrid molecule comprising two tropine molecules conjugated to one caffeine molecule, a conjugated compound represented by formula (VII):
wherein the tropine moiety is conjugated to two separate divalent linkers (L) via a trivalent linker, such as a 1, 2, 3-propanetriol moiety, wherein L may independently be a polyethylene glycol linker (where n is independently 5-20), a polyalkyl linker, e.g., C5-C20An alkyl linker; c5-C6A cycloalkyl linker; c5-C6A cycloalkenyl linker; or ester linkages, such as acetyl linkers, e.g., - (O (CO) CH2) -, wherein one of said independent bivalent linkers is further conjugated to a receptacleA moiety, and wherein one of said independent divalent linkers is further conjugated to R2Group, wherein R2Is a caffeine moiety conjugated at the N1, N3 or N7 position through an N-methyl group. For example, by way of illustration, the hybrid molecule can be a conjugate compound having formula (VII) with a trope moiety conjugated to two separate divalent linkers (L) through 1, 2, 3-propanetriol, the divalent linkers (L) being polyethylene glycol linkers (where n is independently 5-20), wherein one of the separate divalent linkers is further conjugated to the trope moiety, and wherein one of the separate divalent linkers is further conjugated to R2And wherein R is2Independently a caffeine moiety independently conjugated at position N1 through an N-methyl group:
in certain embodiments, the hybrid molecule is a conjugate compound having formula (VII) with a trope conjugated to two separate divalent linkers (L) through 1, 2, 3-propanetriol, the divalent linkers being polyethylene glycol linkers (where n is independently 5-20), wherein one of the separate divalent linkers is further conjugated to a trope moiety, and wherein one of the separate divalent linkers is further conjugated to R2And wherein R is2Independently, a caffeine moiety independently conjugated at the N3 or N7 position of caffeine via an N-methyl group.
In certain embodiments, the pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be in the form of an aqueous composition, an ophthalmic formulation, an ophthalmic aqueous formulation, an eye drop formulation, an eye spray formulation, an ophthalmic pharmaceutical composition contained within a blister package for contact lenses, a topical formulation, a topical ophthalmic composition, an ophthalmic gel formulation, an ophthalmic emulsion, an ophthalmic liposome, a nano-disc, a nano-particle suspension or an ophthalmic ointment.
In certain embodiments, a pharmaceutical composition as disclosed herein may be an ophthalmic aqueous formulation, such as in the form of eye drops. For example, an ophthalmic aqueous formulation as described herein may be packaged in an eye drop bottle and administered as drops. In certain embodiments, the ophthalmic aqueous formulation may be administered as a single administration (i.e., a single dose), which may include one, two, three, or more drops instilled into the eye of the patient. In certain embodiments, one dose of an ophthalmic aqueous formulation described herein is one drop of an aqueous composition from the eye drop bottle.
In certain embodiments, a pharmaceutical composition as disclosed herein may be an ophthalmic gel formulation. For example, the ophthalmic gel formulation may be packaged in an eye drop bottle and administered as drops. In certain embodiments, the ophthalmic gel formulation may be administered as a single administration (i.e., a single dose), which may include one, two, three, or more drops instilled into the eye of the patient. In certain embodiments, one dose of an ophthalmic gel described herein is one drop of the gel composition from the eye drop bottle.
In certain embodiments, a pharmaceutical composition as disclosed herein may be an ophthalmic ointment formulation. For example, the ophthalmic ointment formulation may be packaged in a tube or other squeezable container having a dispensing nozzle through which the ointment strip is to be delivered. In certain embodiments, the ophthalmic ointment formulation may be administered as a single administration (i.e., a single dose), which may include one or more strips into the eye of the patient. In certain embodiments, one dose of an ophthalmic ointment is one ointment composition dispensed through a dispensing tube orifice.
In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may further comprise one or more other ophthalmically acceptable excipients and additives including, for example, carriers, stabilizers, tonicity adjusting agents, preservatives, buffers or tonicity adjusting agents, thickening agents and other excipients.
