Pre-activated thiomer-based mucosal-adhering solid or semi-solid ophthalmic delivery systems

Abstract

The present invention relates to a mucoadhesive solid or semi-solid ophthalmic delivery system comprising a matrix of pre-activated thiomers, preferably in the form of an ophthalmic insert or ophthalmic film. The ophthalmic delivery system of the present invention is useful for ophthalmic drug delivery for the treatment of ophthalmic diseases. The delivery system of the present invention may also be used to alleviate ophthalmic conditions such as dry eye syndrome.

Description

Technical Field

[0001] The present invention relates to the field of ophthalmic preparations and provides a mucoadhesive solid or semi-solid ocular delivery system. The delivery system of the present invention is based on a matrix of pre-activated thiomers and is preferably in the form of an ocular insert or an ocular film. The delivery system of the present invention is useful for ocular drug delivery for the treatment of eye diseases such as, but not limited to, dry eye or glaucoma. Further, the delivery system of the present invention can be used for alleviating eye pathologies.

Background Art

[0002] There are many eye diseases and eye pathologies that require the administration of an active substance directly at the eye level. One of the major problems of topical ocular administration is to obtain and maintain a sufficient amount of the active substance at the site of action for a long time and to deliver an accurate dose of the active substance. There is also a need for a delivery system that enables a controlled sustained release of the active substance over time.

[0003] Most ophthalmic drugs are administered in the form of aqueous eye drops. Aqueous eye drops are easy to use and are more readily tolerated by patients, but have the drawback of being rapidly drained after instillation and have insufficient bioavailability. Further, many ophthalmic drugs are hydrophobic molecules with insufficient solubility in water. Thus, many eye drops are drug suspensions, and since this drug needs to be solubilized in the eye first before being absorbed, it exacerbates the bioavailability problem.

[0004] To optimize drug application to the eye, various alternatives have been developed, such as, for example, reverse phase emulsions, in situ gelling polymers, microspheres, nanoparticles, liposomes or ocular inserts.

[0005] Ophthalmic inserts are solid or semi-solid ophthalmic delivery devices designed to be placed in the conjunctival sac of the eye. Because ophthalmic inserts allow for a longer retention time in the anterior cornea and reduce the amount absorbed systemically, they offer an interesting alternative to eye drops. However, ophthalmic inserts are often not well-received by patients because they cause a foreign body sensation in the eye. Furthermore, if the insert moves around the periphery of the eye, this can also interfere with vision and cause irritation.

[0006] Therefore, attempts are being made to provide mucosal-adhering ophthalmic inserts that are well tolerated by patients and maintain simplicity in their production.

[0007] When an ophthalmic delivery system is placed on the surface of the eye, it first comes into contact with the tear film, which is formed from three layers: a lipid layer, an aqueous layer, and a mucin layer. Therefore, the mucin present beneath the tear film can be targeted to achieve adhesion of the ophthalmic delivery system to the surface of the eye. Several polymers, such as thiomers, have already been tested for their mucosal adhesion properties.

[0008] Thiomers, also known as "thiolated polymers," are polymers having side chains containing free thiol moieties (Bernkop-Schnurch A. et al., Pharm. Res., 1999, 16, 876-881; U.S. Patent No. 7,354,600). The polymer backbone of thiomers typically consists of biodegradable polymers, such as chitosan, hyaluronic acid, gelatin, polyacrylate, cyclodextrin, or silicone. Thiolation of such polymer backbones can be achieved, for example, by coupling a cysteine ​​moiety. Thiomers can form covalent bonds, i.e., disulfide bonds, with the cysteine-rich subdomains of mucins that cover mucous membranes. Such covalent bonds are strong, thus ensuring efficient and long-lasting mucosal adhesion of dosage forms containing thiomers.

[0009] Hornof et al. tested mucosal-adherent ophthalmic inserts based on thiolated poly(acrylic acid) for the sustained release of ophthalmic drugs (Hornof et al., J. Controlled Release, 2003, 419-428). The dried ophthalmic insert is placed in the conjunctival sac of the eye and hydrated in situ to form a hydrogel that exhibits good mucosal adhesion. This hydrogel form does not cause a foreign body sensation, in contrast to conventional ophthalmic inserts, and the mucosal adhesion allows the insert to remain in place. Nevertheless, such thiomeric ophthalmic inserts must be kept at a non-physiological pH (pH 5 in Hornof et al.'s thiomeric ophthalmic inserts) to avoid oxidation of the thiol groups of the thiomer and to maintain them in a reduced form. This is essential to retain a sufficient amount of free thiol groups available for interaction with mucin. Therefore, the main drawback of thiomeric ophthalmic inserts is that their non-physiological pH induces irritation and pain. Furthermore, such pH levels may not be suitable for supporting certain active ingredients that are unstable under these conditions.

[0010] Therefore, there is a need for novel solid or semi-solid ophthalmic delivery systems (including ophthalmic inserts and ophthalmic films) that possess effective mucosal adhesion properties, are well-tolerated by patients, and are suitable for the delivery of a wide range of ophthalmic drugs.

[0011] For this purpose, the applicant provides, in this specification, a mucosal-adherent solid or semi-solid ophthalmic delivery system based on a matrix of pre-activated thiomers.

[0012] Pre-activated thiomers or S-protected thiomers are thiomers in which the thiol portion of the side chain is conjugated by a disulfide bond to mercaptonicotinic acid, mercapto(iso)nicotinamide, or mercaptopyridoxine (U.S. Patent Publication No. 2012 / 0225024). The mucosal adhesive properties of such pre-activated thiomers have been reported, for example, with poly(acrylic acid)-cysteine-2-mercaptonicotinic acid (Iqbal J. et al., Biomaterials, 2012, 33, 1528-1535). Nevertheless, to the knowledge of the applicant, the use of such pre-activated thiomers has not been reported in relation to ophthalmic delivery systems, particularly in the manufacture of ophthalmic inserts or ophthalmic films.

[0013] The presence of pre-activated thiol groups in the thiomer used in the ophthalmic delivery system of the present invention enhances the stability, mucosal adhesion, tackiness, and resistance of the thiomer, thereby providing an ophthalmic delivery system with predicted properties. The delivery system of the present invention particularly offers the advantage of prolonging the residence time of the delivery system at the application site without causing irritation. Patient adherence to treatment is improved when using the delivery system of the present invention compared to when using eye drops, as repeated administration is avoided. When used to deliver ophthalmic drugs, the pre-activated thiomer-based ophthalmic delivery system of the present invention improves the therapeutic properties of the drug by increasing its bioavailability. In particular, the ophthalmic delivery system of the present invention can increase the residence time of the drug, thereby enhancing drug penetration. This also enables sustained release over time and allows for more precise dose delivery compared to doses that can be achieved when using eye drops.

