Ophthalmic pharmaceutical composition

Abstract

Ophthalmic pharmaceutical compositions consisting of cyclopentolate and tropicamide in a weight ratio of 1:2 to 2:1, preferably equal to 1:1, wherein both cyclopentolate and tropicamide are present in a concentration ranging from 0.5% to 1.0% weight / volume, and pharmacologically-acceptable excipients, free of preservative agents and their use, are described.

Description

[0001] “OPHTHALMIC PHARMACEUTICAL COMPOSITION”

[0002] ****

[0003] OBJECT OF THE INVENTION

[0004] The present invention relates to an ophthalmic pharmaceutical composition and its relative use.

[0005] In particular, the present invention relates to an ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide in a weight ratio ranging from 1:2 to 2: 1, preferably equal to 1: 1, wherein both cyclopentolate and tropicamide are present in a concentration ranging from 0.5% to 1.0% weight / volume, and pharmaceutically-acceptable excipients, and its relative use. FIELD OF THE INVENTION

[0006] The assessment of refractive errors, especially in pediatric populations, is usually influenced by the accommodative spasm of the ciliary muscles that allow a variation in the shape of the crystalline lens for focusing objects. An effective way for reducing accommodation fluctuation is to induce cycloplegic refraction in which the ophthalmologist evaluates the cycloplegic refractive error of the crystalline lens, using appropriate cycloplegic and / or mydriatic drugs such as cyclopentolate and tropicamide, well-known drugs used for accommodation relaxation: the cycloplegia test is therefore used for evaluating the power and refractive errors of the eye without the conditioning caused by the tone of the ciliary muscle in both the pediatric population and in adults, but cycloplegia in children is certainly more delicate than in adults.

[0007] Pediatric ophthalmological examinations have various difficulties, even the simple instillation of a few eye-drops into the conjunctival sac can in fact require some time with a non-optimal cooperation at times in younger children who, generally, cry or scream following the ocular instillation. An examination in conditions of cycloplegia / mydriasis however is essential in these patients as the action of the ciliary muscle, more tenacious at this age, can mask refractive defects leading to a non-optimal correction of the hyperopia or myopia present in the patient.

[0008] Thanks to cycloplegic refraction, various vision defects can be diagnosed even in childhood, such as:

[0009] • Esotropia;

[0010] • Anisometropia;

[0011] • Hyperopia;

[0012] Asthenopia;

[0013] • Myopia;

[0014] • Accommodative spasm.

[0015] In children under four years of age, this test is essential as some of these pathologies, such as the so-called "lazy eye" (amblyopia), can be treated effectively only by intervening in preschool age.

[0016] Even in adults, cycloplegic refraction is used for identifying important refractive defects, and mainly:

[0017] • Myopia;

[0018] • Hyperopia;

[0019] • Presbyopia;

[0020] • Astigmatism.

[0021] Finally, the test is essential not only for those who undergo refractive surgery for verifying the correct refractive power, but also in ophthalmic surgery in general, particularly in the pre-operative phases of cataract surgery.

[0022] Cyclopentolate ((RS)-2-(di-methylamino)ethyl-(l-hydroxy-cyclopentyl)- (phenyl) acetate) is a synthetic drug for ocular, cycloplegic and mydriatic use, generally used for effecting an examination of the ocular fundus as it antagonizes the muscarinic receptors of the Ml type of acetylcholine, thus causing the pharmacological paralysis of the ciliary muscles of the eye, therefore cycloplegia, and leading to inhibition of accommodation. Its cycloplegic effects can begin 25- 75 minutes after its instillation, ocular recovery can appear after 6-24 hours but the cycloplegic effect can last up to 48 hours. Major ocular side-effects can include irritation, tearing, allergic blepharoconjunctivitis, and conjunctival hyperemia (Mustafa Duran et al.; Therapeutic Advances in Ophthalmology; 2023; 15:1-9).

