(19) &  

(11) EP 1 938 839 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 45/06 (2006.01) A61K 31/4178 (2006.01) 19.08.2009 Bulletin 2009/34 A61P 27/10 (2006.01)

(21) Application number: 06026169.0

(22) Date of filing: 18.12.2006

(54) Ophthalmic compositions of parasympathetic stimulants and anti-inflammatories for use in the treatment of presbyopia Ophthalmische Zusammensetzungen von parasympathischen Stimulantia und Entzündungshemmer zur Verwendung bei der Behandlung von Presbyopie Compositions ophtalmiques de stimulants parasympathiques et anti-inflammatoires pour le traitement de la presbytie

(84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-00/06135 US-A- 5 488 050 HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI US-B1- 6 273 092 SK TR • DATABASE BIOSIS [Online] BIOSCIENCES (43) Date of publication of application: INFORMATION SERVICE, PHILADELPHIA, PA, 02.07.2008 Bulletin 2008/27 US; 2002, OSTRIN L A ET AL: "Pilocarpine Stimulated Accommodation in Humans." (73) Proprietor: Benozzi, Jorge Luis XP002433091 Database accession no. Buenos Aires (AR) PREV200300154537 & ARVO ANNUAL MEETING ABSTRACT SEARCH AND PROGRAM PLANNER, (72) Inventor: Benozzi, Jorge Luis vol. 2002, 2002, page Abstract No. 2317, ANNUAL Buenos Aires (AR) MEETING OF THE ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY; (74) Representative: Minoja, Fabrizio FORT LAUDERDALE, FLORIDA, USA; MAY 05-10, Bianchetti Bracco Minoja S.r.l. 2002 Via Plinio, 63 20129 Milano (IT)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 938 839 B1