The carrier used in certain embodiments is generally suitable for topical application and may comprise water, and water-miscible solvents, such as C through C7-mixtures of alkanols, plants or minerals containing 0.1 to 5% by weight of hydroxyethyl celluloseOils, ethyl oleate, carboxymethylcellulose and other water-soluble polymers for ophthalmic use, such as carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, ethyl acrylate, polyacrylamide, natural products, such as pectin, alginates, starch derivatives and other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethylether, polyethylene oxide, crosslinked polyacrylic acid, such as neutral Carbopol (Carbopol), or mixtures of those polymers; naturally-occurring phosphatides, for example, lecithin or condensation products of alkylene oxides with fatty acids, for example, polyethylene glycol stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, polyoxyethylene sorbitol monooleate. For example, in certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may also comprise an osmolality adjusting agent, such as sodium chloride, as other ophthalmically acceptable agents. In certain embodiments, other ophthalmically useful agents included with the pharmaceutical compositions disclosed herein can be preservatives, such as benzalkonium chloride (benzalkonium chloride), cetrimide (cetrimonium), sodium perborate (sodium perborate), stabilized oxychloro complex (stabilized oxychloro complex), sofasia (SofZia), polyquaternium-1 (polyquaternium-1), chlorobutanol (chlorobutanol), disodium edetate (edetate disodium), polyhexamethylene biguanide (polyhexamethylene biguanidinium), or combinations thereof. In certain embodiments, other ophthalmically useful agents included with the pharmaceutical compositions disclosed herein can be buffering agents, such as borate, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof. In certain embodiments, other ophthalmically acceptable agents included with the pharmaceutical compositions disclosed herein can be tonicity adjusting agents, such as sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, or mixtures thereof,Potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glucose, mannitol, sorbitol, glucose, sucrose, urea, propylene glycol, glycerol, or a combination thereof.
In certain embodiments, the pharmaceutical composition comprising or consisting of a muscarinic antagonist and a adenylic antagonist may be in a sustained release formulation, such as a sustained release formulation contained within an ophthalmic device, or in the form of a subconjunctival reservoir. For example, in certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist is a sustained release formulation contained within an ophthalmic device, wherein the ophthalmic device may be a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nano-disc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir. When included in an ophthalmic device, a sustained release formulation of a pharmaceutical composition disclosed herein is delivered from the ophthalmic device in a sustained release manner. In certain embodiments, a pharmaceutical composition, such as an ophthalmic composition, comprising or consisting of a muscarinic antagonist and an adenosine antagonist can be distributed substantially uniformly (e.g., at least 50% uniform, such as 80-95% uniform) throughout the ophthalmic device.
In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be formulated as an ophthalmic composition, e.g., as an ophthalmic composition for the treatment of an ophthalmic disorder or condition, such as for the treatment of pre-myopia, myopia or myopia progression. In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be formulated as an ophthalmic composition for the treatment of high myopia (greater than-5.00 diopters (D) (i.e. more negative and further away from 0.00 diopters), such as myopia greater than-6.00 diopters). In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be formulated as an ophthalmic composition for the treatment of moderate myopia (myopia ranging between about-3.00 diopters to about-5.00 diopters). In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be formulated as an ophthalmic composition for the treatment of low myopia (-3.00 diopters or less, i.e. myopia closer to 0.00 diopters). In certain embodiments, a pharmaceutical composition comprising or consisting of a muscarinic antagonist and an adenosine antagonist may be formulated as an ophthalmic composition for the treatment of patients diagnosed with (or at risk of developing) pre-myopia.
The present application also provides a method of treating myopia in a patient in need thereof comprising administering a pharmaceutical composition comprising a muscarinic antagonist and an adenosine antagonist (as disclosed herein). In certain embodiments, the treatment methods disclosed herein prevent, control, slow, reduce, delay, and/or reduce myopia progression in a treated patient, e.g., prevent or control myopia progression in a treated patient. For example, in certain embodiments, the treatment methods disclosed herein control, slow, reduce, delay, and/or alleviate myopia progression in a treated patient relative to untreated patients to the following ranges: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 25-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%. In certain embodiments, the treatment methods disclosed herein prevent or reverse the progression of myopia in the treated patient. A patient with myopia may be at risk of developing myopia (e.g., is anterior myopia) or suffering from high, moderate or low myopia. In certain embodiments, the method of treating myopia in a patient in need thereof, said patient being about 4-18 years of age, or about 16-26 years of age, as disclosed herein.
In certain embodiments, as disclosed herein, a method of treating myopia in a patient in need thereof can increase the choroidal thickness of the eye of the treated patient, e.g., by about 5-100% relative to untreated, such as increasing the choroidal thickness of the eye of the treated patient relative to untreated by the following range: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 25-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.