[0023] Tropicamide ((RS)-N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl) propanamide) is a synthetic analogue of tropic acid, it is an anticholinergic (or parasympatholytic) capable of inhibiting the muscarinic receptors Ml, M2, M4, therefore capable of producing cycloplegia and mydriasis (dilation of the pupil following paralysis of the iris sphincter muscle located around the pupil). It is classified mainly as a mydriatic agent, used for cycloplegic refraction often in sequential administration after cyclopentolate to maximize the cycloplegic effects (Mustafa Duran et al.; Therapeutic Advances in Ophthalmology; 2023; 15:1-9).

[0024] It is in fact characterized by rapid onset in which the mydriatic effect appears 20-30 minutes after its administration, whereas ocular recovery can begin as early as 6 hours after this treatment, with a generally safer profile than cyclopentolate, especially in the pediatric population, but less effective when administered alone. For many types of eye examinations, tropicamide has almost completely replaced atropine even if the cycloplegia produced by this drug is less durable and not total, thus proving to be the drug of choice for emergency room examinations.

[0025] Cyclopentolate and tropicamide are both muscarinic receptor antagonists and for this reason the two compounds are often instilled into the conjunctiva sequentially, starting with the administration of a drop of cyclopentolate instilled one to five times, every 5-15 minutes, followed by the administration of tropicamide, instilled one to five times, every 5 minutes, as in this way the two active ingredients can act together in enhancing cycloplegia and mydriasis (especially for the pediatric population with a dark iris as it is resistant to cycloplegia): for an optimal analysis of the ocular fundus it is in fact necessary to reach maximum cycloplegia and mydriasis, which generally requires a waiting time of 30 to 60 minutes (the methods and times of administration vary with the age and pathologies of the patients, with the colour of the iris and also depend on the possible manifestation of ocular and / or systemic side-effects). It should be pointed out that each ocular administration of the drug is almost inevitably followed by a natural and spontaneous blinking of the eyelid which washes away part of the product administered, and the greater the number of instillations, the greater the quantity of active ingredient that is washed away.

[0026] The correct application of both drugs necessarily requires that the patient, or someone acting on his behalf, immediately after instillation of the drug, presses the lacrimal sac with a finger for at least 10-60 seconds in order to avoid the systemic absorption of the drug accumulated in the lacrimal sac (Information Leaflet for Ciclolux 1% cyclopentolate by Allergan SpA, and Information Leaflet for Visumidriatic 1% tropicamide, Visufarma SpA). The systemic side-effects of cyclopentolate and tropicamide are in fact potentially very dangerous, they include tachycardia and hypertension, ataxia, drowsiness, urinary retention, the onset of psychiatric disorders such as hallucinations, disorientation and confusion with incoherent speech, restlessness and convulsions; they can also include increased intracranial pressure (especially in premature babies) and, in many cases, can also induce increased intraocular pressure, IOP, in a percentage that reaches up to 2% of the population treated, but up to 23% in the case of patients treated suffering from glaucoma.

[0027] Pharmaceutical compositions containing 0.5% or 1% of cyclopentolate are known on the market, such as Ciclolux eye drops (1% cyclopentolate) by Allergan SpA, or 0.5% or 1% tropicamide, such as Tropimil eye drops (0.5% tropicamide) by Farmigea SpA, but combinations of these active ingredients with phenylephrine (al -adrenergic receptor agonist, mydriatic but not cycloplegic), generally present at 2.5%, are also known (for example Visumidriatic_Fenil eye drops containing tropicamide and phenylephrine, and the injectable drug Mydrane containing tropicamide, phenylephrine and lidocaine). Hypertension, tachycardia and decreased heart rate are possible systemic side-effects of phenylephrine, as also of cyclopentolate and tropicamide.

[0028] These compositions are used not only for vision of the ocular fundus (as described above), but also as a treatment for mild inflammation of the anterior part of the eye such as uveitis and keratitis, and finally in cataract surgery which requires a wide and stable pupillary dilation during the entire duration of the surgery, both for phacoemulsification and for implantation of the new lens. These drugs are therefore used not only for topical use, but also for intra-cameral use for better and prolonged ocular dilation during the surgical phase (Savleen Kaur et al.; Indian Journal of Ophthalmology; 2023; Jul 71(7):2656-2661).

