[001] The present invention relates to an ophthalmic composition comprising tropicamide, at least one cyclodextrin at concentrations of less than 2.5%, at least one surfactant at concentrations of less than 2.5%. Said composition is physically stable at neutral pH.

Background art

[002] Tropicamide is a synthesis molecule with mydriatic and cycloplegic action used in ophthalmic formulations at concentrations typically from 0.5% to 1%. The main application is for diagnostic purposes, for the inspection of the fundus and other ocular structures. Therapeutic indications have been reported for cases of con unctivitis, keratitis, iritis, iridocyclitis and uveitis .

[003] Tropicamide (formula I)

Formula (I) is a weak base and the water solubility thereof is rather low and may decrease further in the presence of excipients such as buffers, osmotizing agents, preservatives, generally present in a formulation (Saettone et al . , Int J Pharm 1988, 43; 67-76) .

The water-solubility of Tropicamide increases as pH decreases. 1% tropicamide solutions need a pH of about 5.

[004] The physiological pH of the tear is variable in the range from 6.5 to 7.6, with an average value of 7.0 ± 0.20 (Abelson MB, Arch Ophthalmol 1981, 99; 301) . The administration of eye drops with a pH outside this range are poorly tolerated by the human eye, which reacts by inducing lacrimation to restore physiological pH. Induced lacrimation has, as an inevitable consequence, the lowering of the bioavailability of the active ingredient (Lee VHL et al . , J Ocular Pharmacol 1986, 2; 67-108) .

[005] The currently available Tropicamide eye drops are formulated at acidic pHs from 4.0 to 5.8 (Lik Thai Lim et al., Int J Ophtalmol 2014, 7; 1067-1068) and should be administered in repeated doses, in some cases even 3- 4 times at a distance of 5' . Such a type of administration causes a prolonged discomfort to the patient, since the eye irritated by acidic solutions takes from 20 to 40 minutes to restore its physiological pH (William H et al . , British J Ophthalmol, 1984, 68; 549-552) . [006] Cappello et al . (Int J Pharmaceutics 2001, 213; 75-81) describe the obtainment of a physically stable 1% Tropicamide solution at pH 7.4 in 0.02 M phosphate buffer: The physical stability is obtained by adding 4% hydroxypropyl^-cyclodextrin (ΗΡ-β-CD) . Although the concentration of ΗΡ-β-CD is not high, valid reasons including cost, toxicity and even bioavailability induce the same authors to reduce the ΗΡ-β-CD content. Cappello et al . report, in fact, that the concentration of ΗΡ-β- CD can be reduced from 4% to 0.9% with the association with 0.1% hydroxypropyl methylcellulose, heating the formulation in autoclave at 120°C for 20 minutes, and then stirring the solution for 6 days at room temperature. It is apparent that the procedure, especially for the high temperatures required and the timing, is not industrially scalable.

[007] Carmignani C et al . (Drug Development Industrial Pharmacy 2002, 28; 101-105, 2002) obtain a 1% TRP solution with surfactants. Four 1% TRP solutions are described, containing tyloxapol (TY) , pluronic P85 (PL) , Cremophor (CR) and associations of CR and PL, respectively. Of these 4 solutions, only the first 2 are formulated at neutral pH (7.0-7.2), while for the other two the pH does not exceed pH 6.2, therefore below the tolerability limit of the eye. With regard to surfactants, for TY there is a considerable in vitro toxicity on RAW 264.7 cells (murine macrophage-like ) and on NIH/3T3 cells (murine fibroblasts) . In general, TY toxicity is reduced by associating it with dipalmitoylphosphatidylcholine, which limits the interaction of TY with the cell membrane (Jung-Hua Steven Kuo Pharm Res 2006, 23) . For PL, polymeric surfactants consisting of polyoxyethylene/polyoxypropylene co-polymer blocks, in varying proportions and of different molecular weight, the ophthalmological use is wide. 5,252,246 describes a relatively safe use of pluronic 85 up to 10%. In Carmignani et al . , pluronic P85 is instead used at concentrations higher than 15%, which concentration is above the safety limits. Such a high percentage, 15% PL, required to solubilize 1% TRP at pH 7.2, is therefore poorly tolerated even at neutral pH.

