WO2024180472A1 - Dispositifs oculaires - Google Patents

Dispositifs oculaires Download PDF

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Publication number
WO2024180472A1
WO2024180472A1 PCT/IB2024/051861 IB2024051861W WO2024180472A1 WO 2024180472 A1 WO2024180472 A1 WO 2024180472A1 IB 2024051861 W IB2024051861 W IB 2024051861W WO 2024180472 A1 WO2024180472 A1 WO 2024180472A1
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Prior art keywords
ocular insert
ocular
guar
mucoadhesive polymer
insert
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PCT/IB2024/051861
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English (en)
Inventor
Zahra BASSAMPOUR
Steve Yun ZHANG
Lilanni PEREZ
Ashanti SMITH
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Alcon Inc.
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Publication of WO2024180472A1 publication Critical patent/WO2024180472A1/fr

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    • 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
    • A61K9/0051—Ocular inserts, ocular implants
    • 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
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present disclosure generally relates to polymeric ocular insert technology, and more particularly to dissolvable ocular inserts that release lubricants and drugs into the eye (including, but not limited to the anterior and posterior segments) for an extended duration of time compared to topical drop dosage forms.
  • Ocular inserts are usually composed of a polymeric vehicle containing the drug, have sizes and shapes designed for ophthalmic application, and are mainly used for topical therapy. These inserts are typically placed in the lower fornix conjunctiva and, less frequently, in the upper fornix conjunctiva or on the cornea. Ocular inserts can be prolonged drug release systems for effectively treating eye disorders.
  • Ocular inserts can be divided into two general classes: non-erodible and erodible.
  • Non-erodible ocular inserts are usually made of matrix polymers that are not degradable or water-soluble. They can takes several forms, including, e.g., reservoir systems that are composed of a central reservoir of drug (a liquid, solid or pasty) enclosed by a semipermeable membrane; non-swellable matrix systems that consist of a solid mass comprising a liquid or solid drug dispersed or dissolved therein; or hydrogel systems that are made of water-swellable polymeric materials with drugs dispersed or dissolved therein, etc.
  • drug release kinetics depends mainly on the interactions between the polymer and the drug rather than in physiological conditions of the eye, thus kinetics can easily be changed by manipulating those interactions.
  • the disadvantage with non-erodible ocular inserts is that they must be removed after use.
  • Erodible ocular inserts are usually made of matrix polymers that degrade by hydrolysis or enzymes in the tears or are simply water-soluble (dissolvable by tears).
  • the obvious advantage of erodible ocular inserts is that it is not necessary to be removed after the functional period.
  • the speed of degradation varies depending on the rate of production and removal of the tear fluid or on the concentration of enzymes, which are different for every patient. Consequently, the erodible ocular inserts are more susceptible to variations in the kinetics of drug release than the insoluble ones.
  • LACRISERT® inserts are commercially available erodible ocular inserts that are used to treat dry eye.
  • LACRISERT® insert is a sterile, translucent, solid rod which measures 1.27 mm in diameter and 3.5 mm in length and is made of hydroxy propyl cellulose. For administration, it is placed into the inferior cul-de-sac of the eye beneath the base of the tarsus by a patient or a medical practitioner. Once inserted, the hydroxypropyl cellulose slowly dissolves in the eye over a period of several hours to a day. In the case of dry eye treatment, hydroxypropyl cellulose aids in tear retention by increasing tear viscosity to relieve the symptoms associated with dry eye. However, there also are challenges in using these types of inserts.
  • LACRISERT® inserts are hard and inelastic, tend to dissolve slowly, and can remain in the eye even after 15-20 hours.
  • the rod is hard and inelastic with edges due to rod-shaped design, there are side effects associated with use of LACRISERT® inserts, including blurred vision, foreign body sensation and/or discomfort, ocular irritation or hyperemia, hypersensitivity, photophobia, eyelid edema, and caking or drying of viscous material on eyelashes.