[0029] Scientific reports also describe extemporaneous ophthalmic preparations consisting of cyclopentolate 0.5% in combination with tropicamide 0.5%, (Samuel Kyei et al.; Afri Health Sci; 2017; 17:923-932; A.R. Nishizawa et al.; Can J Ophthalmol; 1988; 23:299-300), they are not indicated however as pharmaceutical compositions, but as simple combinations of two different cycloplegic drugs both at 1% which, when combined in the same volume, therefore halve their concentration. For these combinations, no other data is known, such as, for example, stability over time, excipients and pH.

[0030] It should be pointed out that all cycloplegic / mydriatic pharmaceutical compositions generally contain preservatives, in particular benzalkonium chloride, which is considered superior to other preservatives due to its high antimicrobial capacity, especially in the case of an ophthalmic pharmaceutical composition packaged as a single resealable multidose container. It is known that this preservative can cause corneal irritation and inflammation with epithelial toxicity and increased corneal permeability, especially in patients undergoing chronic treatment in which corneal pathologies can develop, such as, for example, dry eye and corneal disorders or burning (Richard Zhang et al.; The Ocular Surface; 2020; 18: 158-169; H. Chibret; Ann Pharm Fr; 2011; 69(2): 108).

[0031] There are no known ophthalmic pharmaceutical compositions however that exclusively combine cyclopentolate and tropicamide as active ingredients, characterized by the absence of preservatives, which are toxic especially for the pediatric and elderly population. There is therefore a particularly strong need for an "ideal" cycloplegic and mydriatic ophthalmic pharmaceutical composition, i.e. a composition of active agents free of preservatives, especially free of benzalkonium chloride, but stable over time, which causes maximum cycloplegia and mydriasis in the shortest possible time, ensuring the shortest ocular recovery time and, at the same time, requires a reduced number of ocular instillations to limit the discomfort associated with the administration of the composition, especially in the pediatric and elderly population, an ophthalmic composition especially necessary for reducing / eliminating the potential toxic effects due to the systemic absorption of the active ingredients accumulated in the lacrimal sac, an accumulation that necessarily increases with an increase in the number of drops of active ingredients instilled, especially during the above-mentioned sequential administration.

[0032] The objective of the present invention is therefore to identify an ophthalmic pharmaceutical composition free of preservative agents but stable, which overcomes the drawbacks of the known art and which ensures the desired effect, with half the number of ocular instillations compared to the sequential administrations of the individual active ingredients, at the same time reducing collateral damage and thus increasing the compliance and safety of the patients. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention relates to an ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide in a weight ratio of 1:2 to 2: 1, preferably equal to 1 :1, wherein both cyclopentolate and tropicamide are present in a concentration ranging from 0.5% to 1.0% weight / volume, and pharmaceutically- acceptable excipients, free from preservative agents, in particular free from benzalkonium chloride, preferably comprising antioxidant agents.

[0034] The ophthalmic pharmaceutical composition according to the present invention is stable at 25°C for at least 6 months.

[0035] The concentration is expressed as a percentage by weight of the single component with respect to the total volume of the composition (w / v). The present invention further relates to the ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide, in the weight ratios and the relative excipients previously indicated, free from preservative agents, in particular free from benzalkonium chloride, for use in the induction of cycloplegia and mydriasis for the evaluation of the ocular fundus and refractive errors of the eye, for use in inflammations of the anterior part of the eye such as, for example, uveitis and keratitis, and for use in the induction of cycloplegia and mydriasis in ophthalmic surgery, preferably in cataract surgery.

[0036] The administration of the ophthalmic pharmaceutical composition according to the present invention allows a synergistic action in the induction of maximum cycloplegia and mydriasis as it approaches (or even overlaps) the peaks of cycloplegia and mydriasis of cyclopentolate and tropicamide with respect to their sequential instillation, thus maximizing the pharmacological effect; furthermore, the concentrations of cyclopentolate and tropicamide accumulated in the conjunctiva (with a halved number of administrations of the composition according to the present invention with respect to the sequential administrations of cyclopentolate and tropicamide) are higher than the concentrations determined by sequential instillations of cyclopentolate and tropicamide (double in number), as the washout from the conjunctiva of the composition according to the present invention is reduced, the number of administrations of the new ophthalmic pharmaceutical composition being halved.

