USOO9320802B2

(12) United States Patent (10) Patent No.: US 9,320,802 B2 Furumiya et al. (45) Date of Patent: *Apr. 26, 2016

(54) AQUEOUS OPHTHALMIC COMPOSITION (56) References Cited (71) Applicant: ROHTO PHARMACEUTICAL CO., U.S. PATENT DOCUMENTS LTD., Osaka (JP) 6,228,049 B1* 5/2001 Schroeder ...... A61B 10,0233 128/898 (72) Inventors: Chinatsu Furumiya, Osaka (JP); 6,288,049 B1 9, 2001 Morishima et al. Takayuki Miyano, Osaka (JP); Atsuko 2002/0010193 A1 1/2002 Doi et al. Nakata, Osaka (JP); Eri Matsumoto, 2002/0052419 A1 5, 2002 Doi et al. 2006/010O287 A1 5/2006 Okajima et al. Osaka (JP) 2007, OO15693 A1 1/2007 Chang et al. 2009.0062381 A1* 3, 2009 Hirata ...... A61K9/0048 (73) Assignee: ROHTO PHARMACEUTICAL CO., 514,456 LTD., Osaka (JP) 2010.001 1989 A1 1/2010 Arita ...... A61K9/0048 106,217.8 (*) Notice: Subject to any disclaimer, the term of this 2010/0239518 A1* 9, 2010 Matsumura ...... A61K9/0046 patent is extended or adjusted under 35 424/78.04 U.S.C. 154(b) by 0 days. 2013/0274332 A1 10/2013 Furumiya et al. This patent is Subject to a terminal dis FOREIGN PATENT DOCUMENTS claimer. EP 2653155 9, 2013 EP 273O292 5, 2014 (21) Appl. No.: 14/683,579 JP 11-130667 5, 1999 JP 11-180858 7, 1999 (22) Filed: Apr. 10, 2015 JP 2002-003364 1, 2002 JP 2002-356420 12/2002 (65) Prior Publication Data JP 2004-315517 11, 2004 JP 2006-151971 6, 2006 US 2015/0209.437 A1 Jul. 30, 2015 JP 2006-321790 11, 2006 WO 2007 O756O7 7/2007 WO WO 20070756O7 A1 * T 2007 ...... A61K9/0048 Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 13/995,893, filed as International Search Report for PCT/JP2011/080163 dated Feb. 14, application No. PCT/JP2011/080163 on Dec. 27, 2012. 2011, now Pat. No. 9,034,931. Asada, H. et al. Suspension-type eye drop preparation, contains fluorometholone, and polyoxyethylene hydrogenated castor oil or (30) Foreign Application Priority Data polyoxyethylene castor oil. Database WPI, Section Ch. Week 200876, Thomson Scientific, London, GB, Class A96, AN 2008 Dec. 28, 2010 (JP) ...... 2010-292441 NO1735, XP002733276, Nov. 6, 2008. (51) Int. C. * cited by examiner A6 IK 47/10 (2006.01) A6 IK 47/44 (2006.01) Primary Examiner — Sean Basquill A6 IK9/08 (2006.01) Assistant Examiner — Andrew S. Rosenthal A6 IK9/00 (2006.01) (74) Attorney, Agent, or Firm — Wenderoth, Lind & Ponack, A6 IK 47/02 (2006.01) L.L.C. A6 IK 47/26 (2006.01) A6 IK 47/24 (2006.01) (57) ABSTRACT (52) U.S. C. This invention relates to an aqueous ophthalmic composition CPC ...... A61K 47/44 (2013.01); A61 K9/0048 comprising (A) polyoxyethylene castor oil in which the aver (2013.01); A61 K9/08 (2013.01); A61 K47/02 age number of moles of added ethylene oxide is 2 to 12 and (2013.01); A61 K47/10 (2013.01); A61 K47/24 (B) terpenoid. According to the present invention, an aqueous (2013.01); A61 K4726 (2013.01) ophthalmic composition having an improved foam disappear (58) Field of Classification Search ance speed can be obtained. CPC ...... A61K 47/44; A61 K9/0048 See application file for complete search history. 6 Claims, No Drawings US 9,320,802 B2 1. 2 AQUEOUS OPHTHALMIC COMPOSITION addition of both specific polyoxyethylene castor oil and ter penoid to an aqueous ophthalmic composition noticeably TECHNICAL FIELD improves the foam disappearance speed when foam is gener ated by vibration or impact. According to further research, the The present invention relates to an aqueous ophthalmic present inventors found a problem Such that an aqueous oph composition. thalmic composition Such as an eye drops in which a large amount of foam is generated has variation in the drip amount BACKGROUND ART per use. Such a problem is particularly relevant in eye drops and solutions for wearing contact lenses used in a relatively In the field of ophthalmology, Solubilizing agents are added 10 Small amount each time. Large variation in the drip amount to a variety of preparations. In particular, various solubilizing causes disadvantages Such as difficulty in controlling the agents are added to aqueous ophthalmic compositions to help amount per use by users and difficulty in handling. This may dissolution of biologically active components and additives reduce compliance particularly when the aqueous ophthalmic with relatively low water solubility, and the like. One example composition is used as a medical product. The aqueous oph of solubilizing agents used in the field of ophthalmology is a 15 Surfactant. An aqueous formulation containing a Surfactant is thalmic composition of the present invention, however, can known to foam easily, and foam is generated when Subjected reduce variation in the drip amount. to vibration or impact during production or distribution. The present inventors also found that the addition of spe In general, to use an aqueous ophthalmic composition in a cific polyoxyethylene castor oil together with terpenoid manner safe on the eyes, the dissolution check during pro attains the effect of inhibiting reduction interpenoid concen duction is considered important. Of aqueous ophthalmic tration in an aqueous ophthalmic composition held in a con compositions, medical products such as eye drops and eye tainer. washes require foreign matter detection in the production In further research, the present inventors found that an steps. However, when foam is generated in the aqueous oph aqueous ophthalmic composition containing specific poly thalmic composition during production, and disappears at a 25 oxyethylene castor oil and terpenoid in combination low speed, the foam is difficult to distinguish from active enhances preservative efficacy. Typically, nonionic Surfac ingredients and foreign matter. Consequently, dissolution tants are known to have an effect of deactivating antiseptics, check and foreign matter detection take a long period of time, thereby reducing antiseptic action. For this reason, enhanced preventing efficient production. preservative efficacy attained by the combination use ofter Terpenoid is sometimes added to an ophthalmic composi 30 penoid and specific polyoxyethylene