Pharmaceutical compositions for the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma

Abstract

Pharmaceutical compositions are disclosed in the form of orosoluble suckable and chewable tablets consisting of citicoline, nicotinamide and pharmaceutically acceptable excipients, for use in the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma.

Description

[0001] PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND / OR TREATMENT OF DEGENERATION OF THE OPTIC NERVE AND RETINAL NERVE CELLS RESULTING FROM GLAUCOMA

[0002] The object of the invention are pharmaceutical compositions in the form of suckable and chewable orosoluble tablets consisting of citicoline, nicotinamide and pharmaceutically acceptable excipients, for use in the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma.

[0003] State of the art

[0004] Glaucoma is a chronic neurodegenerative disease characterized by damage to the retinal ganglion cells (RGCs) constituting the optic nerve: as a consequence, there is a thinning of the retinal nerve fibres and of the optic nerve itself, and the impairment of the arrival of the signal to the visual cortex. The natural evolution of the untreated disease is progressive: glaucoma- induced optic neuropathy initially damages the visual field in its most peripheral parts, then also in the central part, until the final outcome: complete blindness.

[0005] The most common type of glaucoma is primary open angle glaucoma (POAG), which occurs when a progressive, decisive and prolonged rise in intraocular pressure (IOP) occurs due to an imbalance between the production of aqueous humour in the ciliary body and its outflow into the chamber angle; the resulting damage is so significant that POAG represents one of the leading causes of blindness in the world, both in industrialized and developing countries: it is estimated that 4.5 to 9 million people in the world are blinded by glaucoma.

[0006] Primary angle-closure glaucoma is more rare, making up less than 20% of glaucomas, and in which the intraocular pressure quickly reaches very high levels due to the inability of the intraocular fluid to reach the outflow pathways. The onset of angle-closure glaucoma is often sudden, so much so that it is generally referred to as acute glaucoma.

[0007] A further known type of glaucoma is normal tension glaucoma (NTG), in which the IOP is not altered, but which also induces damage to the RGCs and consequent optic neuropathy.

[0008] Regardless of the specific type of glaucoma, scientific studies have long shown that RGCs undergo apoptosis, i.e., cell death; the damage that glaucoma causes is therefore irreversible.

[0009] Glaucoma is a subtle disease: it is believed that in about 50% of the population over the age of 40 afflicted by glaucoma, the disease is not diagnosed at its onset, but only when the consequences are irreparable.

[0010] The major risk factors are related, in addition to the increase in IOP, to older age, myopia, heredity factors and also, albeit indirectly, to some diseases such as diabetes and arterial hypertension.

[0011] POAG therapy consists essentially in topical treatment with beta-blockers, prostaglandins, alpha-agonists that have the task of eliminating, or at least limiting, the excess aqueous humour that the eye produces, thus reducing the IOP; when the pharmacological therapy finally becomes ineffective, the only possible treatment is surgical, therefore trabeculectomy, which creates a by-pass between the inside and the outside of the eye, so as to make the excess aqueous humour inside the eye flow into the sub-conjunctival spaces and decrease the pressure thereof. In any case, while standard or surgical drug therapy very often reduces IOP and slows the progression of the disease, it does not avert the risk of total vision loss.

[0012] Although the real causes of glaucoma are not yet completely clear, it has been shown that situations of reduced vascularization, increased glial reactivity, neuroinflammation and oxidative stress are mainly involved in the pathophysiology of the disease. Oxidative stress, in particular, linked to the accumulation of free radicals essentially induced by high intraocular pressure, particularly affects RGCs which, as mentioned, undergo death by apoptosis (Dammak A et al, Pharmaceutics, 2021, 13, 1376; Izzotti A et al., MutatRes, 2006, 612, 105-114). Based on this evidence, alongside or as an alternative to standard therapies, different approaches to prevent and / or treat the neurodegenerative damage that glaucoma entails have been explored.

[0013] In fact, pharmaceutical compositions are known, containing active ingredients capable of acting on the above parameters in order to extinguish inflammation, limit oxidative stress and also contribute to the trophism of the optic nerve. In particular, two molecules have been used in this sense: citicoline and nicotinamide.