[008] The need to have an aqueous formulation based on Tropicamide with a neutral pH, well tolerated by the eye so as to obtain a longer pre-corneal residence time and therefore a greater bioavailability of the drug compared to that observed with the currently available compositions, is therefore strongly felt.

Description of the invention

[009] The present invention relates to a neutral pH composition comprising TRP from 0.1% to 1.2%, preferably from 0.2 to 1%, even more preferably from 0.4 to 0.8%, at least one cyclodextrin at concentrations lower than 2.5%, and at least one surfactant, at concentrations lower than 2.5%.

[0010] Said composition, formulated as described in the present invention, proved to be well tolerated when administered to the eye, as well as being physically stable for 24 months.

[0011] The following examples demonstrate how the two excipients cyclodextrin and surfactant, used in combination, surprisingly show a synergistic solubilizing effect such as to allow the reduction of the concentration of the volumes required when they are used individually. This means that the total content given by the sum of cyclodextrin and surfactant, required to keep tropicamide in solution at neutral pH, is lower than the required content of cyclodextrin or surfactant used individually.

[0012] The advantageous effects observed with the formulation according to the present invention are achieved by the synergy between cyclodextrin and a surfactant, where said surfactant consists of a compound other than a cyclodextrin.

[0013] The composition according to the present invention is formulated at room temperature, without requiring long times for the dissolution of tropicamide.

[0014] Said cyclodextrins are preferably γ- or β- cyclodextrins , even more preferably ΗΡ-β-CD. The concentration of ΗΡ-β-CD is from 0.5 to 2.5%, preferably from 0.8 to 2.0%.

[0015] Said surfactants are selected from the group comprising quaternary ammonium salts, hydrophilic non- ionic surfactants such as polyethylene glycol (15)- hydroxystearate (Solutol HS 15 SOL) , polyethylene glycol (40) . Preferably, said surfactant is polyethylene glycol ( 15) -hydroxystearate and is at a concentration ranging from 0.5 to 2.5%, preferably from 0.8 to 2.0%.

[0016] In order to obtain the neutral pH, the composition comprises a phosphate, citrate or borate buffer in a pH range from 6.5 to 7.4 and preferably from pH 6.8 to 7.2. For pH correction, strong acidic solutions or strong bases may be used.

[0017] Said composition, in one embodiment, comprises osmotizing agents preferably selected from the group comprising glycerol, sorbitol, mannitol, trehalose and sodium chloride.

[0018] Said composition, in one embodiment, also comprises viscous polymers preferably selected from the group comprising Carbopol, polyvinyl alcohol, hydroxypropyl cellulose, HP-Guar, dextran and hyaluronic acid, preferably sodium hyaluronate (HA) at concentrations from 0.01 % to 0.25%, or from 0.08 to 0.2%. [0019] Said composition, in one embodiment, also comprises preservatives, preferably selected from the group comprising ethylenediaminetetraacetic acid (EDTA) , benzalkonium chloride or polyhexanide (PHMB) .

[0020] The composition according to the present invention is exemplified in the following examples.

[0021] Examples 1-3: Formulations of TRP + ΗΡ-β-CD + SOL at different TRP concentration

[0022] Examples 4-6: 1% TRP formulations comprising Me-β- CD, Sb-p-CD or γ-CD

Ingredients Example 4 %w/w Example 5 %w/w Example 6 %w/w

TRP 1.0 1.0 1.0

Methyl-β- cyclodextrin 1.5

( e-p-CD)

Sulphobutylether- cyclodextrin (Sb- 2.0

β-CD)