[0037] This consequently makes it possible to use compositions with concentrations lower than 1% weight / volume (to date the most commonly used concentration in the sequential administration of cyclopentolate and tropicamide), such as for example 0.5% weight / volume, both for cyclopentolate and for tropicamide.

[0038] Furthermore, as previously explained, the ophthalmic pharmaceutical composition for use according to the present invention can be administered in half the number of instillations compared to the number of instillations of the sequential administration of cyclopentolate and tropicamide, and said number of instillations can range from 1 to 5, depending on numerous and different factors such as age, colour of the iris, presence of various types of pathologies of the patients treated, preferably for use in a pediatric and / or elderly population.

[0039] For the reasons indicated above, the advantages offered by the administration of the composition object of the invention are:

[0040] • the induction of maximum cycloplegia and mydriasis in the shortest possible time with the shortest ocular recovery time;

[0041] • a drastic reduction / halving in the number of instillations in the production of maximum cycloplegia and mydriasis, significantly reducing the discomforts associated with their administration especially in the pediatric and elderly population;

[0042] • a significant reduction in toxic effects caused by the systemic absorption of drugs accumulated in the lacrimal sac;

[0043] • the intra-cameral administration of a small quantity of a cycloplegic and mydriatic composition that determines a prolonged ocular dilation in the ophthalmic surgical phase, preferably in cataract surgery that requires a wide and stable pupillary dilation throughout the duration of the intervention, both of phacoemulsification and implantation of the new lens;

[0044] • the absence of any form of corneal toxicity as this composition is free from preservatives.

[0045] Preferred compositions according to the present invention consist of:

[0046] • cyclopentolate 0.5% w / v and tropicamide 0.5% w / v, or

[0047] • cyclopentolate 1.0% w / v and tropicamide 1.0% w / v, and pharmaceutically-acceptable excipients, free from preservatives, in particular free from benzalkonium chloride, and preferably in the presence of antioxidant agents.

[0048] Cyclopentolate contains ester bonds that are easily degradable in aqueous solutions, and this degradation causes a time / temperature-dependent decrease in its concentration in the ophthalmic composition, thus undermining the final stability of the ophthalmic pharmaceutical composition containing it.

[0049] The Applicant has perfected an ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide, stable at 25°C for at least 6 months, free from preservative agents (specifically free from benzalkonium chloride), thanks to the particular excipients preferably based on the association of the active ingredients with a buffer system consisting of a weak acid with its salt, in a pH range of 3.5 to 6, preferably 3.5-5, preferably a buffer system consisting of citric acid and sodium citrate, in the presence of salts such as preferably NaCl to maintain an ocular osmolarity value of 300 mOsmol / kg in order to avoid epithelial and corneal irritability phenomena, especially in cases of repeated treatments in the pediatric and / or elderly population, possibly in association with antioxidants that contribute to maintaining a prolonged stability at room temperature of the above- mentioned composition.

[0050] Preferably, the ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide, stable at 25°C for at least 6 months, free from preservative agents (specifically free from benzalkonium chloride), comprise as a pharmaceutically acceptable excipient a buffer system composed of citric acid and sodium citrate for a final pH value within the range of 3.5-5.5, preferably within the range of 3.5-5 or within the range of 4.4-5.5, more preferably within the range of 3.5-5.

[0051] It should be specified that an ophthalmic pharmaceutical composition stable at 25°C for at least 6 months, refers to a composition in which the concentration of the two active ingredients after 6 months at 25°C ranges from 90% to 100% of the initial concentration value, especially in relation to cyclopentolate whose concentration value of 90% -100% falls within the validity range of the active ingredient according to its monograph present in the United States Pharmacopeia (USP).

[0052] Preferred antioxidant agents are for example: sodium metabisulphite, sodium thiosulphate, mannitol, sorbitol, glutathione, trehalose, vitamin E and / or ascorbic acid, sodium metabisulphite is most preferred in a concentration ranging from 0.15 w / v to 0.25% w / v, preferably 0.2% w / v.

