US 2010.001 6395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0016395 A1 Benozzi (43) Pub. Date: Jan. 21, 2010 (54) OPHTHALMIC COMPOSITIONS OF (86). PCT No.: PCT/B07/03780 PARASYMPATHETIC STIMULANTS AND ANTI-NFLAMMATORES FOR USE IN THE S371 (c)(1), TREATMENT OF PRESBYOPA (2), (4) Date: Aug. 10, 2009 (30) Foreign Application Priority Data (76) Inventor: Jorge Luis Benozzi, Buenos Aires (AR) Dec. 18, 2006 (EP) .................................. O6026169.0 Publication Classification Correspondence Address: (51) Int. Cl. YOUNG & THOMPSON A6II 3/478 (2006.01) 209 Madison Street, Suite 500 A6IP27/02 (2006.01) Alexandria, VA 22314 (US) (52) U.S. Cl. ........................................................ 514/397 (57) ABSTRACT (21) Appl. No.: 12/519,910 Ophthalmic compositions for the treatment of presbyopia, including combinations of parasympathomimetics and non (22) PCT Filed: Dec. 6, 2007 steroidal anti-inflammatories. US 2010/001 6395 A1 Jan. 21, 2010 OPHTHALMC COMPOSITIONS OF 0013 The parasympathomimetics present in the combina PARASYMPATHETIC STIMULANTS AND tions of the invention act on the contraction/relaxation ANTI-NFLAMMATORIES FOR USE IN THE strength of the ciliary muscle thus keeping accommodation TREATMENT OF PRESBYOPA levels stable, while NSAIDs preserve such action in time, preventing those physiological degenerations typically occurring in time with presbyopic Subjects. The combinations 0001. The present invention relates to ophthalmic compo of the invention prevent any histological and physical alter sitions comprising parasympathetic stimulants and non-ste ations (fibrosis and rigidity) in the ciliary muscle-Zonula roidal anti-inflammatories for use in the treatment of pres complex. byopia. 0014. The present invention provides successful, stable results in emmetropic and hypermetropic patients for at least PRIOR ART five years; on the other hand, the invention is unsuccessful when shape modification of the lens is prevented by its rigid 0002 Presbiopia, a defect in accommodation, has tradi ity. tionally been treated with the use of corrective lens. 00.15 More particularly, the present invention relates to 0003. In recent years, surgery methods such as scleral ophthalmic compositions of pilocarpine and a NSAID for use expansion band, anterior ciliary Sclerotomy, multifocal in the treatment of presbyopia. intraocular lenses or laser ablation of sclera retrolimbare 0016. According to a preferred aspect of the invention, (U.S. Pat. Nos. 6,263,879 and 6,258,082) have been sug pilocarpine is in form of its hydrochloride and the NSAID is gested to correct presbyopia. All of such techniques are, how diclofenac sodium. ever, controversial, as they do not solve the mechanical prob 0017. The compositions of the invention will contain the lem of accommodation (Mathews S., Scleral Expansion parasympathomimetic agent in amounts ranging from 0.5% Surgery does not Restore Accommodation in Human Pres to 4% and the NSAID in amounts ranging from 0.01 mg. to byopia. Ophthalmology 1999; 106: 873-877). 0.1 mg. 0004 Publications concerning the treatment of presbyo 0018. According to a preferred aspect of the invention, the pia do not take into account Such mechanism and aim at a compositions will contain pilocarpine hydrochloride in con Surgical correction of near vision. centrations ranging from 1% to 2% and diclofenac sodium in 0005 Lin-Kadambi Suggest sympathetic and parasympa amounts ranging from 0.1% to 0.5%. thetic stimulation with adrenergic and cholinergic drugs to (0019. The ophthalmic compositions will be suitably for pharmacologically assist stabilization of the Surgical results. mulated for the topical administration, according to well Pharmacological treatment to treat accommodation in man known procedure and techniques, such as those described in has been reported in previous articles. “Remington's Pharmaceutical Handbook’. 18th edition 0006. According to Rosenfield, treatment with an alpha (June 1995), Mack Publishing Co., N.Y., USA, using conven adrenergic antagonist induced an increase in accommodative tional additives well known in the pharmaceutical technique. amplitude of 1.5D. Said action, however, only lasts two hours Example of said additives are isotonic agents, such as propy (Rosenfield M. The influence of Alpha-adrenergic-agents on lene glycol, Sodium chloride, potassium chloride, glycerine, tonic accommodation. Current Eye Research, Vol. 9, 3, 1990, Sorbitol, mannitol, and the like; buffers, such as boric, phos pp. 267-272). phoric, acetic, carbonic, citric acids, and the like; stabilizers, 0007 According to Nyberg, van Alphen et al., therapy Such as ethylenediaminetetraacetic acids, Sodium hydrogen with alpha-adrenergic-agents was not satisfactory in presby Sulphite, and the