castor oil, which is a tion to provide a cooling sensation during application (see nonionic surfactant, is a completely unexpected effect. Patent Literature 1). Unfortunately, when an ophthalmic The present inventors also found the following as a result of composition containing terpenoid is stored in a container, the extensive research. Polyoxyethylene castor oil in which the terpenoid concentration is known to be reduced with time. average number of moles of added ethylene oxide is 2 to 12 This is presumably because of adsorption of terpenoid on the 35 has low water Solubility and is easily isolated in an aqueous container, Volatilization of terpenoid, or the like; however, an solution; however, the addition of the polyoxyethylene castor effective solution to this problem has not been found. oil together with terpenoid, which also has low water solubil CITATION LIST ity, can Surprisingly inhibit separation of the components in 40 the aqueous ophthalmic composition, allowing for stable use Patent Literature for a long period of time. Specifically, in this research, the present inventors found that although the specific polyoxy PTL 1: JP2004-315517A ethylene castor oil and terpenoid are each likely to precipitate or be isolated in an aqueous ophthalmic composition when SUMMARY OF INVENTION 45 used alone, the combination use of these components Surpris ingly provides an effect of inhibiting separation of both poly Technical Problem oxyethylene castor oil and terpenoid. The present invention was accomplished as a result of The present invention was made in light of the prior art further research based on these findings. described above, and a main object is to provide an aqueous 50 Specifically, the present invention provides ophthalmic ophthalmic composition having a high foam disappearance compositions according to the following embodiments. speed when foam is generated by vibration or impact, par 1-1. An aqueous ophthalmic composition comprising (A) ticularly, the aqueous ophthalmic composition easily foam ing due to inclusion of a solubilizing agent Such as a Surfac polyoxyethylene castor oil in which the average number of tant. 55 moles of added ethylene oxide is 2 to 12 and (B) terpenoid. Another object of the present invention is to provide a 1-2. The aqueous ophthalmic composition according to Item method for inhibiting reduction in terpenoid concentration 1-1, wherein component (A) is at least one member selected over time in an aqueous ophthalmic composition containing from the group consisting of polyoxyethylene castor oil 3 and terpenoid. polyoxyethylene castor oil 10. A further object of the present invention is to provide an 60 1-3. The aqueous ophthalmic composition according to Item aqueous ophthalmic composition having further improved 1-1 or 1-2, wherein the content of component (A) is 0.01 to 3 various effects. w/v '% based on the total amount of the aqueous ophthalmic composition. Solution to Problem 1-4. The aqueous ophthalmic composition according to any 65 one of Items 1-1 to 1-3, wherein component (B) is at least one To solve the above problems, the present inventors con member selected from the group consisting of menthol, cam ducted extensive research, and Surprisingly found that the phor, geraniol, borneol, and eucalyptus oil. US 9,320,802 B2 3 4 1-5. The aqueous ophthalmic composition according to any ing adding (A) polyoxyethylene castor oil in which the aver one of Items 1-1 to 1-4, wherein the content of component (B) age number of moles of added ethylene oxide is 2 to 12 and is 0.0001 to 1 w/v '% based on the total amount of the aqueous (B) terpenoid to the aqueous ophthalmic composition. ophthalmic composition. 5. A method for improving a foam disappearance speed in an 1-6. The aqueous ophthalmic composition according to any 5 aqueous ophthalmic composition comprising a surfactant one of Items 1-1 to 1-5, wherein the total amount of compo other than (A) polyoxyethylene castor oil in which the aver nent (B) is 0.01 to 1,000 parts by weight per 100 parts by age number of moles of added ethylene oxide is 2 to 12, the weight of the total amount of component (A). method comprising adding component (A) and (B) terpenoid 1-7. The aqueous ophthalmic composition according to any to the aqueous ophthalmic composition. one of Items 1-1 to 1-6, wherein the total amount of compo 10 6. A method for reducing variation in drip amount during use nent (B) is 2 to 15 parts by weight per 100 parts by weight of in an aqueous ophthalmic composition comprising a Surfac the total amount of component (A). tant other than (A) polyoxyethylene castor oil in which the 1-8. The aqueous ophthalmic composition according to any average number of moles of added ethylene oxide is 2 to 12, one of Items 1-1 to 1-7, which further comprises a buffer. the method comprising adding component (A) and (B) terpe 1-9. The aqueous ophthalmic composition according to any 15 noid to the aqueous ophthalmic composition. one of Items 1-1 to 1-8, wherein the buffer is a boric acid The present invention provides methods for enhancing pre buffer. servative efficacy in an aqueous ophthalmic composition 1-10. The aqueous ophthalmic composition according to Item according to the following embodiments. 1-8 or 1-9, wherein the content of the buffer is 0.01 to 10 w/v 7. A method for enhancing preservative efficacy in an aqueous % based on the total amount of the aqueous ophthalmic com ophthalmic composition, the method comprising adding (A) position. polyoxyethylene castor oil in which the average number of 1-11. The aqueous ophthalmic composition according to any moles of added ethylene oxide is 2 to 12 and (B) terpenoid to one of Items 1-1 to 1-10, which further comprises a nonionic the aqueous ophthalmic composition. Surfactant other than component (A). 