  • the invention provides an ocular insert which comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof; (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof; (c) at least one humectant; and (d) a polyphenolic compound in an amount to provide the ocular insert with an on-eye dissolution time of about 20 hours or longer, wherein said at least one first mucoadhesive polymer selected
  • the invention provides a method for producing a readily usable ocular insert of the invention (as described above), comprising the steps of: obtaining an ocular insert that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, and (c) at least one humectant, wherein said at least one first mucoadhesive polymer and
  • the invention provides a method for producing an ocular insert, comprising the step of: obtaining a solution for casting an ocular insert that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, (c) at least one humectant, and (d) a polyphenolic compound in an amount to provide the ocular insert with an on
  • the invention provides a method for using of an ocular insert of the invention (as described above) for treating a disease or disorder of an eye of a subject, comprising administering a pre-hydrated ocular insert of the invention into the eye.
  • the term “ocular insert” refers to a sterile, thin solid or semisolid (gel) article that is placed into the cul-de-sac or conjuctival sac of an eye when being used by a patient and optionally impregnated with a drug.
  • soluble in reference to a compound or material in a solvent, means that the compound or material can be dissolved in the solvent to give a solution with a concentration of at least about 0.1% by weight at room temperature (i.e., from about 20°C to about 30°C).
  • insoluble in reference to a compound or material in a solvent, means that the compound or material can be dissolved in the solvent to give a solution with a concentration of less than 0.005% by weight at room temperature (as defined above).
  • a “mucoadhesive polymer” refers to a polymer capable of bind to a mucus or mucous membrane that adheres to epithelial surfaces (e.g., the gastrointestinal tract, the lung, the eye, etc.), as known to a person skilled in the art. It should point out that mucoadhesive polymers have been widely described in the literature. See, for example, the article entitled “Mucoadhesive Drug Delivery System: A Review” by Dharmendra et al. in Int. J. Pharm. Biol. Arch. 2012, 3(6):1287-1291 and the article entitled “Polymers in Mucoadhesive Drug-Delivery Systes: A Brief Note” published by Roy et al. in Designed Monomers and Polymers 2009, 12(6):483-495.
  • a “galactomannan polymer” refers to guar or chemically-modified guars.
  • chemically-modified guars include without limitation hydroxypropyl guar (HP-guar), hydroxyethyl guar (HE-guar), methyl guar, ethyl guar, propyl guar, carboxymethyl guar, carboxymethylhydroxypropyl guar, hydroxypropyltrimonium chloride guar, and combination thereof.
  • the invention is directed to an ocular insert which is dissolvable in tears and made of at least one carboxyl-containing (i.e., COOH-containing) mucoadhesive polymer, at least one hydroxyl-containing (i.e., OH-containing) mucoadhesive polymer, a humectant, and a polyphenolic compound.
  • the invention is partly based on the discovery that a polyphenol compound can function as a crosslinker to crosslink a carboxyl- containing mucoadhesive polymer with a hydroxyl-containing mucoadhesive polymer via non-covalent hydrogen bonds, thereby increasing the on-eye dissolution time of the ocular insert.
  • an ocular insert of the invention can be pre-hydrated to form a hydrogel and then be placed in the eye. It is also discovered that by varying the amount of the polyphenol compound in an ocular insert, one can control the dissolution time of the ocular insert in the eye.
  • the invention provides an ocular insert which comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof (preferably selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, and combinations thereof, more preferably selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, carboxymethyl guar, and combination thereof, even more preferably selected from the group consisting of hyaluronic acid, alginic acid, carboxymethyl guar, and combinations thereof, most preferably being hyaluronic
  • Hyaluronic acid is an unsulphated glycosaminoglycan composed of repeating disaccharide units of N-acetylglucosamine (GIcNAc) and glucuronic acid (GlcUA) linked together by alternating beta-1 ,4 and beta-1 ,3 glycosidic bonds.
  • Hyaluronic acid is also known as hyaluronan, hyaluronate, or HA.
  • hyaluronic acid also includes salt forms of hyaluronic acid such as sodium hyaluronate.
  • a preferred hyaluronic acid is sodium hyaluronate.
  • the weight average molecular weight of the hyaluronic acid used in insert of the present invention may vary, but is typically weight average molecular weight of 0.1 to 3.0M Daltons. In one embodiment, the hyaluronic acid has a weight average molecular weight of 0.5 to 2.0MDaltons. In another embodiment, the hyaluronic acid has a weight average molecular weight of 1 .5 to 2.0 M Daltons.
