Chemically and physically stable topical ophthalmic formulations based on nepafenac

Abstract

The present invention relates to topical ophthalmic formulations based on nepafenac which are particularly stable both from a chemical and physical point of view.

Description

[0001] describe

[0002] The present invention is applicable in the medical field and in particular relates to particularly stable topical ophthalmic formulations based on nepafenac (NPF).

[0003] In ophthalmology, topical use of nepafenac (NPF) is preferred over many other NSAIDs due to its excellent pharmacokinetic profile, even at the subretinal level.

[0004] For this reason, NPF is widely used to treat post-surgical inflammatory and pain states and is approved for the prevention of cystoid macular edema and certain neurodegenerative diseases affecting the retina.

[0005] However, from a chemical point of view, nepafenac is characterized by a very low water solubility (0.014 mg / ml), which makes it difficult to formulate in aqueous solutions.

[0006] In fact, to date, the only commercially available pharmaceutical preparations for ophthalmic use are represented by NPF suspensions in concentrations of 0.1% and 0.3%.

[0007] It is known that suspensions are characterized by poor patient compliance due to the foreign body sensation and irritation caused by the particles, inducing excessive tearing and subsequent washing away of the drug, thus preventing it from reaching high concentrations in the ocular tissues.

[0008] The same is true for nepafenac.

[0009] Considerable formulation efforts have been devoted to its suspension with the aim of improving its pharmacokinetic profile.

[0010] Several authors have evaluated the use of poloxamers, transdermal absorption enhancers, viscosizing or gelling polymers and even nanoparticle systems (NLCs) in thermosensitive hydrogels with the goal of increasing the precorneal residence time of the drug and improving its transcorneal penetration.

[0011] In 2013, Alcon introduced a new 0.3% NPF suspension (ILEVRO 0.3% or NEVANAC 0.3%) that showed better ocular bioavailability thanks to certain technical expedients; in fact, the new suspension offers both the use of HP-guar gum in addition to carbomer (a polymer known to increase the residence time before the cornea), as well as a reduction in the particle size of NPF to about one third of that of the 0.1% suspension.

[0012] While this type of drug release system is technologically advanced, it still involves very viscous suspensions which have the limitations listed above.

[0013] In contrast, formulation studies to obtain stable aqueous NPF solutions have been poor to date.

[0014] The only ones involved complex formation with β-cyclodextrin (β-CD), in particular hydroxypropyl β-CD (Hpβ-CD)a,b,c and sulfobutyl ether β-CD (SBEβ-CD)a,b, where the maximum NPF concentration studied was 0.1%.

[0015] Such studies have been performed to investigate both the stoichiometry of the NPF / β-CD complex and possible pharmacokinetic improvements relative to the commercial suspension in terms of transcorneal penetration and precorneal residence time.

[0016] The results have shown that NPF in solution has 18 times the rate of transcorneal penetration and 11 times the residence time of Nevanac 0.1%.

[0017] Nonetheless, these efforts have failed to describe formulations that are sufficiently stable over time to enable their pharmaceutical use. Summary of the invention

[0018] The inventors of the present patent application have surprisingly found that it is possible to produce ophthalmic formulations based on nepafenac that are stable from both a chemical and physical point of view; such formulations can be stored at room temperature for at least 24 months, always maintaining a nepafenac titer above 90%.

[0019] Purpose of the Invention

[0020] In a first object, the present patent application describes a topical pharmaceutical formulation based on nepafenac comprising methyl-β-cyclodextrin for ophthalmic use.

[0021] In one aspect of the invention, such formulations include a suitable hydrophilic polymer.

[0022] In another aspect, the formulations of the invention include additional active ingredients.

[0023] In a further aspect, the formulations described have a pH comprised between 7.1 and 7.9 and preferably comprised between 7.5-7.8.

[0024] In a second object of the present invention, the use of methyl-β-cyclodextrin for stabilizing an ophthalmic pharmaceutical formulation comprising nepafenac for topical use is described.

[0025] In a third object, a process for preparing the formulation of the invention is described.

[0026] In a fourth object, the preparations of the invention are described for medical use.

[0027] In particular, medical uses are described for the treatment of post-operative inflammatory and painful states, for the prevention of cystoid macular edema, for the treatment of retinal neurodegenerative diseases.

[0028] In a fifth object, a method for the ophthalmic treatment of post-operative inflammatory and / or painful states, for the prevention of cystoid macular edema, for the treatment of retinal neurodegenerative diseases is described, comprising administering the formulation of the invention to a patient in need thereof. DETAILED DESCRIPTION

[0029] According to a first object, the present invention describes ophthalmic pharmaceutical formulations based on nepafenac for topical use which are stable from a chemical and physical point of view.