8. A method for enhancing preservative efficacy in an aqueous 1-12. The aqueous ophthalmic composition according to Item 25 ophthalmic composition comprising (B) terpenoid, the 1-11, wherein the nonionic Surfactant other than component method comprising adding (A) polyoxyethylene castor oil in (A) is at least one member selected from the group consisting which the average number of moles of added ethylene oxide of polyoxyethylene Sorbitan fatty acid esters, polyoxyethyl is 2 to 12 to the aqueous ophthalmic composition. ene hydrogenated castor oils, polyoxyethylene-polyoxypro The present invention also provides methods for inhibiting pylene block copolymers, and polyoxyethylene castor oils in 30 separation of an aqueous ophthalmic composition according which the average number of moles of added ethylene oxide to the following embodiments. is 20 or more. 9. A method for inhibiting separation of an aqueous oph 1-13. The aqueous ophthalmic composition according to Item thalmic composition, the method comprising adding (A) 1-11 or 1-12, wherein the content of the nonionic surfactant polyoxyethylene castor oil in which the average number of other than component (A) is 0.001 to 3 w/v '% based on the 35 moles of added ethylene oxide is 2 to 12 and (B) terpenoid to total amount of the aqueous ophthalmic composition. the aqueous ophthalmic composition. 1-14. The aqueous ophthalmic composition according to any 10. A method for inhibiting separation of an aqueous oph one of Items 1-1 to 1-13, which is placed in a polyethylene thalmic composition comprising (A) polyoxyethylene castor terephthalate container. oil in which the average number of moles of added ethylene 1-15. The aqueous ophthalmic composition according to any 40 oxide is 2 to 12, the method comprising adding (B) terpenoid one of Items 1-1 to 1-14, which is placed in a container on to the aqueous ophthalmic composition. which a polyethylene nozzle is mounted. 11. A method for inhibiting separation of an aqueous oph 1-16. The aqueous ophthalmic composition according to any thalmic composition comprising (B) terpenoid, the method one of Items 1-1 to 1-15, which is an eye drops. comprising adding (A) polyoxyethylene castor oil in which 1-17. The aqueous ophthalmic composition according to any 45 the average number of moles of added ethylene oxide is 2 to one of Items 1-1 to 1-15, which is an eye wash. 12 to the aqueous ophthalmic composition. 1-18. The aqueous ophthalmic composition according to any The present invention also provides methods for inhibiting one of Items 1-1 to 1-15, which is a solution for wearing a reduction interpenoid concentration over time according to contact lens. the following embodiments. 1-19. The aqueous ophthalmic composition according to any 50 12. A method for inhibiting reduction interpenoid concentra one of Items 1-1 to 1-15, which is a contact lens care solution. tion over time in an aqueous ophthalmic composition held in The present invention provides methods for improving the a container, the method comprising adding (A) polyoxyeth foam disappearance speed in the aqueous ophthalmic com ylene castor oil in which the average number of moles of position, and methods for reducing variation in the drip added ethylene oxide is 2 to 12 and (B) terpenoid to the amount during use according to the following embodiments. 55 aqueous ophthalmic composition. 2. A method for improving a foam disappearance speed in an 13. The method for inhibiting reduction interpenoid concen aqueous ophthalmic composition, the method comprising tration over time according to Item 12, wherein the container adding (A) polyoxyethylene castor oil in which the average holding the aqueous ophthalmic composition is a polyethyl number of moles of added ethylene oxide is 2 to 12 and (B) ene terephthalate container on which a polyethylene nozzle is terpenoid to the aqueous ophthalmic composition. 60 mounted. 3. A method for improving a foam disappearance speed in an 14. A method for imparting, to an aqueous ophthalmic com aqueous ophthalmic composition comprising (A) polyoxy position containing (B) terpenoid and being held in a con ethylene castor oil in which the average number of moles of tainer, an effect of inhibiting reduction interpenoid concen added ethylene oxide is 2 to 12, the method comprising add tration over time in the aqueous ophthalmic composition, the ing (B) terpenoid to the aqueous ophthalmic composition. 65 method comprising adding (A) polyoxyethylene castor oil in 4. A method for reducing variation in drip amount during use which the average number of moles of added ethylene oxide in an aqueous ophthalmic composition, the method compris is 2 to 12 to the aqueous ophthalmic composition. US 9,320,802 B2 5 6 15. The method according to Item 14, wherein the container the field of ophthalmology, which requires particularly high holding the aqueous ophthalmic composition is a polyethyl safety against bacterial contamination, it is possible to reduce ene terephthalate container on which a polyethylene nozzle is contamination of the aqueous ophthalmic composition dur mounted. ing use and the risk of microorganism infection or the like The present invention also provides a method for maintain 5 caused by the contamination. ing cooling sensation of an aqueous ophthalmic composition (4) The aqueous ophthalmic composition of the present according to the following embodiment. invention inhibits the reduction in terpenoid concentration 16. A method for maintaining cooling sensation of an aqueous over time when the composition is held in a container. This ophthalmic composition, the method comprising adding (A) enables the composition to stably exhibit the cooling sensa polyoxyethylene castor oil in which the average number of 10 tion due to terpenoid and the effect of the present invention for moles of added ethylene oxide is 2 to 12 and (B) terpenoid to a long period of time. the aqueous ophthalmic composition. (5) The aqueous ophthalmic composition of the present The present invention also provides use according to the invention inhibits separation of poorly soluble components following embodiments. Such as terpenoid and polyoxyethylene castor oil in which the 17. Use of (A) polyoxyethylene