  • a galactomannan polymer refers to a galactomannan (e.g., guar) and/or a chemically modified galactomannan.
  • a galactomannan is a polysaccharide consisting of a mannose backbone with galactose side groups (more specifically, a (1-4)- linked beta-D-mannopyranose backbone with branch points from their 6-positions linked to alpha-D-galactose, (i.e. 1 -6-linked alpha-D-galactopyranose).
  • the ratio of D-galactose to D-mannose in galactomannan can vary, but generally will be from about 1 :2 to 1 :4.
  • Galactomannans having a D-galactose:D-mannose ratio of about 1 :2 are most preferred.
  • Preferred galactomannan is guar.
  • Galactomannans may be obtained from numerous sources. Such sources include guar gum, locust bean gum and tara gum, as further described below.
  • Guar gum is the ground endosperm of Cyamopisis tetragonolobus (L.) Taub.
  • the water soluble fraction (85%) is called "guaran” (molecular weight of 220,000), which consists of linear chains of (1-4)-p-D mannopyranosyl units with a-D-galactopyranosyl units attached by (1-6) linkages.
  • the ratio of D-galactose to D-mannose in guaran is about 1 :2.
  • the gum has been cultivated in Asia for centuries and is primarily used in food and personal care products for its thickening property. It has five to eight times the thickening power of starch.
  • Guar gum may be obtained, for example, from Rhone-Polulenc (Cranbury, N.J.), Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp, Md.).
  • Locust bean gum or carob bean gum is the refined endosperm of the seed of the carob tree, ceratonia siliqua.
  • the ratio of galactose to mannose for this type of gum is about 1 :4.
  • Cultivation of the carob tree is old and well known in the art.
  • This type of gum is commercially available and may be obtained from TIC Gum, Inc. (Bekamp, Md.) and Rhone-Polulenc (Cranbury, N.J.).
  • Tara gum is derived from the refined seed gum of the tara tree.
  • the ratio of galactose to mannose is about 1 :3.
  • Tara gum is not produced in the United States commercially, but the gum may be obtained from various sources outside the United States.
  • a chemically-modified galactomannan is a derivative of a galactomannan in which some (but not all) of hydrogen atoms of the hydroxyl groups are substituted with an organic group.
  • preferred chemically-modified glactomannans includes without limitation hydroxyethyl-substituted galactomannan (e.g., hydroxyethyl guar), hydroxypropyl galactomannan (e.g., hydroxypropyl guar), C1-C3 alkyl galactomannan (e.g., methyl guar, ethyl guar, propyl guar), carboxymethyl galactomannan (e.g., carboxymethyl guar), carboxymethylhydroxypropyl galactomannan (e.g., carboxymethylhydroxypropyl guar), hydroxypropyltrimonium chloride galactomannan (e.g., hydroxypropyltrimonium chloride guar), and combinations thereof
  • Hydroxyethyl guar, hydroxypropyl guar, methyl guar, ethyl guar, propyl guar, carboxymethyl guar, carboxymethylhydroxypropyl guar, and hydroxypropyltrimonium chloride guar are well known and are commercially available.
  • modified galactomannans of various degree of substitution are commercially available from Rhone- Poulenc (Cranbury, N.J.).
  • At least one humectant may be added to the one or more polymers to facilitate fabrication of a moisturiser delivery system and also provide improved lubrication, hydration and comfort upon insertion.
  • humectant may be low or high-molecular weight compounds, including not limited to, polyethylene glycol (PEG) and derivatives thereof, and polyvinylpyrrolidone (PVP).
  • polyvinylpyrrolidone is characterized by its viscosity in aqueous solution relative to that of water and expressed as a K value in the range of 10-120.
  • PVP K15, K30, 60, 90, 120 has a molecular weight of 8K, 60K, 400k, 1.3 M and, 3M Daltons, respectively.
  • the weight average molecular weight of the PVP used in an ocular insert of the present invention may vary but is typically weight average molecular weight of 60K to 3M Daltons.
  • the PVP has a weight average molecular weight of 400K to 2.5 M Daltons.
