WO2021156735A1

WO2021156735A1 - Stable ophthalmic formulations based on low-concentration povidone iodide in plastic containers

Info

Publication number: WO2021156735A1
Application number: PCT/IB2021/050813
Authority: WO
Inventors: Danilo Aleo; Barbara MELILLI; Maria Grazia Saita; Fabiola SPITALERI; Sergio Mangiafico; Melina Cro
Original assignee: Medivis S.R.L.
Priority date: 2020-02-03
Filing date: 2021-02-02
Publication date: 2021-08-12
Also published as: EP4100063A1

Abstract

The present invention relates to topical ophthalmic formulations based on low-concentration povidone iodide, which are stable even when stored in plastic containers.

Description

"Stable ophthalmic formulations based on low- concentration povidone iodide in plastic containers"

DESCRIPTION

The present invention is applicable to the medical field, and in particular relates to topical ophthalmic formulations based on povidone iodide

(PVP-I).

PVP-I is a complex between iodine and polyvinylpyrrolidone containing on average 10% by weight of available iodine (iodine titratable with thiosulfate) and not more than 6.6% by weight of the iodide ion.

5% PVP-I solutions are used for preoperative ocular prophylaxis only after local anesthesia, as instillation causes burning and redness of the eye.

It is further reported that galenic ophthalmic preparations with 2.5% PVP-I are decidedly poorly tolerated, while those with a PVP-I content between 1 and 1.25% are better tolerated; in fact, the instillation thereof causes only temporary burning and solutions below 1% of PVP-I could have a better compliance. (Community Eye Health 2003, Vol 16 No.

48: 63).

In addition to the fundamental aspect of ocular tolerability, it should be emphasized that diluted aqueous solutions of PVP-I have markedly greater antimicrobial activity with respect to the same concentrated solutions.

This fact is correlated to an increase in the concentration of molecular iodine, also called free iodine (Journal of Hospital Infection. 1985, 6

Suppl ., 13-23); in particular, the latter is found to be at concentrations of about 1 ppm in 10% solutions of PVP-I and about 20 ppm for 0.1% concentrations of

PVP-I. Rackur et al. explain this phenomenon with the presence of polymeric aggregates of PVP capable of trapping the molecular iodine.

Such aggregates disintegrate in diluted solutions, releasing the molecular iodine in solution

(The importance of standardization of the aqueous povidone-iodine formulations, Proc. Inti. Symp. on

Povidone, Digenis D.J ., Ansell J ., eds ., University of Kentucky College of Pharmacy, 1983, 99).

For aqueous solutions, the maximum free iodine is reached for PVP-I concentrations close to 0.1%; what has been said so far is shown in Figure 1.

Various works confirm that the bactericidal action of medicinal compositions based on PVP-I is to be attributed only to the free molecular iodine and not to that available which is titratable with thiosulfate (Control of the Amount of Free Molecular

Iodine in Iodine Germicides. J. Pharm. Pharmacol.

1997, 49: 1195-1199; Increased Bactericidal Activity of Dilute Preparations of Povidone-Iodine Solutions.

Journal Of Clinical Microbiology, Apr. 1982, 635-

639).

All these observations undoubtedly suggest the desirability of obtaining ophthalmic preparations at the lowest possible concentrations of PVP-I.

It is known, however, that the diluted solutions of PVP-I decrease the concentration thereof over time; the more they are diluted, the more rapidly this occurs.

Such a decrease is caused by the loss of molecular iodine, as it is capable of passing through the walls of the container.

The influence of the type of packaging material on the stability of an aqueous solution of PVP-I at different concentrations is decisive and is described in many patent documents and in various technical bulletins (Povidone-Iodine Technical Information

August 2010 supersedes issue dated June 2008, BASF). As can be seen in Figure 2, the losses are greater for low-concentration solutions of PVP-I and for more permeable materials such as low-density polyethylene.

High density polyethylene has a greater containment action for concentrations above 1%; for lower values solution stability problems arise.

