US 2004OO52877A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0052877 A1 Nakayama et al. (43) Pub. Date: Mar. 18, 2004
(54) EYE DROPS (86) PCT No.: PCT/P01/08605 (76) Inventors: Hisayuki Nakayama, Hyogo (JP); (30) Foreign Application Priority Data Hiroshi Aki, Hyogo (JP); Fukiko Nemoto, Hyogo (JP) Oct. 3, 2000 (JP)...... 2OOO-3O3485 Correspondence Address: Publication Classification MERCHANT & GOULD PC P.O. BOX 2903 (51) Int. Cl." ...... A61K 35/78 MINNEAPOLIS, MN 55402-0903 (US) (52) U.S. Cl...... 424/756 (21) Appl. No.: 10/381,609 (57) ABSTRACT A type of eye drops, characterized in that it comprises ginger (22) PCT Filed: Sep. 28, 2001 perfume as a refrigerant. US 2004/0052877 A1 Mar. 18, 2004
EYE DROPS 0008 Thus, the present invention provides eye drops to which ginger perfume is added as a refreshing agent. TECHNICAL FIELD Wherein the concentration of ginger perfume can be Selected as desired, but is usually 0.00005 to 1.0 w/v %, preferably 0001. The present invention relates to eye drops contain 0.0001 to 0.5 w/v. '76, and more preferably 0.001 to 0.3 w/v ing ginger perfume. %. 0009 Addition of ginger perfume to eye drops may be BACKGROUND OF THE INVENTION made by addition of ginger perfume or by addition of the 0002 Eye drops are widely used for treatment of allergy ingredients extracted from ginger rhizome. Therefore, the and inflammation of the cornea and conjunctiva, infection of present invention also provides eye drops to which the the cornea and conjunctiva, glaucoma, cataract and the like ingredients extracted from ginger rhizome are added as a and Xerosis corneae and the like, prevention of corneal refreshing agent. disorders while wearing contact lenses, and treatment of eye fatigue of various degree including asthenopia, and a variety BEST MODE FOR CARRYING OUT THE of ophthalmologic diseases and Symptoms Such as irritation, INVENTION foreign-body Sensation and the like. Among them, Such eye 0010. In the present invention, “eye drops” may be eye drops are widely available in the market that contain one or drops in various dosage forms which are used by instilling more ingredients which Serve, upon instillation, to provide drops to the eye. AS acqueous eye drops, there are included refreshing Stimulation to the eye (hereinafter referred to as eye drops in which water is used as a base and various “refreshing agents”) for refreshment, and are intended essential ingredients (for example, active ingredients, iso mainly for uncomfortable Subjective Symptoms like com tonizer, buffer, preservative and the like) are dissolved or paratively mild eye fatigue or itching or to drowsiness. dispersed (Suspended, emulsified and the like) in it in accordance with the purpose of the eye drops. 0003. However, only a very limited number of com pounds are known as refreshing agents for eye drops, Such 0011. In the present invention, the phrase “ingredients extracted from ginger rhizome” means ingredients which as menthol and borneol. Considering the diversity of recent can be obtained by extraction from ginger rhizome by consumers’ taste, there must be potential needs, with respect various methods, regardless of the means for extraction. to eye drops which provide refreshing feeling, also for Ginger rhizome, either raw or dried, may be used. In order product groups employing a wider variety of refreshing to use those ingredients in eye drops of the present inven agents than before. tion, those peculiar ingredients contained in ginger rhizome 0004. Against the above background, it is the purpose of may be added to the eye drops which were collected by the present invention to provide eye drops containing a extraction from ginger rhizome with water (warm water or hot water), extraction with organic Solvents Such as acetone, refreshing agent different from those which have been ethanol, chloroform, benzene and diethyl ether, extraction known. with water and an organic Solvent, or by distillation from hot 0005 Apart from nutritional