[0030] In particular, the formulation of the present invention comprises an amount of nepafenac comprised between about 0.1% and 0.5% and preferably comprised between about 0.1% and 0.3% (weight / total weight of the formulation).

[0031] From a chemical point of view, stable means that the active ingredient nepafenac is shown not to be degraded even after a long period of time in the formulation of the present invention and maintains a high titer.

[0032] Such stabilizing effects may also be shown to be associated with any additional active ingredients included in the formulation.

[0033] For the purposes of the present invention, in the described formulations, the nepafenac titer is ≥97% at 6 months, preferably ≥96% at 9 months, more preferably ≥95% at 12 months, even more preferably ≥93% at 18 months, and still more preferably ≥92% at 24 months.

[0034] From a physical point of view, stable means that no precipitation, aggregation, flocculation, phase separation phenomena are observed in the formulations of the present invention.

[0035] Preferably, no such phenomenon is observed at 6 months, preferably at 9 months, more preferably at 12 months, even more preferably at 18 months and still more preferably at 24 months.

[0036] According to the present invention, the described formulations are stable because they include methyl-β-cyclodextrin (hereinafter abbreviated as Metβ-CD).

[0037] In one aspect of the invention, Metβ-CD is present in an amount comprised between about 1-5% and preferably comprised between about 3-5% (weight - total weight of the formulation).

[0038] According to one aspect of the present invention, the formulation of the present invention may include one or more hydrophilic polymers.

[0039] Preferably, such polymers are selected from polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA); thus, polyvinyl pyrrolidone and / or polyvinyl acetate may be present in the formulation.

[0040] Such polymers are each present in the formulation in an amount comprised between about 0.5 and 1.5% (weight / total weight of the formulation).

[0041] For the purposes of the present invention, the preferred polyvinylpyrrolidone is PVP 30, although other types of PVP are equally possible, such as, for example, PVP 15, 60, 90, 120, etc.

[0042] For purposes of the present invention, the preferred polyvinyl acetate is PVA 28-99, although other types of PVA are equally possible, such as, for example, PVA 4-88, 8-88, 28-99, and the like.

[0043] The use of PVP and PVA does not exclude the use of other hydrophilic polymers compatible with ophthalmic applications or associations therebetween.

[0044] According to an alternative aspect of the invention, in addition to the hydrophilic polymers described above, hyaluronic acid may be used, preferably in an amount of about 0.05-0.15% and more preferably about 0.10-0.15% (weight / total weight of the formulation), in order to make the preparation more mucoadhesive and impart rheological characteristics that improve its acceptability to patients.

[0045] For the purposes of the present invention, the formulation has a pH comprised between about 7.1 and 7.9 and preferably comprised between about 7.5-7.8.

[0046] The formulation of the invention may include a preservative having a bacteriostatic effect, for example selected from the group comprising benzalkonium chloride, cetrimide or polyhexanide (PHMB) and sodium metabisulfite.

[0047] According to another aspect of the invention, the described formulations may also contemplate the presence of other pharmacologically active molecules (active ingredients).

[0048] These can be chosen from the group comprising: the polyunsaturated fatty acids EPA and DHA (both in the form of the ethyl ester EE and the acid AA), cortisones selected from: dexamethasone (DEX); betamethasone and hydrocortisone (HYD), both in the form of the phosphates (DEX-P, HYD-P) and the free alcohols (DEX-OH, HYD-OH); other cortisones for ophthalmic use.

[0049] As regards other components of the formulations of the invention, these may include:

[0050] - a buffer system comprising a buffer selected from the group comprising: a sodium phosphate buffer system which may be replaced by sodium citrate and / or potassium citrate or other buffers compatible with ophthalmic use;

[0051] - Osmotic agent selected from the group consisting of glycerol, mannitol, trehalose, sorbitol, in a concentration suitable to obtain a solution with an osmotic pressure comprised between about 240 and 350 mOsm / kg. The latter two in particular, do not cause changes in the stability of the formulation.

[0052] In one aspect of the invention, the formulation described comprises nepafenac in an amount of about 0.1-0.5%, Metβ-CD in an amount of about 3-5%, a hydrophilic polymer in an amount of about 0.5-1%, and has a pH of about 7.5-7.8.