[0053] These antioxidant agents, and in particular sodium metabisulphite, contribute to maintaining the stability of the composition according to the present invention, for at least 6 months at 25°C even in the absence of preservative agents, as demonstrated in the following examples.

[0054] The ophthalmic pharmaceutical composition object of the present invention is an aqueous solution, sterilized as known to skilled persons in the field for aqueous ocular pharmaceutical forms, i.e. eye drops-collyrium, preferably sterilized by filtration with 0.2 pm filters, packaged as a single-use dose or multi-use dose of eye drops-collyrium, which keeps its sterility unchanged at 25 °C for at least 6 months even in the absence of preservative agents, such as in particular benzalkonium chloride.

[0055] The composition according to the present invention comprises pharmaceutically-acceptable excipients, such as a buffer system for a final pH value within the range of 3.5-6.0, wherein said buffer system is preferably composed of a weak acid and a salt thereof such as, for example, acetic acid and a salt thereof, boric acid and a salt thereof, or citric acid and a salt thereof, preferably sodium citrate for a final pH value within the range of 3.5-5.0, or is composed of the saline phosphate buffer containing sodium phosphate for a final pH value close to 6.0; the preferred buffer system is based on citric acid and sodium citrate for a final pH value within the range of 3.5 -5.0.

[0056] The compositions according to the present invention can also comprise, as pharmaceutically-acceptable excipients, chelating systems such as, for example, EDTA, as free acid or as its salt, i.e. disodium EDTA, tetrasodium EDTA, dipotassium EDTA, or calcium disodium EDTA, or EGTA, in saline solutions appropriately prepared for ensuring an ocular osmolarity value of approximately 300 mOsmol / kg in accordance with scientifically acceptable standards according to the Italian and / or European Pharmacopoeia such as, for example, the saline solution composed of NaCl and water.

[0057] The preferred ophthalmic pharmaceutical composition according to the present invention consists of cyclopentolate 0.5% w / v and tropicamide 0.5% w / v, or cyclopentolate 1.0% w / v and tropicamide 1.0% w / v, and is characterized by being free from preservative agents, in particular free from benzalkonium chloride, also containing a buffer system based on citric acid / sodium citrate for a final pH value ranging from 3.5 to 5.0, and the saline solution composed of NaCl and water for an ocular osmolarity value of 300 mOsmol / kg, with the possible presence of antioxidant agents, preferably sodium metabisulphite.

[0058] EXAMPLE 1

[0059] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients; pH 5,0

[0060] An 0.1M solution of citric acid was prepared using water for injectable solutions; 50 ml of the 0.1M citric acid solution thus prepared was poured into a 100 ml flask and, activating magnetic stirring, 1 M NaOH was slowly added to reach pH 3.5.

[0061] Keeping the magnetic stirring active, 1 g of cyclopentolate was added, awaiting its complete solubilization (about 5 minutes). 1g of tropicamide was then added awaiting its complete solubilization until a clear solution was obtained (about 30 minutes). 0.2991g of NaCl were subsequently added and the whole mixture was left under stirring until a transparent solution was obtained.

[0062] The solution was brought to pH 5.00 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in single-use doses.

[0063] EXAMPLE 2

[0064] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of Cyclopentolate 0.5% w / v and Tropicamide 0.5% w / v and relative excipients; pH 4.4

[0065] An 0.1M solution of citric acid was prepared using water for injectable solutions; 50 ml of the 0.1M citric acid solution thus prepared were poured into a 100 ml flask and, on activating the magnetic stirrer, 0.5 g of cyclopentolate were added awaiting its complete solubilization (about 5 minutes). 0.5 g of tropicamide were then added awaiting its complete solubilization until a clear solution was obtained (about 30 minutes)..

[0066] 0.48 g of NaCl were subsequently added and the mixture was left under stirring until a clear and transparent solution was obtained.

[0067] The solution was brought to pH 4.4 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 gm filters and packaged in a single resealable multidose container.