[0014] To be suitable for use in the eye, the solid or semi-solid delivery system of the present invention faces several characteristics, including having a shape and size suitable for placement in the eye, and allowing for proper hydration with controlled expansion. [Overview of the Initiative]

[0015] Therefore, the present invention relates to a mucosal-adherent solid or semi-solid ophthalmic delivery system comprising a pre-activated thiomeric matrix, wherein the matrix comprises at least one pre-activated thiomer selected from polymer compounds having side chains of 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine, covalently bonded to a thiolated polymer backbone via disulfide bonds.

[0016] In one embodiment, the ophthalmic delivery system is an ophthalmic insert or an ophthalmic film.

[0017] In one embodiment, the polymer backbone is selected from (meth)acrylic acid, (meth)acrylic acid esters, (meth)acrylamide, vinylpyrrolidone, vinyl alcohol, vinylimidazole, vinylcaprolactam, divinylglycol, polycarbophil, carbomer, allylamine, (trimethylated) chitosan, hyaluronic acid, pectin, alginate, (crosslinked) polyallylamine, polylysine, polyornithine, polyaminoamide, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose, which optionally exhibit free thiol groups as side chains, as (crosslinked) homopolymers or copolymers.

[0018] In one embodiment, the side chain of the polymer compound is S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteine-disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-homocysteine-disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteamine-disulfide, S-(2- or 6-mercapto(iso)nicotinamide) S-(6-mercaptopyridoxine)-N-acetylcysteine ​​disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-thioglycolate disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-3-thiopropionic acid disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-4-thio Butanoic acid disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptobenzoic acid disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptonicotinic acid disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-glutathione disulfide, S-(2- or 6-mercapto(iso)nicotin Selected from S-(6-mercaptopyridoxine)-thioethylamidine disulfide, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-4-thiobutylamidine disulfide, and S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptoaniline disulfide; the above side chains are attached to the polymer backbone via amide, amidine, or ester bonds.

[0019] In one embodiment, the pre-activated thiomer forming the matrix is ​​in the form of nanofibers, preferably nanofibers obtained by electrospinning.

[0020] In one embodiment, the ocular delivery system of the present invention further comprises one or more pharmaceutically effective substances; preferably, the pharmaceutically effective substances are selected from intraocular pressure (IOP) lowering agents, such as prostaglandin analogs, cholinergics, β-blockers, α-adrenergic receptor agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, NO donors and combinations thereof; anti-inflammatory agents, such as corticosteroid anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs; anti-infective agents, such as macrolides, aminosides, rifamycin, antiviral agents, and antifungal drug therapies; anti-allergic agents, such as H1-antihistamines and mast cell stabilizers; and dry eye treatment agents.

[0021] In one embodiment, the ophthalmic delivery system of the present invention further comprises one or more pharmaceutically acceptable excipients selected from thickeners, gelling agents, plasticizers, solubilizers, stabilizers, penetration enhancers, diluents, binders, disintegrants, channeling agents, lubricants, and buffers. In one embodiment, the thickener and gelling agent is selected from high molecular weight crosslinked polyacrylic acid polymers, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives, polyethylene glycol, and hyaluronic acid; the plasticizer is glycerol; the solubilizer and stabilizer is selected from cyclodextrin; the penetration enhancer is reduced form of glutathione; the diluent is selected from sugar alcohols; the binder is selected from sugars and their derivatives, disaccharides, polysaccharides and their derivatives, cellulose, modified cellulose, sugar alcohols, and synthetic polymers; the disintegrant is selected from crosslinked polymers and modified starches; the lubricant is selected from magnesium stearate, calcium hydrogen phosphate, starch, crystalline cellulose, and colloidal silicon dioxide; the channeling agent is selected from sodium chloride and polyethylene glycol.

[0022] In one embodiment, the ophthalmic delivery system of the present invention comprises one or more pharmaceutically acceptable excipients selected from high molecular weight crosslinked polyacrylic acid polymers, polyvinyl alcohol, polyvinylpyrrolidone, cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyethylene glycol, hyaluronic acid, glycerol, cyclodextrin, reduced forms of glutathione, sorbitol, xylitol, mannitol, sugars and their derivatives, sucrose, lactose, polysaccharides and their derivatives, starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate, colloidal silicon dioxide, and sodium chloride.

[0023] The present invention also provides a mucosal-adherent solid or semi-solid ocular delivery system for use in the treatment and / or prevention of eye diseases or ocular conditions. In one embodiment, the eye disease or ocular condition is selected from open-angle glaucoma, macular edema, uveitis, dry eye disease, conjunctivitis, keratitis, blepharitis, endophthalmitis, trachoma, postoperative allergy, and seasonal allergy.

[0024] Furthermore, the present invention relates to the use of a pre-activated thiomer for the manufacture of a mucosal-adherent solid or semi-solid ophthalmic delivery system, preferably an ophthalmic insert or ophthalmic film, wherein the pre-activated thiomer is selected from polymer compounds having side chains of 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine, covalently bonded to a thiolated polymer backbone via disulfide bonds. [Modes for carrying out the invention]

[0025] definition In this invention, the following terms have the following meanings.

[0026] The term "administer" or a variation thereof (e.g., "administering") means providing an active substance, either alone or as part of a pharmaceutically acceptable formulation, to a patient to be treated or prevented of a condition, symptom, or disease.

[0027] The term "carbomer" refers to a synthetic high molecular weight polyacrylic acid crosslinked with allyl sucrose or allyl pentaerythritol. Examples of carbomers include Carbopol 971 and 974, which are polyacrylic acids crosslinked with allyl pentaerythritol and polymerized in ethyl acetate.

[0028] The term "electrospinning" refers to a process for creating a network of three-dimensional polymer nanofibers. Electrospinning uses an electric charge to draw very fine fibers from a liquid. Methods for performing electrospinning are known to those skilled in the art.

[0029] The term "human" refers to a subject of either sex at any stage of growth (i.e., neonatal, infant, juvenile, young adult, adult).