Glass is the least permeable container and, therefore, more suitable for storing low- concentration PVP-I solutions; since it is impossible to obtain an ophthalmic preparation totally sealed in a glass container which does not include a plastic dropper, in this case it must be considered that solutions diluted below 1% may not be sufficiently stable and therefore not commercially feasible even when contained in this material.

The previous patent application WO 2017/175075 in the name of the same Applicant describes aqueous formulations, in which an oil phase and a surfactant can be present, based on PVP-I at low concentrations, storable in glass containers with polypropylene, polyethylene or bromobutyl rubber droppers. Such formulations can maintain a PVP-I titer above 85% for a period of 24 months under refrigerated conditions of 4 ± 2°C.

However, such formulations cannot be stored in plastic containers, since, being permeable, they allow iodine to pass through; in fact, after a few months, these formulations show a PVP-I titer loss which does not allow the marketing of such solutions.

The possibility of having PVP-I solutions in plastic containers would allow the production of these formulations in the standard containers used by major manufacturing companies, which include disposable vials of different plastic materials, currently impossible to be made of glass.

Patent application CN 101 987 109 describes an ophthalmic composition comprising povidone-iodide, glucocorticoids and beta-cyclodextrins or derivates thereof.

SUMMARY OF THE INVENTION

The inventors of the present patent application have surprisingly found that it is possible to obtain ophthalmic formulations based on PVP-I at low concentrations, which allow to overcome at least partially the drawbacks of the known formulations.

OBJECT OF THE INVENTION

In a first object, the present patent application describes topical pharmaceutical formulations for ophthalmic use comprising povidone iodide at a concentration between 0.05% and 1% and a cyclodextrin.

In a second object, the present invention describes such formulations for medical use.

In a particular aspect, the medical use is described in presurgical ocular prophylaxis.

In a third object, the present invention describes a method for the presurgical treatment of a patient comprising the step of administering to said patient a topical formulation for ophthalmic use according to the present invention.

In a fourth object, a method for storing the formulations of the invention in a packaging container is described.

In a particular aspect, such a method is described for storage up to 24 months.

The method for preparing such formulations and a container for storing them represent further objects of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the correlation between the free iodine and microbial reduction after 15 seconds in aqueous solutions of PVP-I at various concentrations;

Figure 2 shows the results of the assays on the influence of the packaging and concentration on the stability of the PVP-I solutions.

DETAILED DESCRIPTION OF THE INVENTION

According to a first object, the present invention describes aqueous ophthalmic pharmaceutical formulations comprising povidone iodide at a concentration of about 0.05-1% (w/w) and a cyclodextrin.

In a preferred aspect, the formulations described comprise povidone iodide in an amount of about 0.1-0.7% (w/w).

The formulations of the invention comprise povidone iodide with a free iodine content between 8 and 120 ppm.

In an aspect of the invention, the povidone iodide used has an available iodine content of about

9-12% (w/w), and preferably 10%.

For the purposes of the present invention, alternatively to a cyclodextrin, a derivate thereof can be used.

In particular, cyclodextrin, or a derivate thereof, is comprised in an amount of about 0.01-3% and preferably about 0.2-0.8%.

For the purposes of the present invention, the cyclodextrin, or a derivate thereof, is selected from the group comprising: β-cyclodextrin (β-CDX), hydroxypropyl β-cyclodextrin (ΗΡ-β-CDX), sulfobutyl ether β-cyclodextrin (SΒΕ-β-CDΧ), methyl-β- cyclodextrin (Μe-β-CDX), γ-cyclodextrin (γ-CDX), hydroxypropyl γ-cyclodextrin (ΗΡ-γ-CDX); or mixtures thereof.

In a preferred aspect, said cyclodextrin, or derivate thereof, is methyl- β-cyclodextrin (Me-β-

CDX).

According to a particular aspect of the present invention, the formulations described further comprise an oil phase.