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Description domethacin. [0012] Therefore, the present invention relates to [0001] The present invention relates to ophthalmic ophtalmic compositions comprising combinations of par- compositions comprising parasympathetic stimulants asympathomimetics and non-steroidal anti-inflammato- and non-steroidal anti-inflammatories for use in the treat- 5 ries for the treatment of presbyopia. ment of presbyopia, [0013] The parasympathomimetics present in the combinations of the invention act on the contraction/re- PRIOR ART laxation strength of the ciliary muscle thus keeping ac- commodation levels stable, while NSAIDs preserve such [0002] Presbyopia, a defect in accomodation, has tra- 10 action in time, preventing those physiological degenera- ditionally been treated with the use of corrective lens. tions typically occurring in time with presbyopic subjects. [0003] In recent years, surgery methods such as scle- The combinations of the invention prevent any histolog- ral expansion band, anterior ciliary sclerotomy, mulfiifo- ical and physical alterations (fibrosis and rigidity) in the cal intraocular lenses or laser ablation of sclera retrolim- ciliary muscle-zonula complex. bare (U.S. Pat. Nos. 6263879 and 6258082) have been 15 [0014] The present invention provides successful, sta- suggested to correct presbyopia. All of such techniques ble results in emmetropic and hypermetropic patients for are, however, controversial, as they do not solve the me- at least five years; on the other hand, the invention is chanical problem of accommodation (Mathews S., Scle- unsuccessful when shape modification of the lens is pre- ral Expansion Surgery does not Restore Accommodation vented by its rigidity. in Human Presbyopia. Ophthalmology 1999; 106: 20 [0015] More particularly, the present invention relates 873-877). to ophthalmic compositions of pilocarpine and a NSAID [0004] Publications concerning the treatment of pres- for use in the treatment of presbyopia. byopia do not take into account such mechanism and [0016] According to a preferred aspect of the invention, aim at a surgical correction of near vision. pilocarpine is in form of its hydrochloride and the NSAID [0005] Lin-Kadambi suggest sympathetic and para- 25 is diclofenac sodium. sympathetic stimulation with adrenergic and cholinergic [0017] The compositions of the invention will contain drugs to pharmacologically assist stabilization of the sur- the parasympathomimetic agent in amounts ranging gical results. Pharmacological treatment to treat accom- from 0.5% to 4% and the NSAID in amounts ranging from modation in man has been reported in previous articles. 0.01 mg. to 0.1 mg. [0006] According to Rosenfield, treatment with an al- 30 [0018] According to a preferred aspect of the invention, pha-adrenergic antagonist induced an increase in ac- the compositions will contain pilocarpine hydrochloride commodative amplitude of 1.5 D. Said action, however, in concentrations ranging from 1% to 2% and diclofenac only lasts two hours (Rosenfield M. The influence of Al- sodium in amounts ranging from 0.1% to 0.5%. pha-adrenergic-agents on tonic accommodation. Cur- [0019] The ophthalmic compositions will be suitably rent Eye Research, vol. 9, 3, 1990, pp. 267-272). 35 formulated for the topical administration, according to [0007] According to Nyberg, van Alphen et al., therapy well known procedure and techniques, such as those de- with alpha-adrenergic-agents was not satisfactory in scribed in "Remington’s Pharmaceutical Handbook", presbyopic patients. 18th edition (June 1995), Mack Publishing Co., N.Y., [0008] Nolan (U.S. Pat. No. 6,273,092) reports that USA, using conventional additives well known in the topical application of acetylcholine and physostygmine 40 pharmaceutical technique. Example of said additives are to presbyopic patient gives poor results and does not isotonic agents, such as propylene glycol, sodium chlo- solve blurred distant vision. ride, potassium chloride, glycerine, sorbitol, mannitol, and the like; buffers, such as boric, phosphoric, acetic, DISCLOSURE OF THE INVENTION carbonic, citric acids, and the like; stabilizers, such as 45 ethylenediaminetetraacetic acids, sodium hydrogen sul- [0009] The present invention relates to the pharmaco- phite, and the like; pH agents, such as citric, phosphoric, logical treatment of presbyopia, without surgical interven- hydrochloric, acetic acids, sodium or potassium hydrox- tion. ide, sodium carbonate or bicarbonate, and the like; sol- [0010] It has in fact been found that alterations of visual ubilizers, such as polysorbate, polyethylene glycol, pro- accommodation can be treated by stimulating the sym- 50 pylene glycol, macrogol 4000, and the like; thickening pathetic innervation which induces accommodation for and dispersing agents, such as cellulose derivatives, so- near vision by use of parasympathomimetics and that dium alginate, polyvinyl alcohol, carboxyvinylpolymer, said results can be maintained in time by treatment with polyvinyl pyrrolidone, and the like. non-steroidal anti-inflammatories (NSAIDs). [0020] The results of the pharmacological experimen- [0011] According to the invention, non-steroidal anti- 55 tation with the compositions of the invention are reported inflammatories can be selected from the group consisting the following. of diclofenac, ketorolac, bromfenac, flurbiprofen, supro- fen, pranoprofen, oxyphenbutazone, bendazac, in-