[0030] The term "mucoadhesion" refers to the attractive force between a substance (substance or material) and mucus or mucosa. From the perspective of the present invention, a "mucoadhesive ophthalmic delivery system" is an ophthalmic delivery system that strongly interacts with mucus or mucosa. In a preferred embodiment, the ophthalmic delivery system of the present invention covalently binds to mucus or mucosa through the formation of a disulfide bond between a thiomer and the natural mucin present therein. The formation of this disulfide bond is promoted by the use of a pre-activated thiomer.

[0031] The term "nanofiber" refers to a fiber with an average diameter of less than 5000 nm.

[0032] The term "ophthalmic delivery system" refers to a delivery system that enables the administration of an effective pharmaceutical component or substance of interest, such as a drug or lubricant, to a target via the eye or a part thereof. "Solid or semi-solid ophthalmic delivery systems" refers to solid or semi-solid dosage forms, including ophthalmic inserts and ophthalmic films. In particular, "semi-solid" refers to dosage forms that may be highly viscous, such as ophthalmic inserts in hydrogel form.

[0033] The term "ophthalmic film" refers to a solid or semi-solid, consistent, two-dimensional film designed to be placed in the conjunctival sac or on the surface of the conjunctiva, with its size and shape specifically designed for ophthalmic applications. Preferably, the ophthalmic film is sterile. The ophthalmic film may be folded to form a three-dimensional device, which may be useful, for example, to facilitate the placement of the film into the eye.

[0034] The term "ophthalmic insert" refers to a solid or semi-solid, consistent, three-dimensional device designed to be placed in the conjunctival sac or on the surface of the conjunctiva, with its size and shape specifically designed for ophthalmic applications. Preferably, the ophthalmic insert is sterile. Optionally, the ophthalmic insert may be multilayered. The ophthalmic insert may be in a dry or hydrated form. In the latter case, in this invention, the ophthalmic insert is in the form of a hydrogel pellet.

[0035] The term “ocular disease” refers to any disease affecting any area of ​​the eyeball, including the surface of the eyeball, the anterior and posterior parts of the eye, and the eyelids (preferably the inner surface of the eyelids). The ocular tissue of interest may, but is not limited to, the corneal tissue, conjunctiva, eyelids, trabeculum, iris, ciliary body, uvea, choroid, retina, or macula.

[0036] The term "ocular pathology" refers to any condition affecting either the eyeball or the eyelid. Examples of ocular pathology include postoperative eye conditions, dry eye symptoms, and eye symptoms due to seasonal allergies.

[0037] The term "patient" refers to a mammal that is waiting for, receiving, or is currently / may be a subject of medical treatment. In one embodiment, the patient is a human. In another embodiment, the patient is an animal.

[0038] The expression "pharmaceutically acceptable" refers to the components of a pharmaceutical preparation that are compatible with each other and are not harmful to the recipient.

[0039] The expression "pharmaceutically acceptable excipients and / or adjuvants" refers to substances that, when administered to animals, preferably humans, do not cause adverse reactions, allergic reactions, or other undesirable reactions. This includes all inert substances, such as solvents, co-solvents, antioxidants, surfactants, stabilizers, emulsifiers, buffers, pH modifiers, preserving agents or preserving agents, antibacterial and antifungal agents, isotonic agents, granulating agents or binders, lubricants, disintegrants, lubricants, diluents or fillers, adsorbents, dispersants, suspending agents, coatings, bulking agents, release agents, absorption retarders, sweeteners, and fragrances. For administration to humans, the formulation must meet the standards of sterility, pyrogenicity, overall safety, and purity required by regulatory authorities, such as the FDA or EMA.

[0040] The term "polycarbophil" refers to a synthetic polymer produced by crosslinking polyacrylic acid with divinyl glycol and calcium counterions.

[0041] The term "polymer compound" refers to a polymer. In the sense of this invention, a polymer compound may include a "polymer skeleton" having "side chains".

[0042] The terms “prevent,” “prevent,” and “prevention,” as used herein, refer to methods of delaying or preventing the onset of a condition or disease and / or its associated symptoms, preventing a patient from developing a condition or disease, or reducing the risk to a patient who is developing a condition or disease.

[0043] The term "subject" refers to mammals, including humans and animals. In one embodiment, the subject is diagnosed with a disease. In one embodiment, the subject is a patient who is waiting for or receiving medical treatment, or who has been / is / may have been / are a subject for medical treatment in the past / present / future, or who is being monitored for the onset or progression of a disease. In one embodiment, the subject is a patient who is being treated and / or monitored for the onset or progression of a disease. In one embodiment, the subject is male. In another embodiment, the subject is female. In one embodiment, the subject is adult. In another embodiment, the subject is child.

[0044] The term “therapeutic dose,” “effective dose,” or “therapeutic effective dosage” refers to the amount or dosage of an active substance intended to (1) delay or prevent the onset of a disease in a subject, (2) reduce the severity or frequency of a disease, (3) delay or halt the progression, exacerbation, or worsening of one or more symptoms of a disease affecting a subject, (4) bring about remission of symptoms of a disease affecting a subject, or (5) cure a disease affecting a subject, without causing significant negative or adverse side effects in the subject. A therapeutic dose may be administered before the onset of a disease for a preventive or prophylactic effect. Alternatively, a therapeutic dose may be administered after the onset of a disease for a therapeutic effect.

[0045] The term “treatment” or “treatment” refers to a therapeutic treatment (whose purpose is to prevent or delay a particular condition or disease). “Treatment” of a disease, disorder, or condition in a subject or mammal is successful if, after receiving treatment according to the present invention, the subject or mammal exhibits: some degree of reduction of one or more symptoms associated with a specific disease or condition; and an observable and / or measurable reduction or absence of one or more of the following: improvement of quality of life issues. The above parameters for evaluating the success of treatment or improvement of disease are readily measurable by prescribed methods familiar to a physician.

[0046] The term "thiomer" or "unactivated thiomer" refers to a thiolated polymer, i.e., a polymer having side chains with free thiol moieties. This polymer backbone can be a biodegradable polymer, such as chitosan, hyaluronic acid, gelatin, polyacrylate, cyclodextrin, or silicone. Thiolation of such a polymer backbone can be carried out, for example, by coupling a cysteine ​​moiety.

[0047] The terms “pre-activated thiomer” or “S-protected thiomer” refer to thiomers in which the thiol portion of the side chain is conjugated via a disulfide bond to mercaptonicotinic acid, mercapto(iso)nicotinamide, or mercaptopyridoxine. Examples of pre-activated thiomers are disclosed in U.S. Patent Publication No. 2012 / 0225024.