[0053] Specific examples of such prepared formulations are shown in Table 1 below (composition in % w / total weight of the formulation):

[0054] Table 1

[0055]

[0056] In a preferred aspect of the invention, the formulation described comprises nepafenac in an amount of about 0.1-0.3%, Metβ-CD in an amount of about 3.5-4%, a hydrophilic polymer in an amount of about 0.5-1%, and has a pH of about 7.5-7.8.

[0057] Specific examples of such prepared formulations are shown in Tables 2A and 2B below (composition in % w / total weight of the formulation):

[0058] Table 2A

[0059]

[0060]

[0061] Table 2B

[0062]

[0063]

[0064] According to a second object of the present invention, the use of methyl-β-cyclodextrin for chemically and physically stabilizing an ophthalmic pharmaceutical preparation comprising nepafenac for topical use is described.

[0065] In particular, such formulations are the formulations described in the present patent application.

[0066] According to a third object, a process for preparing an ophthalmic pharmaceutical formulation comprising nepafenac for topical use is described.

[0067] In particular, the method comprises a step of dissolving the active ingredient nepafenac in a solution comprising Metβ-CD and optionally a selected hydrophilic polymer, wherein such solution has a pH comprised between 7.1 and 7.9 and preferably comprised between 7.5-7.8.

[0068] In one aspect of the invention, such a dissolving step may be performed at a temperature comprised between 20°C and 120°C.

[0069] In another aspect of the invention, such a step may be performed in a time comprised between 10 and 30 minutes.

[0070] After the dissolution step is completed, the osmotic agent, any additional hydrophilic polymers are added and finally the final step of adjusting the pH to the desired value is performed.

[0071] In a fourth object, a preparation according to the invention as described above for medical use is described.

[0072] In particular, medical uses are described for the treatment of post-operative inflammatory and / or painful states, for the prevention of cystoid macular edema, for the treatment of retinal neurodegenerative diseases.

[0073] In a fifth object, the present invention describes a method for the ophthalmic treatment of post-operative inflammatory and / or painful states, for the prevention of cystoid macular edema, and for the treatment of retinal neurodegenerative diseases, comprising administering a formulation as described in this patent application to a patient in need thereof.

[0074] The present invention will be better illustrated by the following examples, which are not to be construed as limiting.

[0075] Examples 1-6

[0076] stability

[0077] The following is a comparative study between ophthalmic formulations containing Metβ-CD and formulations containing other β-cyclodextrins. Unlike formulations containing Metβ-CD, those containing other cyclodextrins show a degradation rate of the active ingredient, which after a few months leads to a content of NPF significantly lower than 90% of its initial titer, or even undergoes the formation of precipitates (see Table 3).

[0078] Table 3

[0079]

[0080]

[0081] Table 4 below shows stability data for the formulations of Examples 1 to 6.

[0082] Table 4

[0083]

[0084]

[0085] As shown by the results of the tests carried out, formulations containing NPF complexed with Metβ-CD have a considerable additional stability when formulated in the presence of hydrophilic polymers, in particular polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA). These polymers allow the stability of NPF to be increased to 98% after 24 months of storage at 25°C, limiting the degradation to a few by-products, each of which does not exceed 1% relative to the nominal titer of NPF. No such advantage was observed when NPF was formulated with cyclodextrins other than Metβ-CD.

[0086] Example 7

[0087] stability

[0088] Tables 5-10 below show the results of stability studies conducted on Formulations 1-6 described in this patent application.

[0089] Table 5. Stability study of formulation 1 at 25°C

[0090]

[0091] Table 6. Stability study of formulation 2 at 25°C

[0092]

[0093] Table 7. Stability study of formulation 3 at 25°C

[0094]

[0095]

[0096] Table 8. Stability study of formulation 4 at 25°C

[0097]

[0098] Table 9. Stability study of formulation 5 at 25°C

[0099]

[0100] Table 10. Stability study of formulation 6 at 25°C

[0101]

[0102]

[0103] Example 8

[0104] stability

[0105] Tables 11-15 show the stability studies of Formulations 9-13 at 25°C where the presence of cortisone or omega-3 was anticipated.

[0106] Table 11. Stability study of Formulation 9 at 25°C.

[0107]

[0108] Table 12. Stability study of formulation 10 at 25°C

[0109]

[0110]

[0111] Table 13. Stability study of formulation 11 at 25°C

[0112]

[0113] Table 14. Stability study of formulation 12 at 25°C

[0114]

[0115] Table 15. Stability study of Formulation 13 at 25°C.

