TWI292325B - Composition for dry eye treatmentand use of an emulsion in preparing the same - Google Patents

Description

1292325 A7

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the treatment of dry eye, and in particular to a method for forming artificial tears on the surface of the eye 3 to inhibit evaporation and delivery of an effective drug to the surface of the eye to treat eye diseases. combination. Prior Art The primary concern of the present invention is a method of treating dry eye by lubricating the eye and reducing fluid from the corneal surface. This cornea works normally to maintain the surface in moisture and in a state of lubrication, which is impaired when the eye has dry eye. The eyes are dehydrated and dehydrated, resulting in various discomforts such as dry eyes and burning and rubbing sensations. However, if the dry eye is more serious, the degree of visual acuity will be lost. If the visual acuity is continuously lost and not corrected, it will cause permanent damage. Dry eye syndrome can exacerbate the exposed surface of the eye and can cause complete loss of function of the corneal tissue. In extreme cases, this may require a membranous graft. When S eyes cover contact lenses, the symptoms associated with dry eye syndrome may worsen. Contact lenses accelerate the rate at which liquid evaporates from the eye, and the presence of contact lenses results in the formation of a meniscus that promotes evaporation even when the eye has sufficient natural tear film. Treatments typically prescribed for dry eye are alleviated by topical application of a tear film substitute. The tear film substitute increases the apparent volume of the liquid on the anterior surface of the eye. A typical composition such as a tear film substitute comprises a soluble polymer solution. No. 4,421,740 to Trager, which discloses a method for applying the Chinese National Standard (CNS) A4 specification (21〇x) by lecithin, phospholipid, and viscosity adjustment. 297 mm) 1292325 A7 ______B7____ V. INSTRUCTION DESCRIPTION (2) An artificial tear composition formed by an aqueous hypotonic solution of the agent. The prior art in which it is specifically related is the following U.S. patent, in which Korb is a co-inventor. Therefore, these patents will be referred to hereinafter as K〇rb patents: I. 4,914,088 (1990) II. 5,278,15 1 (1994) III. 5,371,108 (1994) IV. 5,294,607 (1994)

The Korb patent states that the surface of the eye of a normal eye is coated with a tear film consisting of: (a) an inner layer of mucus that is in contact with the surface of the eye (b) an aqueous intermediate layer of the source of wetting, and (c) a lipid that reduces evaporation of moisture from the film. Outer layer. When the outer layer (c) of the tear film is defective, it produces ‘‘dry eye,. Patent 1 to the dry eye treatment patent disclosed and claimed involves the application of a disc grease to the eye, which forms an artificial tear film on the eye, replicates a normal lipid outer layer and maintains the eye in a wet state. Patent I is directed to the artificial tear film formed by: "a composite phospholipid layer having a net positive or negative charge, according to the Korb patent, the net positive or negative charge meaning in the case of both, for the surface film of the eye The charged molecules in the coating, repel each other, and, when repelled with each other, maintain the integrity of the phospholipids within them, so the effect is, for example, the barrier mitigates evaporation." Therefore, the inventor It is included in this patent. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)~ ----------------- 1292325 V , invention description (3) Patent I fails to take into account that the surface of the treated eye is anionic and therefore will have electrostatic interaction with the charged coating depending on the polarity of the charge. According to patent 1 charge polarity and 雒 so because of any polarity The charged molecules in the membrane can repel each other. The important aspect of the invention is not only that it has a positive net charge, but also the intensity and distribution of the charge, which can cause the membrane to electrostatically adhere to the surface of the entire anion-charged eye. Provided Wet gas barrier. A weak positive charge cannot achieve this result because, as in the present invention, positively charged molecules in the membrane covering the surface of the eye electrostatically attract negatively charged molecules on the surface, and the resulting static pairing is neutral. And the pairings will not be mutually exclusive.

Korb Patent II discloses an ophthalmic treatment composition comprising "a layer of a complex phospholipid having a net charge, and a layer of a substantially non-polar oil on the phospholipid layer", the amount of which is "caused to cause Significantly prolonged visual blurring below." According to Patent II, preferred phospholipids are "net negatively charged" because negatively charged molecules will be repelled by the negatively charged surface of the eye, thus allowing dimensionality: relative thickness of the aqueous layer Conversely, the present invention pertaining to a positively charged composition utilizes the fact that the surface of the substrate is negatively charged - (anionic), so that the composition is electrostatically attracted to the surface to prevent moisture from being absorbed from the surface of the eye. Escape from the sound, and time.