[0048] The term "pre-activated thiomeric matrix" refers to a matrix primarily made from pre-activated thiomeric compounds.

[0049] Detailed explanation Therefore, the present invention relates to ophthalmic delivery systems, and more particularly to solid or semi-solid ophthalmic delivery systems. The ophthalmic delivery system of the present invention exhibits mucosal adhesion properties that allow the delivery system to be maintained on the surface of the eye for a long period of time. In fact, the ophthalmic delivery system of the present invention is based on a pre-activated thiomeric matrix, that is, a matrix mainly made from one or more pre-activated thiomers. Upon hydration, the pre-activated thiomeric matrix of the ophthalmic delivery system of the present invention forms a hydrogel that adheres to the eye.

[0050] Therefore, in one embodiment, the present invention provides a mucosal-adherent solid or semi-solid ophthalmic delivery system comprising a matrix of pre-activated thiomers.

[0051] In one embodiment, the matrix includes at least one pre-activated thiomer.

[0052] In one embodiment, the pre-activated thiomer is selected from polymer compounds having a side chain of vitamin B3 or vitamin B6 derivative covalently bonded to the thiolated polymer backbone via a disulfide bond. In one embodiment, the pre-activated thiomer is selected from polymer compounds having a side chain of 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine covalently bonded to the thiolated polymer backbone via a disulfide bond. In a preferred embodiment, the pre-activated thiomer is selected from polymer compounds having a side chain of 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, or 6-mercaptopyridoxine covalently bonded to the thiolated polymer backbone via a disulfide bond.

[0053] The term "thiolated polymer skeleton" refers to a polymer having a free thiol moiety, preferably a polymer skeleton having a side chain containing a free thiol moiety. In a pre-activated thiomer, mercaptonicotinic acid, mercapto(iso)nicotinamide, or mercaptopyridoxine is bonded to some or all of the thiol moieties of the thiolated polymer skeleton via disulfide bonds.

[0054] In one embodiment, the polymer backbone is selected from (crosslinked) homopolymers or copolymers consisting of (meth)acrylic acid, (meth)acrylic acid esters, (meth)acrylamide, vinylpyrrolidone, vinyl alcohol, vinylimidazole, vinylcaprolactam, divinyl glycol, polycarbophil, carbomer, allylamine, (trimethylated) chitosan, hyaluronic acid, pectin, alginate, (crosslinked) polyallylamine, polylysine, polyornithine, polyaminoamide, and cellulose derivatives (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose), which optionally exhibit free thiol groups as side chains. In one embodiment, the polymer backbone is a biodegradable polymer, such as alginate, chitosan, hyaluronic acid, gelatin, or polyacrylate. In certain embodiments, the polymer backbone is selected from polycarbophil, poly(acrylic acid), and carbomers (e.g., Carbopol 971 NF and Carbopol 974 NF). In certain embodiments, the polymer backbone is selected from chitosan, hyaluronic acid, and cellulose derivatives (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose).

[0055] In one embodiment, thiolation of the polymer skeleton, such as those described above, can be carried out by coupling a portion selected from cysteine, homocysteine, cysteamine, N-acetylcysteine, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione, thioethylamidine, 4-thiobutylamidine, and mercaptoaniline via amide, amidine, or ester bonds. Preferably, thiolation of the polymer skeleton is carried out by coupling with cysteine ​​or cysteamine.

[0056] In one embodiment, in the pre-activated thiomer used in the delivery system of the present invention, the side chains present in the polymer backbone are S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide-, or S-(6-mercaptopyridoxine)-cysteine-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide-, or S-(6-mercaptopyridoxine)-homocysteine-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-cysteamine-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-N-acetylcysteine-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-thioglycolic acid-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-3-thiopropionic acid-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-4-thiobutanoic acid-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-mercaptobenzoic acid-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-mercaptonicotinic acid-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-glutathione-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-thioethylamidine-disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide- or S-(6-mercaptopyridoxine)-4-thiobutylamidine-disulfide, and S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, S-6,6'-dithionicotinamide-, or S-(6-mercaptopyridoxine)-mercaptoaniline-disulfide Selected from, The above side chains are attached to the polymer backbone via amide bonds, amidine bonds, or ester bonds.

[0057] In this specification, S-(2- or 6-mercaptonicotinic acid)- means S-(2-mercaptonicotinic acid)- or S-(6-mercaptonicotinic acid)-, and S-(2- or 6-mercapto(iso)nicotinamide)- means S-(2-mercaptonicotinamide)-, S-(2-mercaptoisonicotinamide)-, S-(6-mercaptonicotinamide)-, or S-(6-mercaptoisonicotinamide)-.

[0058] In one embodiment, the pre-activated thiomer used in the delivery system of the present invention is disclosed in U.S. Patent Publication No. 2012 / 0225024, the contents of which are incorporated herein by reference.

[0059] In certain embodiments, the pre-activated thiomers used in the present invention include poly(acrylic acid)-cysteine, polycarbophil-cysteine, carboxymethylcellulose-cysteine, chitosan-cysteine, hydroxypropylcellulose-cysteine, alginate-cysteine, pectin-cysteine, hyaluronic acid-cysteine, (polymer of acrylic acid and divinyl glycol)-cysteine, poly(acrylic acid)-cysteamine, polycarbophil-cysteamine, carboxymethylcellulose-cysteamine, chitosan-cysteamine, and hydroxypropylcellulose. Selected from polymer compounds having side chains of 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine, covalently bonded via disulfide bonds to a thiolated polymer backbone selected from --cysteamine, alginate-cysteamine, pectin-cysteamine, hyaluronic acid-cysteamine, and (acrylic acid and divinyl glycol copolymer)-cysteamine.

[0060] In certain embodiments, the pre-activated thiomer used in the delivery system of the present invention is selected from poly(acrylic acid)-cysteine-2-mercaptonicotinic acid and chitosan-cysteine-6-mercaptonicotinic acid. In certain embodiments, the pre-activated thiomer is poly(acrylic acid)-cysteine-2-mercaptonicotinic acid. In another particular embodiment, the pre-activated thiomer is chitosan-cysteine-6-mercaptonicotinic acid.

[0061] In one embodiment, the mucosal adhesion properties of a pre-activated thiomer can be adjusted according to the molecular weight of the polymer. For anionic and cationic pre-activated thiomers, highly efficient mucosal adhesion properties can be achieved at intermediate molecular weights, preferably in the range of 100 kDa to 1000 kDa, and preferably 300 kDa to 700 kDa.