ingredients such as starch, water, Steam distillation, with carbon dioxide and the like. It fiber, minerals, and trace amount of protein and fat, ginger is also possible to use one or more Synthetic products of rhizome contains a variety of peculiar ingredients which those ingredients extractable from ginger rhizome, for provide basis for its uses for Seasonings, cosmetics and as example, Zingerone, gingerol, curcumin, pinene, myrcene, crude drugs. Those include, for example, (6)-gingerol, (8)- farnesene, geraniol, limonene and the like. gingerol, (10)-gingerol, Zingerone, (6)-Shogaol, (8)-Shogaol, 0012. In the present invention, Such ginger perfume may (10)-shogaol, Zingiberene, (6)-paradol, (8)-paradol, (10)- be used that contains, usually in a liquid medium, extracts of paradol, Zingiberol, (4)-gingediol, (6)-gingediol, (8)-ginge ginger rhizome or its main ingredients, in particular, aro diol, (10)-gingediol, (6)-methylgingediol, (4)-gingediac matic ingredients. A ginger perfume employed may be a etate, (6)-gingediacetate, hexahydrocurcumin, curcumin, product which is commercially available. Examples of com bisabolene, Sesquiphellandrene, pinene, myrcene, farnesene, mercially available ginger perfumes include Ginger Flavor geraniol, limonene, neral and the like. manufactured by OGAWA & CO.,LTD., Ginger Oil manu factured by TAKASAGO INTERNATIONAL CORPORA 0006 Ginger rhizome is used as an aromatic stomachic, TION, and the like. as a crude drug for enhancing metabolism and preventing increase in blood cholesterol, and as a crude drug for 0013 There is no definite range within which the amount alleviating chest pain, abdominal pain, backache, diarrhea of ginger perfume added to eye drops should fall, but Such and the like. It is also used for promoting Sweating against a range, in general, may be from 0.00005 to 1.0 w/v/o, a cold. However, its use as a refreshing agent for eye drops preferably from 0.0001 to 0.5 w/v %, and more preferably from 0.001 to 0.3 w/v %, in accordance with intended degree has not been known. of refreshing feeling to be provided, from slightly felt refreshing feeling to the Strong refreshing feeling. DISCLOSURE OF THE INVENTION 0014 AS to other ingredients of eye drops than those 0007. In the process of investigation for a novel refresh extracted from ginger rhizome, it is possible, like conven ing agent for eye drops, the present inventors have found tional eye drops, to add various basic ingredients Such as that ingredients extracted from ginger rhizome can be used isotonizers, buffers, pH adjusting agents, preservatives and for the purpose. The present invention has been completed Surfactants, and various active ingredients Such as Vitamins, as a result of Studies based on the findings. vasoconstrictor, antihistamic agents, anti-inflammatory US 2004/0052877 A1 Mar. 18, 2004 agents, antiallergic agents and antimicrobials as desired and of purified water. While boiling the mixture, water vapor in accordance with respective purposes. Thus, for example, from boiling purified water contained in another round ingredients extracted from ginger rhizome may be added in bottom flask (B) is introduced for about 1 hour, and the place of Such refreshing agents as 1-menthol and borneol, in distilled water vapor from the round-bottom flask (A) is various eye drops which were formulated using those cooled through a Liebig condenser and collected. Chloro refreshing agents. Further, a refreshing agent Such as a form is added to the extract obtained and mixed by Shaking, monoterpenoid may be added to the eye drops of the present chloroform phase is collected, and the extract of ginger invention, together with ginger perfume. Eye drops having rhizome is obtained by evaporating the Solvent under deeper refreshing feeling can be obtained by addition of a reduced pressure. refreshing agent Such as a monoterpenoid. Examples of monoterpenoids include menthol, camphor, borneol, geraniol, menthone, cineol, limonene, eugenol, citral, Reference