Korb Patent III also discloses a composition in which the grease has a net, or positive, charge' resulting in the molecules in the tear film coating the surface of the eye while maintaining the integrity of the film with each other. In Korb Patent 1 ¥, the eye treatment composition is in the belt aa fresh (cns) _ A4 size _ X 297 嫠 -6 - 1292325 A7 B7 5, invention description (4 electrophospholipids and non-polar oils in metastable A mixture of aqueous emulsions. The gist of the present invention is that the emulsion T coated on the surface of the eye to form a film thereon has a net positive charge uniformly dispersed throughout the film, so that it is electrostatically attracted to the entire anionic eye surface, where The molecules on the surface of the membrane do not repel each other 'but attract to the surface of the eye. The other prior art is AUergan's pc patent publication W〇95/3ΐ2ΐι(ΐ"5年ηΑμ日). This announcement reveals the local An emulsion for use in clearing tissues comprising cyclosporine mixed with the marijuana oil. As mentioned in the publication, cyclosporine comprises a group of cyclic oligopeptides, the main component of which is a ring: A (CuHmNnO^) In view of the foregoing, it is a primary object of the present invention to provide an improved method and composition for treating dry eye by topical application of an emulsion to the surface of the eye, the emulsion. Tear film Electrically adhering to the entire surface of the eye and lubricating the eye and inhibiting the evaporation of moisture therefrom. Among the significant advantages of the method and composition according to the present invention are the following: A. The tear film derived from the emulsion has a strong net positive charge, Uniformly dispersed throughout the surface of the membrane where it is electrostatically attracted to the entire area of the negatively charged eye surface and without uncoated areas. Month B. Electrostatic attraction between the artificial tear film and the surface of the eye maintains adhesive contact A prolonged residence time and tear film can not be easily washed away. C. Tear film coating on the surface of the eye has no adverse effects, because the film does not contain toxic or other harmful agents. · Another object of the present invention is to provide a method for the treatment of eye diseases Above the therapeutic agent, the paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇χ297 mm) 1292325 A7 ι____ B7 V. Invention Description (5~)~' ' ~ The composition of the description, for example: ring Spore A, which delivers the agent to the eye when the composition is administered topically. The agent is released from the coating film to the surface of the eye for a prolonged period of time, wherein the film is electrostatically contacted. In short, A method and composition for treating dry eye, which achieves the purpose by topical application of a ritual to the surface of the eye, which forms a tear film to lubricate the eye and inhibit evaporation therefrom. The emulsion is composed of water, wherein the emulsion is composed of water, wherein Dispersing a mixture comprising phospholipids, apolar oils, and a net positive charge throughout the membrane, causing the membrane to be electrostatically attracted to the anionic surface of the eye where the membrane adheres to the eye and cannot be washed away. The mixture may be insoluble. A therapeutic agent, such as cyclosporine, is effective against ocular diseases and is delivered to the eye by a membrane. DETAILED DESCRIPTION OF THE INVENTION Cyclosporin A (CsA), a fat-soluble cyclic endecapeptide, is a An effective and well established immunomodulatory drug for oral use. When used in an oral formulation, the bioavailability of CsA is limited because the drug is insoluble in water and is readily and immediately separated into solids upon contact with water. Furthermore, bioavailability is highly dependent on the complex interactions between the formulation and the physiological environment of the lumen. It has been found that CsA is effective in the treatment of immunoregulatory dry keratoconjunctivitis (KCS or dry eye) by enhancing or restoring tears secreted by the lacrimal gland of patients with this dry eye condition. Dry eye syndrome is characterized by long-term dryness of the conjunctiva and cornea, as well as reduced tear secretion and altered tear film composition. In order to enhance the effect of CsA treatment, it is necessary to increase the absorption of the drug in the lacrimal gland and the tissue of the conjunctiva and the cornea, in order to inhibit the inflammation of the eye for a suitable dose of the drug without significantly exposing the whole body to eight. This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1292325 A7 B7 V. Description of invention (6) Because the aqueous solubility of CsA is between about 2 〇 and 3 〇 "years ..., there is not enough Aqueous formula can be used for ocular administration of this drug. Furthermore, if cyclosporine is administered orally to treat KCS, adverse side effects such as hirsutism or renal dysfunction may occur due to side effects of systemic circulation. In addition, due to the hydrophobicity of the drug Sexual nature, so the concentration of CsA in oral formulations is limited. The csa penetration of animal eyes was studied using CsA formula based on olive oil and corn oil. It was found that the local CsA formula or the original solvent can be used. The local toxic effect of the cornea. When using CsA in eucalyptus oil, in the in vitro examination of the cornea, histological studies showed that the corneal epithelium had several necrotic cells and rare keratotrophin keratinization. The investigators confirmed that the possible toxic effects were due to local dissolution of CsA in olive oil. The conclusion reached is that eucalyptus oil (rather than CsA) is a surface epithelial cell deficiency in the cornea. Therefore, because of its high hydrophobicity, CsA needs to be formulated with compatible media. It is not always biocompatible for ophthalmic administration, and there may be some problems with stability, such as: olive oil The rancid. The disadvantage of the corn oil concentrate ointment formulation is that it can worsen the symptoms of dry eye syndrome (early burning, redness, and itching). The emulsion can be produced by reducing the oil content and dispersing the oil phase in the aqueous phase. Reducing problems associated with unpleasant sensations and worsening symptoms. I have found that when using sesame oil to develop an emulsion dose, there is an additional benefit to dry eye patients because of the long eye retention time of the emulsion vehicle. On the patient's eye, the droplets of the castor oil in the emulsion form a lipid layer on the tear film to reduce the evaporation of the limited natural tears produced. The pair has an f-potential value in the range of 34 to 45 mV and an average droplet size on the paper. The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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The study of positively charged submicron emulsions containing phospholipids at 50 to 25 nm, supporting the significant advantages of emulsion vehicles when they carry a net positive charge rather than a negative or neutral charge. The electrostatic attraction between the positively charged submicron oil droplets and the negatively charged corneal eye surface in the emulsion results in longer docking or residence times, which is beneficial for local drug flow enhancement. Thus, a positively charged submicron emulsion of CsA enhances the local concentration of this agent in the conjunctiva and cornea, which is the target eye tissue. Therefore, the positively charged emulsion according to the present invention is far more effective than the negatively charged emulsion having a similar composition. I. The following are representative formulations of compositions for treating dry eye and other ocular diseases in accordance with the present invention. Formulation (1) is a positive blank emulsion that is topically applied to the surface of the eye to create an artificial tear film on the surface. Formulation (2) is a CsA positive emulsion having the same composition as Formulation (1) 'Adding cyclosporine. The resulting membrane function, such as a vehicle, delivers the drug to the surface of the eye. Cyclosporin A 0.00 0.20 Castor oil 2.50 2.50 Lipoid E-80 0.50 0.50 stearylamine 0.12 0.12 Vitamin E 0.01 0.01 Pluronic F-68 0.42 0.42 Glycerin 2.25 2.25 Ammonium methoxide 0.01 0.01 Add steam to water 100.00 100.00 -10- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1292325 A7 __ _B7 V. Description of invention (8) Lipid E-8 is a non-polar phospholipid, stearylamine is a cationic lipid and thus gives an emulsion (It also includes non-polar castor oil) net positive charge. Plur〇nic F-68 is a trademark of polyhydroxyalkylene 188, a polyoxyalkyline derived from polypropylene glycol. Polyhydroxylene 188 is an emulsifier and a glycerin such as a penetrant in the formulation. The benzalkonium chloride gas is a cationic surfactant preservative which acts as a preservative for the emulsion and enhances the positive charge imparted to the emulsion by the cationic lipid. Vitamin E acts like lipophilic antioxidants and eye lubricants. In practice, the composition may include a cationic lipid oleylamine rather than a cationic lipid stearylamine. The relative percentages of the ingredients included in the composition are not limited to those mentioned above. Therefore, the relative percentage of castor oil can be in the range of 〇. 5 to 10%, the phospholipid (Lipoid E-80) is in the range of 0.1 to 2.0%, and the cationic f-monthly mussel is in the range of 0.1 to 0.5%, and The emulsifier (pjur〇njjc f_68) is in the range of 0.5 to 2.0%. However, it is important that the emulsion carries a net positive charge of sufficient strength to cause electrostatic attraction of the emulsion to the surface when forming a film on the anionic surface of the eye, regardless of the relative range of such components, so that it adheres to the surface and cannot be easily washed. except.