[0014] Citicoline (cytidine-5-diphosphocholine) is a substance physiologically produced in our body, in particular in the liver, starting from the amino acid cysteine, and has long been known for its neuroprotective effect; it has been studied and tested for the treatment of neurodegenerative diseases such as senile dementia, Parkinson's disease, Alzheimer's disease, cerebrovascular accidents and glaucoma (Grieb P, Rejdak R., J Neurosci Res, 2002, 67, 143- 148). The mechanism of action of citicoline is multifaceted: it seems to preserve cardiolipin and sphingomyelin (belonging to the category of phospholipids and fundamental for maintaining the integrity of mitochondrial and cell membranes), reduce glutamate concentration (thus turning off neuroinflammation), activate mitochondrial function, stimulate glutathione synthesis, thus acting on free radicals, limiting oxidative stress.

[0015] The scientific literature reports important results obtained with citicoline administered by intramuscular injection (Vimo M. et al. Acta Ophthalmol Scand Suppl. 2000, 232, 56-7; Parisi V, Doc Ophthalmol., 2005, 110, 91-102) and in oral solution (Morreale Bubella R. et al, Ottica Fisiopatol, 2011, XVI, 171-177), in the treatment of glaucoma.

[0016] Nicotinamide, also known as niacinamide or vitamin B3, is the precursor of the coenzyme nicotinamide adenine dinucleotide (NAD+), an essential molecule in mitochondrial activity, to which a powerful antioxidant activity is ascribed. The involvement of NAD+ in the metabolism of RGCs and retinal degeneration has long been known (Jadeja RN et al., OxidMed Cell Longev, 2020, doi: 10.1155 / 2020 / 2692794); the ability of nicotinamide to reduce the vulnerability of RGC mitochondria and prevent glaucoma in rats has also been demonstrated (Williams PA, Science, 2017, 355, 756-760). In humans, nicotinamide has confirmed its ability to improve retinal functions in glaucomatous patients when administered orally, in the form of swallowable tablets (Hui F et al., Clin Exp Ophthalmol, 2020, 1-12).

[0017] For all these reasons, citicoline and nicotinamide have been tested and used in pharmaceutical compositions suitable for the treatment of glaucoma and damage to the RGCs and the optic nerve, both as individual active ingredients and in association with each other (EP2538918; WO2022238833). Further compositions are also known in which citicoline and nicotinamide are associated with other active ingredients, such as coenzyme Q10 and hydroxyproline (W02020106746), or natural substances such as Gingko biloba extracts, curcumin, green tea, etc. (US20200390726), for the same purposes. In the latter cases, it is evident that the activity of the compositions derives from the mixture of numerous active ingredients, widely known for their antioxidant effect. In this context it should be emphasized that the administration of formulations containing several active ingredients to elderly patients, who are generally object to concomitant drug treatments, may give rise to interactions and / or completely undesirable adverse events.

[0018] The compositions mentioned above and known to date are formulated for oral administration (swallowable tablets or capsules, granules to be suspended in water, liquids) or topical administration (eye drops).

[0019] Generically understood oral forms are certainly preferred, because they allow the administration of more adequate doses of active ingredients that, through the circulatory stream, effectively reach the therapeutic target. Known oral dosage forms are swallowable tablets and capsules, granules and oral solutions. For example, WO2022238833 discloses a liquid formulation of citicoline and nicotinamide; CN116919910 claims exclusively chewable tablets, meeting precise technical requirements. Other particular pharmaceutical forms containing the active ingredients of interest are known, such as lozenges, i.e., extremely hard tablets intended to be sucked but not chewed (CN117442570). In general, such pharmaceutical forms, while ensuring the specific activity of the active ingredients, are not suitable for administration to all types of patients. In fact, glaucoma is a disease that manifests especially in old age, therefore the typical patient is an elderly person, often with difficulty in swallowing; moreover, the glaucomatous patient unfortunately experiences a progressive loss of vision, which may compromise his / her ability to independently manage the dosage and the correct intake of drugs.

[0020] Tablets and capsules, for example for dysphagic patients, in whom the ability to swallow is significantly reduced or in any case compromised, are difficult to take and can even increase the risk of suffocation; granules to be suspended in water require, indeed, the use of water for the extemporaneous preparation of the product to be taken, and this can already be a problem; they also do not ensure that the dysphagic patient or even simply the elderly are able to correctly take the entire product, with the risk that the dose of active ingredients ingested is lower than necessary; finally, ingesting a formulation on an aqueous basis can be problematic for a dysphagic patient, but for an elderly patient, although not dysphagic, even simply dosing a liquid from a multidose bottle or having to pour it into the mouth from a single-dose stick can be complicated: the risk is, as for granules, ingesting doses of incomplete and inadequate active ingredients.

