MX2012014248A - Ophthalmic composition containing a nanoparticulated pharmaceutical system and manufacturing process. - Google Patents

Abstract

Described is a composition of ophthalmic application that contains, amongst others, a controlled-release nanoparticulated pharmaceutical system. In addition, the nanoparticulated pharmaceutical system is formed by an inorganic nano-crystalline core and one or more layers of a polyhydroxy compound and coating particles of one or more drugs, this system increasing the bioavailability and enhancing the effect of the drug over the intraocular pressure due to the nanometric or micrometric size of the aquasomes, favoring the penetration of therapeutic doses through the ocular membrane, consequently, the dose to be applied into the eye being substantially reduced, therefore reducing the side effects of the drug which would appear during the treatment. The nanoparticualated pharmaceutical system acts as a release vehicle for the drug (s), protecting, preserving and vectorizing the biological molecules of the ocular system.

Description

OPHTHALMIC COMPOSITION CONTAINING A SYSTEM NANOPARTICULATED PHARMACEUTICAL AND ITS PROCESS DEVELOPMENT FIELD OF THE INVENTION The present invention relates to the pharmaceutical industry, specifically to a composition comprising a nanoparticulate pharmaceutical system for ophthalmic application.

BACKGROUND OF THE INVENTION The drugs for ophthalmic use that have been developed during the last years are mainly in the form of: suspension, solution, emulsion and ointment; either for external treatment (conjunctivitis, blepharitis, dry keratitis, etc.), or infraocular (glaucoma, uveitis, endophthalmitis, among others). The bioavailability of the drug, in this form of administration, is determined by the characteristics of both the vehicle and the drug, it is also limited by blinking and lacrimal replacement that prevents permanence for a certain time to allow the complete diffusion of the drug. .

Due to the above, the strategies to improve the ophthalmic formulations have consisted in: increasing the bioavailability by using viscosifying agents, gels, absorption promoters, prodrugs, liposomes; and by controlled release of drugs using nanoparticles or inserts.

In the state of the art, in situ formation gels, oil-in-water emulsions (which keep the drug in solution and prevent blurred vision), liposomes (which increase drug retention), in the form of nanoparticles that work both for hydrophilic and hydrophobic drugs; and in the form of microparticles to obtain a sustained release. (Palma et al, 2007).

Nanoparticles are solid colloidal particles with a size between 1 and 1000 nm (Balogh, L.P. 2010), they can be used as adjuvants or as transporters where the drug is dissolved, trapped, encapsulated, adsorbed and / or bound.

The nanoparticles have changed the direction in the development of nanotechnology due to its great potential in therapeutics, as well as its stability in biological fluids and during storage, the reduction of side effects, the control of the release and the increase of the bioavailability because they penetrate and usually Adhere four times more to the inflamed ocular tissue than to healthy tissue. (Alonso M, 2001, D. Campos A., 2004, Okada M., 1980).

The acuosomes are nanoparticulate systems that are characterized by being constituted mainly by a nucleus of nanocrystalline composition and a self-assembly of several coatings. Due to their properties and advantages, these nanoparticles can be used as controlled release vehicles of different substances to protect, preserve and vector fragile biological molecules such as peptides, polypeptides, proteins and genes. Also, it has applications as an oxygen carrier vehicle, dyes, to name a few.

Obtaining it basically consists of the synthesis of an inorganic nanocrystalline nucleus with a modified non-covalent surface and a film of a polyhydroxy compound. The coated particles are adsorbed with drugs or antigens.

In the state of the art, there are compositions comprising core particles with a size of 10 to 1000 nm constituted by a metal, ceramic or a polymer; and a basic or modified sugar coating or an oligonucleotide (US pat 5,219,577; US Pat 5,460,830), containing antivirals (US Pat. 5,462,751), its use in vaccines (US pat. 5,178,882), as a substitute for red blood cells (US Pat. Pat. 5,306,508; US Pat. 5,464,634), in a treatment for the human immuno-deficiency (US pat. 5,334,394), its use in gene therapy (US Pat. 5,460,831), the production process (US Pat. 5,462,750) and its application in devices such as: containers, implant devices, electrodes, pumps , syringes, needles, conduits, applicators, electrical devices and tubes (US Pat 5,441,739).