castor oil in which the aver 15 average number of moles of added ethylene oxide is 2 to 12. age number of moles of added ethylene oxide is 2 to 12 and This enables the composition to stably maintain the proper (B) terpenoid, for production of an aqueous ophthalmic com ties of the aqueous ophthalmic composition. position. (6) The aqueous ophthalmic composition of the present 18. The use according to Item 17, wherein the aqueous oph invention can maintain a cooling sensation during use; there thalmic composition is according to any one of Items 1-1 to fore, the ophthalmic composition provides good feeling of 1-19. use and can be used in a very comfortable manner. Further, the present invention provides use according to the The aqueous ophthalmic composition of the present inven following embodiments. tion has the aforementioned excellent effects and can be 19. Use of a composition as an aqueous ophthalmic compo effectively used in a safer and more comfortable manner for a sition, the composition comprising (A) polyoxyethylene cas 25 long period of time. tor oil in which the average number of moles of added ethyl ene oxide is 2 to 12 and (B) terpenoid. DESCRIPTION OF EMBODIMENTS 20. The use according to Item 19, wherein the composition is according to any one of Items 1-1 to 1-19. In the present specification, the unit of content “6” indi The present invention also provides compositions accord 30 cates w/v '% and is the same as g/100 mL. ing to the following embodiments. In the present specification, the abbreviation “POE' means 21. A composition for use as an aqueous ophthalmic compo polyoxyethylene unless otherwise specified. sition, the composition comprising (A) polyoxyethylene cas In the present specification, the abbreviation “POP” means tor oil in which the average number of moles of added ethyl polyoxypropylene unless otherwise specified. ene oxide is 2 to 12 and (B) terpenoid. 35 In the present specification, contact lenses include various 22. The composition according to Item 21, which is recited in types of contact lenses such as hard lenses, oxygen-perme any one of Items 1-1 to 1-19. able hard lenses, soft lenses (including silicone hydrogel The present invention further provides methods for pro lenses), and color lenses unless otherwise specified. ducing an aqueous ophthalmic composition according to the 1. Aqueous Ophthalmic Composition following embodiments. 40 The aqueous ophthalmic composition of the present inven 23. A method for producing an aqueous ophthalmic compo tion contains polyoxyethylene castor oil in which the average sition comprising adding (A) polyoxyethylene castor oil in number of moles of added ethylene oxide is 2 to 12 (herein which the average number of moles of added ethylene oxide after sometimes referred to as component (A)). By using the is 2 to 12 and (B) terpenoid to a carrier containing water. polyoxyethylene castor oil in combination with terpenoid 24. The method according to Item 23, wherein the aqueous 45 described below, the aforementioned excellent effects of the ophthalmic composition is according to any one of Items 1-1 present invention can be attained. to 1-19. Polyoxyethylene castor oil is a known compound obtained by addition polymerization of ethylene oxide with castor oil, Advantageous Effects of Invention and several kinds of polyoxyethylene castor oils having a 50 different average number of moles of added ethylene oxide The present invention attains the following various effects. are known. The average number of moles of added ethylene (1) According to the present invention, the combination use oxide in the polyoxythylene castor oil used as component (A) of terpenoid and polyoxyethylene castor oil in which the in the present invention is 2 to 12. Specific examples thereof average number of moles of added ethylene oxide is 2 to 12 include polyoxyethylene castor oil 3 in which the average can improve the foam disappearance speed in the aqueous 55 number of moles of added ethylene oxide is 3, and polyoxy ophthalmic composition. Consequently, dissolution check ethylene castor oil 10 in which the average number of moles and foreign matter detection during the production of the of added ethylene oxide is 10. aqueous ophthalmic composition can be performed in a short These polyoxyethylene castor oils may be used singly or in period of time, thus improving production efficacy. any combination of two or more. Note that polyoxyethylene (2) Since the aqueous ophthalmic composition of the 60 castor oil used in the present invention is a compound that is present invention has the aforementioned feature, it reduces different from and can be distinguished from polyoxyethyl variation in the drip amount due to foaming during use. ene hydrogenated castor oil obtained by addition polymeriza Therefore, the present invention enables easy control of the tion of ethylene oxide with hydrogenated castor oil. amount used and easy handling by users, thereby improving The content of component (A) in the aqueous ophthalmic compliance. 65 composition of the present invention is suitably determined (3) The aqueous ophthalmic composition of the present according to the kind of component (A), the kind of compo invention has enhanced preservative efficacy. Thus, even in nent (B) used in combination with component (A), the prepa US 9,320,802 B2 7 8 ration form of the aqueous ophthalmic composition, etc. For satisfied. To fully exhibit the effects of the present invention, example, the total amount of component (A) is 0.01 to 3 w/v. i.e., improvement of the foam disappearance speed, inhibi %, preferably 0.02 to 2 w/v %, more preferably 0.02 to 1 w/v tion of variation in the drip amount during use, inhibition of %, even more preferably 0.05 to 1 w/v '%, even more prefer reduction interpenoid concentration over time, enhancement ably 0.05 to 0.6 w/v%, even more preferably 0.2 to 0.6 w/v %, of preservative efficacy, inhibition of separation of poorly particularly preferably 0.2 to 0.4 w/v '%, and most preferably soluble