[0021] The present invention overcomes the state of the art with the development of tablets consisting solely of citicoline, nicotinamide and pharmaceutically acceptable excipients, formulated so as to be orosoluble, suckable, and therefore suitable for dysphagic or even edentulous patients, but also chewable, so that they can be easily taken also by those who do not have chewing problems, without the danger of compromising the therapeutic dosage.

[0022] It should be noted that when mention is made of orosoluble tablets, tablets are referred to which, placed in the oral cavity, dissolve in a short time but not instantly, as instead required for orosoluble tablets (ODT - Orodispersible Tablets), which, from international repertoires, must be dispersed in the mouth within 3 minutes, according to the European Pharmacopoeia (Ph. Eur.5. 1 / 2005:0478 ), and within 30 seconds according to FDA guidelines (h tips : / / ww w. fda go v / 'medi a / 70877 / downl oad) . The tablets of the invention, to be used in the prevention and / or treatment of glaucoma and degeneration of the optic nerve and retinal nerve cells resulting therefrom, are also characterized by excellent palatability and total masking of the taste of the active ingredients, and are of such dimensions that they can be easily handled; such features contribute considerably to improving patient compliance.

[0023] Description of the Invention

[0024] The object of the invention are pharmaceutical compositions in the form of suckable and chewable orosoluble tablets consisting of citicoline, nicotinamide and pharmaceutically acceptable excipients, for use in the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma, which offer the following advantages:

[0025] • they are orosoluble and suckable, therefore suitable for patients who are dysphagic, edentulous and / or have difficulty chewing, and also chewable, therefore usable by anyone;

[0026] • they are not gummy, therefore they avoid the discomfort of accidental adhesion to dental prostheses;

[0027] • they contain citicoline and nicotinamide as the only active ingredients, therefore minimizing possible interference with concomitant pharmacological therapies;

[0028] • the dosage envisages one tablet administered once a day;

[0029] • they ensure the intake of the full dose of active ingredients prescribed;

[0030] • as they are orosoluble, they dissolve in the oral cavity in 20 minutes, therefore they immediately begin to release a portion of active ingredients, making them available for absorption through the vessels present therein and subtracting them from the first liver passage;

[0031] • they are adequately resistant from a mechanical point of view and of dimensions suitable for easy handling;

[0032] • they do not require being taken with liquids;

[0033] • they are pleasant to the palate, in terms of taste and sensation; in this case, this is a decisive feature, because citicoline has a decidedly unpleasant taste;

[0034] • they are free of lactose and gluten, therefore suitable for those who are intolerant.

[0035] The Applicant has surprisingly found that the above-described active ingredients, in the specifically identified doses, suitably formulated with selected excipients and processed according to a specific process, result in the formation of suckable and chewable orosoluble tablets perfect for administration to elderly patients suffering from glaucoma, possibly also dysphagic, with chewing difficulties or edentulous. The administration in a single daily dose, the ease of intake for the patient, who does not have to calculate doses or pour from bottles or single-dose sticks, mean that the tablets of the invention represent a clear surpassing of the state of the art.

[0036] The tablets of the invention consist solely of citicoline and nicotinamide as active ingredients, combined with pharmaceutically acceptable excipients.

[0037] Citicoline: nootropic substance, with proven efficacy in some pathologies of the central nervous system where it acts at different levels; it is able in particular to restore the levels of phosphatidylcholine, the most abundant phospholipid in the membranes of nerve cells, to promote the synthesis of acetylcholine, to act as a powerful antioxidant and to stimulate the synthesis of myelin. The usefulness of citicoline in the prevention and treatment of optic nerve degeneration from glaucoma is widely proven (Lopez-Coviella I et al., J Neurochem, 1995, 65, 889-94; Roberti G et al., IntJMolSci, 2015, 16, 28401-17).

[0038] The citicoline used according to the invention is preferably Cognizin®, synthesized through a fermentation process in modified strains of E. coli B that guarantees a stable and allergen-free product (EP 1939210).

