MXPA96000140A - Use of tocyferyl derivatives of vitamin e in oftalmi compositions - Google Patents

Abstract

Ophthalmic compositions containing vitamin E tocopheryl derivatives that are comfortable and non-irritant are described, and the new use of ophthalmic agents together with vitamin E tocopheryl derivatives in the preparation of compositions to significantly reduce the discomfort and irritation associated with administration topical ophthalmic of ophthalmic agents alone, in addition, these tocopheryl derivatives of vitamin E significantly increase the aqueous solubility of certain poorly soluble ophthalmic agents

Description

USE OF VITAMIN E TOCOPHERYL DERIVATIVES IN OPHTHALMIC COMPOSITIONS BACKGROUND OF THE INVENTION The present invention relates generally to ophthalmic compositions. In particular, the present invention relates to the use of certain vitamin E tocopheryl derivatives to provide non-irritating and comfortable ophthalmic compositions. In addition, the present invention relates to the use of those tocopheryl derivatives of vitamin E for incrementai * the solubility of poorly soluble ophthalmic agents in aqueous compositions. For purposes of the present specification, the vitamin E tocopheryl derivatives useful in the present invention should be referred to as tocopheryl derivatives of vitamin E or vitamin E derivatives or "TPGS". The sensations of itching and burning, as well as general discomfort, are usually associated with the topical ophthalmic application of certain types of ophthalmic agents. It is considered that such ocular discomfort is due to the presence of certain functional groups in these agents. Examples of such ocular discomfort agents include, but are not limited to: blockers such as betapolol; prostanglandins and prostaglandin derivatives; muscarinics such as pilocarpjna; < x-aclr nérgi os such as epinephrine, clonidine and apraclon id ina; col ers such as carbachol; and nonsteroidal anti-inflammatory drugs ("NSAIDs") such as diclofenac and suprofen. Several attempts have been made to formulate topical ophthalmic compositions to reduce the inherent discomfort associated with those ophthalmic agents. Such attempts include those described in US 4, 559, 433 (Han et al.), US 14,911,920 (Jan. and others), US 5, 093, J 26 (Jan. and others, and (JS 5,212,162 (Missel et al.). Han et al. describes the addition of xanthine derivatives, such as to caffeine, to diminish the itching associated with topical ocular application of NSAJDs The two references of 3ani and others teach about the addition of certain ion exchange resins to blocking compositions to increase comfort and provide sustained release Missel et al. teaches combinations of gelling polysaccharides and finely divided drug carrier substrates ("DCS") that provide sustained and comfortable sustained release ophthalmic compositions In addition, US, 4,960,799 (Nagy) describes water-stable ophthalmic compositions containing diclofenac and / or pharmaceutically acceptable salts thereof Nagy compositions include EOTA and a solubilizer such as or ethoxylated castor oil.

BRIEF DESCRIPTION OF THE INVENTION It has been unexpectedly discovered that the addition of certain vitamin E tocopheryl derivatives to the ophthalmic compositions provides such comfortable and non-irritating compositions. It has also been discovered that these vitamin E derivatives greatly improve the aqueous solubility of many compounds that are only sparingly soluble in aqueous compositions.