Example 4 pinene, linalol, fenchyl alcohol, ionone, Safranal, terpinene and the like. Among these, menthol, camphor, borneol, Extraction of Ingredients from Ginger Rhizome geraniol, menthone, cineol and limonene are used particu 0020. Two hundred g of the dried ginger rhizome is larly preferably. These can be used alone or two or more of minced, and placed in the extraction chamber of a Super them can be used in combination as desired. The concen critical carbon dioxide extraction equipment, and the equip tration of monoterpenoids is usually from 0.0005 to 0.1 w/v ment is run. Supercritical carbon dioxide is introduced in the % and preferably from 0.001 to 0.06 w/v. '76, though it extraction chamber of the equipment. The Supercritical depends on the amount of ginger perfume added. carbon dioxide flowing out after being contacted with the 0.015 Further, the eye drops of the present invention may minced dried ginger rhizome is then introduced into a be instilled while wearing contact lenses of various types Separation chamber, which are under normal pressure. Car Such as non-oxygen gas permeable hard contact lenses, bon dioxide is Separated from the extracted ingredients in oxygen gas permeable hard contact lenses and Soft contact the Separation chamber and evaporates, giving ginger rhi lenses, and, in particular, advantageously instilled while Zome extract as an oil left in the Separation chamber. wearing Soft contact lenses. 0021
0025 (Result) Example 2 0026. The following table shows the length of time required for restoration of the condition in which the eyes 0030) are consistently open and the number of times of blinking during the period, as mean values of each group. Chlorpheniramine maleate 0.03 g TABLE 2 Dipotassium glycyrrhizinate 0.25 g Sodium chloride 0.5g Formulas Measurement items Results Sodium L-glutamate 0.2g Benzalkonium chloride 0.005 g TP-26 Time for restoration 226.7 seconds Chlorobutanol 0.2g Number of times of blinking 7.2 times 1-Menthol 0.01 g TP-27 Time for restoration 143.9 seconds Ginger rhizome extract 0.2g Number of times of blinking 3.3 times Polyoxyethylenehydrogenated castor oil 60 0.3g TP-30 Time for restoration 473.9 seconds Number of times of blinking 15.6 times Sodium hydroxide C.S. Saline Time for restoration 25.3 seconds Purified water C.S. Total amount 100 ml Number of times of blinking 1.3 times (pH = 5.5) *Length of time from immediately after instillation to restoration of the baseline condition, in which the eyes are persistently open. 0031 Chlorobutanol, chlorpheniramine maleate, dipotas 0027. As shown in Table 2, with formula TP-30, remark ably prolonged time for restoration (about 3-fold) and sium glycyrrhizinate, Sodium chloride, Sodium L-glutamate increased number of times of blinking (about 5-fold) were and benzalkonium chloride were Sequentially dissolved in noted compared with those with formula TP-27, which about 70 ml of purified water, and to the solution were added contained 1-menthol as a refreshing agent. This means that 1-menthol and the ginger rhizome extract (the hot water ginger perfume at the above-mentioned concentration is extract in Reference Example 2) dispersed with polyoxy several-times more potent than 0.002 w/v % 1-menthol with ethylene-hydrogenated castor oil 60, and, after pH was regard to refreshing feeling. Further, with formula TP-26 containing both ginger perfume and 1-menthol, both of the adjusted to 5.5 by sodium hydroxide, purified water was time for restoration and the number of times of blinking added to make the total volume of 100 ml. This was were about one half of those with TP-30. This seems to be sterilized by filtration, and filled in 15-ml containers of due to the anesthetic effect of 1-menthol, which might have polyethylene terephthalate. weaken the refreshing Stimulation by ginger perfume. Fur ther, no irritation to tissues was observed in any of the Example 3 rabbits in groSS Visual observation of the cornea, conjunctiva and nictitating membrane. 