like; pH agents, such as citric, phosphoric, opic patients. hydrochloric, acetic acids, sodium or potassium hydroxide, 0008 Nolan (U.S. Pat. No. 6,273,092) reports that topical sodium carbonate or bicarbonate, and the like; solubilizers, application of acetylcholine and physostygmine to presby Such as polysorbate, polyethylene glycol, propylene glycol, opic patient gives poor results and does not solve blurred macrogol 4000, and the like; thickening and dispersing distant vision. agents, such as cellulose derivatives, sodium alginate, poly vinyl alcohol, carboxyvinylpolymer, polyvinyl pyrrolidone, DISCLOSURE OF THE INVENTION and the like. 0020. The results of the pharmacological experimentation 0009. The present invention relates to the pharmacological with the compositions of the invention are reported the fol treatment of presbyopia, without Surgical intervention. lowing. 0010. It has in fact been found that alterations of visual 0021 Materials and Methods accommodation can be treated by stimulating the sympa 0022 100 Presbiopic patients of both sexes, of age 40 to thetic innervation which induces accommodation for near 65, were treated with the compositions of the invention. vision by use of parasympathomimetics and that said results Exclusion criteria concerned patients with myopia or astig can be maintained in time by treatment with non-steroidal matism higher than 1 dioptre, and hypermetropia greater than anti-inflammatories (NSAIDs). 3 dioptres as well as those with corneal, lens and vitreous 0011. According to the invention, non-steroidal anti-in opacitis, and chronic general pathologies. flammatories can be selected from the group consisting of diclofenac, ketorolac, bromfenac, flurbiprofen, Suprofen, 0023) 4 Different groups of presbyopic population were pranoprofen, oxyphenbutaZone, bendaZac, indomethacin. differentiated: 0012. Therefore, the present invention relates to ophtalmic 0024 Group 1: Pure presbyopics compositions comprising combinations of parasympathomi 0025 Group 2: Presbyopics with hypermetropia metics and non-steroidal anti-inflammatories for the treat 0026 Group 3: Presbyopics with phorias ment of presbyopia. 0027 Group 4: Presbyopics with glaucoma US 2010/001 6395 A1 Jan. 21, 2010 0028 Patients of all groups were treated with eye drops of 0049) 10 patients have been under treatment for 6 years different concentrations and combinations of medicaments 0050 20 patients have been under treatment for 5 years acting on the ocular sympathetic innervation. 0051 30 patients have been under treatment for 4 years 0029 Pure presbyopic patients (Group 1) were topically 0.052 40 patients have been under treatment for 3 years treated with 1% pilocarpine hydrochloride--0.5% diclofenac 0053 80 patients have been under treatment for 2 years Sodium, at 6hr intervals during the daily hours; treatment was 0054 96 patients have been under treatment for 1 year. Suspended at night. 0055 Results 0056 Group 1: 100% of patients experienced correction 0030 Presbyopics with hypermetropia (Group 2) were of presbyopia. topically treated with 2% pilocarpine hydrochloride+0.5% 0057 Group 2: 48% of patients abandoned the use of diclofenac sodium, at 6 hr intervals during the daily hours. eyeglasses, 44% only use eyeglasses for near vision with 2 to 0031 Presbyopic patients with phorias (Group 3) were 3 dioptres less than those required before treatment, accord topically treated with 1% pilocarpine hydrochloride at 6 hr ing to their original hypermetropy, and 8% of patients aban intervals during the daily hours, together with an orthoptic doned treatment. treatment directed to stimulate fusion and accommodation 0.058 Group 3: 89.47% of patients abandoned eyeglasses convergence. This orthoptic treatment was performed by and have good near vision, 10.53% did not experience training the patient in the use of an exercising Software, which improvements in their near vision. then the patient used without the need of professional help. 0059 Group 4: 100% of patients had good near vision 3-Minute sessions were carried out daily for a period of 15 without glasses and maintained their ocular hypertension days and were repeated yearly. under control. 0032 Presbyopics patients with glaucoma (Group 4), 0060 Patients who discontinued the treatment experi were topically treated with 2% pilocarpine hydrochloride+0. enced regression of visual sharpness to that before treatment. 5% diclofenac sodium at 6hr intervals during the 24 hours i.e. No worsening of presbyopia was observed, conversely in including nighttime. Regular hypotensive medication used by Some patients accommodation was better than before starting the patients was maintained. treatment. 0033 All patients were monitored after one week treat 1. Ophthalmic compositions