γ-Cyclodextrin 2.5

SOL 2.5 2.5 2.5

Sodium phosphate

dibasic 0.2 0.2 0.2 dodecahydrate

Sodium phosphate

0, 065 0, 065 0, 065 monobasic bihydrate

Glycerol 0.9 0.9 0.9

Mannitol 2.0 2.0 2.0

Sodium

0.15 0.15 0.15 Hyaluronate

EDTA-Na ₂ *2H ₂ 0 0.025 0.025 0.025

PHMB 0.001 0.001 0.001

Purified water up to 100 g up to 100 g up to 100 g

[0023] Examples 7-9: 1% TRP formulations comprising

Cremophor, Tween 80, Pluronic

[0024] Examples 10-14: 1% TRP formulations comprising thickening agents

Example Example Example Example Example

Ingredients 10 11 12 13 14

%w/w %w/w %w/w %w/w %w/w

TRP 1.0 1.0 1.0 1.0 1.0

ΗΡ-β-CD 2.0 2.0 2.0 2.0 2.0

SOL 2.5 2.5 2.5 2.5 2.5

Sodium

phosphate

0.2 0.2 0.2 0.2 0.2 dibasic

dodecahydrate

Sodium

phosphate

0, 065 0, 065 0, 065 0, 065 0, 065 monobasic

bihydrate

Glycerol 0.9 0.9 0.9 0.9 0.9 Mannitol 2.0 2.0 2.0 2.0 2.0

Hydroxypropyl

0.4

methyl cellulose

Carbopol 0.2

Polyvinyl

0.5

alcohol

HP-Guar 1.0

Dextran 5.0

EDTA-Na ₂ *2H ₂ 0 0.025 0.025 0.025 0.025 0.025

PHMB 0.001 0.001 0.001 0.001 0.001 up to 100 up to up to ip to 100 up to 100

Purified water

g 100 g 100 g g g

[0025] Examples 15-19 (comparative) : formulations similar the formulations of Examples 10-14 but which DO NOT comprise cyclodextrins

[0026] Examples 20-22 (comparative) : formulations similar the formulations of Examples 7-9 but which DO NOT comprise a surfactant

Ingredients Example 20 %w/w Example 21 %w/w Example 22 %w/w

TRP 1.0 1.0 1.0

ΗΡ-β-CD 2.0 2.0 2.5 Sodium

phosphate

0.2 0.2 0.2 dibasic

dodecahydrate

Sodium

phosphate

0, 065 0, 065 0, 065 monobasic

bihydrate

Glycerol 0.9 0.9 0.9

Mannitol 2.0 2.0 2.0

Sodium

0.15 0.15 0.15 Hyaluronate

EDTA-Na ₂ *2H ₂ 0 0.025 0.025 0.025

PHMB 0.001 0.001 0.001

Puri fied

up to 100 g up to 100 g up to 100 g water

[0027] Examples 23-24 (comparative) : formulations similar the formulations of Examples 1-2 but which DO NOT comprise a surfactant

[0028] Below are given the stability studies related to the formulations of Examples 1 to 24.

[0029] It should be noted that, as for the comparative Examples 15 to 24, the same studies could not be conducted because the TRP in said formulations did not go into solution when operating at 25°C or, within one month from preparation, the formation of a precipitate occurred . [0030] Conversely, for the formulations comprising the components according to the present invention, the following data were obtained.

[0031] Stability of the formulations of Examples 1-5 at a temperature of 25 ± 2°C.

[0032] Stability of the formulations of Examples 6- -10 at a temperature of 25 ± 2°C.

PH 6.9 7.1 7.0 6.9 7.0 mOsm/kg 298 302 300 294 295

% TRP 0.9 1.0 0.9 1.0 1.0

24 PH 6.8 6.9 6.9 6.9 6.9 mOsm/kg 301 303 302 298 301 33] The compositions of Examples 11-14 comprise TRP, ΗΡ-β-CD and Solutol at the same concentrations included in the composition according to Example 2 and Example 10, the difference being the presence of thickening agents. The stability data obtained are superimposable with the data obtained in the absence of thickening agents, confirming that the stabilization effect is obtained due to the synergistic effect of cyclodextrins and surfactant and it is not affected by the addition of thickening agents.