[0068] EXAMPLE 3

[0069] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of cyclopentolate 1% w / v and tropicamide 1% w / v and relative excipients; pH 4,4

[0070] A solution containing both active ingredients at 1.0% w / v in an 0.1M citrate buffer was prepared as per Example 1, 0.37g ofNaCl were then added and the whole mixture was left under stirring until a transparent solution was obtained.

[0071] The solution was brought to pH 4.4 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 gm filters and packaged in single-use doses.

[0072] EXAMPLE 4

[0073] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients with antioxidant agent; pH 5,0

[0074] A solution containing both active ingredients at 1.0% w / v in an 0.1M citrate buffer was prepared as per Example 1, 0.2 g of sodium metabisulphite and 0.25 g of NaCl were then added and the whole mixture was left under stirring until a transparent solution was obtained.

[0075] The solution was brought to pH 5.00 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in single-use doses.

[0076] EXAMPLE 5

[0077] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of cyclopentolate 1% w / v and tropicamide 1% w / v and relative excipients with antioxidant agent; pH 4,0 A solution containing both active ingredients at 1.0% w / v in an 0.1M citrate buffer was prepared as per Example 1, 0.2 g of sodium metabisulphite and 0.2 g of NaCl were then added and the whole mixture was left under stirring until a transparent solution was obtained.

[0078] The solution was brought to pH 4.00 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in single-use doses.

[0079] EXAMPLE 6

[0080] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of Cyclopentolate 0.5% w / v and Tropicamide 0.5% w / v and relative excipients with antioxidant agent; pH 4,4

[0081] A solution containing both active ingredients at 1.0% w / v was prepared as per Example 2, 0.2 g of sodium metabisulphite and 0.4 g of NaCl were then added and the whole mixture was left under stirring until a limpid and transparent solution was obtained.

[0082] The solution was brought to pH 4.40 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in a single resealable multidose container.

[0083] EXAMPLE 7

[0084] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of cyclopentolate 1% w / v and tropicamide 1% w / v and relative excipients with antioxidant agent; pH 4,4

[0085] A solution containing both active ingredients at 1.0% w / v in an 0.1M citrate buffer was prepared as per Example 1, 0.2 g of sodium metabisulphite and 0.25 g of NaCl were then added and the whole mixture was left stirring until a transparent solution was obtained.

[0086] The solution was brought to pH 4.4 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in single-use doses.

[0087] EXAMPLE 8

[0088] Preparation of 100 ml of the ophthalmic pharmaceutical composition consisting of cyclopentolate 0.5% w / v and tropicamide 0.5% w / v and relative excipients with antioxidant agent; pH 4,0

[0089] A solution was prepared with both active ingredients at 1.0% w / v as per Example 2, 0.2 g of sodium metabisulphite and 0.38 g of NaCl were then added and the whole mixture was left under stirring until a clear and transparent solution was obtained.

[0090] The solution was brought to pH 4.00 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in a single resealable multi-dose container.

[0091] EXAMPLE 9 Preparation of 100 ml of the pharmaceutical composition consisting of

[0092] Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients; pH 4,0

[0093] An 0.1M citric acid solution was prepared using water for injectable solutions; 50 ml of the 0.1M citric acid solution thus prepared was poured into a 100 ml flask and, on activating the magnetic stirrer, 1 M NaOH was slowly added to reach a pH of 3.0.

[0094] Keeping the magnetic stirrer active, 1 g of cyclopentolate was then added awaiting its complete solubilization (about 5 minutes). 1 g of tropicamide was then added awaiting its complete solubilization until a clear solution was obtained (about 30 minutes).

[0095] 0.2 g of NaCl were subsequently added and the whole mixture was left under stirring until a transparent solution was obtained.

[0096] The solution was brought to pH 3.5 with IM NaOH and then brought to a final volume of 100 ml with water for injectable solutions, under stirring for a few minutes. The solution thus obtained was sterilized by filtration with 0.2 pm filters and packaged in single-use doses.