components, etc., it is desirable to satisfy the ratio 0.2 to 0.3 w/v '% based on the total amount of the aqueous such that the total amount of component (B) is 0.01 to 1,000 ophthalmic composition of the present invention. parts by weight, preferably 0.1 to 500 parts by weight, more In the aqueous ophthalmic composition of the present preferably 0.5 to 100 parts by weight, even more preferably invention, the amount of component (A) is preferably 0.05 to 10 0.3 w/v '% to inhibit foaming of the aqueous ophthalmic 0.5 to 80 parts by weight, particularly preferably 0.5 to 50 composition, and the amount of component (A) is preferably parts by weight, and most preferably 1 to 25 parts by weight 0.025 to 0.4 w/v '% to attain the preservative efficacy of the relative to 100 parts by weight of the total amount of compo aqueous ophthalmic composition. nent (A). In particular, when the ratio is such that the total The aforementioned content of component (A) is prefer 15 amount of component (B) is 2 to 15 parts by weight per 100 able to further improve an effect of improving the foam dis parts by weight of the total amount of component (A), the appearance speed in the aqueous ophthalmic composition, extremely excellent effects are exhibited. effect of reducing variation in the drip amount during use, As described below, various pharmacologically active effect of improving preservative efficacy, or effect of inhibit components, biologically active components, etc., can be ing separation. The aforementioned content of component added, according to the purpose of use, to the aqueous oph (A) is also preferable to further improve an effect of inhibiting thalmic composition of the present invention, and various the reduction interpenoid concentration over time when the kinds of additives can also be added. In this case, to improve composition is contained in a container. the solubility of biologically active components, additives, It is necessary for the ophthalmology composition of the etc., it is preferable to further add a surfactant other than present invention to containterpenoid (hereinafter sometimes 25 component (A) as a solubilizing agent. Typically, the addition referred to as component (B)) in addition to component (A). of such a surfactant increases foaming; however, even for an The combination use of component (A) and component (B) aqueous ophthalmic composition that is likely to make foam attains the aforementioned effects, i.e., effects of improving by the addition of a surfactant other than component (A), the the foam disappearance speed, reducing variation in the drip foam disappearance speed can be increased by the addition of amount during use, inhibiting reduction interpenoid concen 30 tration over time, enhancing preservative efficacy, inhibiting component (A) together with component (B) based on the the separation of poorly soluble components, and the like. aforementioned criteria. As a result, the production efficacy Terpenoid used as component (B) is not particularly lim can be improved, and variation in the drip amount can be ited as long as it is pharmacologically (pharmaceutically) or reduced. Furthermore, the effects of the present invention, physiologically acceptable in the field of medicine. Examples 35 Such as inhibition of reduction in terpenoid concentration of the terpenoid include menthol, camphor, borneol, geraniol, over time, can be further increased. cineol, citronellol, menthone, carvone, anethole, eugenol, The Surfactant other than component (A), which can be limonene, linalool, linallyl acetate, and derivatives thereof. added to the aqueous ophthalmic composition of the present These compounds may be in the d form, 1 from, or d1 form. invention, is not particularly limited as long as it is a pharma Essential oil containing any of the above compounds can be 40 cologically (pharmaceutically) or physiologically acceptable used as terpenoid in the present invention. Examples of Such surfactant in the field of medicine. The surfactant may be a essential oil include eucalyptus oil, bergamot oil, peppermint nonionic Surfactant, ampholytic Surfactant, anionic Surfac oil, cool mint oil, spearmint oil, mint oil, fennel oil, cinnamon tant, or cationic Surfactant. oil, rose oil, and the like. These terpenoids can be used alone Specific examples of the nonionic Surfactant that can be or in a combination of two or more. 45 added to the aqueous ophthalmic composition of the present Of components (B), menthol, camphor, geraniol, borneol, invention include POE (20) sorbitan monolaurate (polysor and the like are preferable to suitably exhibit the effects of the bate 20), POE (20) sorbitan monopalmitate (polysorbate 40), present invention. Examples of the preferable essential oil POE (20) sorbitan monostearate (polysorbate 60), POE (20) containing any of the above compounds include cool mint oil, sorbitan tristearate (polysorbate 65), POE (20) sorbitan peppermint oil, mint oil, camphor oil, eucalyptus oil, and the 50 monooleate (polysorbate 80), and like POE sorbitan fatty acid like. Menthol, camphor, geraniol, borneol, and eucalyptus oil esters; POE (60) hydrogenated castor oil (polyoxyethylene are preferable examples, and 1-menthol, d-camphor, dl-cam hydrogenated castor oil 60) and like POE hydrogenated cas phor, geraniol, d-borneol, and eucalyptus oil are further pref tor oils; POE (9) lauryl ether and like POE alkyl ethers; POE erable examples. (20) POP (4) cetyl ether and like POE-POP alkyl ethers; POE To suitably exhibit the effects of the present invention, the 55 (196) POP (67) glycol (poloxamer 407 and pluronic F127), content of component (B) in the aqueous ophthalmic compo POE (200) POP (70) glycol, and like polyoxyethylene-poly sition of the present invention is 0.0001 to 1 w/v%, preferably oxypropylene block copolymers; polyoxyethylene castor oil 0.001 to 0.1 w/v%, more preferably 0.003 to 0.06 w/v %, and 20, polyoxyethylene castor oil 35, polyoxyethylene castor oil further preferably 0.003 to 0.02 w/v % based on the total 