[0039] Citicoline is present in the compositions of the invention in a concentration ranging between 350 and 600 mg, preferably between 450 and 550 mg, even more preferably equal to 500 mg with respect to the final weight of the tablet.

[0040] Nicotinamide: as with citicoline, its involvement in degenerative phenomena in the optic nerve in the presence of glaucoma has been studied and proven for some time; serum levels of nicotinamide in glaucomatous patients are in fact very low. It has been shown in animal models that nicotinamide administration not only protects against neurodegeneration but, at higher doses, also reduces intraocular pressure (Williams PA,. J Glaucoma. 2017;26(12): 1161-1168). In the context of the invention, nicotinamide is used in a concentration ranging between 45 and 75 mg, preferably between 50 and 70 mg, even more preferably equal to 54 mg with respect to the final weight of the tablet.

[0041] The doses used are appropriately calibrated because, if on the one hand citicoline and nicotinamide benefit from an excellent tolerability and safety profile, on the other hand the administration of very high doses can generate, especially for nicotinamide, undesirable side effects (nausea, flushing) or real forms of toxicity (Ferrell M et al, Nat Med, 2024, 30(2):424- 434).

[0042] It should also be taken into account that, especially in the case of products to be administered to patients undergoing multiple drug treatments, interactions with other drugs are possible.

[0043] The dosages of the active ingredients described above guarantee the optimal pharmacological effect through the administration of a single tablet once a day. The absence of additional active ingredients also avoids any risk of interaction or interference with other therapies.

[0044] Finally, the excipients are selected and calibrated so as to impart to the tablets of the invention the features of consistency, strength, size, palatability, chewability, orosolubility and suckability illustrated above.

[0045] A first object of the invention is therefore constituted by pharmaceutical compositions in the form of suckable and chewable orosoluble tablets consisting of citicoline, nicotinamide and pharmaceutically acceptable excipients comprising a bulking agent selected from sorbitol and mannitol in a concentration between 400 mg / g and 500 mg / g with respect to the final weight of the tablet.

[0046] The bulking agents constitute the largest mass within the tablets and play a fundamental role, being the main ones responsible for the orosolubility: the preferred bulking agent is sorbitol.

[0047] The anti-caking agents can be selected from silica dioxide, cellulose derivatives, calcium silicate, magnesium salts of fatty acids, tribasic calcium phosphate, polyvinylpyrrolidone, mono- and diglycerides of fatty acids, talc and mixtures thereof; preferably, the anti-caking agents are a mixture of silica dioxide, hydroxypropyl cellulose, magnesium salts of fatty acids, polyvinylpyrrolidone, mono- and diglycerides of fatty acids.

[0048] The sweeteners are selected from xylitol, fructose, sucralose, maltose, neohesperidin DC, maltitol, trehalose, acesulfame K and mixtures thereof, and preferably consist of a mixture of xylitol, sucralose, neohesperidin DC, acesulfame K.

[0049] With regard to flavourings, they have been identified particularly accurately precisely by virtue of the active ingredients used. In fact, citicoline has a bitter and acidic taste at the same time, and a detailed analysis of the aromatic component was necessary, in order to give the tablets of the invention a pleasant organoleptic profile.

[0050] The final tablet weight ranges from 950 to 2000 mg, and is preferably 2000 mg.

[0051] It should be emphasized that, for the reasons described above, the concentrations of the active ingredients citicoline and nicotinamide do not vary with respect to the possible changes in final weight of the single tablet, unlike what instead occurs for the excipient.