DETAILED DESCRIPTION OF THE INVENTION Tocopheryl derivatives of vitamin E are water-soluble biologically active vitamin E analogues. These vitamin E derivatives have been used as alternatives to vitamin E, especially when water solubility is desired. In addition, the Patent of E.U.A. No. 3,102,076 describes the use of these derivatives to solubilize vitamins intimate in water of natural occurrence, such as vitamins A, D and E. The use of these vitamin E derivatives has also been reported to improve the absorption of the vitamin. A and the c? > by i.na. See, for example, Sol ', al, RJ et al., "I provement of Cyclosporin Absorption in Ohildren after Liver Tran plantat ion by Means of Water-soluble Vita in E", The lancet 336: 212-215 (1991), and Argao, EA et al., "< x-Toco? Hecyl Polyethylen Glycol-1000 succinate Enhances the Absorption of Vitamin D in" hronic Dhslestatic Liver disease of Jnfancy And Chiluhod ", Pediatpc Res. 31 (2): 146-150 <; 1992). Tocopheryl derivatives of vitamin E useful in the compositions of the present invention are polyoxyalkyl glycosides highly soluble in water of tocopheryl esters of vitamin E of a dicycloproteic acid. Representative characters of this type include the isocyclic polioether esters of vitamin E tocopheryl esters of a dicarboxylic acid wherein the polyoleic ester portion of the ester (sometimes referred to only as the polyoxyethylene glycol portion of the ester) has a molecular weight in the scale of approximately 600 to approximately 6,000, preferably in the range of approximately 600 to approximately 1,500. Such methods and methods for the preparation are described in US Patent No. 2,660,749 (Cawley et al.). The most preferred ester is the succinate of -tocof i Ipol io leti lenglical (1000), a polyexyl ester and glycol ester of succinate of < x-tocopheron in Junde the polyae and lengl icol portion of the molecule has an average molecular weight of about 1000. In general, one or more vitamin E derivatives are used in the compositions of the present invention in an amount T nor a about 30% by weight (p%). If the vitamin E derivatives are used as solubilization agents, it is preferred to use an amount between about 0.1 and about 20 in pee, very preferably between "" approximately 0.1 and about 5"? When the vitamin E derivatives are used to improve comfort, it is preferred to use an amount between approximately 0.1 and approximately 20% by weight, more preferable between approximately 0.5 and approximately 10% by weight. Suitable ophthalmic agents that can be included in the compositions of the present invention and administered by the method of the present invention include, but are not limited to, the racemic and enantiomeric forms and ophthalmically acceptable salts and esters of the following types of compounds : Agents for glauca, such as blockers (for example betaxalolol, thymol, and carteolol); «-agonists, (for example apraclonidine, and 2-substituted amino imidazolines) related); carbonic anhydrase inhibitors; dopamine agonists and antagonists; miotic mycotic cells (for example pilocarpine and carbachol); prostaglandin and postaglandin derivatives; ACE inhibitors; stabilizers (eg, glucarticaids and angiostatic steroids); and calcium channel blockers; Ant i-h ipei-tensors; non-steroidal anti-inflammatory agents; which include but are not limited to those classified as aryl- or heteroaryl-alkanoic acids such as diclofenac, flurbiprafe, suprofen, cetacolac, indametacin and cetoprsfen; Steroidal anti-inflammatory agents such as "'uorometoluna, dexamethasone, predncoluna, terahydritector 1 1 sol and tt i ame molona; antibacterials and agents against infections, such as anoglycosides (for example trcibamycin), quinolones (for example ciprofloxa ina and oflola apna), beta lactams (for example cef aos-pop ñas such as cef amlando); Anti fungal agents, such as natamycin; Antivirals, such as acicluvir and gane ícluvir; Anti-cataract and antioxidizing agents; Apti -allergic; Anti-metallites, such as 5-f lua? -ourac? 1 (5-FU) and metatrexate; Immunosuppressants, such as ciclosporin, Fr'-506 and leflummide; Growth factors such as EGF, FGF, PDGF, and Frofarmacos of the drug classes noted above.

Ophthalmic agent ions may also be used in the compositions of the present invention. Furthermore, in formulations without ophthalmic agents, the present invention can also be used to supply tears in the prevention or treatment of dry eye. Possibly Monday of the present invention may include other ophthalmically acceptable components, for example, pH regulators; (for example, phosphate, borate and citrate), chelating agents (for example • v ~ DTA), preservatives (for example benzalkonium urea, Polyquide, i and Ovpied1"-) and tonicity agents (sodium chloride and mannitol) The compositions of the present invention may also include viscosity modifying agents such as cellulose ethers, such as hydroxypropyl ether cellulose.