40, polyoxyethylene castor oil 50, polyoxyethylene castor oil amount of the aqueous ophthalmic composition of the present 60 60, and like polyoxyethylene castor oils in which the average invention. When essential oil containing terpenoid is used as number of moles of added ethylene oxide is 20 or more. In the component (B), the content of the essential oil is determined compounds listed above, each of the numbers in the paren such that the total amount of terpenoid in the essential oil is theses shows the number of moles of the added compounds. satisfied the aforementioned content. Specific examples of the ampholytic Surfactant that can be The ratio of component (B) to component (A) in the aque 65 added to the aqueous ophthalmic composition of the present ous ophthalmic composition of the present invention is not invention include alkyldiaminoethylglycine or salts thereof particularly limited as long as the aforementioned content is (e.g. hydrochloride). US 9,320,802 B2 9 10 Further, specific examples of the cationic Surfactant that salts thereof (ammonium acetate, potassium acetate, calcium can be added to the aqueous ophthalmic composition of the acetate, Sodium acetate, etc.), and aspartic acid or salts thereof present invention include benzalkonium chloride, benzetho (sodium aspartate, magnesium aspartate, potassium aspar nium chloride, and the like. tate, etc.). Of the buffers, boric acid buffers (especially, com Specific examples of the anionic Surfactant that can be bination of boric acid and borax) are preferable. added to the aqueous ophthalmic composition of the present When the buffer is added to the aqueous ophthalmic com invention include alkylbenzene Sulfonate, alkylsulfate, poly position of the present invention, the content of the buffer oxyethylene alkyl sulfate, aliphatic C.-sulfomethyl ester, cannot be uniformly determined, and it varies depending on C-olefin sulfonic acid, and the like. the kind of the buffer to be used, the kinds and contents of the Nonionic surfactants are preferable, and POE sorbitan fatty 10 other components, the preparation form of the aqueous oph acid esters, POE hydrogenated castor oils, POE-POP block thalmic composition, etc. For example, the total amount of copolymers, and polyoxyethylene castor oils in which the the buffer is 0.01 to 10 w/v %, preferably 0.05 to 5 w/v %, average number of moles of added ethylene oxide is 20 or more preferably 0.1 to 2.5 w/v '%, and even more preferably more are more preferable. Polysorbate 80, polyoxyethylene 0.1 to 1 w/v '% based on the total amount of the aqueous hydrogenated castor oil 60, poloxamer 407, and polyoxyeth 15 ophthalmic composition. ylene castor oil 35 are particularly preferable. The aqueous ophthalmic composition of the present inven In the aqueous ophthalmic composition of the present tion may further include a tonicity agent. The tonicity agent invention, the Surfactants other than component (A) can be that can be added to the aqueous ophthalmic composition of used singly or in a combination of two or more. the present invention is not particularly limited as long as it is When the surfactant is added to the aqueous ophthalmic a pharmacologically (pharmaceutically) or physiologically composition of the present invention, the content of the Sur acceptable tonicity agent in the field of medicine. Examples factant is suitably determined according to the kind of the of the tonicity agent include disodium hydrogen phosphate, Surfactant, the kinds and the contents of other components, Sodium dihydrogen phosphate, potassium dihydrogen phos the preparation form of the aqueous ophthalmic composition, phate, Sodium hydrogen Sulfite, sodium sulfite, potassium etc. For example, the total amount of the surfactant other than 25 chloride, calcium chloride, Sodium chloride, magnesium component (A) is 0.001 to 3 w/v %, preferably 0.01 to 2 w/v. chloride, potassium acetate, sodium acetate, Sodium bicar %, more preferably 0.05 to 1 w/v '%, and particularly prefer bonate, sodium carbonate, Sodium tiosulfate, magnesium Sul ably 0.1 to 1 w/v '% based on the total amount of the aqueous fate, glycerin, propylene glycol, and the like. Of these tonicity ophthalmic composition. agents, preferable examples include glycerin, propylene gly The aqueous ophthalmic composition of the present inven 30 col, Sodium chloride, potassium chloride, calcium chloride, tion preferably includes a buffer, by which the pH of the and magnesium chloride. Sodium chloride and glycerin are aqueous ophthalmic composition of the present invention can more preferable, and sodium chloride is particularly prefer be adjusted. A buffer that can be added to the aqueous oph able. These tonicity agents can be used singly or in a combi thalmic composition of the present invention is not particu nation of two or more. larly limited as long as it is a pharmacologically (pharmaceu 35 When a tonicity agent is added to the aqueous ophthalmic tically) or physiologically acceptable buffer in the field of composition of the present invention, the content of the tonic medicine. Examples of such a buffer include boric acid buff ity agent cannot be uniformly determined, and it varies ers, phosphoric acid buffers, carbonic acid buffers, citric acid depending on the kind of the tonicity agent to be used. For buffers, acetic acid buffers, aspartic acid, aspartic acid salts, example, the total amount of the tonicity agent is 0.01 to 10 and the like. These buffers can be used in combination. 40 w/v %, preferably 0.05 to 5 w/v%, and more preferably 0.1 to Examples of boric acid buffers include boric acid or boric 3 w/v '%, based on the total amount of the aqueous ophthalmic acid salts such as alkali metal salt of boric acid and alkaline composition. earth metal salt of boric acid. Examples of phosphoric acid The pH of the aqueous ophthalmic composition of the buffers include phosphoric acid orphosphoric acid salts such present invention is not particularly limited as long as it is as alkali metal phosphate and alkaline earth metal phosphate. 