  • the PVP has a weight average molecular weight of 1 to 1.5 M Daltons.
  • the weight average molecular weight of the PEG used in insert of the present invention is typically less than 20K Daltons and may vary but is typically weight average molecular weight of 200 to 9000 Daltons. In one embodiment, the PEG has a weight average molecular weight of 300 to 1000 Daltons. In another embodiment, the PEG has a weight average molecular weight of 350 to 450 Daltons.
  • the humectant PVP is present in an amount of from about 0.1 % to about 10% w/w, about 0.5% to about 5% w/w, about 1 .0 % to about 3% w/w, or about 1% to about 2.5% w/w by dry weight of the ocular insert, provided that the sum of the %w/w of all components in an ocular insert is 100 %w/w.
  • the humectant PEG is present in an amount of from about 0.1 % to about 10% w/w, about 0.5% to about 5% w/w, about 1 .0 % to about 3% w/w, or about 1% to about 2.5% w/w by dry weight of the ocular insert, provided that the sum of the %w/w of all components in an ocular insert is 100 %w/w.
  • any suitable polyphenolic compound can be used in the invention.
  • preferred polyphenolic compounds include without limitation tannic acid, lignans, stilbenes, hydroxyphenylpropenes, oleuropein, rutin, catechin, curcuminoids, flavonoids, and combinations thereof.
  • the polyphenolic compound can be present in an ocular insert in an amount of from about 1% to about 15% w/w, preferably from about 2% to about 12.5% w/w, more preferably from about 3% to about 10% w/w.
  • the on-eye dissolution time of an ocular insert of the invention can be fine-tuned by varying the amount of the polyphenolic compound in the ocular insert.
  • the overall dry weight or mass of the ocular insert may be in the range of about 0.5 to about 10 mg, about 1 to about 9 mg, or about 2 to about 8 mg, and in particular embodiments may be from about 2.5 to about 6 mg.
  • the ocular insert may be of any size or shape suitable for administration to the eye.
  • Exemplary shapes include film, a rod, a sphere, an oval, a ring, a square, a rectangle, a triangle, or an irregular shape having a maximum size in any single dimension of 5-7 mm.
  • the ocular insert has a thickness of about 30-300 pm, about 30-300 pm, or about 30-100 pm.
  • the ocular insert of the invention can have an on-eye dissolution time of at least 20 hours, preferably at least 22 hours, more preferably at least 24 hours.
  • the on-eye dissolution time can be determined by determining the dissolution time of an ocular insert in saline or phosphate-buffered saline (PBS) known to a person skilled in the art, for example, according to the procedures described in Example 1 .
  • PBS phosphate-buffered saline
  • an ocular insert has a multilayered structure and comprises a first polymer layer sandwiched between two second polymer layers, wherein the first polymer layer has a first H-bonding crosslinking density (due to the presence of a higher amount of a polyphenolic compound) and the second polymer layers have a second H- bonding crosslinking density (due to the presence of a lower amount of the polyphenolic compound), wherein the first H-bonding crosslinking density is higher than the second H- bonding crosslinking density.
  • an ocular insert of the invention can have a well-controlled disintegration kinetics for each layers, i.e., the outer polymer layers can be disintegrated (dissolved) first whereas the inner polymer layer can be disintegrated (dissolved) later.
  • Such an ocular insert can offer more flexibility to tune properties of selected layers to achieve desired overall dissolution profile.
  • the ocular insert does not include an additional pharmaceutically active agent.
  • the mucoadhesive polymers making up the ocular insert may slowly be released in the eye due to the slowly disintegration of the hydrogel body of the ocular insert, thereby relieving the symptoms associated with dry eye.
  • the ocular insert may include one or more additional pharmaceutically active agents.
  • the one or more pharmaceutically active agents may be selected from the group of ocular lubricants, anti-redness relievers such as brimonidine tartrate, tetrahydrozoline, naphazoline, cooling agents such as menthol, steroids and nonsteroidal anti-inflammatory agents to relieve ocular pain and inflammation, antibiotics, anti-histamines such as olopatadine, anti-virals, antibiotics and anti-bacterials for infectious conjunctivitis, anti-muscarinics such as atropine and derivatives thereof for myopia treatment, and glaucoma drug delivery such as prostaglandin and prostaglandin analogs such as travoprost, or therapeutically suitable combinations thereof.