[0052] In particular, the preferred excipients and their relative concentrations are: bulking agents: sorbitol, in a concentration between 400 mg / g and 500 mg / g, preferably between 433 mg / g and 445 mg / g with respect to the final weight of the tablet; anti-caking agents: silica dioxide, in a concentration between 50 mg / g and 150 mg / g, preferably between 100 mg / g and 105 mg / g with respect to the final weight of the tablet; hydroxypropyl cellulose, in a concentration between 30 mg / g and 50 mg / g, preferably equal to 35 mg / g with respect to the final weight of the tablet; magnesium salts of fatty acids, in a concentration between 10 mg / g and 30 mg / g, preferably equal to 20 mg / g with respect to the final weight of the tablet; polyvinylpyrrolidone, in a concentration between 5 mg / g and 20 mg / g of unit dose, preferably equal to 10 mg / g; mono- and di glycerides of fatty acids, in a concentration between 2 mg / g and 10 mg / g, preferably equal to 5 mg / g with respect to the final weight of the tablet; sweeteners: xylitol, in a concentration between 60 mg / g and 80 mg / g, preferably between 75 mg / g and 80 mg / g with respect to the final weight of the tablet; sucralose, in a concentration between 0.1 mg / g and 1 mg / g, preferably equal to 0.35 mg / g with respect to the final weight of the tablet; neohesperidin DC, in a concentration between 0.01 mg / g and 0.2 mg / g, preferably equal to 0.07 5mg / g with respect to the final weight of the tablet; acesulfame K, in a concentration between 0.01 mg / g and 0.2 mg / g, preferably equal to 0.075 mg / g with respect to the final weight of the tablet; flavourings: cola flavouring, in a concentration between 5 mg / g and 20 mg / g, preferably equal to 12.5 mg / g with respect to the final weight of the tablet; natural lemon flavouring, in a concentration between 5 mg / g and 20 mg / g, preferably equal to 10 mg / g with respect to the final weight of the tablet.

[0053] As mentioned, within the scope of the invention, a fundamental role is played by the preparation process of the tablets; in fact, the Applicant has surprisingly discovered that the selection of the excipients described above, mixed according to specific criteria and in a precise sequence, gives the tablets of the invention the features which make them orosoluble, suckable and chewable. The process disclosed below is characterized by the pre-mixing of sets of ingredients and by the calibration of the features and compression values of the resulting powder.

[0054] A further object of the invention is therefore the process for preparing orosoluble suckable and chewable tablets, containing citicoline and nicotinamide as the only active ingredients, which comprises:

[0055] Step 1 : weighing the ingredients and sieving with 3mm mesh sieves;

[0056] Step 2: in a bi-conical steel drum, mixing citicoline and an anti-caking agent, preferably silica dioxide, until a homogeneous mixture is obtained, obtaining Premix 1; this step prevents the adhesion of citicoline to the punches of the tablet machine used at the end of the process; Step 3: in a second bi-conical steel drum, mixing of sweeteners, preferably sucralose, neohesperidin, acesulfame K, anti-caking agents, preferably mono- and diglycerides of fatty acids and flavourings, preferably cola flavouring and lemon flavouring, obtaining Premix 2; thereby the low dosed components of the formulation are distributed in a completely homogeneous manner;

[0057] Step 4: in the bi-conical drum containing the Premix 1, insertion, in sequence and in order, of Premix 2, of sorbitol or mannitol as a bulking agent, sorbitol, of a sweetener, preferably xylitol, of nicotinamide, of further anti-caking agents, preferably hydroxypropyl cellulose, magnesium salts of fatty acids, polyvinylpyrrolidone, mixing until completely homogeneous.

[0058] It is essential, for the purposes of making the tablets of the invention, that the process steps are carried out in the exact sequence described.

[0059] At the end, the bi-conical drum containing the mixture to be compressed will be connected to the loading hopper of the tablet machine, which, properly set, will result in the formation of the tablets.

[0060] The tablets produced as described above are not only chewable, but also orosoluble and suitable for being sucked; this peculiarity is not at all obvious. In fact, chewability and orosolubility / suckability are achieved with different compositions. In particular, the suckable orosoluble tablet is characterized by containing highly hygroscopic bulking agents, which represent the greatest mass within the tablets themselves, of a cellulosic type (for example, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, etc.), which by absorbing the saliva present in the oral cavity favour the erodibility of the tablet. If chewed, precisely by virtue of the bulking agents used, the fragments obtained further disintegrate into minute flakes that, moistened by saliva, risk creating an unwanted mixture inside the oral cavity with possible serious consequences in the case of dysphagic elderly patients.

[0061] The tablets of the invention, on the contrary, thanks to the choice of sorbitol or mannitol as bulking agent, are simultaneously suckable and chewable; they dissolve without chewing in short times, in particular in 20 minutes, completely comparable to those of commercially available orosoluble tablets and, when chewed, do not flake off in minute flakes.

[0062] Some preparation examples of the tablets of the invention are given below; the mixing times, strongly influenced by the volumes of powders employed, will be established by the person skilled in the art.