Unlike the present invention, in the aforementioned background it has not been possible to generate a solution or pharmaceutical composition for ophthalmic application that has the ability to remain the necessary time in the eye for the drug to penetrate and alleviate the condition.

In the present invention, the use of a novel nanoparticulate pharmaceutical system type acuosoma is described that provides the enhancement of the therapeutic effect of the specific agent favoring penetration.

OBJECTIVE OF THE INVENTION The object of the present invention is to provide a process for the preparation of a nanoparticulate pharmaceutical system capable of forming a colloidal solution of ophthalmic application.

Another objective of the present invention is to obtain an ophthalmic application composition in the form of a colloidal solution containing the nanoparticulate pharmaceutical system, which offers greater bioavailability of the drug and, consequently, greater efficacy and efficiency.

Likewise, more objects and advantages of the present invention may be apparent from the study of the present description and the accompanying drawings for purposes that are purely illustrative and not limiting.

BRIEF DESCRIPTION OF THE INVENTION The present invention consists of a nanoparticulate pharmaceutical system containing one or more drugs used in ophthalmic therapeutics, said system is comprised of an inorganic nanocrystalline nucleus, one or more monomolecular layers of a polyhydroxy compound preferably formed by hydrogen bonds and non-covalent bonds and coating particles of one or more drugs and / or biomolecules with analgesic and / or lubricating and / or antiinflammatory activity and / or unique and / or antimicrobial and / or antioxidant antihistamines preferably formed by hydrogen bonds and non-covalent bonds. Examples of drugs to be used in this nanoparticulate pharmaceutical system can be descriptive and non-limiting, a non-steroidal anti-inflammatory known as Indometacin, for use as a reducer of intraocular pressure and inhibitor of prostaglandin-forming cyclooxygenase in the eye; or the active principle called pilocarpine, for ophthalmic application in the treatment of conditions such as Sjögren's syndrome, rosacea and dry eye syndrome, among others.

From the nanoparticulate pharmaceutical system, a composition is formulated that forms a colloidal solution, favoring stability and control in the release of the drug (s) and / or biomolecules in a quantitative manner and thus facilitating the bioavailability and penetrability of the active principle, which contributes a greater efficacy, efficiency and safety to the composition, since the permanence of the solution allows the perfect diffusion of the drug as well as its penetration through the ocular membrane.

BRIEF DESCRIPTION OF THE FIGURES Figure 1. Nanocrystalline nuclei.

Figure 2. Diffragrams of the nanoparticle system loaded with indomethacin.

Figure 3. Nanoparticulate pharmaceutical system.

Figure 4. Thermograms of Lactose (L), pure Indomethacin (I), the physical mixture of L + l + calcium phosphate (PM) and the aquosome (A).

Figure 5. Dissolution profiles of Indomethacin (I), physical mixture (PM) and aqueous (A).

DETAILED DESCRIPTION OF THE INVENTION The present invention comprises a nanoparticulate pharmaceutical system and its manufacturing process. The system is used to formulate a composition that forms a colloidal solution of ophthalmic application.