  • the invention provides a method for producing a readily usable ocular insert of the invention (as described above), comprising the steps of: obtaining an ocular insert that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, and (c) at least one humectant, wherein said at least one first mucoadhesive polymer and
  • the invention provides a method for producing an ocular insert, comprising the step of: obtaining a solution for casting an ocular insert that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, (c) at least one humectant, and (d) a polyphenolic compound in an amount to provide the ocular insert with an on
  • first mucoadhesive polymers can be used in these two aspects of the inventions.
  • second mucoadhesive polymers can be used in these two aspects of the inventions.
  • humectants can be used in these two aspects of the inventions.
  • a person skilled in the art knows well how to carry out a solution casting. For example, one can dispose a solution containing all the necessary components of an ocular insert in a mold (an open container with a flat bottom) and evaporate the solvent to form a film. Subsequently, one can punch out an ocular from the film.
  • One preferred evaporation method would be a freeze-drying method as well known to a person skilled in the art. It is believed that ocular inserts prepared according to a method involving a step of freeze- drying can have an improve surface, reduce the dissolution rate of the porous insert material, and decrease time needed for vision to return to baseline.
  • the invention provides a method for using of a ocular insert of the invention (as described above) for treating a disease or disorder of an eye of a subject, comprising administering the ocular insert into the eye.
  • An ocular insert comprising:
  • a polyphenolic compound in an amount to provide the ocular insert with an on-eye dissolution time of about 20 hours or longer, wherein said at least one first mucoadhesive polymer and said at least one second mucoadhesive polymer are together present in the ocular insert in an amount of from about 65% to about 98% by weight of the ocular insert.
  • said at least one first mucoadhesive polymer is selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, and combinations thereof.
  • polyphenolic compound is selected from the group consisting of tannic acid, lignans, stilbenes, hydroxyphenylpropenes, oleuropein, rutin, catechin, curcuminoids, flavonoids, and combinations thereof.
  • the ocular insert of any one of embodiments 1 to 27, wherein the ocular insert has a layered structure and comprises a first polymer layer sandwiched between two second polymer layers, wherein the first polymer layer has a first H-bonding crosslinking density and the second polymer layers have a second H-bonding crosslinking density, wherein the first H-bonding crosslinking density is higher than the second H-bonding crosslinking density.
  • ocular insert of embodiment 29, wherein said one or more additional pharmaceutical active agents are selected from the group consisting of ocular lubricants, anti-redness relievers (such as brimonidine tartrate, tetrahydrozoline, naphazoline), cooling agents (such as menthol), steroids and nonsteroidal anti-inflammatory agents to relieve ocular pain and inflammation, antibiotics, anti-histamines (such as olopatadine), anti-virals, antibiotics and anti-bacterials for infectious conjunctivitis, anti-muscarinics (such as atropine and derivatives thereof) for myopia treatment, and glaucoma drug delivery (such as prostaglandin and prostaglandin analogs such as travoprost), and therapeutically suitable combinations thereof.
  • anti-redness relievers such as brimonidine tartrate, tetrahydrozoline, naphazoline
  • cooling agents such as menthol
  • a method for producing an ocular insert of any one of embodiments 1 to 30, comprising the step of:
  • a solution that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, and (c) at least one humectant, wherein said at least one first mucoadhesive polymer and said at least one second mucoadhesive polymer are together present in the ocular insert in an amount of from about 75% to about 99% by weight
  • a method for producing an ocular insert of any one of embodiments 1 to 30, comprising the step of:
  • a solution for casting an ocular insert that comprises (a) at least one first mucoadhesive polymer selected from the group consisting of hyaluronic acid, alginic acid, carboxyl methyl cellulose, polygalacturonic acid, carboxymethyl guar, carboxymethylhydroxypropyl guar, xanthan gum, chitosan, polyacrylic acid, and a combination thereof, (b) at least one second mucoadhesive polymer selected from the group consisting of a galactomannan polymer, hydroxypropylmethylcellulose (HPMC), dextran, mannan, a tamarind seed polysaccharide (TSP), xyloglucan gum, polyvinyl alcohol, and a combination thereof, (c) at least one humectant, and (d) a polyphenolic compound in an amount to provide the ocular insert with an on-eye dissolution time of about 20 hours or longer, wherein said at least one first mucoadhesive poly
  • a method for using of an ocular insert of any one of embodiments 1 to 30 for treating a disease or disorder of an eye of a subject comprising administering the ocular insert into the eye.