Lipoid E80 v PlUr〇nic F_68, in combination with stearylamine, improves the stability of the emulsion droplets by enhancing the mechanical strength of the interfacial film formed around the droplets, preferably in the submicron range. The following composition in accordance with the present invention, which is important to the heart of the heart, is administered topically to the anionic surface of the eye, the phospholipids and castor oils included in the formulation are uncharged, and the submicron droplets are imparted. The aggregated net positive charge is derived from a cationic surfactant plus a cationic preservative. -11 - Ϊ Paper scale applicable to China National Necklace (CNS) A4 specification --- I292325 Description of the invention This formula is superior to the dry eye treatment in which the charge imparted to the droplet is only derived from phospholipids (eg K〇rb patent) The point of the composition is that when the formulation of the present invention is used, the positive charge of the agent is uniformly dispersed throughout the entire area of the artificial tear film produced when the emulsion is applied to the anionic surface of the eye. This results in electrostatic attraction of the entire area of the surface of the eye, so there is no uncoated and untreated portion. Therefore, the present invention provides a treatment for dry eye disease in which moisture evaporation is inhibited throughout the surface of the eye and moisture is not allowed from it. Dissipate. Preparation of the composition Polyhydroxyl 188 (Pluronic F-68) penetrant (glycerol) and benzalkonium chloride were dissolved in the aqueous phase. First, 丨ip〇id E-8〇 was dissolved in ethanol (1:5) and then dispersed in the aqueous phase. The ethanol is evaporated during the heating process of the aqueous phase. The antioxidant (α-tocopherol), the cationic lipid stearylamine (or oleylamine), and CsA are dissolved in the castor oil phase. The two phases were separately heated to 7 (rc. The aqueous phase was slowly blended into the oil phase and mixed with a magnetic stirrer. The resulting mixture was further heated to a temperature of 85 ° C. The resulting crude emulsion was emulsified for 5 minutes, Use a high shear p〇lytr〇n mixer and then rapidly cool to below 20 C. After cooling in an ice bath, the emulsion is homogenized for 5 minutes using a two-stage homogenizer valve combination. After further rapid cooling below 2〇t The pH was adjusted to 7.0 using 0.1 N hydrochloric acid. The emulsion was then filtered through a TE membrane filter paper (Schleicher & Schuell, Dassel, Germany) having a pore size of 0.45 #m. Finally, the emulsion was packaged in a deuterated glass bottle under nitrogen and then It is sterilized by autoclaving of 12PC for 15 minutes. The droplets of the desired emulsion are in the submicron range and the important ones are to be locally applied to the eye-12-