[0062] The synthesis of pre-activated thiomers can be carried out by reaction of a thiolated polymer backbone with 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine.

[0063] The pre-activated thiomer used in this invention may be produced by the method disclosed in U.S. Patent Publication No. 2012 / 0225024.

[0064] In one embodiment, a matrix fabricated from a nanofiber network of pre-activated thiomers can be formed by applying electrospinning techniques to the pre-activated thiomers. This offers the advantage of being able to control the rate of release of the active substance present in the delivery system by changing the density of the nanofiber network constituting the matrix.

[0065] In one embodiment, the ophthalmic delivery system of the present invention does not contain a pre-activated thiomer. In another embodiment, the ophthalmic delivery system of the present invention contains at least one pre-activated thiomer and at least one pre-activated thiomer. "Pre-activated thiomer" refers to a thiomer.

[0066] The present invention also relates to the use of a pre-activated thiomer for the manufacture of a mucosal-adherent solid or semi-solid ophthalmic delivery system, preferably an ophthalmic insert or ophthalmic film, wherein the pre-activated thiomer is selected from polymer compounds having side chains of 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide, or 6-mercaptopyridoxine, covalently bonded to a thiolated polymer backbone via disulfide bonds.

[0067] In addition to the pre-activated thiomer, excipients and adjuvants may be used to formulate the ophthalmic delivery system of the present invention. Preferably, the excipients and adjuvants are pharmaceutically acceptable. Such suitable excipients and adjuvants are obvious to those skilled in the art and are mentioned in the latest edition of Remington's Pharmaceutical Sciences.

[0068] In one embodiment, the ophthalmic delivery system of the present invention further comprises one or more pharmaceutically acceptable excipients selected from thickeners, gelling agents, plasticizers, solubilizers, stabilizers, penetration enhancers, diluents, binders, disintegrants, lubricants, channeling agents, and buffers.

[0069] Examples of thickeners and gelling agents include high molecular weight crosslinked polyacrylic acid polymers (e.g., Carbopol), polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC)), polyethylene glycol, and hyaluronic acid.

[0070] Glycerol is an example of a plasticizer.

[0071] Examples of particularly effective solubilizers and stabilizers for pharmaceutical ingredients include cyclodextrins and nonionic surfactants.

[0072] An example of a penetration enhancer is reduced glutathione (GSH; 0.1%~1%).

[0073] Examples of diluents include sugar alcohols, such as sorbitol, xylitol, or mannitol.

[0074] Examples of binders include sugars and their derivatives; disaccharides, such as sucrose or lactose; polysaccharides and their derivatives, such as starch, cellulose, or modified cellulose, such as crystalline cellulose and cellulose ethers, such as hydroxypropylcellulose (HPC); sugar alcohols, such as xylitol, sorbitol, or mannitol; and synthetic polymers, such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG).

[0075] Examples of disintegrants include cross-linked polymers, such as polyvinylpyrrolidone or carboxymethylcellulose, and modified starches, such as sodium starch glycolate.

[0076] Examples of lubricants include magnesium stearate, calcium hydrogen phosphate, starch, crystalline cellulose, and colloidal silicon dioxide.

[0077] An example of a buffering agent is phosphate-buffered saline.

[0078] Examples of channeling agents include sodium chloride (NaCl) and polyethylene glycol with a molecular weight of 400 to 1500 g / mol.

[0079] In one embodiment, the ophthalmic delivery system of the present invention comprises one or more pharmaceutically acceptable excipients selected from high molecular weight crosslinked polyacrylic acid polymers, polyvinyl alcohol, polyvinylpyrrolidone, cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyethylene glycol, hyaluronic acid, glycerol, cyclodextrin, reduced forms of glutathione, sorbitol, xylitol, mannitol, sugars and their derivatives, sucrose, lactose, polysaccharides and their derivatives, starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate, colloidal silicon dioxide, and sodium chloride.

[0080] The excipients and adjuvants present in the ophthalmic delivery system of the present invention may allow for control of their expansion after hydration. In fact, it is desirable to avoid a system that becomes too large in volume after hydration, as this would make it unsuitable for ophthalmic use.

[0081] Furthermore, the excipients and adjuvants present in the ophthalmic delivery system of the present invention can enable control of the hardness of the ophthalmic delivery system, particularly in systems used in a dry form.

[0082] Furthermore, the selection of excipients and adjuvants present in the ophthalmic delivery system of the present invention may enable control over the rate of release of the active substance present in the delivery system.

[0083] The ophthalmic delivery system of the present invention enables the delivery of an active substance, preferably a pharmaceutically effective substance, to the eye of a target that requires it.

[0084] In one embodiment, the ophthalmic delivery system of the present invention further comprises at least one pharmaceutically effective substance. In another embodiment, the ophthalmic delivery system of the present invention further comprises one or more pharmaceutically effective substances. Furthermore, the ophthalmic delivery system of the present invention may comprise a combination of pharmaceutically effective substances.

[0085] In one embodiment, the pharmaceutically effective substance is selected from antiglaucoma drugs (particularly intraocular pressure (IOP) lowering agents), anti-inflammatory drugs, anti-infective drugs, anti-allergic drugs, and dry eye treatment agents. Preferably, the pharmaceutically effective substance is an ophthalmic drug.

[0086] In one embodiment, the antiglaucoma agent includes an IOP-reducing agent. In one embodiment, the IOP-reducing agent is an IOP-reducing agent that can be used to treat open-angle glaucoma. Examples of IOP-reducing agents include prostaglandin analogs, cholinergics, β-blockers, α-adrenergic receptor agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, NO donors, and combinations thereof. In one embodiment, a combination of one or more IOP-reducing agents, preferably a combination of at least two classes of IOP-reducing agents, is used. Examples of prostaglandin analogs include latanoprost, bimatoprost, travoprost, tafluprost, and latanoprostenbunod. In a particular embodiment, the active substance is bimatoprost. Examples of cholinergics include pilocarpine, ecothiopart, and carbachol. Examples of β-blockers include timolol and nadolol. Examples of α-adrenergic receptor agonists include brimonidine and apraclonidine. Examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide, acetalozamide, and metazolamide. An example of a Rho kinase inhibitor is netaludil. An example of an NO donor is latanoprostenbunod.