Preferably, said oil phase is represented by triglycerides and, even more preferably, by medium chain triglycerides (MCT).

In particular, said medium chain triglycerides

(MCTs) can be present in an amount of about 0-3%

(w/w) and preferably about 0.1-1% (w/w).

In accordance with a further aspect, the formulations described further comprise a surfactant.

In a preferred aspect, where the compositions of the invention comprise an oil portion, these also comprise a surfactant.

For the purposes of the present invention, the surfactant is selected from the group comprising

Triton and Tween; more in particular, the surfactant can be Triton 405 or Tween 80 or it can be d-α- tocopheryl polyethylene glycol 1000 succinate (TPGS) or Solutol HS 15.

In particular, the d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is comprised in an amount of about 0-4% (w/w) and preferably about 0.2-

2% (w/w).

For the purposes of the present invention, the formulations described are characterized by a pH of

4.5-6.9 and preferably about 5.4-6.1.

In this regard, a buffering agent selected from phosphates and/or citrates can be used.

Strong bases can be used for the final pH correction.

In an aspect of the invention, the formulations further comprise an osmotizing agent.

To this end, glycerol and/or sodium chloride can be used.

In an aspect of the invention, the formulations described further comprise one or more dissolved viscosizing agents.

Viscosizing agents can be selected from the group comprising: sodium hyaluronate and other agents compatible with ophthalmic use, such as, for example: carbopol, polyvinyl alcohol and hydroxypropyl methylcellulose .

For the purposes of the present invention, the sodium hyaluronate can be comprised in an amount of about 0.01-0.2% and preferably about 0.04-0.08%

(w/w).

In accordance with a second object, there are described the formulations of the invention for medical use.

In an aspect of the present invention, such formulations are described for medical use in presurgical ocular prophylaxis.

In a third object, the present invention describes a method for the treatment of a patient comprising the step of administering to said patient a topical formulation for ophthalmic use according to the present invention.

In particular, such a treatment is carried out before surgery on the eye of said patient and is therefore a presurgical treatment.

In accordance with a fourth object, the present invention describes a method for preparing the ophthalmic pharmaceutical formulations reported above.

In particular, such a method includes the preparation of the oil phase, which is then added to the aqueous phase.

According to a further object, a method for storing the formulations of the invention in a packaging container is described.

In particular, such a method comprises the step of storing a formulation according to what is described above in a container made of a material selected from a glass or a plastic material.

In a preferred aspect of the present invention, such a container is made of a plastic material.

For the purposes of the present invention, said plastic material is selected from the group comprising: low density polyethylene (LDPE), high density polyethylene (HDPE), polyethylene terephthalate (PET), polypropylene (PP).

According to a preferred aspect, such a storage lasts for a period of at least 3-24 months. In particular, the formulation of the invention stored according to the method described is capable of maintaining the titer within 90% of the initial titer after 24 months of storage under refrigerated conditions (4°C ± 2).

In an aspect of the present invention, such a method is also carried out in the presence of a dropper made of the same plastic material or one of the other plastic materials mentioned, which is in contact at least partially with the formulation contained.

In accordance with a further object of the present invention, a glass or a plastic material container is described, containing an ophthalmic pharmaceutical formulation according to the above description.

In an aspect of the invention, such a container can comprise a dropper made of plastic material or one of the other plastic materials mentioned, which is in contact at least partially with the formulation contained.

The present invention will be better shown by the following examples, which are not to be understood as limiting. EXAMPLES 1-3

Formulations at various concentrations of PVP-I in the presence of cyclodextrin

In table 2 below, the stability data of the formulations of Examples 1-3 in polypropylene and in glass are compared. It is surprising that in the case of plastic storage, such formulations have a greater stability, which goes beyond any possible prediction.