45 within a pharmacologically (pharmaceutically) or physi Examples of carbonic acid buffers include carbonic acid or ologically acceptable range in the field of medicine. The pH carbonic acid salts such as alkali metal carbonate and alkaline of the aqueous ophthalmic composition of the present inven earth metal carbonate. Examples of citric acid buffers include tion is, for example, 4.0 to 9.5, preferably 5.0 to 9.0, more citric acid or alkali metal citrate, alkaline earth metal citrate, preferably 6.2 to 8.5, even more preferably 6.5 to 8, and and the like. As a boric acid buffer or a phosphoric acid buffer, 50 particularly preferably about 6.5 to 7.5. a hydrate of boric acid salt or a hydrate of phosphoric acid salt The osmotic pressure of the aqueous ophthalmic compo can be used. More specifically, examples of the boric acid sition of the present invention is not particularly limited as buffer include boric acid or salts thereof (sodium borate, long as it is within a range acceptable to the human body. The potassium tetraborate, potassium metaborate, ammonium osmotic pressure ratio of the aqueous ophthalmic composi borate, borax, etc.); examples of the phosphoric acid buffer 55 tion of the present invention is, for example, preferably 0.5 to include phosphoric acid or salts thereof (disodium hydrogen 5.0, more preferably 0.6 to 3.0, and particularly preferably 0.7 phosphate, sodium dihydrogen phosphate, potassium dihy to 2.0. The osmotic pressure can be adjusted using an inor drogen phosphate, trisodium phosphate, dipotassium phos ganic salt, polyhydric alcohol, Sugar alcohol, Sugar, etc., phate, calcium monohydrogen phosphate, calcium dihydro according to a known method in the technical field of the gen phosphate, etc.); examples of the carbonic acid buffer 60 present invention. The osmotic pressure ratio is the ratio of the include carbonic acid or salts thereof (sodium bicarbonate, osmotic pressure of a sample to 286 mOsm (osmotic pressure Sodium carbonate, ammonium carbonate, potassium carbon of 0.9 w/v '% aqueous sodium chloride solution) based on the ate, calcium carbonate, potassium bicarbonate, magnesium Japanese Pharmacopoeia, 15" revision. The osmotic pressure carbonate, etc.); examples of the citric acid buffer include can be measured with reference to the osmotic measurement citric acid or salts thereof (sodium citrate, potassium citrate, 65 method (freezing point depression method) described in the calcium citrate, Sodium dihydrogen citrate, disodium citrate, Japanese Pharmacopoeia. To obtain a reference solution (0.9 etc.); examples of the acetic acid buffer include acetic acid or w/v '% sodium chloride solution) for measuring the osmotic US 9,320,802 B2 11 12 pressure ratio, Sodium chloride (standard reagent according Zoate, butyl parahydroxybenzoate, oxyquinoline Sulfate, to the Japanese Pharmacopoeia) is dried for 40 to 50 minutes phenethyl alcohol, benzyl alcohol, and Glokill (trade name, at 500 to 650° C., and then allowed to cool in a desiccator Rhodia Co., Ltd.). (silica gel). 0.900 g of the resultant is accurately measured, The aqueous ophthalmic composition of the present inven and the resultant is then dissolved in purified water, thus tion can be prepared by adding a desired amount of each of accurately preparing 100 mL of the solution. Alternatively, a component (A) and component (B), and if necessary, other commercially available reference solution (0.9 w/v '% aque components to a carrier in a manner Such that the aqueous ous Sodium chloride Solution) for measuring the osmotic ophthalmic composition has a desired concentration. For pressure ratio can be used. example, eye drops, Solutions for wearing contact lenses, eye As long as the effects of the present invention are attained, 10 washes, or contact lens care solutions are prepared by dis the aqueous ophthalmic composition of the present invention Solving or Suspending the aforementioned components in may include, in addition to the aforementioned components, purified water, adjusting the pH and osmotic pressure to the a suitable amount of a various pharmacologically active com predetermined levels, and Subjecting these to sterilization ponent and/or a biologically active component singly or in treatment by filter sterilization, etc. Regarding the dissolution combination. Such components are not particularly limited, 15 of components (A) and (B), and the dissolution of compo and examples include effective components in ophthalmo nents with a high hydrophobic property, components having logical drugs described in, for example, Standards for an effect of helping dissolution Such as Surfactants may be Approval for the Manufacture (Import) of Non-prescription added beforehand, then the mixture is stirred, after which Drugs 2000 (Ippanyou Iyakuhin Seizou (vunyuu) syounin purified water is added thereto, followed by dissolution or Kizyun 2000), compiled under supervision of the Pharmaceu Suspension. tical Council. Specific examples of the components used in The present invention provides, as a method for producing ophthalmological drugs include the following components. an aqueous ophthalmic composition, a method comprising Antihistamines such as iproheptine, diphenhydramine adding (A) polyoxyethylene castor oil in which the average hydrochloride, chlorphenylamine maleate, ketotifen fuma number of moles of added ethylene oxide is 2 to 12 and (B) rate, and pemirolast potassium. 