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Line paper size applies to China National Standard (CNS) A4 size (210 X 297 mm) 1292325 V. Description of invention (w surface emulsion should be sterile. hL · Bureau according to the invention (4) engraved on the surface of the eye to treat dry eye syndrome The emulsion ' can also be used as a vehicle to deliver a therapeutic agent to the eye to treat an eye disease. The treatment of the eye is made by dripping the antibiotic agent into the eye, and the number of drops applied to the eye is determined by the physician. Prescription. Because this number defines the application of the drug to the eye of the sword, # ', her user must be careful to accommodate the limited amount of drops and do not allow the applied liquid to escape from the eye. But in practice, it is difficult to drip the liquid to the eye Do not allow liquid to flow out of the eye line because the surface of the eye can only hold a small amount of liquid. The advantage of using the emulsion according to the invention as a vehicle to deliver a therapeutic agent to the eye is to 'cover the entire surface of the eye and distribute the therapeutic agent in it. An emulsion on an anionic surface that electrostatically adheres to the surface, so all of the predetermined dose of the therapeutic agent is delivered to the eye, and because the coating is electrostatically adhered to the eye surface The face and the inability to wash out, the residence time of the treatment is prolonged, and thus the therapeutic agent is more effective. ^ The fact that the droplets in the charged emulsion according to the invention are sub-micron size has implications. When the droplet size is in the micrometer range When compared to the electrical density that can be produced, this micron size results in a much higher electrical density per unit area of the emulsion film, and thus a more powerful net power. As mentioned, we have revealed that cyclosin A is a blend of emulsions. Good pharmacy. But as long as other water-insoluble agents have the nature and non-polarity of the treatment of dry eye similar to cyclosporine, if the drug carries a negative charge, then the amount of cationic component included in the emulsion must be Can provide net positive electricity-13- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1292325 A7 B7 V. Invention description (11) The amount of charge. Therefore, it can be blended with Among the agents in the emulsions of the present invention, there are those belonging to the family of tacrolimus (disclosed in U.S. Patent No. 4,894,366). Celolins (8丨1*〇1丨111113) (rapamycin 1^93111>^11) in U.S. Patent No. 3,993,749. Although preferred embodiments of the invention have been disclosed, it should be understood There are many variations that can be made without departing from the spirit of the invention. w 14 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1292325 Application deadline 90. ϋ - 2 Case No. 090127296 Category 6 / Κ 兮//j) 7