0032) Example 1 0028) Tetrahydrozoline hydrochloride 0.05 g Chlorpheniramine maleate 0.03 g Potassium L-aspartate 1 g Sodium chloride 0.5g Tetrahydrozoline hydrochloride 0.05 g Sodium L-glutamate 0.2g Chlorpheniramine maleate 0.03 g Benzalkonium chloride 0.005 g Potassium L-aspartate 1 g Chlorobutanol 0.2g Sodium chloride 0.5g 1-Menthol 0.03 g Sodium L-glutamate 0.2g d1-Camphor 0.01 g Benzalkonium chloride 0.005 g Borneol 0.01 g Chlorobutanol 0.2g Extract of ginger rhizome 0.01 g 1-Menthol 0.01 g Polyoxyethylene hydrogenated castor oil 60 0.3g Ginger rhizome extract 0.2g Sodium hydroxide C.S. Polyoxyethylenehydrogenated castor oil 60 0.3g Purified water C.S. Sodium hydroxide C.S. Total amount 100 ml Purified water C.S. Total amount 100 ml (pH = 5.5) (pH = 5.5) 0033 Chlorobutanol, tetrahydrozoline hydrochloride, 0029 Chlorobutanol, tetrahydrozoline hydrochloride, chlorpheniramine maleate, potassium L-aspartate, Sodium chlorpheniramine maleate, potassium L-aspartate, Sodium chloride, Sodium L-glutamate and benzalkonium chloride chloride, Sodium L-glutamate and benzalkonium chloride were sequentially dissolved in about 70 ml of purified water, were sequentially dissolved in about 70 ml of purified water, and to this were added 1-menthol, dl-camphor, borneol and and to the Solution were added 1-menthol and the ginger rhizome extract (the acetone extract in Reference Example the ginger rhizome extract (the acetone extract in Reference 1) dispersed with polyoxyethylenehydrogenated castor oil Example 1) dispersed with polyoxyethylenehydrogenated 60, and, after pH was adjusted to 5.5 by sodium hydroxide, castor oil 60, and, after pH was adjusted to 5.5 by Sodium purified water was added to make the total volume of 100 hydroxide, purified water was added to make the total ml. This was sterilized by filtration, and filled in 15-ml volume of 100 ml. This was sterilized by filtration, and filled containers of polyethylene terephthalate. in 15-ml containers of polyethylene terephthalate. US 2004/0052877 A1 Mar. 18, 2004
Example 4 Example 6 0034) 0038
Tetrahydrozoline hydrochloride 0.05 g Tetrahydrozoline hydrochloride 0.05 g Chlorpheniramine maleate 0.03 g Chlorpheniramine maleate 0.03 g Aminoethylsulfonic acid 1.0 g Potassium L-aspartate 1 g Sodium chloride 0.5g Sodium chloride 0.5g Sodium L-glutamate 0.2g Sodium L-glutamate 0.2g Benzalkonium chloride 0.005 g Benzalkonium chloride 0.005 g Chlorobutanol 0.2g 1-Menthol 0.04 g Chlorobutanol 0.2g Ginger Oil T1* 0.02 g 1-Menthol 0.01 g Polyoxyethylenehydrogenated castor oil 60 0.3g Ginger rhizome extract 0.05 g Sodium hydroxide C.S. Polysorbate 80 0.2g Purified water C.S. Sodium hydroxide C.S. Total amount 100 ml Purified water C.S. (pH = 5.5) Total amount 100 ml *Ginger Perfume manufactured by TAKASAGO INTERNATIONAL (pH = 5.5) CORPORATION. 0039 Chlorobutanol, tetrahydrozoline hydrochloride, 0.035 Chlorobutanol, tetrahydrozoline hydrochloride, chlorpheniramine maleate, aminoethylsulfonic acid, Sodium chlorpheniramine maleate, potassium L-aspartate, Sodium chloride, Sodium L-glutamate and benzalkonium chloride were sequentially dissolved in about 70 ml of purified water, chloride, Sodium L-glutamate and benzalkonium chloride and to this were added 1-menthol and Ginger Oil Ti dis were sequentially dissolved in about 70 ml of purified water, persed with polyoxyethylenehydrogenated castor oil 60, and to this were added 1-menthol and the ginger rhizome and, after pH was adjusted to 5.5 by Sodium hydroxide, extract (the hot water extract in Reference Example 2) purified water was added to make the total volume of 100 dispersed with polysorbate 80, and, after pH was adjusted to ml. This was sterilized by filtration, and filled in 15-ml 5.5 by sodium hydroxide, purified water was added to make containers of polyethylene terephthalate. the total volume of 100 ml. This was sterilized by filtration, and filled in 15-ml containers of polyethylene terephthalate. Example 7 0040 Example 5 