[0063] Example 1: preparation of suckable and chewable orosoluble tablets (weight=2000 mg) containing 527 mg of citicoline and 70 mg of nicotinamide

[0064] Preparation:

[0065] Step 1 : all the ingredients are weighed and sieved with 3mm mesh sieves;

[0066] Step 2: in a bi-conical steel drum, citicoline and silica dioxide are mixed, until a homogeneous mixture is obtained, obtaining Premix 1;

[0067] Step 3 : in a second bi-conical steel drum sucralose, neohesperidin, acesulfame K, mono- and diglycerides of fatty acids, cola flavouring and lemon flavouring are mixed, obtaining Premix 2;

[0068] Step 4: in the bi-conical drum containing Premix 1 are inserted, strictly in order, Premix 2, sorbitol, xylitol, nicotinamide, hydroxypropyl cellulose, magnesium salts of fatty acids and polyvinylpyrrolidone, mixing until completely homogeneous;

[0069] Step 5: the bi-conical drum containing the mixture obtained from Step 4 is connected to the loading hopper of the tablet machine;

[0070] Step 6: the mixture obtained from Step 5 is compressed with setting of the appropriate machine parameters.

[0071] The tablets obtained as described are subsequently passed to blistering and finally to secondary packaging.

[0072] Example 2: preparation of suckable and chewable orosoluble tablets (weight=2000 mg) containing 500 mg of citicoline and 54 mg of nicotinamide

[0073] Preparation: see Example 1.

[0074] The tablets obtained according to the Examples reported have a weight of 2000 mg, are square-shaped, with a side of 16 mm, and have a hardness between 16-19 kp (kilopond), evaluated as described in Ph. Eur. 5.0, 2.9.8. “Resistance to crushing of tablets”. These values make the tablet suitable both for the blistering process (at the time of packaging) and deblistering (at the time of consumption) and for the chewability parameter, which is easy, in terms of the force to be applied.

[0075] In order to demonstrate the above, experiments were carried out in which the dissolution of the tablets of the invention was compared to that of commercially available orosoluble tablets, specifically "Sam eFast® Advance".

[0076] Example 3: evaluation of the degree of dissolution of tablets prepared as per Example 1 towards commercial orosoluble tablets.

[0077] Tested types:

[0078] Sample: tablets prepared as per Example 1;

[0079] Control: "SameFast® Advance" orosoluble tablets (Fidia farmaceutici), having the following composition:

[0080] - Active ingredients: S-Adenosyl-L-Methionine Disulfate 250 mg; Vitamin B12 18pg; Folic Acid 400 pg;

[0081] - Bulking agent: microcrystalline cellulose;

[0082] - Sweeteners: mannitol, xylitol, sucralose, acesulfame K, neohesperidin DC;

[0083] - Anti-caking agents: fatty acids, magnesium oxide, silicon dioxide - Acidifiers: citric acid;

[0084] - Flavourings.

[0085] A "Dissolution test for solid dosage forms" was set up using a dissolver with rotating blade (SotaxAT7 Smart) as indicated in Ph. Eur. 5.0, 2.9.3 (Paddle Apparatus) and in USP 711 (USP Apparatus 2), repeating the tests in triplicate. The dissolver was filled with 1 litre of milli- Q water (dissolution medium) and set at 37°C. Once the temperature was reached in a stable manner, the tablet to be tested was introduced and the stirring of the blade was set to 200 rpm, verifying that the tablet itself did not come into contact with either the blade or the walls of the dissolver due to the swirling motion. At predetermined time intervals (0-3-6-9-12-15-20 minutes) and with the help of a long tweezer, the tablet was withdrawn while taking care not to break it, gently dried with paper to remove water on the surface and weighed. The weights over time were recorded and the % of dissolved tablet was calculated at each interval with respect to the starting weight, according to the following formula: tablet starting weight (g) — tablettweight (g)

[0086] % dissolved tablet? = - — - - — — — — - x 100 tablet starting weight g) where t = reference time point.

[0087] The % values, referring to the average of the three tests, are shown in Figure 1.

[0088] Already after 3 minutes the sample is dissolved for more than 20%, a value that doubles after 6 minutes, while practically total dissolution is reached at around 20 minutes.