(JPMC), hicirox iet ilcelulosa (HFC), et i 1 h idrox iet icelcellulose, hydroxypropylcellulose, methycellulose, and carboxy and ilcellulose; carbomers (Car-b pol); alcohol pol i v iní 1 ico, polivini lpirrolidona; alginates; carrageenans; and guar, caray, agarose, carob, tragacanth and xanthan gums. The concentration of the viscosity modifiers will vary from about 0.1 to about 5% by weight, although such formulations will generally have a viscosity between approximately 10 and approximately 1000 centipaise. Ophthalmic compositions containing TFGS may additionally contain polymers that can withstand the sol-a-gel transition by exposure to physical or chemical stimuli, such as changes in pH, ionic concentration, and / or temperature. The ophthalmic agents contained in the compositions of the present invention can optionally be encapsulated in microparticles. These charged microparticles can be dispersed in aqueous vehicles having TPGS to improve comfort. In addition, the water-soluble or water-insoluble complexes of the ophthalmic agent can be incorporated into a vehicle containing TPGS. Example of the 6 Water soluble complexes include traditional complexes formed between the ophthalmic agent and caffeine, cyclodexamins, salicylates, benzoates. Examples of water-insoluble complexes include ophthalmic-drug-resin complexes. The following examples are presented to illustrate various aspects of the present invention, although it is not intended to limit the scope of the invention in any aspect.

EXAMPLE 1 The following formulations are representative of the preferred compositions of the present invention.

FORMULATION (% IN WEIGHT) JNGRFDJENTFS A B C D E F G Diclofenac sodium 0.1 0.1 0.1 0.1 0.1 0.1 Dexamethasone - 0.1 Vitamin E TPGS (1000) 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Trometamine 0.23 0.23 0. 3 1.2 1.2 - 0.23 Boric acid 1.0 1.0 1.0 1.5 1.5 - 1.0 Manitol 4.0 - - 3.0 4.0 - 4.0 Benzalkonium Chloride 0.01 0.01 0.01 0.100.01 0.01 NaCl 0.7 0. Disodium FDTA 0.1 0.1 .1 0.1 0.1 HPMC 0.1 0.3 0.1 0.3 Argin ina - 0.5 - HCl and / or NaOH pH at 7.4 Purified water 100 * Preparation: Formulation D was prepared as follows, and formulations A-C and E-G were prepared in a similar manner. A 10 * base solution of vitamin E TPGS was prepared as follows. Approximately 150 g of vitamin E TPGS were melted in a beaker by heating on a hot plate with stirring to ensure homogeneity. Approximately 100 g (g) of melted TPGS was added to 600 ml of double distilled water near boiling. This mixture was stirred and allowed to cool to room temperature to ensure complete dissolution. Sufficient water was then added to the solution to make one liter of the bd'fe solution. Sodium diclofenac was added to (0.3 g) of the base solution to 90 ml of the TPGS solution after the complete dissolution of diclofenac, each of the following ingredients was added sequentially to the solution with stirring until that each ingredient was completely dissolved before adding the following ingredient: 1.5 g of arginine; 9.0 g of mannitol, 4. g of boric acid, 3.6 g of trameta ina and 0.3 g of sodium edetate. To the previous solution, 6.0 ml of a 0.5% solution of benzalcomo chloride was added, followed by the addition of 15 ml of a 2 * HPMC solution. An additional 150 ml of water was added and the pH of the formulation was adjusted to 7.4 HCl and / or NaOH. To the resulting solution, enough water was added to bring the total volume of the solution to 300 ml. The collapse of the final solution was approximately 300mOs / 1"g.