Chinese Manual Replacement Page (September 95) Patent Specification - Name Chinese Composition for dry eye treatment and emulsion for use in the preparation of this composition English COMPOSITION FOR DRY EYE TREATMENT AND USE OF AN EMULSION IN PREPARING THE SAME Name

1. Simon Bennetta SIMON BENITA 2. Gregory Lambert GREGORY LAMBERT Nationality, residence name (name) Nationality 1. Israel 2. Belgium 1. 33/3 Harazin Street, Mayfash, Israel 2· No. 30, Katis Road, Freiburg, France III. Applicant residence, residence (office)

1. YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM, JERUSIA, JERUSALEM, Israel 2. NOVAGALIPHARMA SA, France, France 2. France 1. Jaffa Elound, Jerusalem, Israel Monshafa Campus High-Tech Park 2. No.1, Peel Fountain Road, Evry, France 1 Abraham Barak ABRAHAM BARAK 2 Reinibin - Israel RENEE BEN-ISRAEL 2 · Bernard Van der Kuy BERNARD VAN DERKOOY Applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

Patent Application Replacement of Chinese Patent Application (July 1993) I------Application Range 2. A composition for treating dry eye, comprising an emulsion, wherein the mixture is dispersed in water, the mixture comprising a non-polar 1 polar oil, a non-toxic emulsifier and a net positive emulsion Charged cationic lipid: When the tear film is formed when the emulsion is topically applied to the surface of the eye, it is electrostatically attracted to the anionic eye surface. According to the composition of claim 1, the # emulsion is prepared to produce submicron droplets. 3. The composition according to claim 1, wherein the oil is castor oil. 4. The composition according to claim 1, wherein the phospholipid is Lipoid E-80. 5. The composition of claim 1, wherein the cationic lipid is a hard amine. 6. The composition of claim 1, wherein the cationic lipid is oleylamine. 7. The composition according to claim 4, wherein the relative percentage of the fat in the emulsion is in the range of from 0.1 to 5·5. 8. A composition according to claim 1 wherein the mixture comprises vitamin bismuth. 9. The composition of claim 1, wherein the mixture further comprises an emulsifier. I. The composition according to claim 9 wherein the emulsifier is a poloxamer. II. The composition according to the scope of claim 10, wherein the emulsifier in the emulsion 74755-9307l2.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding Patent application The relative percentage is in the range of 〇·5 to 2.〇. 12. According to the composition of the scope of the patent application, item #, the mixture of #1 includes glycerin. Y匕 13. Root shots Please use the composition of item i, which includes a cationic preservative. 14. According to the composition of the patent item 1, the preservative ammonium chloride.疋 15. The composition according to claim 1 of the patent application, which does not comprise a therapeutic agent for treating eye diseases. % ' 16. The use of an emulsion for the preparation of a composition for treating dry eye, wherein in the emulsion, a mixture is dispersed in water 'The mixture comprises a non-polar, non-polar oil, a non-toxic emulsifier and a second A cationic positively charged cationic lipid that is electrostatically attracted to the anionic eye surface when the emulsion is applied topically to the surface of the eye to form a tear film. According to the use of item 16 of the scope of the patent application, wherein the emulsion is prepared to produce submicron droplets. 18. The composition according to claim 16 wherein the oil is lotus oil. 19. The composition according to claim 16 wherein the cans are a composition of the invention of claim 16 wherein the cationic lipid is stearylamine. 21. The composition of claim 16 wherein the cationic lipid is oleylamine. -2- 74755-9307l2.doc This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 2. A composition according to claim 19, wherein the relative percentage of phospholipids in the emulsion is in the range of 〇. The composition of claim 16 wherein the mixture comprises vitamin E. The composition according to claim 16 wherein the mixture further comprises an emulsifier. • The composition according to claim 24, wherein the emulsifier is a poloxamer. • A composition according to claim 25, wherein the relative percentage of emulsifier in the emulsion is in the range of from 至5 to 2.0%. 7. The composition according to claim 16 wherein the mixture further comprises glycerin. 2 8 . The use according to item 16 of the patent application, wherein the composition further comprises a cationic preservative. 2 9. The composition according to claim 16 wherein the preservative is #alkane gas. ·,, '卞 3 0. According to the application of Section 6 of the patent application, the level of human body does not include a therapeutic agent for treating eye diseases. 74755-930712.doc β ; paper scale suitable for s s home standard (CNS) Α 4 specifications (2 〇χ 297 dong) --- ^ _