[0087] In one embodiment, the anti-inflammatory agent may be used for postoperative treatment after eye surgery, or for the treatment of macular edema, uveitis, or dry eye disease. Examples of anti-inflammatory agents include corticosteroid anti-inflammatory agents (dexamethasone, fluorometholone, rimexolone, fluocinolone, fluticasone, loteprednol) and nonsteroidal anti-inflammatory agents (bromfenaxesquihydrate, amfenac, nepafenac, aspirin, ibuprofen, ketorolac, tromethamine, diclofenac, flurbiprofen). In certain embodiments, the active substance is dexamethasone or a salt thereof, for example, dexamethasone sodium phosphate.

[0088] In one embodiment, an anti-infective agent may be used for postoperative treatment following eye surgery (including, but not limited to, cataract surgery), or for the treatment of conjunctivitis, keratitis, blepharitis, endophthalmitis, trachoma, or any other bacterial, fungal, or viral infection. Examples of anti-infective drugs, though not limited to them, include macrolides, aminosides, rifamycin, antivirals, and antifungal drugs (moxifloxacin, natamycin, azithromycin, mupirocin, erythromycin, ciprofloxacin, netylmycin, besifloxacin, gatifloxacin, gentamicin sulfate, levofloxacin, ofloxacin, sodium sulfacetamide, tobramycin, bacitracin zinc, polymyxin B sulfate, neomycin, and neomycin sulfate, acyclovir, valacyclovir, famciclovir, itraconazole, posaconazole, and voriconazole).

[0089] In one embodiment, anti-allergic drugs may be used in the context of seasonal allergies. Examples of anti-allergic drugs include H1-antihistamines and mast cell stabilizers (oxymetazoline hydrochloride, cetirizine hydrochloride).

[0090] In one embodiment, the dry eye treatment agent includes an immunosuppressant, such as cyclosporine or tacrolimus.

[0091] In further embodiments, the ophthalmic delivery system of the present invention also enables the delivery of other active substances, including ophthalmic relief agents for conditions such as dry eye. Examples of such ophthalmic relief agents include lubricants, such as polyvinyl acid (PVA) or polyvinylpyrrolidone (PVP).

[0092] In one embodiment, the ophthalmic delivery system of the present invention contains an active substance in an amount ranging from 0.01% to 50% by weight of the total weight of the delivery system, preferably 0.1(w / w)% to 20(w / w)%; more preferably 0.1(w / w)% to 10(w / w)%.

[0093] The present invention also relates to the use of the mucosal-adherent solid or semi-solid ocular delivery system of the present invention in the treatment and / or prevention of eye diseases or ocular conditions. In particular, the ocular delivery system of the present invention is useful for delivering one or more active substances to the target ocular level. The target ocular tissue may be, but is not limited to, corneal tissue, conjunctiva, eyelid, trabeculum, iris, ciliary body, uvea, choroid, retina, or macula. The ocular delivery system of the present invention is useful for use in humans and veterinary medicine.

[0094] In one embodiment, the present invention provides a mucosal-adherent solid or semi-solid ocular delivery system for use in the treatment and / or prevention of eye diseases or ocular conditions.

[0095] The present invention also relates to the use of the mucosal-adherent solid or semi-solid ophthalmic delivery system of the present invention for the manufacture of pharmaceuticals for the treatment and / or prevention of eye diseases or ophthalmic conditions.

[0096] Furthermore, the present invention relates to a method for treating and / or preventing an eye disease or ocular condition in a patient, comprising the step of administering a mucosal-adherent solid or semi-solid ocular delivery system according to the present invention to a target site in the eye of a patient in need. The mucosal-adherent solid or semi-solid ocular delivery system of the present invention is preferably placed in the conjunctival sac of the eye of a patient in need.

[0097] The ophthalmic delivery system of the present invention enables the treatment of diseases of the anterior and posterior parts of the eye.

[0098] In one embodiment, the eye disease or condition is selected from open-angle glaucoma, macular edema, uveitis, dry eye disease, conjunctivitis, keratitis, blepharitis, endophthalmitis, trachoma, postoperative allergy, and seasonal allergy. In one embodiment, the eye disease is dry eye. In one embodiment, the eye disease is open-angle glaucoma.

[0099] In one embodiment, the mucosal-adhering solid or semi-solid ophthalmic delivery system of the present invention may also be used to alleviate symptoms of dry eye. This is particularly effective when the ophthalmic delivery system contains a lubricant as described above.

[0100] In one embodiment, the mucosal-adherent solid or semi-solid ophthalmic delivery system of the present invention is contained within a unit dosage form.

[0101] The ophthalmic delivery system of the present invention can be used in a dry or hydrated form. In one embodiment, the ophthalmic delivery system of the present invention is in a dry form, i.e., it contains a limited amount of water, if present. In such a case, after being placed in the conjunctival sac or on the surface of the conjunctiva, the delivery system of the present invention is hydrated in situ, and the hydrated pre-activated thiomeric matrix forms a mucosal-adherent hydrogel (i.e., an in situ gelation process). In another embodiment, the ophthalmic delivery system of the present invention is in a hydrated form, i.e., the pre-activated thiomeric matrix is ​​hydrated in the form of a hydrogel.

[0102] The solid or semi-solid ophthalmic delivery system of the present invention can be an ophthalmic insert or an ophthalmic film.

[0103] In one embodiment, the solid or semi-solid ophthalmic delivery system of the present invention is an ophthalmic insert, i.e., a solid or semi-solid, consistent three-dimensional device designed to be placed in the conjunctival sac or on the surface of the conjunctiva, the size and shape of which are designed specifically for ophthalmic applications. In one embodiment, the ophthalmic insert is in a dried form. In another embodiment, the ophthalmic insert is hydrated and in the form of hydrogel pellets.

[0104] In one embodiment, the ophthalmic delivery system of the present invention electrospins an ophthalmic insert. Preferably, the ophthalmic insert is formed alone from a pre-activated thiomer matrix optionally containing an active substance, i.e., the ophthalmic insert does not contain any further layers or substances.

[0105] The ophthalmic insert can be obtained by direct compression of a pre-activated thiomer which may be in a lyophilized form. When containing an active substance, the ophthalmic insert can be obtained by direct compression of a mixture of the active substance dispersed in a pre-activated thiomer.