The nanoparticulate pharmaceutical system can be formulated in multilayer form consisting of: • an inorganic nanocrystalline core, which can be chosen from: brushite, h id roxyapatite and other solid forms of calcium phosphate, graphite and / or combinations thereof. Figure 1 , • one or more monomolecular layers of a pharmaceutically acceptable polyhydroxy compound which are preferably formed by hydrogen bonds and non-covalent bonds; the polyhydroxy compound can be chosen, but without limiting among: lactose, cyclodextrin, hydroxypropylmethylcellulose, cellulose, dextrose, fructose, maltose, arabinose, glucose, mannitol, sorbitol, xylitol and / or combinations thereof and coating particles of one or more drugs, coating preferably formed by hydrogen bonds and non-covalent bonds; said drugs may have activity: analgesic, for example: diclofenac sodium, fenoprofen, indomethacin, ketoprofen and ketorolac and / or lubricant, for example: hyaluronic acid, polyvinyl alcohol, glycerin and sodium hyaluronate and / or anti-inflammatory, for example: chamomile oil, cyclosporine, chondroitin, dexamethasone, diclofenac, diclofenac sodium, fenoprofen, fluorometalone, Hammamelis virginiana, indomethacin, ketoprofen, ketorolac, meloxicam, nepafenac, prednisolone and rimexolone and / or antihistamine, for example: antazoline, phenylephrine, naphazoline and tetrizolin and / or antimicrobial, for example: ciprofloxacin, chlorhexidine, erythromycin, gramicin, lomefloxacin, metronidazole, natamycin, neomycin, ofloxacin, polyaminopropyl-biguanide, polyquarternary 1, polymyxin B, sulfacetamide, zinc sulphate and tobramycin and / or antioxidant, for example: folic acid, hyaluronic acid, B complex, blackberry and lutein extract and / or others of ophthalmological utility, for example: Hydroxyalkomphosphonate, oxymetazoline, tetrahydroxoline and sodium salts and / or their pharmaceutically acceptable salts and / or polymorphs and / or solvatomorphs and / or co-crystals.

The conjugation of the inorganic nanocrystalline nucleus and the monomolecular layers of the polyhydroxy compound-drug in the nanoparticulate pharmaceutical system increases the ocular bioavailability enhancing the effect of the drug due to the nanometric size of the acuosomes, favoring the penetration in therapeutic doses through the ocular membrane, consequently, the dose to be applied to the eye is considerably reduced, reducing the adverse effects of the drug in question that may occur during treatment.

The nanoparticulate pharmaceutical system, in general, is formed by an inorganic nucleus of brushite, hydroxyapatite and / or other solid forms of calcium phosphate, graphite and / or combinations of these, obtained, in the case of brushite and hydroxyapatite, by precipitation of a solution of calcium chloride with a solution of phosphates; a coating prepared from solutions of different concentration of lactose, cyclodextrin a, hydroxypropylmethylcellulose, cellulose, dextrose, fructose, maltose, arabinose, glucose, mannitol, sorbitol, xylitol and / or combinations thereof and, one or more drugs that can have analgesic, lubricant, anti-inflammatory, antihistaminic, antimicrobial, antioxidant or combinations thereof, charged in the system by adsorption to the inorganic nuclei.

The manufacturing process of the nanoparticulated pharmaceutical ophthalmic dosage system is characterized by keeping in a specific range the variables of system agitation and rate of dosing of the reagents to obtain a specific amount of the inorganic component in the nucleus, besides controlling the size of the core particle, from 60 to 120 nm, and the agglomerate of crystals.

The process for the formation of the nanoparticulate pharmaceutical system is divided into three stages: 1. Formation of inorganic nuclei.

• Prepare a solution of calcium salts and a solution of phosphate salts, • precipitate the above solutions in a ratio of 1: 5 calcium salts and phosphate salts, respectively, mixing by dripping at speeds of 1 to 12 mL / min under sonication of between 20 to 150 pulses, for a period of 90 min and stirring constant mechanics, between 60 to 100 rpm, during and after precipitation, · Vacuum filtering through a nitrocellulose membrane of 0.22 μ? T? Y • Dry by evaporation at reduced pressure to obtain the inorganic cores of brushite, hydroxyapatite and other solid forms of calcium phosphate.

Coating with polyhydroxy compound.

• Prepare a solution in concentrations between 0.03 and 0.09 of the polyhydroxy compound chosen from: lactose cyclodextrin, hydroxypropylmethylcellulose, cellulose, dextrose, fructose, maltose, arabinose, glucose, mannitol, sorbitol, xylitol and / or combinations thereof, • resuspend the inorganic nuclei, product of the previous stage, in double-distilled water in a ratio of 1: 1 p / v, • mix the polyhydroxy compound solution with the inorganic cores of brushite, h id roapatite and other solid forms of calcium phosphate resuspended in water, in a ratio of 1: 100 v / v with constant mechanical agitation of between 60 to 100 rpm, for 90 min. , • vacuum filtering through a nitrocellulose membrane of 0.22 pm and • Dry by evaporation at reduced pressure.