[0089] It is evident that the sample under examination, despite having been formulated with a non-cellulosic bulking agent, has a dissolution profile that is absolutely comparable to that of the control, which instead contains a standard bulking agent for orosoluble tablets, specifically, microcrystalline cellulose. This result, completely unexpected, allows to state that the tablets of the invention, as well as chewable, can be defined as orosoluble suckable.

[0090] As anticipated, it should be added that, considering that one of the fundamental features of the tablets is the uniformity of distribution of the active ingredients, the fact that during sucking the tablet of the invention rapidly loses a substantial part of its mass implies an equally consistent release of the active ingredients, whose absorption therefore already begins in the oral cavity, avoiding the effect of first liver passage which, as is known, subtracts part of the active ingredients from the bloodstream.

[0091] It is therefore evident from the experimental data presented that the tablets of the invention, consisting solely of citicoline, nicotinamide and a careful selection of excipients, prepared with a specific process, are surprisingly orosoluble, suckable and chewable and represent a clear overcoming of the state of the art in the field of oral compositions for the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma.

Claims

CLAIMS1. Pharmaceutical compositions in the form of suckable and chewable orosoluble tablets consisting of citicoline, nicotinamide and pharmaceutically acceptable excipients comprising a bulking agent selected from sorbitol and mannitol in a concentration between 400 mg / g and 500 mg / g with respect to the final weight of the tablet.

2. Compositions according to claim 1, wherein the concentration of citicoline ranges between 350 and 600 mg, preferably between 450 and 550 mg, even more preferably is equal to 500 mg with respect to the final weight of the tablet and the concentration of nicotinamide ranges between 45 and 75 mg, preferably between 50 and 70 mg, even more preferably equal to 54 mg with respect to the final weight of the tablet.

3. Compositions according to claim 1 or 2, wherein the bulking agent is sorbitol in a concentration between 433 mg / g and 445 mg / g with respect to the final weight of the tablet.

4. Compositions according to the preceding claims, wherein the pharmaceutically acceptable excipients comprise anti-caking agents selected from silica dioxide, cellulose derivatives, calcium silicate, magnesium salts of fatty acids, tribasic calcium phosphate, polyvinylpyrrolidone, mono- and diglycerides of fatty acids, talc, preferably silica dioxide, hydroxypropyl cellulose, magnesium salts of fatty acids, polyvinylpyrrolidone, mono- and diglycerides of fatty acids.

5. Compositions according to claim 4, wherein the anti-caking agents are:- silica dioxide, in a concentration between 50 mg / g and 150 mg / g, preferably between 100 mg / g and 105 mg / g;- hydroxypropyl cellulose, in a concentration between 30 mg / g and 50 mg / g, preferably equal to 35 mg / g;- magnesium salts of fatty acids, in a concentration between 10 mg / g and 30 mg / g, preferably equal to 20 mg / g;- polyvinylpyrrolidone, in a concentration between 5 mg / g and 20 mg / g, preferably equal to 10 mg / g;- mono- and diglycerides of fatty acids, in a concentration between 2 mg / g and 10 mg / g, preferably equal to 5 mg / g, the concentrations being expressed with respect to the final weight of the tablet.

6. Composition according to one of the preceding claims, having the followingcomposition:

7. Composition according to any one of claims 1 to 5, having the following composition:

8. Compositions according to claims 1-7 for use in the prevention and / or treatment of degeneration of the optic nerve and retinal nerve cells resulting from glaucoma.

9. Process for preparing pharmaceutical compositions in the form of orosoluble suckable and chewable tablets of claims 1-7 comprising or consisting of the sequence in the order of the following steps:1) weighing the ingredients and sieving2) mixing citicoline and a first anti-caking agent until a homogeneous mixture called Premix 1 is obtained;3) mixing anti-caking agents and any other excipients, obtaining a mixture called Premix 2;4) sequential mixing of Premix 1, Premix 2, sorbitol or mannitol as bulking agent, sweeteners, nicotinamide and the additional anti-caking agents until homogeneous.

10. Preparation process according to claim 9, wherein the anti-caking agent in step 2) is silica dioxide, the anti-caking agents in step 3) are selected from mono- and diglycerides of fatty acids, the bulking agent is sorbitol, the further anti-caking agents are selected from hydroxypropyl cellulose, magnesium salts of fatty acids, polyvinylpyrrolidone.

Images