[0106] The ophthalmic insert may be of any size and shape, but is suitable for placement in the eye, and is preferably in the shape of a rod, strip, thread, donut, disc, oval, or crescent. In one embodiment, the ophthalmic insert is convex on one side and concave on the other. The ophthalmic insert has a smooth surface that does not exhibit any angles on its surface and does not cause irritation to the eye or eyelid. Preferably, the cross-section of the ophthalmic insert is circular, square, or rectangular. Preferably, the insert is sized and shaped to easily fit the eye or a part thereof. In one embodiment, the ophthalmic insert has a thickness in the range of 0.1 mm to 5 mm, preferably 0.5 mm to 2 mm, more preferably 0.5 mm to 1.5 mm. In one embodiment, the ophthalmic insert has a length in the range of 1 mm to 10 mm, preferably 2 mm to 5 mm. In one embodiment, the ophthalmic insert has a width in the range of 1 mm to 10 mm, preferably 2 mm to 5 mm.

[0107] In another embodiment, the solid or semi-solid ophthalmic delivery system of the present invention is an ophthalmic film, i.e., a solid or semi-solid, consistent, two-dimensional film designed to be placed in the conjunctival sac or on the surface of the conjunctiva, the size and shape of which are specifically designed for ophthalmic applications. In one embodiment, the ophthalmic film is in a dry form. In another embodiment, the ophthalmic film is in a hydrated form.

[0108] The ophthalmic film may be rectangular, circular, ellipsoidal, or any other suitable shape. Preferably, the ophthalmic film has a thickness in the range of 0.01 μm to 1000 μm, preferably 0.5 μm to 500 μm. If the ophthalmic film is circular, it may have a diameter in the range of 2 mm to 20 mm, preferably 5 mm to 10 mm. The ophthalmic film may also be curved for proper placement on the surface of the eye.

[0109] Ophthalmic films can be obtained by evaporation of a solvent from a pre-activated thiolated polymer solution containing an optional active substance. Alternatively, ophthalmic films can be obtained by printing techniques, such as inkjet printing.

[0110] Furthermore, the present invention relates to a kit comprising a solid or semi-solid ophthalmic delivery system. The kit may include instructions for use in the treatment and / or prevention of ophthalmic diseases or conditions. The kit may also include an applicator, preferably a sterile applicator. [Examples]

[0111] The present invention is further illustrated by the following examples.

[0112] Example 1: Ophthalmic insert An ophthalmic insert containing (i) a pre-activated thiomeric matrix of poly(acrylic acid)-cysteine-2-mercaptonicotinic acid and (ii) bimatoprost as the active ingredient was prepared by direct compression of the lyophilized active ingredient and the pre-activated thiomeric matrix simultaneously.

[0113] [Table 1]

[0114] The pre-activated thiomeric poly(acrylate)-cysteine-2-mercaptonicotinic acid was synthesized as described above (Iqbal J. et al., Biomaterials, 2012, 33, 1528-1535).

[0115] Bimatoprost was dispersed in an aqueous solution of a pre-activated thiomer, and this dispersion was freeze-dried. 1.5 mg, 2 mm diameter inserts were prepared by directly compressing the freeze-dried powder into tablets.

[0116] The obtained ophthalmic insert exhibits properties suitable for use in the eye (size, shape, stability, adhesion), good mucoadhesive properties, and is well tolerated. Bimatoprost is released from the ophthalmic insert with an appropriate release profile.

[0117] Example 2: Ophthalmic film (i) An ophthalmic film containing a pre-activated thiomer matrix of chitosan-cysteine-6-mercaptonicotinic acid and (ii) sodium dexamethasone phosphate as an active substance was prepared by solvent evaporation.

[0118] [Table 2]

[0119] The pre-activated thiomer of chitosan cysteine-6-mercaptonicotinic acid was synthesized as reported above.

[0120] This film was obtained by solvent casting. Sodium dexamethasone phosphate, the pre-activated thiomer, and glycerol were dissolved in an optimal solvent system, cast, dried in a hot air dryer (40 °C - 50 °C), and then cut into unit dosage forms.

[0121] The obtained ophthalmic film exhibits properties suitable for use in the eye (size, shape, stability, adhesion), good mucoadhesive properties, and is well tolerated. Dexamethasone is released from the ophthalmic film with an appropriate release profile.

[0122] Example 3: Characterization of ophthalmic inserts in vitro The ophthalmic inserts of the present invention are characterized with respect to their bioadhesive properties and swelling after hydration.

[0123] Bioadhesion assay Objective: This assay aims to determine the mucosal adhesion properties of the insert of the present invention by measuring the duration of bioadhesion of the insert to animal mucosa under a continuous flow of biological fluid.

[0124] Method: The insert is deposited onto a section of animal mucosa, and 10 μl of biofluid is applied to adhere the insert to the mucosa. The section of animal mucosa is then placed on a support glass platform positioned horizontally and at a 45-degree angle. A reservoir and peristaltic pump placed above the glass platform continuously flow the biofluid onto the glass platform. The biofluid flows over the insert adhered to the mucosa, and the drained fluid is collected below the glass platform. The time it takes for the insert to dissolve or detach from the animal mucosa is determined. This measures the duration of adhesion of the insert to the animal mucosa.

[0125] Furthermore, the discharged fluid collected at predetermined points in time is assayed to quantify the drug released from the insert over time.

[0126] Expansion and hydration assay Objective: This assay aims to determine the hydration properties and expansion behavior of the insert of the present invention by measuring their properties for incorporating water and forming a gel of defined dimensions.

[0127] Methods: The methods for determining the behavior of water uptake and expansion were derived from those previously described by Hornof et al. (Hornof M. et al., Journal of Controlled Release, 2003, 89, 419-428). Water uptake was determined by gravimetric measurement. The inserts were hydrated with a defined volume of simulated tears in a closed container to prevent evaporation during the assay and incubated at 32°C, the surface temperature of the eye. The weight of the inserts was determined at different time points to evaluate the rate of water uptake. The size of the inserts was measured visually to determine the propension tendency of the inserts.

[0128] Example 4: Evaluation of ophthalmic inserts in vivo Objective: To test in vivo the ophthalmic insert of the present invention in terms of adhesion to the surface of the eye and non-harmfulness (absence of deterioration of the surface of the eye, no conjunctival / corneal inflammation or infection, and no eye pain).

[0129] Methods: This assay was performed in rats. These animals were housed under controlled conditions. Prior to all experimental procedures, all rats underwent a thorough examination of the eye surface (slit lamp, fluorescein test, corneal mechanical sensitivity, and in vivo confocal microscopy) to verify that the non-transplanted animals were free from inflammation or infection, or even damage or trauma to the eye surface.