Adsorption of the drug.

• Prepare a solution of the selected drug (s) in a pharmaceutically acceptable concentration, dissolved in a solvent that is chosen from: acetone, chloroform or ethyl ether, and / or mixture thereof in different proportions according to the physicochemical nature of the drug, • mix the drug solution with the inorganic nuclei coated with the polyhydroxy compound in a ratio of 1: 1 w / v, maintaining a constant mechanical agitation between 60 to 100 rpm, • vacuum filtering through a nitrocellulose membrane of 0.22 pm and • Dry by evaporation at reduced pressure.

For the characterization and design of the nanoparticulate pharmaceutical system, instrumental analytical techniques were required, such as powder X-ray diffractometry (Figure 2), scanning electron microscopy, transmission electron microscopy and granulometric analysis. With these, the distribution of the obtained particle size is determined, as well as the morphological characteristics of the nanoparticulate system.

By means of the images obtained by scanning electron microscopy, during the manufacturing process of the present nanoparticulate pharmaceutical system (Figure 3), the core surface area is calculated and based on the molecular size of the polyhydroxy compound, the amount of the latter is added. to the system to obtain a molecular film.

The nanoparticulate pharmaceutical system obtained according to the The aforementioned process is formulated into a composition useful in the treatment of eye diseases in mammals. In this way the nanoparticulate pharmaceutical system is loaded in a pharmaceutically acceptable vehicle for ophthalmic administration, specifically with a viscosity in a range between 25 and 50 cps since this determines the residence time in the eye.

Tests were carried out to determine the structural characterization of the acuosomes, by means of the structural scanning calorimetry method, in which a comparison was made between the lactose (L) indomethacin contained in acuosomas (A), the pure indomethacin (I) and a physical mixture (PM) of the components of the accusome. Figure 4 shows the thermograms of Lactose that present a signal at 151 ° C, this signal is associated with the loss of water and a signal at 219 ° C that corresponds to its melting point. The thermogram of pure indomethacin has an endotherm of 162 ° C corresponding to its melting point. In the physical mixture (lactose + indomethacin + calcium phosphate) shows small signals at 148 ° C and 160 ° C that can be attributed to lactose and indomethacin, as well as three broad endotherms at 75, 190 and 203 ° C. In the study interval in which the samples were analyzed (50-260 ° C), no signal corresponding to the inorganic core of calcium phosphate was observed. The aquasomnas show a broad endotherm at 77.9 ° C and a melting point at 205.6 ° C. The profile of this thermogram points to a different molecular arrangement between the organic compounds presented by the physical mixture.

On the other hand indomethacin release tests were carried out by the dialysis method. Figure 5 shows the release behavior of both indomethacin, physical mixture (lactose + indomethacin + calcium phosphate) and the aquasome. In comparison with the physical mixture, the aquasomes released twelve times more indomethacin in the first twenty minutes. After 400 minutes and until 24 hours, this release was maintained in a 1.6 to one ratio.

The composition containing the nanoparticulate pharmaceutical system is formulated as follows: a) Pharmaceutical system nanoparticulate in 0.06 to 0.6% b) one or more electrolytes that can be chosen from: sodium chloride, potassium chloride and sodium bicarbonate, in 3.0 to 71%, c) one or more viscosifying agents that can be chosen from the cellulose derivatives; methylcellutose, carboxymethylcellulose, hydroxypropylmethylcellulose, xanthan gum, tragacanth gum and gum arabic, among others in 20 to 50%, d) one or more surfactants which may be chosen from betaines and imidazolines derivatives: alkyl dimethyl betaine, alkyl amide propyl dimethyl betaine, as well as other polymers obtained from natural sources, by synthesis or modification of both by physical, chemical or biotechnological processes in 0.05 to 0.5%, e) one or more pH regulating agents that can be chosen from: sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, pH 7 to 7.5 f) one or more pharmaceutically acceptable excipients for ophthalmic application which may be chosen from: polyacrylic acid, carbomer, carboxymethylcellulose, dextran 70, guar gum, hydroxypropylcellulose, polyethylene glycol, povidone and propylene glycol in 30 to 90%. g) optionally one or more preservatives that can be chosen from methyl, ethyl, propyl or butyl paraben, or other pharmaceutically acceptable preservatives, in amounts of 0.2 to 0.5% (w / w).