  • the on-eye dissolution time is measured as follows. Ocular inserts (i.e., film disks) having a diameter of 6 mm and a thickness of 50 microns are cut out from a film obtained from solution casting. The ocular inserts (film disks) each have a weight of about 2.6 mg.
  • the ocular inserts are placed in the wells of a multi-well plate, one ocular insert (film disk) in one well.
  • PBS phosphate-buffered saline
  • the plate is placed in orbital shaker and shaken at an agitation speed (RPM) of 25 RPM (units) until the ocular insert has dissolved (complete disintegration by visual inspection). The dissolution time is recorded.
  • PEG represent polyethylene glycol
  • PEG-400 represents polyethylene glycol having a number average molecular weight of 400 Daltons
  • PVP represents polyvinylpyrrolidone
  • HA represents hyaluronic acid
  • HP-guar represents hydroxypropyl guar
  • TA represents tannic acid
  • PBS represents a phosphate-buffered saline which has a pH of 7.2 ⁇ 0.2 at 25°C and contains about 0.044 wt.% NaH 2 PO 4 H 2 O, about 0.388 wt.% Na 2 HPO 4 2H 2 O, and about 0.79 wt.% NaCI and
  • wt.% represents weight percent
  • DI water represents deionized water.
  • Ocular inserts (film disks) having a diameter of 6 mm and a thickness of 50 microns are cut out from a film obtained from solution casting.
  • the ocular inserts each have the following composition: 49.5% w/w/ of HA; 49.5% w/w of HP Guar; 1% w/w of PEG-400.
  • Ocular inserts are placed in the wells of a multi-well plate, one ocular insert per well. A 2mL of an aqueous solution is added into each well with one ocular insert therein. PBS is used as control.
  • a testing solution containing 2% by weight of TA is prepared by dissolving tannic acid (TA) in DI water to give the specified concentration.
  • the dissolution times of the ocular inserts are determined as described in Example 1 .
  • the pHs of the solutions with ocular inserts immersed therein are determined. The results are reported in Table 1.
  • Ocular inserts (film disks) having a diameter of 6 mm and a thickness of 50 microns are cut out from a film obtained from solution casting.
  • the ocular inserts have the compositions shown in Table 2.
  • Ocular inserts are placed in the wells of a multi-well plate, one ocular insert per well. A 2mL of PBS is added into each well with one ocular insert therein. Ocular inserts free of tannic acid are used as control. The dissolution times of the ocular inserts are determined as described in Example 1 . The pHs of the solutions with ocular inserts immersed therein are determined. The results are reported in Table 2. Table 2

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de manière générale un dispositif oculaire soluble dans les larmes, composé d'au moins un polymère mucoadhésif contenant un carboxyle (p. ex., un COOH), d'au moins un polymère mucoadhésif contenant un hydroxyle (p. ex., un OH), d'un humectant et d'un composé polyphénolique. Le composé polyphénolique peut servir d'agent de réticulation pour réticuler un polymère mucoadhésif contenant un carboxyle avec un polymère mucoadhésif contenant un hydroxyle par le biais de liaisons hydrogène non covalentes, augmentant ainsi le temps de dissolution du dispositif oculaire dans l'œil. Grâce à l'augmentation du temps de dissolution dans l'œil, un dispositif oculaire de l'invention peut être préalablement hydraté pour former un hydrogel et être ensuite placé dans l'œil. En faisant varier la quantité de composé polyphénolique dans un dispositif oculaire de l'invention, il est possible de réguler le temps de dissolution du dispositif oculaire dans l'œil.
PCT/IB2024/051861 2023-02-28 2024-02-27 Dispositifs oculaires WO2024180472A1 (fr)

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