EXAMPLE 2 The following formulation is another representative composition of the present invention, wherein a prostaglandin was formed in complex with cyclodextrin and is formulated in accordance with the teachings of the present invention. 13 INGREDIENT CONCENTRATION (* by weight) Prosta landina 0.25 Hydro i ro i 1-ß-c i lodextr ina 3.0 Trometain ina 1.2 Boric acid 1.5 Mannitol 1.0 Benzalkonium Chloride 0.0.1. EDTA Disodium 0.1 Vitamin E TPGS (1000) 3.0 HCl / NaOH pH to 74. Purified Water q.s. 100 * Prepare ion: Appropriate amounts of tromethamine, boric acid, mapitol, BAC and EDT were added to 90 ml of a base solution at .10 * of TPGS. In a separate vessel, 9 g of hydroxypropyl 1-β-iclodextrin were dissolved in 150 ml of water. To these were added 0.75 g of a prostaglandin. The two solutions were mixed together later, adjusting the pH to 7.4 and water was added to bring the volume up to 300 ml.

EXAMPLE 3 The following formulation is another representative composition of the present invention, wherein a prostaglandin linked to Dualite® > (resins of 7 lolest iramin, available from Rohm &Haas, Philadelphia, Fennsylvania), is formulated in accordance with 1.1 > n the teachings of the present invention.

INGREDIENT CONCENTRATION (* by weight) Pros ag land ina 0.25 I) uol? Te '"> 0.25 Vitamin E TPGS 3.0 Tro e a ina 1.2 Boric acid 1.5 Mani ol 4.0 Benzalkonium chloride 0.01 FDTA Disodium 0.3 HCl / NaOH pH to 7.4 Purified water q.s. 100 * Preparation: A prostagland was dissolved (.75 g) in 200 ml of water. Finely divided Duolite (0.75 g) was added, and the solution allowed to equilibrate for 2 hours, during which time about 95 * of the drug was bound to the resin. In a repaired vessel, prudent amounts of tromethamine, boric acid, BAC, sodium edetate and amthol were added to 90 ml of the 10 * TPGS base solution. The two parts were then mixed and the pH was adjusted to 7.4 with HCl and / or NaOH. A sufficient amount of water was added to the formulation to bring the final volume to 300 ml.

The invention has been described by reference to certain preferred embodiments; however, it must be understood that it can be modalized in other specific ways or variations thereof without departing from the spirit or essential characteristics. The embodiments described above are therefore considered as illustrative in all respects and not co-or restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - An ophthalmic composition comprising: a therapeutically effective amount of one or more ophthalmic agents selected from the group consisting of: anti glaucous agents, belt tensioning agents, anti-inflammatory agents, non-sterile aggregates, steroidal antimicrobial agents, antibacterial agents, agents against infections, agents with fungi, anti-viral agents, anti-cataract agents, anti-oxidants, anti-allergens, anti-metabolites, immunosuppressants, anti-viral factors , and prodrugs thereof; an amount of a vitamin E tocopheryl derivative effective to significantly reduce the discomfort and irritation associated with topical ophthalmic administration of said ophthalmic agent; and a vehicle of chemically acceptable.

2. The composition of unfority with claim 1, characterized further park the ophthalmic agent is a non-steroidal anti-inf lamate agent.