In addition to the composition described above, the nanoparticulate pharmaceutical system has the ability to be administered to the eye in the form of gel, suspension, ointment, cream, emulsion and / or solution and has water-like properties that allow it to protect and conserve molecules due to to its conformation where the drug is chemically adsorbed, favoring its bioavailability and decreasing its adverse effects. In addition, its administration can be conventionally or by means of single or multidose ocular application devices such as a brush, microsyringes, spatula, pencil, brush, sprinkler, patch, inserts, contact lens, dropper or ampules. The release of the active ingredient can be controlled, delayed, sustained, pulsatile, prolonged, immediate or the combination thereof, depending on the matrix design of the nanoparticulate pharmaceutical system, the type of pharmaceutical composition and the method of administration.

The following examples are intended to illustrate the invention, not to limit it, any variation thereof falling within the scope of the present invention.

EXAMPLES Next, the compositions employed during the development of the present invention are described: Example 1. Nanoparticulate pharmaceutical system loaded with indomethacin dissolved in acetone Example 2. Nanoparticulate pharmaceutical system loaded with indomethacin dissolved in ethanol Example 3. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin Example 4. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin Example 5. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin Example 6. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin Example 7. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin Example 8. Composition containing a nanoparticulate pharmaceutical system loaded with indomethacin These examples of nanoparticulate pharmaceutical systems loaded with indomethacin favor the reduction of the intraocular pressure improving the stability, the release of the drug and its bioavailability. On the other hand, Indomethacin inhibits prostaglandin-forming cyclooxygenase in the eye and stabilizes the blood-aqueous barrier, which favors its ophthalmic application in the treatment of different eye diseases such as Sjögren's syndrome, rosacea and dry eye syndrome, among others.

Example 9. Composition containing a nanoparticulate pharmaceutical system loaded with diclofenac It is noted that the best method known to the applicant to carry out the invention is that which results from the present description.

Claims (35)

R E I V I N D I C A C I O N S Having described the invention, it is considered as a novelty and therefore the content of the following claims is claimed as property:

1. Pharmaceutical composition of ophthalmic application comprising: a) A nanoparticulate pharmaceutical system, b) one or more electrolytes, c) one or more viscosifying agents, d) one or more surfactants, e) one or more pH regulating agents. f) one or more pharmaceutically acceptable excipients for ophthalmic application and g) optionally one or more conservatives.

2. Pharmaceutical composition for ophthalmic application according to claim 1, characterized in that the nanoparticulate pharmaceutical system of part a) can be formulated in multilayer form and comprises in turn: i. An inorganic nanocrystalline nucleus, ii. one or more monomolecular layers of pharmaceutically acceptable polyhydroxy compound and iii. coating of one or more drugs and / or biomolecules with analgesic and / or lubricating and / or antiinflammatory and / or antihistamine and / or antimicrobial and / or antioxidant and / or other ophthalmological or combinations thereof.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, characterized in that the inorganic nanocrystalline nucleus of item i) of the nanoparticulate pharmaceutical system can be chosen from: brushite, hydroxyapatite, and / or other solid forms of calcium phosphate and / or combinations thereof.

Pharmaceutical composition for ophthalmic application according to rei indications 1 and 2, characterized in that the inorganic nanocrystalline nucleus of item i) of the nanoparticulate pharmaceutical system has a particle size of 60 to 120 nm.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, characterized in that the monomolecular layer (s) of the pharmaceutically acceptable polyhydroxy compound of part i) of the nanoparticulate pharmaceutical system are linked to the inorganic nanocrystalline nucleus by means of non-covalent bonds, preferably hydrogen bonds .