[0130] Animals are anesthetized with gas anesthesia, and the insert to be tested is unilaterally placed in the conjunctival sac below the rat's eye. The insert is left in place in the animal's eye for 7 days, and the results are observed. At the end of the insert's application, the gas anesthesia is stopped, and the animals are rapidly awakened. The animals' behavior during this time is observed. Next, clinical evaluations of the integrity of the eye surface (slit lamp, fluorescein test, presence of the insert in the conjunctival sac), and the mechanical sensitivity of the cornea (von Frey test) and spontaneous pain (indicator of palpebral fissure closure) are performed regularly in stressed animals over the following 7 days. On day 7, a detailed examination of the eye surface is performed in vivo using a confocal microscope while the animals are under general anesthesia. The implant is removed, rapidly frozen, and subjected to bacteriological testing.

Claims

1. A mucosal-adhering solid or semi-solid ophthalmic delivery system comprising a pre-activated thiomeric matrix and one or more ophthalmic drugs, wherein the ophthalmic delivery system is an ophthalmic insert or an ophthalmic film. The matrix comprises at least one pre-activated thiomer selected from polymer compounds having side chains of 2-mercaptonicotinic acid or 6-mercaptonicotinic acid covalently bonded to a thiolated polymer backbone via disulfide bonds, The one or more ophthalmic drugs mentioned above are selected from anti-glaucoma drugs; anti-inflammatory drugs; macrolide drugs, aminosides, rifamycin, and antiviral drugs; anti-infective drugs; anti-allergic drugs; and dry eye treatment agents; Ocular delivery system.

2. An ophthalmic insert, a mucosal-adherent solid or semi-solid ophthalmic delivery system according to claim 1.

3. A mucosal-adherent solid or semi-solid ophthalmic delivery system according to claim 1 or 2, wherein the polymer backbone is selected from (meth)acrylic acid, (meth)acrylic acid esters, (meth)acrylamide, vinylpyrrolidone, vinyl alcohol, vinylimidazole, vinylcaprolactam, divinylglycol, polycarbophil, carbomer, allylamine, (trimethylated) chitosan, hyaluronic acid, pectin, alginate, (crosslinked) polyallylamine, polylysine, polyornithine, polyaminoamide, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose (crosslinked) homopolymer or copolymer, the polymer backbone may exhibit free thiol groups as side chains.

4. The side chain of the polymer compound is S-(2- or 6-mercaptonicotinic acid)-cysteine-disulfide; S-(2- or 6-mercaptonicotinic acid)-homocysteine-disulfide; S-(2- or 6-mercaptonicotinic acid)-cysteamine-disulfide; S-(2- or 6-mercaptonicotinic acid)-N-acetylcysteine-disulfide; S-(2- or 6-mercaptonicotinic acid)-thioglycolic acid-disulfide; S-(2- or 6-mercaptonicotinic acid)-3-thiopropionic acid disulfide; S-(2- or 6-mercaptonicotinic acid)-4-thiobutanoic acid-disulfide; S-(2- or 6-mercaptonicotinic acid)-mercaptobenzoic acid-disulfide; S-(2- or 6-mercaptonicotinic acid)-mercaptonicotinic acid-disulfide; S-(2- or 6-mercaptonicotinic acid)-glutathione-disulfide; S-(2- or 6-mercaptonicotinic acid)-thioethylamidine-disulfide; S-(2- or 6-mercaptonicotinic acid)-4-thiobutylamidine disulfide; and S-(2- or 6-mercaptonicotinic acid)-mercaptoaniline-disulfide; Selected from, The side chains are bonded to the polymer backbone via amide bonds, amidine bonds, or ester bonds. A mucosal-adhering solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 3.

5. A mucosal-adherent solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 4, wherein the pre-activated thiomer forming the matrix is ​​in the form of nanofibers.

6. The mucosal-adherent solid or semi-solid ocular delivery system according to any one of claims 1 to 5, wherein the antiglaucoma agent is an IOP-reducing agent selected from prostaglandin analogs, cholinergics, β-blockers, α-adrenergic receptor agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, NO donors, and combinations thereof.

7. The mucosal-adherent solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 5, wherein the anti-inflammatory agent is selected from corticosteroid anti-inflammatory agents and nonsteroidal anti-inflammatory agents.

8. The mucosal-adhering solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 5, wherein the anti-allergic agent is selected from H1-antihistamines and mast cell stabilizers.

9. A mucosal-adhering solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 8, further comprising one or more pharmaceutically acceptable excipients selected from thickeners, gelling agents, plasticizers, solubilizers, stabilizers, penetration enhancers, diluents, binders, disintegrants, lubricants, channeling agents, and buffers.

10. A mucosal-adhering solid or semi-solid ophthalmic delivery system according to claim 9, wherein the thickener and gelling agent is selected from high molecular weight crosslinked polyacrylic acid polymer, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives selected from hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), and hydroxypropylcellulose (HPC), polyethylene glycol, and hyaluronic acid; the plasticizer is glycerol; the solubilizer and stabilizer is selected from cyclodextrin; the penetration enhancer is reduced form of glutathione; the diluent is selected from sugar alcohols; the binder is selected from sugars, disaccharides, polysaccharides, cellulose, modified cellulose, sugar alcohols, and synthetic polymers; the disintegrant is selected from crosslinked polymers and modified starch; the lubricant is selected from magnesium stearate, calcium hydrogen phosphate, starch, crystalline cellulose, and colloidal silicon dioxide; and the channeling agent is selected from sodium chloride and polyethylene glycol.

11. A mucosal-adhering solid or semi-solid ophthalmic delivery system according to any one of claims 1 to 10, comprising one or more pharmaceutically acceptable excipients selected from high molecular weight crosslinked polyacrylic acid polymer, polyvinyl alcohol, polyvinylpyrrolidone, cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, polyethylene glycol, hyaluronic acid, glycerol, cyclodextrin, reduced form of glutathione, sorbitol, xylitol, mannitol, sugars, sucrose, lactose, polysaccharides, starch, sodium starch glycolate, magnesium stearate, calcium hydrogen phosphate, colloidal silicon dioxide, and sodium chloride.

12. A mucosal-adherent solid or semi-solid ocular delivery system according to any one of claims 1 to 11, for use in the treatment and / or prevention of eye diseases or ocular conditions.

13. The mucosal-adhering solid or semi-solid ocular delivery system according to claim 12, wherein the aforementioned eye disease or condition is selected from open-angle glaucoma, macular edema, uveitis, dry eye disease, conjunctivitis, keratitis, blepharitis, endophthalmitis, trachoma, postoperative allergy, and seasonal allergy.

Images