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Materials and Methods plasty was carried out by shooting in 360° spots in the iris constrictor muscle. The laser intensity and [0021] 100 Presbiopic patients of both sexes, of age the size of the spot, were adapted to the intensity of 40 to 65, were treated with the compositions of the in- iris pigmentation. vention. Exclusion criteria concerned patients with myo- 5 • Topical treatment was modified in case of conjunc- pia or astigmatism higher than 1 dioptre, and hyper- tiva inflammation. metropia greater than 3 dioptres as well as those with • When ocular tension was not ideal, hypotensive corneal, lens and vitreous opacitis, and chronic general medication was modified prior to presbyopia treat- pathologies. ment. [0022] 4 Different groups of presbyopic population 10 • Orthoptic treatment was corrected in case of patient were differentiated: astenopia. • Treatment was suspended in case of intolerance to Group 1: Pure presbyopics medication. Group 2: Presbyopics with hypermetropia Group 3: Presbyopics with phorias 15 RESULTS AND CONCLUSIONS Group 4: Presbyopics with glaucoma [0030] [0023] Patients of all groups were treated with eye drops of different concentrations and combinations of 100 Patients were treated: 2 patients showed intol- medicaments acting on the ocular sympathetic innerva- 20 erance to pilocarpine hydrochloride (diarrhoea and tion. dyspepsia), 2 patients (presbyopics with hyper- [0024] Pure presbyopic patients (Group 1) were topi- metropia) did not obtain the desired improvement in cally treated with 1% pilocarpine hydrochloride + 0.5% visual sharpness. diclofenac sodium, at 6 hr intervals during the daily hours; 10 patients have been under treatment for 6 years treatment was suspended at night. 25 20 patients have been under treatment for 5 years [0025] Presbyopics with hypermetropia (Group 2) 30 patients have been under treatment for 4 years were topically treated with 2% pilocarpine hydrochloride 40 patients have been under treatment for 3 years + 0.5% diclofenac sodium, at 6 hr intervals during the 80 patients have been under treatment for 2 years daily hours. 96 patients have been under treatment for 1 year. [0026] Presbyopic patients with phorias (Group 3) 30 were topically treated with 1% pilocarpine hydrochloride Results at 6 hr intervals during the daily hours, together with an orthoptic treatment directed to stimulate fusion and ac- [0031] commodation convergence. This orthoptic treatment was performed by trainig the patient in the use of an exercising 35 Group 1: 100% of patients experienced correction software, which then the patient used without the need of presbyopia. of professional help. 3-Minute sessions were carried out Group 2: 48% of patients abandoned the use of eye- daily for a period of 15 days and were repeated yearly. glasses, 44% only use eyeglasses for near vision [0027] Presbyopics patients with glaucoma (Group 4), with 2 to 3 dioptres less than those required before were topically treated with 2% pilocarpine hydrochloride 40 treatment, according to their original hypermetropy, + 0.5% diclofenac sodium at 6 hr intervals during the 24 and 8% of patients abandoned treatment. hours i.e. including nighttime. Regular hypotensive med- Group 3: 89.47% of patients abandoned eyeglasses ication used by the patients was maintained. and have good near vision, 10.53% did not experi- [0028] All patients were monitored after one week ence improvements in their near vision. treatment and monthly during the first three months to 45 Group 4: 100% of patients had good near vision evaluate dosage and side-effects. without glasses and maintained their ocular hyper- [0029] Controls included: tension under control.

Near and distant visual sharpness [0032] Patients who discontinued the treatment expe- Myosis 50 rienced regression of visual sharpness to that before Conjunctiva treatment. No worsening of presbyopia was observed, Ocular tension conversely in some patients accommodation was better Astenopia than before starting treatment. Tolerance 55 • When visual sharpness was not desired, dosages Claims were changed and accommodation was checked. • When myosis was not tolerated, argon laser irido- 1. Ophthalmic compositions for the treatment of pres-

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byopia, comprising combinations of parasympatho- das nicht-steroidale, antiflammatorische Mittel Dicl- mimeties and non-steroidal anti-inflammatories. ofenak oder seine Salze ist.

2. Compositions as claimed in claim 1, wherein the par- 5. Zusammensetzungen gemäß den Ansprüchen 1 bis asympathomimetic agent is pilocarpine or its salts. 5 3, enthaltend Pilocarpinhydrochlorid in Konzentra- tionen, im Bereich von 1 bis 2% und Diclofenak Na- 3. Compositions as claimed in claim 1, wherein the non- trium in Mengen, im Bereich von 0, 1 % bis 0,5%. steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, ketorolac, brom- 6. Kombinierte Verwendung von Parasympathomime- fenac, flurbiprofen, suprofen, pranoprofen, oxy- 10 tika und nicht-steroidalen antientzündungshemmen- phenbutazone, bendazac, indomethacin. den Mitteln zur Herstellung eines Medikaments für die Behandlung von Presbyopie. 4. Compositions as claimed in claim 3, wherein the non- steroidal anti-inflammatory agent is diclofenac or its 7. Verwendung gemäß Anspruch 6, wobei das para- salts. 15 sympathometische Mittel Pilocarpin oder seine Sal- ze ist. 5. Compositions as claimed in claims 1 - 3, containing pilocarpine hydrochloride in concentrations ranging 8. Verwendung gemäß Anspruch 6, wobei das nicht- from 1% to 2% and diclofenac sodium in amounts steroidale antientzündungshemmende Mittel ausge- ranging from 0.1 % to 0.5%. 20 wählt ist aus der Gruppe, bestehend aus Diclofenak, Ketorolak, Bromfenak, Flurbiprofen, Suprofen, Pra- 6. The combined use of parasympathomimetics and noprofen, Oxyphenbutazon, Bendazak, Indometha- non-steroidal anti-inflammatories for the preparation zin. of a medicament for the treatment of presbyopia. 25 9. Verwendung gemäß Anspruch 7, wobei das nicht- 7. The use as claimed in claim 6, wherein the parasym- steroidale antientzündungshemmende Mittel Dicl- pathomimetic agent is pilocarpine or its salts. ofenak oder seine Salze ist.