Table 2. Stability of the formulations of Examples 1-3 at a temperature of 4 ± 2ºC

EXAMPLES 4-8

PVP-I formulations in PP containers at various concentrations of MCT and TPGS and various concentrations of Methyl-β-cyclodextrin

Table 4. Stability of the formulations of Examples 4-8 at a temperature of 4 ± 2ºC

EXAMPLES 9-12

PVP-I formulations with various cyclodextrins in PP container

Table 6. Stability of the formulations of Examples 9-12 at a temperature of 4 ± 2ºC

EXAMPLES 13-15

PVP-I formulations with Me-β-CDX in various plastic containers

Table 8. Stability of the formulations of Examples 13-15 at a temperature of 4 ± 2ºC

Claims

CLAIMS:

1. A pharmaceutical ophthalmic formulation comprising povidone iodide at a concentration of

0.05-1% (w/w) and a cyclodextrin or a derivate thereof.

2. A formulation according to the preceding claim, wherein said cyclodextrin or derivate thereof is comprised in an amount of about 0.01-3% (w/w) and preferably about 0.2-0.8% (w/w).

3. A formulation according to claim 1 or 2, wherein said povidone iodide is comprised in an amount of about 0.1-0.7 (w/w).

4 . A formulation according to any one of the preceding claims, wherein said cyclodextrin or a derivate thereof is selected from the group comprising: β-cyclodextrin (β-CDX), hydroxypropyl β- cyclodextrin (ΗΡ-β-CDX), sulfobutyl ether β- cyclodextrin (SΒΕ-β-CDΧ), methyl-β-cyclodextrin (Me- β-CDX), γ-cyclodextrin (γ-CDX), hydroxypropyl γ- cyclodextrin (ΗΡ-γ-CDX), or mixtures thereof.

5. A formulation according to any one of the preceding claims, wherein said cyclodextrin or derivate thereof is methyl-β-cyclodextrin (Me-β-CDX).

6. A formulation according to any one of the preceding claims, further comprising an oil phase.

7. A formulation according to the preceding claim, wherein said oil phase comprises triglycerides .

8. A formulation according to the preceding claim, wherein said triglycerides are medium chain triglycerides and are comprised in an amount of about

0-3%, and preferably about 0.1-1% (w/w).

9. A formulation according to any one of the preceding claims, further comprising a surfactant.

10. A formulation according to the preceding claim, wherein said surfactant is selected from the group comprising Triton, which is preferably Triton

405, and Tween, which is preferably Tween 80, or is d-α-tocopheryl polyethylene glycol 1000 succinate

(TPGS) or Solutol HS 15.

11. A formulation according to the preceding claim, wherein said d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is comprised in an amount of about 0-4% (w/w), and preferably about 0.2-

2% (w/w).

12. A formulation according to any one of the preceding claims, characterized by a pH of 4.5-6.9, and preferably about 5.4-6.1.

13. A formulation according to any one of the preceding claims, further comprising buffering agents selected from phosphates and/or citrates.

14. A formulation according to any one of the preceding claims, further comprising a viscosizing agent and/or an osmotizing agent.

15. A formulation according to any one of the preceding claims for medical use.

16. A formulation according to any one of the preceding claims for medical use in presurgical ocular prophylaxis.

17. A method for storing a formulation according to any one of claims 1 to 16 comprising the step of storing said formulation in a container made of a material selected from a glass or plastic a material.

18. A method according to the preceding claim, wherein said plastic material is selected from the group comprising: low density polyethylene (LDPE), high density polyethylene (HDPE), polyethylene terephthalate (PET), polypropylene (PP).

19. A method according to the preceding claim, wherein the formulation according to any one of claims 1 to 16 is characterized by a titer within 90% of the initial titer after 24 months of storage under refrigerated conditions (4°C ± 2).

20. A container made of a glass or plastic material containing a pharmaceutical ophthalmic formulation according to any one of claims 1 to 16.

21. A method for treating a patient comprising the step of administering to said patient a topical formulation for ophthalmic use according to any one of claims 1 to 14.

22. A method according to the preceding claim, wherein said treatment is carried out before a surgical intervention on the eye of said patient.