EP4100063A1 - Stable ophthalmic formulations based on low-concentration povidone iodide in plastic containers - Google Patents
Stable ophthalmic formulations based on low-concentration povidone iodide in plastic containersInfo
- Publication number
- EP4100063A1 EP4100063A1 EP21707371.7A EP21707371A EP4100063A1 EP 4100063 A1 EP4100063 A1 EP 4100063A1 EP 21707371 A EP21707371 A EP 21707371A EP 4100063 A1 EP4100063 A1 EP 4100063A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formulation according
- cyclodextrin
- formulation
- cdx
- formulations
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 63
- 238000009472 formulation Methods 0.000 title claims abstract description 58
- 229920003023 plastic Polymers 0.000 title claims abstract description 20
- 239000004033 plastic Substances 0.000 title claims abstract description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 title claims abstract description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 title claims abstract description 14
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229940069328 povidone Drugs 0.000 title claims abstract description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229920000858 Cyclodextrin Polymers 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 11
- 239000011521 glass Substances 0.000 claims description 9
- 239000004743 Polypropylene Substances 0.000 claims description 8
- -1 polyethylene terephthalate Polymers 0.000 claims description 8
- 229920001155 polypropylene Polymers 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 claims description 5
- 229920001903 high density polyethylene Polymers 0.000 claims description 5
- 239000004700 high-density polyethylene Substances 0.000 claims description 5
- 229920001684 low density polyethylene Polymers 0.000 claims description 5
- 239000004702 low-density polyethylene Substances 0.000 claims description 5
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 5
- 238000003860 storage Methods 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 4
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 4
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 4
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 claims description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 3
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 3
- 150000003626 triacylglycerols Chemical class 0.000 claims description 3
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 claims description 2
- 239000001116 FEMA 4028 Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229920001304 Solutol HS 15 Polymers 0.000 claims description 2
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 claims description 2
- 229960004853 betadex Drugs 0.000 claims description 2
- 239000006172 buffering agent Substances 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims 2
- 238000011477 surgical intervention Methods 0.000 claims 1
- 230000000699 topical effect Effects 0.000 abstract description 3
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 11
- 239000011630 iodine Substances 0.000 description 11
- 229910052740 iodine Inorganic materials 0.000 description 11
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920000153 Povidone-iodine Polymers 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 229960001621 povidone-iodine Drugs 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 2
- 206010011409 Cross infection Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
Definitions
- such a method includes the preparation of the oil phase, which is then added to the aqueous phase.
- such a container is made of a plastic material.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT202000002038 | 2020-02-03 | ||
| PCT/IB2021/050813 WO2021156735A1 (en) | 2020-02-03 | 2021-02-02 | Stable ophthalmic formulations based on low-concentration povidone iodide in plastic containers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4100063A1 true EP4100063A1 (en) | 2022-12-14 |
Family
ID=70480498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP21707371.7A Pending EP4100063A1 (en) | 2020-02-03 | 2021-02-02 | Stable ophthalmic formulations based on low-concentration povidone iodide in plastic containers |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP4100063A1 (en) |
| WO (1) | WO2021156735A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL9002049A (en) * | 1990-09-18 | 1992-04-16 | Dagra Pharma Bv | EYE-VISION PREPARATION CONTAINING A POVIDON IODINE SOLUTION. |
| CN101987109B (en) * | 2009-08-05 | 2012-07-04 | 天津金耀集团有限公司 | Ophthalmic composition containing povidone iodine and cyclodextrin included glucocorticoid |
| ITUA20162425A1 (en) * | 2016-04-08 | 2017-10-08 | Medivis S R L | Ophthalmic composition comprising PVP-I |
-
2021
- 2021-02-02 WO PCT/IB2021/050813 patent/WO2021156735A1/en unknown
- 2021-02-02 EP EP21707371.7A patent/EP4100063A1/en active Pending
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| Publication number | Publication date |
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| WO2021156735A1 (en) | 2021-08-12 |
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