0036) Chlorpheniramine maleate 0.03 g Sodium chloride 0.5g Benzalkonium chloride 0.005 g Tetrahydrozoline hydrochloride 0.05 g Chlorobutanol 0.2g Chlorpheniramine maleate 0.03 g 1-Menthol 0.04 g Aminoethylsulfonic acid 1.0 g Zingerone 0.0005g Sodium chloride 0.5g Polyoxyethylenehydrogenated castor oil 60 0.3g Sodium L-glutamate 0.2g Sodium hydroxide C.S. Benzalkonium chloride 0.005 g Purified water C.S. Chlorobutanol 0.2g Total amount 100 ml 1-Menthol 0.01 g (pH = 5.5) Ginger Flavor R70549* 0.2g Polyoxyethylenehydrogenated castor oil 60 0.3g *manufactured by ALDRICHCHEMICAL COMPANY Sodium hydroxide C.S. Purified water C.S. Total amount 100 ml 0041 Chlorobutanol, chlorpheniramine maleate, sodium (pH = 5.5) chloride and benzalkonium chloride were dissolved in about 70 ml of purified water, and to this were added 1-menthol * Ginger Flavor (extract by steam distillation) manufactured by OGAWA & and Zingerone dispersed with polyoxyethylenehydrogenated CO.,LTD. castor oil 60, and, after pH was adjusted to 5.5 by Sodium hydroxide, purified water was added to make the total 0037 Chlorobutanol, tetrahydrozoline hydrochloride, volume of 100 ml. This was sterilized by filtration, and filled chlorpheniramine maleate, aminoethylsulfonic acid, Sodium in 15-ml containers of polyethylene terephthalate. chloride, Sodium L-glutamate and benzalkonium chloride were sequentially dissolved in about 70 ml of purified water, Example 8 and to this were added 1-menthol and Ginger Flavor dis 0.042 persed with polyoxyethylenehydrogenated castor oil 60, and, after pH was adjusted to 5.5 by Sodium hydroxide, purified water was added to make the total volume of 100 Naphazoline hydrochloride 0.003 g ml. This was sterilized by filtration, and filled in 15-ml Neostigmine methylsulfate 0.005 g containers of polyethylene terephthalate. US 2004/0052877 A1 Mar. 18, 2004
Example 10 -continued 0046) Allantoin 0.1 g Chlorpheniramine maleate 0.03 g Sodium chondroitin sulfate 0.1 g Boric acid 1 g Naphazoline hydrochloride 0.003 g Benzalkonium chloride 0.005 g Dipotassium glycyrrhizinate 0.1 g Chlorobutanol 0.2g Diphenhydramine hydrochloride 0.05 g Ginger rhizome extract 0.001 g d-C-Tocopherol acetate 0.05 g Polyoxyethylenehydrogenated castor oil 60 0.3g Aminoethylsulfonic acid 1 g Hydrochloric acid C.S. Boric acid 1 g Sodium hydroxide C.S. Benzalkonium chloride 0.005 g Purified water C.S. Chlorobutanol 0.2g Total amount 100 ml Ginger rhizome extract 0.1 g (pH = 5.5) Polysorbate 80 0.3g Hydrochloric acid C.S. Sodium hydroxide C.S. 0.043 Chlorobutanol, naphazoline hydrochloride, neo Purified water S.S. Stigmine methylsulfate, allantoin, chlorpheniramine male ate, Sodium chondroitin Sulfate, boric acid and benzalko Total amount 100 ml nium chloride were sequentially dissolved in about 70 ml of (pH = 5.5) purified water, and to this was added the ginger rhizome extract (the extract by carbon dioxide in Reference Example 4) dispersed with polyoxyethylenehydrogenated castor oil 0047 Chlorobutanol, naphazoline hydrochloride, dipo 60, and, after pH was adjusted to 5.5 by hydrochloric acid tassium glycyrrhizinate, diphenhydramine hydrochloride, or Sodium hydroxide, purified water was added to make the aminoethylsulfonic acid and boric acid were Sequentially total volume of 100 ml. This was sterilized by filtration, and dissolved in about 70 ml of purified water, and to this were filled in 15-ml containers of polyethylene terephthalate. added d-O-tocopherol acetate dispersed with polyoxyethyl enehydrogenated castor oil 60 and the ginger rhizome Example 9 extract (the extract by Steam distillation in Reference Example 3) dispersed with polysorbate 80, and, after pH was 0044) adjusted to 5.5 by hydrochloric acid or sodium hydroxide, purified water was added to make the total volume of 100 ml. This was sterilized by filtration, and filled in 15-ml Neostigmine methylsulfate 0.005 g containers of polyethylene terephthalate. Allantoin 0.1 g Chlorpheniramine malleate 0.03 g Panthenol 0.05 g Example 11 