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, characterized in that for the formation of the monomolecular layer (s) of polyhydroxy-pharmaceutically acceptable compound of the insert // ') of the nanoparticulate pharmaceutical system can be chosen from: lactose, cyclodextrin , hydroxypropylmethylcellulose, cellulose, dextrose, fructose, maltose, arabinose, glucose, mannitol, sorbitol, xylitol or others that form non-covalent bonds, preferably hydrogen bonds and / or combinations thereof.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, characterized in that the coating layer (s) of one or more drugs of item iii) of the nanoparticulate pharmaceutical system are bound to the monomolecular layer (s) of pharmaceutically acceptable polyhydroxy-compound by links non-covalent, preferably hydrogen bonds.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, characterized in that the coating particles of one or more drugs of item iii) of the nanoparticulate pharmaceutical system are chosen from among those having activity: analgesic, lubricating, anti-inflammatory, antihistaminic, antimicrobial, antioxidant and others of ophthalmological utility or combinations thereof.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with analgesic activity are chosen from: diclofenac sodium, fenoprofen, indomethacin, ketoprofen and ketorolac and / or their pharmaceutically acceptable salts and / or amorphous and / or polymorphs and / or sun vatomorphs and / or co-crystals.

Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with lubricating activity are chosen from: hyaluronic acid, polyvinyl alcohol, glycerin and sodium hyaluronate and / or their pharmaceutically acceptable salts and / or amorphous and / or polymorphs and / or solvatomorphs and / or co-crystals.

Ophthalmic application pharmaceutical composition according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with anti-inflammatory activity are chosen from: chamomile oil, cyclosporin, chondroitin, dexamethasone, diclofenac, diclofenac sodium, fenoprofen, fluorometalone , Hammamelis virginiana, indomethacin, ketoprofen, ketorolac, meloxicam, nepafenac, prednisolone and rimexolone and / or their pharmaceutically acceptable and / or amorphous and / or polymorph salts and / or solvatomorphs and / or co-crystals.

12. Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with antihistaminic activity are chosen from: antazoline, phenylephrine, naphazoline and tetrizolin and / or their pharmaceutically acceptable and / or amorphous salts and / or polymorphs and / or solvatomorphs and / or co-crystals.

13. Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with antimicrobial activity are chosen from: c lo proff loxacin, chlorhexidine, erythromycin, gramicin, lomefloxacin, metronidazole, natamycin, neomycin, ofloxacin, polyaminopropylbiguanide, polyquarternary 1, polymyxin B, sulfacetamide, zinc sulphate and tobramycin and / or their pharmaceutically acceptable and / or amorphous and / or polymorph salts and / or solvatomorphs and / or co-crystals.

14. Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with antioxidant activity are chosen from: folic acid, hyaluronic acid, B complex, blackberry extract and lutein and / or their pharmaceutically acceptable salts and / or amorphous and / or polymorphs and / or solvatomorphs and / or co-crystals.

15. Pharmaceutical composition for ophthalmic application according to claims 1 and 2, wherein the drug (s) of the nanoparticulate pharmaceutical system with some activity of ophthalmological utility are chosen from: hydroxyalkylphosphonate, oxymetazoline, tetrahydroxoline and sodium salts their pharmaceutically acceptable salts, and / or amorphous and / or polymorphs and / or solvatomorphs and / or co-crystals.

16. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the nanoparticulate pharmaceutical system of part a) is in a proportion between 0.06 to 0.6%.

17. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the electrolyte (s) of item ib) are chosen from among: sodium chloride, potassium chloride and sodium bicarbonate.

18. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the electrolyte (s) of item ib) are in a proportion between 3.0 to 71%.

19. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the viscosifying agent (s) of part c) are chosen from: cellulose derivatives; methylcelutose, carboxymethylcellulose, hydroxypropylmethylcellulose xanthan gum, tragacanth gum and gum arabic.

20. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the viscosifying agent or agents of part c) are present in a proportion of between 20 to 50%.

21. Pharmaceutical composition of ophthalmic application according to the indication rei 1, wherein the surfactant (s) of subsection d) are chosen from: carboxymethylcellulose (CMC) and h id rox i pro pi I me ti l-ce I u a a ( HPMC), as well as other polymers obtained from natural sources, by synthesis or the modification of both by physical, chemical or biotechnological processes.

22. Ophthalmic application pharmaceutical composition according to claim 1, wherein the surfactant (s) of item d) are in a proportion between 0.05 to 0.5%.

23. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the pH regulating agent (s) of item e) are chosen from: sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid.

24. Ophthalmic application pharmaceutical composition according to claim 1, wherein the pH regulating agent (s) of item e) act at a pH of between 7 and 7.5.

25. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the excipient (s) f) are chosen from: polyacrylic acid, carbomer, carboxymethylcellulose, dextran 70, guar gum, hydroxypropylcellulose, polyethylene glycol, povidone and propylene glycol or other pharmaceutically acceptable for its ophthalmic application.

26. Pharmaceutical composition for ophthalmic application according to claim 1, wherein the excipient (s) f) are in a proportion of between 30 to 90%.

27. Ophthalmic application pharmaceutical composition according to claim 1, wherein the preservative agent (s) of part g) are chosen from: methyl, ethyl, propyl or butyl paraben, or other pharmaceutically acceptable agents.

28. Ophthalmic application pharmaceutical composition according to claim 1, wherein the preservative agent (s) of item g) are in a proportion between 0.2 to 0.5% (W / W).

29. Process for preparing the pharmaceutical composition for ophthalmic application according to the indications 1 to 28, characterized in that the following steps are carried out: i. Formation of the inorganic nanocrystalline core, prepare a solution of calcium salts and a solution of phosphate salts, precipitate the above solutions in a 1: 5 ratio of calcium salts and phosphate salts; respectively, mixing by dripping at speeds of 1 to 12 mL / min, under sonication of between 20 to 150 pulses, for a period of 90 min and constant mechanical agitation, between 60 to 100 rpm, during and after precipitation, filter vacuum by a nitrocellulose membrane of 0.22 μ? t? and drying by evaporation under reduced pressure. I. Formation of the monomolecular layer or layers of pharmaceutically acceptable polyhydroxy compound, prepare a solution in concentrations between 0.03 and 0.09 M of the polyhydroxy compound, resuspend the inorganic nuclei, product of the previous stage, in double-distilled water in a ratio of 1: 1 w / v, mix the solution of polyhydroxy compound with the inorganic nuclei of brushite, hydroxyapatite, and / or other solid forms of calcium phosphate and / or combinations thereof, resuspended in water, in a ratio of 1: 100 v / v with mechanical agitation constant, between 60 to 100 rpm, for 90 min, vacuum filtering through a nitrocellulose membrane of 0.22 μ? and drying by evaporation under reduced pressure. Adsorbing the drug to the inorganic core coated with the polyhydroxy compound, preparing a solution of the drug (s) in pharmaceutically acceptable concentration dissolved in a solvent selected from: acetone, chloroform or ethyl ether, and / or mixing them in different proportions according to the physicochemical nature of the drug, mix the drug solution with the inorganic nuclei coated with the polyhydroxy compound in a ratio of 1: 1 w / v, maintaining a constant mechanical agitation of between 60 to 100 rpm, vacuum filtering through a nitrocellulose membrane of 0.22 μ ?? and drying by evaporation under reduced pressure.

30. Pharmaceutical composition for ophthalmic application according to claims 1 to 29, characterized in that it has a viscosity in a range of between 25 and 50 cps.

31. Pharmaceutical composition for ophthalmic application according to claims 1 to 30, characterized in that it forms a colloidal solution.

32. Use of the pharmaceutical composition for ophthalmic application according to claims 1 to 31, for the preparation of a medicament useful in the treatment of eye diseases in mammals.

33. Use of the nanoparticulate pharmaceutical system according to claims 1 to 32, wherein the medicament is adapted to be used as: gel, suspension, ointment, cream, emulsion and / or solution.

34. Use of the nanoparticulate pharmaceutical system according to claims 35 and 33 wherein the medicament is adapted for use by: single-dose or multi-dose ocular application devices such as a brush, microsyringe, spatula, pencil, brush, spray, patch, inserts, lens contact, dropper or ampules.

35. Use of the nanoparticulate pharmaceutical system according to claims 35 to 34, wherein the medicament is adapted to be released in a controlled, delayed, sustained, pulsatile, prolonged, immediate or combination thereof form.