3. The confrmity composition L in claim 2, further characterized in that the anti-inflammatory or steroidal agent comprises an aryl- or heteroaryl-alkanoic acid, to an ophthalmically acceptable salt, ester or amide thereof. 4.- L *? composition according to claim 3, face also raised because the non-steroidal anti-inflammatory agent is selected from the group consisting of: diclofenac, f lurbiprof in, suprofen, ketoralac, intimetacin, ketoprofen and salts, ophthalmically acceptable esters or amides thereof. 5. The composition according to claim 4, further characterized in that the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac and its ophthalmically acceptable salts, esters or amides. 6. The composition according to claim 4, further characterized in that the anti-inflammatory agent na steraidal is selected from the group consisting of suprofen and its ophthalmically acceptable salts, esters or amides. 7. The composition according to claim 1, further characterized in that the tocopheryl derivatives of vitamin E are selected from one or more polyoxyethylene glycol esters of vitamin E of a succinic acid tocopheryl ester wherein the polyoxiet portion is selected. Illeglycol of the ester has a molecular weight on a scale between about 600 and about 60000. 6. The composition according to claim 7, further characterized in that the polyoxie and glycol portion of the ester has an average molecular weight of about 1000. The composition of the composition and claim 1, bristling face further, because the concentration of the tocopherol derivative of vitamin E or approximately 30% by weight. 10. The composition according to claim 9, further characterized in that the concentration of the tocopheryl derivative of vitamin E is between 0.1 and approximately 20 * by weight. 11. The composition according to claim 10, further characterized in that the concentration of the vitamin E tocopheryl derivative is between * approximately 0.5 and approximately 10 * by weight. 12. The use of an ophthalmic agent selected from the group consisting of anti-glaucous agents, anti-hypertensive agents, anti-infants, anti-steroidal agents, anti-inflammatory agents, steroidal anti-vaccines, anti-inflammatory agents infections, fungal agents, antiviral agents, anti-cataract agents, anti-oxidants, anti-allergens, anti-metabolites, suppressants, growth factors, and prodrugs thereof, in the preparation of a composition of a derivative of Tocopherol of vitamin E, for the preparation of compositions to significantly reduce the discomfort and irritation associated with the ophthalmic administration of the ophthalmic agent alone. 13. The use of an ophthalmic agent according to claim 1, further characterized in that the "ophthalmic agent" is a non-steroidal anti- non-steroidal agent and is for topical ophthalmic application 1

4. The use of an ophthalmic agent in accordance with claim 13, characterized in addition, because the nonsteroidal anti-inf lamatous agent comprises an aryl- or beteroaryl-alkanoic acid, or an ophthalmically acceptable salt, ester or amide thereof. 1

5. The use of an ophthalmic agent in accordance with claim 14, further characterized in that the non-steroidal additive anti-inf agent is selected from the group consisting of diclofenac and its ophthalmically acceptable salts, esters or amides 16.- New use of a derivative of vitamin E tocaferyl in the preparation of fields Cycres with one or more ophthalmic agents that are irritating to the eye, effective in significantly reducing the discomfort and irritation associated with topical ophthalmic administration of said agent of alma. Use of a vitamin E diplexel derivative according to claim 16, further characterized in that the tocopheryl derivative of vitamin E is selected from one or more polyethylene glycol ester of vitamin E of a succinic acid tocopheryl ester wherein the polyoleethylene glycol portion of the ester has a molecular weight on a scale between about 600 and about 6000. 1

6. The use of a vitamin 16 tocopheryl derivative. according to claim 17, further characterized in that the polyoxie i lengl icol portion of the ester has an average molecular weight of approximately 1000. 19. The use of a vitamin E tocopheryl derivative according to claim 16, further characterized in that the concentration of the tocopheryl derivative of vitamin E is less than approximately 30 * by weight. 20.- Fl use of a vitamin tocopheryl derivative E in accordance with claim 19, further characterized in that the concentration of the vitamin tocopheryl derivative E is approximately 0.1 and approximately 20 * in weight. 21.- The use of a vitamin diphtheria derivative E according to claim 20, further characterized in that the concentration of the tocafecillin derivative of vitamin E is about 10 * by weight. USE OF VITAMIN E TOCOPHERYL DERIVATIVES IN OPHTHALMIC COMPOSITIONS SUMMARY OF THE INVENTION Ophthalmic compositions containing vitamin E tocopheryl derivatives that are comfortable and non-irritating are described, and the new use of ophthalmic agents together with tocopheryl derivatives of vitamin E in the preparation of compositions to significantly reduce the discomfort and irritation associated with the topical ophthalmic administration of ophthalmic agents alone; moreover, those derivatives of vitamin E tocopheryl significantly increase the aqueous solubility of certain poorly soluble ophthalmic agents. RM / mvs * crm #