8. The use as claimed in claim 6, wherein the non-ster- oidal anti-inflammatory agent is selected from the 30 Revendications group consisting of diclofenac, ketorolac, brom- fenac, flurbiprofen, suprofen, pranoprofen, oxy- 1. Compositions ophtalmiques pour le traitement de la phenbutazone, bendazac, indomethacin. presbytie, comprenant des combinaisons de para- sympathomimétiques et d’anti-inflammatoires non 9. The use as claimed in claim 8, wherein the non-ster- 35 stéroïdiens. oidal anti-inflammatory agent is diclofenac or its salts. 2. Compositions selon la revendication 1, dans lesquel- les l’agent parasympathomimétique est la pilocarpi- ne ou ses sels. Patentansprüche 40 3. Compositions selon la revendication 1, dans lesquel- 1. Ophthalmische Zusammensetzungen zur Behand- les l’agent anti-inflammatoire non stéroïdien est lung von Presbyopie, umfassend Kombinationen choisi dans le groupe constitué du diclofénac, du ké- von Parasympathomethika und nicht-steroidalen torolac, du bromfénac, du flurbiprofène, du suprofè- antientzündungshemmenden Mitteln. 45 ne, du pranoprofène, de l’oxyphenbutazone, du ben- dazac, de l’indométhacine. 2. Zusammensetzungen gemäß Anspruch 1, wobei das parasympathometische Mittel Pilocarpin oder 4. Compositions selon la revendication 3, dans lesquel- seine Salze ist. les l’agent anti-inflammatoire non stéroïdien est le 50 diclofénac ou ses sels. 3. Zusammensetzungen gemäß Anspruch 1, wobei das nicht-steroidale antientzündungshemmende 5. Compositions selon les revendications 1 à 3, conte- Mittel ausgewählt ist aus der Gruppe, bestehend aus nant du chlorhydrate de pilocarpine dans des con- Diclofenak, Ketorolak, Bromfenak, Flurbiprofen, Su- centrations allant de 1 % à 2 % et du diclofénac so- profen, Pranoprofen, Oxyphenbutazon, Bendazak, 55 dique dans des quantités allant de 0,1 % à 0,5 %. Indomethazin. 6. Utilisation combinée de parasympathomimétiques 4. Zusammensetzungen gemäß Anspruch 3, wobei et d’anti-inflammatoires non stéroïdiens pour la pré-

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paration d’un médicament destiné au traitement de la presbytie.

7. Utilisation selon la revendication 6, dans laquelle l’agent parasympathomimétique est la pilocarpine 5 ou ses sels.

8. Utilisation selon la revendication 6, dans laquelle l’agent anti-inflammatoire non stéroïdien est choisi dans le groupe constitué du diclofénac, du kétorolac, 10 du bromfénac, du flurbiprofène, du suprofène, du pranoprofène, de l’oxyphenbutazone, du bendazac, de l’indométhacine.

9. Utilisation selon la revendication 8, dans laquelle 15 l’agent anti-inflammatoire non stéroïdien est le diclo- fénac ou ses sels.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 6263879 B [0003] • US 6273092 B [0008] • US 6258082 B [0003]

Non-patent literature cited in the description

•MATHEWS S. Scleral Expansion Surgery does not • ROSENFIELD M. The influence of Alpha-adrener- Restore Accommodation in Human Presbyopia. gic-agents on tonic accommodation. Current Eye Re- Ophthalmology, 1999, vol. 106, 873-877 [0003] search, 1990, vol. 9 (3), 267-272 [0006] • Remington’s Pharmaceutical Handbook. Mack Pub- lishing Co, June 1995 [0019]

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