[0116]

[0117] In such a formulation, the additional active ingredients (DEX-P, HYD-P, DEX-OH and EPA and DHA) showed a chemical stability of more than 90% after 24 months at 25°C and, as surprisingly can be seen, their presence did not affect the stability of the NPF.

[0118] From the foregoing description, the advantages provided by the formulation of the present invention will become apparent to those skilled in the art.

[0119] Firstly, liquid ophthalmic formulations can be prepared that are highly desired by patients and therefore show high acceptability (compliance).

[0120] Furthermore, these formulations have shown high stability from both a physical and chemical point of view, contributing to a surprisingly long shelf life, up to 24 months.

[0121] The presence of additional active ingredients in the formulations of the invention does not in any way lead to a reduction in their stability; thus, the present invention allows the preparation of formulations comprising more than one drug.

Claims

1. An ophthalmic pharmaceutical preparation comprising nepafenac and methyl-β-cyclodextrin, wherein: Nepafenac is dissolved in a solution comprising methyl-β-cyclodextrin, wherein nepafenac is present in an amount comprised between 0.1% and 0.5% by weight based on the total weight of the formulation, methyl-β-cyclodextrin is included in an amount comprised between 1 and 5%, and the ophthalmic pharmaceutical formulation further comprises a hydrophilic polymer selected from the group comprising: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and hyaluronic acid.

2. The ophthalmic pharmaceutical preparation according to claim 1, wherein Nepafenac is present in an amount comprised between 0.1% and 0.3% by weight based on the total weight of the formulation.

3. The ophthalmic pharmaceutical preparation according to claim 1, wherein Methyl-β-cyclodextrin is included in an amount comprised between 3-5% by weight, based on the total weight of the formulation.

4. The ophthalmic pharmaceutical preparation according to claim 1, wherein The polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) are each present in the composition in an amount comprised between 0.5 and 1.5% by weight, based on the total weight of the formulation.

5. The ophthalmic pharmaceutical preparation according to claim 1, wherein The hyaluronic acid is present in an amount of 0.05-0.15% by weight based on the total weight of the formulation.

6. The ophthalmic pharmaceutical preparation according to claim 1, wherein The hyaluronic acid is present in an amount of 0.10-0.15% by weight based on the total weight of the formulation.

7. The ophthalmic pharmaceutical preparation according to claim 1, further comprising one or more additional active ingredients for ophthalmic use.

8. The ophthalmic pharmaceutical preparation according to claim 7, wherein The active ingredients include: polyunsaturated fatty acids or derivatives thereof, and cortisone.

9. The ophthalmic pharmaceutical preparation according to claim 1, having a pH comprised between 7.1 and 7.

9.

10. The ophthalmic pharmaceutical preparation according to claim 1, having a pH comprised between 7.5 and 7.

8.

11. The ophthalmic pharmaceutical preparation according to claim 1, further comprising one or more of the following: a preservative, a buffer system, a permeation agent.

12. A method for preparing an ophthalmic pharmaceutical preparation according to any one of claims 1 to 11, comprising: A step of dissolving nepafenac in a solution comprising Metβ-CD and optionally a hydrophilic polymer, wherein such solution has a pH comprised between 7.1 and 7.9, a step of adding an osmotic agent, any other hydrophilic polymer and a subsequent step of adjusting said pH to the desired value.

13. The method according to claim 12, wherein: Such a solution has a pH comprised between 7.5 and 7.

8.

14. Use of methyl-β-cyclodextrin for stabilizing an ophthalmic pharmaceutical preparation comprising nepafenac, wherein: Nepafenac is dissolved in a solution comprising methyl-β-cyclodextrin, wherein nepafenac is present in an amount comprised between 0.1% and 0.5% by weight based on the total weight of the formulation, methyl-β-cyclodextrin is included in an amount comprised between 1 and 5%, and the ophthalmic pharmaceutical formulation further comprises a hydrophilic polymer selected from the group comprising: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and hyaluronic acid.

15. An ophthalmic pharmaceutical preparation according to any one of claims 1 to 11 for use as a medicament.

16. An ophthalmic pharmaceutical preparation according to any one of claims 1 to 11 for use as a medicament for the treatment of postoperative inflammation and / or pain states, for the prevention of cystoid macular edema, for the treatment of retinal neurodegenerative diseases.

17. Use of a formulation according to any one of claims 1 to 11 in the manufacture of a medicament for the ophthalmic treatment of postoperative inflammation and / or pain states, for the prevention of cystoid macular edema, for the treatment of retinal neurodegenerative diseases.

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