[0097] EXAMPLE 10

[0098] Stability test

[0099] The ophthalmic pharmaceutical composition consisting of Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients, at pH 4.4, prepared according to Example 3 (sample A), was compared with the pharmaceutical composition consisting of Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients with antioxidant agent, at pH 4.4, prepared according to Example 7 (sample B), in order to analyze and evaluate the respective stabilities at 25°C at 3, 6 and 12 months vs the initial control.

[0100] Therefore, for n=3 samples A and n=3 samples B, the actual % of both cyclopentolate and tropicamide was initially determined to set the initial control % at TO (which had to correspond with the theoretical % of 1% w / v for each of the two active ingredients), samples A and samples B were subsequently placed in a climatic chamber at a controlled temperature of 25°C for 3 months (T3), 6 months (T6) and 12 months (T12), at the end of which the actual % of the two active ingredients in the samples tested was determined again in order to verify their stability vs TO. The analysis was carried out by HPLC with separation on a C18 column and UV detector at 210 nm, (n=3 samples A and B for T3, n=3 samples A and B for T6, and n=3 samples A and B for T12); the values indicated in the table represent the % of active ingredient contained in the sample tested vs the theoretical value, and are the average of the measurements effected, which were found to be completely similar in the samples of the individual groups tested (n=3 per group).

[0101] It should therefore be specified that “100% vs theoretical” means that in the sample analyzed the concentration of the active ingredient is equal (i.e. 100%) to the theoretical value, in this case equal to 1% w / v; whereas, for example, “83% vs theoretical” means that the sample tested contains 83% of the theoretical active ingredient.

[0102] Results:

[0103] In this case the test effected indicates that: sample A, free of preservative agents and also free of antioxidant agents, keeps the concentration of active ingredients unchanged up to T6 at a temperature of 25°C; both samples are stable at a temperature of 25°C up to T6, the presence of the antioxidant agent however allows sample B (characterized like sample A by being free of preservative agents such as benzalkonium chloride) to keep both active ingredients stable even at T12, for a concentration stability of the active cyclopentolate equal to 90% of its initial value, whereas the stability of tropicamide is equal even to 100% of its initial concentration value. All samples were also found to be sterile at all Ts, tested by microbiological examination as known to skilled person in the field (according to Ph. Eur. 2.6.12).

[0104] It should be specified that the value of 90% concentration at T12 indicated above falls within the validity range of the cyclopentolate according to the monograph of the active ingredient present in the United States Pharmacopeia (USP).

[0105] EXAMPLE 11

[0106] Stability test

[0107] In order to analyze and evaluate their respective stabilities (at 25°C at T3 and T6 vs the initial control, TO), two different ophthalmic pharmaceutical compositions were prepared consisting of: sample A, composed of Cyclopentolate 0.5% w / v and Tropicamide 0.5% w / v and relative excipients, at pH 4.0, prepared according to Example 8, and sample B, consisting of Cyclopentolate 1% w / v and Tropicamide 1% w / v and relative excipients, at pH 4.0, prepared according to Example 9. Both samples are characterized by being free of preservative agents such as benzalkonium chloride, whereas sample A also contains Sodium metabisulphite as antioxidant agent.

[0108] Therefore, for n=3 samples A and n=3 samples B, the actual % of both cyclopentolate and tropicamide was initially determined to set the initial control % at TO; subsequently, n=6 samples A and n=6 samples B were placed in a climatic chamber at a controlled temperature of 25°C for 3 months (T3) and 6 months (T6), at the end of which the actual % of the two active ingredients in the samples tested was determined again to verify their stability vs TO. The analysis was carried out by HPLC as described for Example 10.

[0109] Results: Also in this case, the test effected indicates how both samples are stable at a temperature of 25°C up to T6, maintaining the cyclopentolate values at T6 higher than 90% of the initial concentration, therefore falling within the validity range established by the USP. All samples were also found to be sterile at all Ts tested by microbiological examination as known to skilled person in the field (according to Ph. Eur. 2.6.12).