In certain embodiments, as disclosed herein, a method of treating myopia in a patient in need thereof can control, reduce, retard, and/or alleviate axial (or longitudinal) growth of the eye of the treated patient, e.g., control, retard, reduce, retard, and/or alleviate axial (or longitudinal) growth of the eye of the treated patient by about 5-100% relative to untreated, such as control, retard, reduce, retard, and/or alleviate axial (or longitudinal) growth of the eye of the treated patient relative to untreated in the following ranges: between about 5-95%, between about 5-90%, between about 5-80%, between about 5-70%, between about 5-60%, between about 5-50%, between about 5-40%, between about 5-30%, between about 5-20%, between about 10-100%, between about 20-90%, between about 25-90%, between about 30-90%, between about 40-90%, between about 50-90% or between about 75-90%.
In certain embodiments, as disclosed herein, a method of treating myopia in a patient in need thereof can comprise administering a pharmaceutical composition comprising a muscarinic antagonist and administering a pharmaceutical composition comprising an adenosine antagonist. For example, the method of treatment may comprise co-administration of the muscarinic antagonist and the adenosine antagonist as separate pharmaceutical compositions (or agents) rather than in a single mixed pharmaceutical composition. In certain embodiments, the method of treating myopia in a patient in need thereof may comprise simultaneous co-administration of a pharmaceutical composition comprising a muscarinic antagonist and a pharmaceutical composition comprising an adenosine antagonist, or sequential co-administration (administration of a muscarinic antagonist followed by administration of an adenosine antagonist, or administration of an adenosine antagonist followed by administration of a muscarinic antagonist). In certain embodiments, the method of treating myopia in a patient in need thereof can comprise administering a hybrid molecule comprising a muscarinic antagonist conjugated to an adenosine antagonist. In certain embodiments, a method of treating myopia in a patient in need thereof can comprise administering a hybrid molecule comprising one or more muscarinic antagonist molecules conjugated to one or more adenosine antagonist molecules.
In certain embodiments, as disclosed herein, a method of treating myopia in a patient in need thereof can comprise treating the patient for a period of time between about 1 month and 10 years, for example, a period of time of at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years, at least 7 years, or at least 9 years.
In certain embodiments, as disclosed herein, the method of treating myopia in a patient in need thereof can result in less severe adverse side effects relative to atropine monotherapy. For example, as disclosed herein, methods of treating myopia using a pharmaceutical composition comprising a muscarinic antagonist and a adenylate antagonist can result in a treated patient having a smaller increase in pupil size relative to atropine monotherapy. In certain embodiments, as disclosed herein, methods of treating myopia using a pharmaceutical composition comprising a muscarinic antagonist and a adenylate antagonist can result in a treated patient having less reduction in amplitude of accommodation relative to atropine monotherapy.
In certain embodiments, the pharmaceutical composition may be administered directly to the eye of the patient ophthalmically, or may be administered topically to the patient, as disclosed herein, for the treatment of myopia in a patient in need thereof. For example, in certain embodiments, the pharmaceutical composition may be administered to the eye in the form of an eye drop formulation, an eye spray formulation, an eye gel formulation, an ophthalmic emulsion, an ophthalmic liposome, a nano-disc, a nano-particle suspension, or an ophthalmic ointment, in accordance with the methods of treating myopia as disclosed herein. For example, in certain embodiments, the pharmaceutical composition may be administered ophthalmically to the eye of a patient by an ophthalmic device, wherein the ophthalmic device may be a contact lens, an ocular insert, a corneal onlay, a corneal inlay, a nano-disc, a liposome, a nanoparticle, a punctal plug, or a hydrogel matrix with a microfluidic reservoir, according to the methods of treating myopia as disclosed herein. In certain embodiments, the pharmaceutical composition may be administered in a sustained release manner from the ophthalmic device.
In certain embodiments, as disclosed herein, the pharmaceutical composition may be administered 1, 2, 3, 4, or 5 times per day, for example, 1-3 times per day, such as 1 time per day, for methods of treating myopia in a patient in need thereof.
Examples
The following eye drop formulations were used in primate eyes (animal 656 and animal 659, corresponding to examples 1 and 2, respectively) to show changes in choroidal thickness: 0.1 wt.% atropine monotherapy (0.3 wt.% atropine in 0.1 wt.% sterile aqueous solution of hydroxy-propylmethylcellulose ("HPMC)), 1.4 wt.% caffeine monotherapy (1.4 wt.% caffeine citrate in 0.3 wt.% sterile aqueous solution of HPMC), and 0.1 wt.% atropine/1.4 wt.% caffeine combination therapy (0.1 wt.% atropine and 1.4 wt.% caffeine citrate in 0.3 wt.% sterile aqueous solution of HPMC).
For the measurement of changes in choroidal thickness, it has been noted that increased choroidal thickness has been used as an indicator of the degree of effectiveness affecting changes in eye growth, indicating a possible correlation with evaluating effectiveness in the treatment of myopia.
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