Potassium L-aspartate 1 g Boric acid 1 g 0048) Benzalkonium chloride 0.005 g Chlorobutanol 0.2g Ginger India PFICO, 0.005 g Polysorbate 80 0.3g Sodium chloride 0.55g Hydrochloric acid C.S. Potassium chloride 0.15g Sodium hydroxide C.S. Boric acid 0.5g Purified water S.S. Borax 0.05 g Benzalkonium chloride 0.005 g Total amount 100 ml Ginger Essential Oil 0.02 g (pH = 5.5) Polysorbate 80 0.3g Purified water S.S. * Ginger Perfume (extract by carbon dioxide) sold by MORIMURA BROS. INC. Total amount 100 ml (pH = 7.3) 0.045 Chlorobutanol, neostigmine methylsulfate, allan *Ginger Perfume (extract by steam distillation) sold by TREE OF LIFE toin, chlorphenirS amine maleate, panthenol, potassium CO.,LTD. L-aspartate, boric acid and benzalkonium chloride were sequentially dissolved in about 70 ml of purified water, and 0049 Sodium chloride, potassium chloride, boric acid, to this was added Ginger India PFICO dispersed with borax and benzalkonium chloride were Sequentially dis polysorbate 80, and, after pH was adjusted to 5.5 by hydro solved in about 70 ml of purified water, and to this was chloric acid or Sodium hydroxide, purified water was added added Ginger Essential Oil dispersed with polysorbate 80, to make the total volume of 100 ml. This was sterilized by and purified water was added to make the total Volume of filtration, and filled in 15-ml containers of polyethylene 100 ml. This was sterilized by filtration, and filled in 15-ml terephthalate. containers of polyethylene terephthalate. US 2004/0052877 A1 Mar. 18, 2004
Example 12 1. Eye drops to which ginger perfume is added as a refreshing agent. 0050 2. The eye dropS according to claim 1, wherein the concentration of the ginger perfume is from 0.00005 to 1.0 w/v 96. 3. The eye drops according to claim 1 or 2, wherein the Ginger Flavor R70544* 0.02 g ginger perfume is an extract of ginger rhizome. 1-Menthol 0.0025 g 4. The eye drops according to claim 3, wherein the extract Sodium chloride 0.9 g of ginger rhizome is an extract with an organic Solvent. Polyoxyethylenehydrogenated castor oil 60 0.2g 5. The eye drops according to claim 3, wherein the extract Hydrochloric acid C.S. of ginger rhizome is an extract with hot water. Sodium hydroxide C.S. 6. The eye drops according to claim 3, wherein the extract Purified water S.S. of ginger rhizome is an extract by Steam distillation. 7. The eye drops according to claim 3, wherein the extract Total amount 100 ml of ginger rhizome is an extract with carbon dioxide. (pH = 5.5) 8. The eye drops according to one of claims 3 to 7, wherein the concentration of the extract of ginger rhizome is * Ginger Flavor (extract by steam distillation) manufactured by OGAWA & from 0.001 to 0.3 w/v 96. CO.,LTD. 9. The eye drops according to one of claims 1 to 8, to which a monoterpenoid is further added. 10. The eye drops according to claim 9, wherein the 0051 Sodium chloride was dissolved in about 70 ml of monoterpenoid is at least one Selected from a group con purified water, and to this were added 1-menthol and Ginger Sisting of menthol, camphor, borneol, geraniol, menthone, Flavor R70544 dispersed with polyoxyethylene hydroge cineol and limonene. nated castor oil 60, and, after pH was adjusted to 5.5 by 11. The eye drops according to claim 9 or 10, wherein the hydrochloric acid or Sodium hydroxide, purified water was concentration of the monoterpenoid is from 0.0005 to 0.1 added to make the total volume of 100 ml. This was w/v 96. sterilized by filtration, and filled in 15-ml containers of 12. The eye drops according to one of claims 1 to 11, polyethylene terephthalate. wherein the eye drops are eye drops for use while wearing a contact lens. INDUSTRIAL APPLICABILITY 13. A method for production of the eye drops according to one of claims 1 to 12, wherein the method comprises adding 0.052 The present invention can provide eye drops con ginger perfume to eye drops. taining a refreshing agent which is a totally different type from conventional ones. k k k k k