[0110] This result is possible thanks to the particular formulation of the pharmaceutical compositions object of the invention, which are characterized by being free of preservative agents and in particular free of benzalkonium chloride (toxic for the corneal epithelium), but which are stabilized by excipients comprising or mainly consisting of a buffer system composed of a weak acid and its salt, within a pH range of 3.5 to 6.0, and by a saline solution composed of NaCl and water for an ocular osmolarity value of 300 mOsmol / kg, with the possible presence of antioxidant agents which contribute to extending the stability period of the active ingredients.

Claims

CLAIMS1. An ophthalmic pharmaceutical composition consisting of cyclopentolate and tropicamide in a weight ratio of 1 :2 to 2: 1, preferably equal to 1 : 1, wherein both cyclopentolate and tropicamide are present in a concentration ranging from 0.5% to 1.0% weight / volume, and pharmaceutically acceptable excipients, free of preservatives.

2. The ophthalmic pharmaceutical composition according to claim 1, wherein said composition is free of benzalkonium chloride.

3. The ophthalmic pharmaceutical composition according to claim 1 or claim 2, wherein said composition contains as excipients, antioxidant agent, preferably sodium metabisulphite, sodium thiosulphate, mannitol, sorbitol, glutathione, trehalose, vitamin E and / or ascorbic acid, more preferably sodium metabisulphite in a concentration ranging from 0.15 to 0.25% weight / volume, preferably 0.2% weight / volume.

4. The ophthalmic pharmaceutical composition according to one or more of claims 1-3, stable at 25°C for at least 6 months.

5. The ophthalmic pharmaceutical composition according to one or more of claims 1 to 4, wherein cyclopentolate and tropicamide are present in a weight ratio equal to 1 :1, and wherein both cyclopentolate and tropicamide are present in a concentration equal to 0.5% weight / volume.

6. The ophthalmic pharmaceutical composition according to one or more of claims 1 to 4, wherein cyclopentolate and tropicamide are present in a weight ratio equal to 1 :1, and wherein both cyclopentolate and tropicamide are present in a concentration equal to 1% weight / volume.

7. The ophthalmic pharmaceutical composition according to one or more of the previous claims, wherein said composition is an aqueous solution comprising as a pharmaceutically-acceptable excipient a buffer system composed of a weak acid and a salt thereof such as, for example, acetic acid and a salt thereof, boric acidand a salt thereof, or citric acid and sodium citrate, for a final pH value within the range of 3.5 -6.0, preferably 3.5 -5.0.

8. The ophthalmic pharmaceutical composition according to one or more of the previous claims, wherein said composition is an aqueous solution comprising as a pharmaceutically-acceptable excipient a buffer system composed of citric acid and sodium citrate for a final pH value within the range of 3.5 -5.5, preferably within the range of 3.5-5 or within the range of 4.4-5.5, more preferably within the range of 3.5-5.

9. The ophthalmic pharmaceutical composition according to one or more of the previous claims, wherein said composition is an aqueous solution comprising as a pharmaceutically-acceptable excipient a buffer system composed of saline phosphate buffer containing sodium phosphate for pH values close to 6.0.

10. The ophthalmic pharmaceutical composition according to one or more of the previous claims, for use in the induction of cycloplegia and mydriasis for the evaluation of the ocular fundus and refractive errors of the eye, for use in inflammations of the anterior part of the eye such as, for example, uveitis and keratitis, and / or for use in the induction of cycloplegia and mydriasis in ophthalmic surgery, preferably in cataract surgery.

11. The ophthalmic pharmaceutical composition for use according to claim 10, wherein cyclopentolate and tropicamide are present in a weight ratio equal to 1 : 1, and wherein both cyclopentolate and tropicamide are present in a concentration equal to 0.5% weight / volume.

12. The ophthalmic pharmaceutical composition for use according to claim 10, wherein cyclopentolate and tropicamide are present in a weight ratio equal to 1 : 1, and wherein both cyclopentolate and tropicamide are present in a concentration equal to 1.0% weight / volume.

13. The ophthalmic pharmaceutical composition for use according to one or more of claims 10-12, wherein said composition is administered in half the number of instillations compared to the number of instillations of the sequentialadministration of cyclopentolate and tropicamide, preferably for use in a pediatric and / or elderly population.

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