25 terpenoid to a water-containing carrier. Decongestants such as tetrahydrozoline hydrochloride, The aqueous ophthalmic composition of the present inven naphazoline hydrochloride, naphazoline Sulfate, epinephrine tion means an ophthalmic composition in which the content hydrochloride, ephedrine hydrochloride, and methylephe of water exceeds 85 w/v '% or more based on the total amount drine hydrochloride. of the aqueous ophthalmic composition. The content of water Disinfectants such as cetyl pyridinium, benzalkonium 30 in the aqueous ophthalmic composition is preferably 90 w/v. chloride, benzethonium chloride, chlorhexidine hydrochlo % or more, more preferably 92 w/v '% or more, even more ride, chlorhexidine gluconate, and polyhexanide hydrochlo preferably 95 w/v.9% or more, and particularly preferably 97 ride. w/v '% or more. Vitamins such as flavin adenine dinucleotide Sodium, Pharmacologically (pharmaceutically), or physiologically cyanocobalamin, retinol acetate, retinol palmitate, pyridox 35 acceptable water in the field of medicine can be used as the ine hydrochloride, pantenol, calcium pantothenate, and toco water used in the aqueous ophthalmic composition of the pherol acetate. present invention. Examples of water include distilled water, Amino acids such as potassium aspartate and magnesium water, purified water, sterile purified water, water for injec aspartate. tion, distilled water for injection, and the like. The dosage Antiphlogistics such as dipotassium glycyrrhizinate, pra 40 form of the aqueous ophthalmic composition in the present noprofen, allantoin, aZulene, Sodium azulene Sulfonate, gua invention is not particularly limited as long as it is usable in iaZulene, berberine chloride, berberine sulfate, lysozyme the field of ophthalmology. The dosage form is preferably chloride, and licorice. liquid. These definitions are based on the Japanese Pharma Others such as Sodium cromoglicate, sodium chondroitin copoeia, 15" revision. Sulfate, sodium hyaluronate, Sulfamethoxazole, and sodium 45 Examples of the aqueous ophthalmic composition of the Sulfamethoxazole. present invention include eye drops (also called as oph Further, as long as the effects of the invention are attained, thalmic Solutions or ophthalmic drugs) note that examples of various additives can be suitably selected and added to the the eye drops also include eye drops that can be instilled into aqueous ophthalmic composition by a known method accord the eyes during use of contact lenses, eye washes (also ing to the application, preparation form, etc. The additives can 50 referred to as collyria or eye lotions) note that examples of be added singly or in a combination in a Suitable amount. the eyewashes also include eyewashes that can wash the eyes Examples of the additives include those described in Japanese during use of contact lenses. Solutions for wearing contact Pharmaceutical Excipients Directory 2007 (edited by the lenses, contact lens care products, (disinfectant solutions for International Pharmaceutical Excipients Council Japan). contact lenses, storage solutions for contact lenses, cleansing Typical components include the following additives. 55 Solutions for contact lenses, cleansing-storage Solutions for Carriers such as water, water-containing ethanol, and like contact lenses, and disinfectant-storage-cleansing solutions aqueous carriers. for contact lenses (multiple-purpose solutions for contact Sugars Such as cyclodextrin. lenses)), etc. The aqueous ophthalmic composition of the Sugar alcohols such as Xylitol, Sorbitol, and mannitol, present invention ensures an improved foam disappearance wherein these compounds may be in the d form, 1 form, or d1 60 speed and low variation in the drip amount during use. Thus, form. in particular, the aqueous ophthalmic composition of the Antiseptics, disinfectants, and antibacterial agents such as present invention is preferably used in eye drops and solutions alkyldiaminoethylglycine hydrochloride, Sodium benzoate, for wearing contact lenses, which are used in a particularly ethanol, benzalkonium chloride, benzetonium chloride, chlo Small amount each time, and is particularly preferably used in rhexidine gluconate, chlorobutanol, Sorbic acid, potassium 65 eye drops. Sorbate, sodium dehydroacetate, methyl parahydroxyben The aqueous ophthalmic composition of the present inven Zoate, ethyl parahydroxybenzoate, propyl parahydroxyben tion has an excellent antiseptic effect due to improved preser US 9,320,802 B2 13 14 vative efficacy, and it has an excellent effect of inhibiting the a constituent material. Thus, a container having a spout that reduction interpenoid concentration over time. For this rea contains polyethylene or polypropylene as a constituent son, the present invention is preferably used as a multi-dose material can be effectively used. aqueous ophthalmic composition, i.e., an aqueous oph Examples of polyethylene include high-density polyethyl thalmic composition that is used more than once after the 5 ene, low-density polyethylene, and the like. Of these, a spout commercial product is opened. The aqueous ophthalmic com containing low-density polyethylene as a constituent material position can be stably stored for a few days, a few weeks, or is preferable. As a spout, a nozzle used in a container for eye longer. drops is preferable. As the container that holds the aqueous ophthalmic com As a preferable combination of a container that holds the position of the present invention, a container that can be 10 typically used to hold an aqueous ophthalmic composition aqueous ophthalmic composition of the present invention and can be used. The container may be made of glass or plastic. a container spout periphery, it is possible to use a combination When a plastic container is used to hold the aqueous oph of a polyethylene terephthalate container and a polyethylene thalmic composition of the present invention, although con container spout periphery, more preferably a combination of stituent materials of the plastic container are not particularly 15 a polyethylene terephthalate eye drop container and a poly limited, polyethylenenaphthalate, polyarylate, polyethylene ethylene nozzle, and particularly preferably, a combination of terephthalate, polypropylene, polyethylene, and polyimide a polyethylene terephthalate eye drop container and a low can be used alone or in a mixture of two or more, or as a density polyethylene nozzle. Such a combination can signifi copolymer thereof. Examples of the copolymers include cantly exhibit the effect of reducing variation in the drip copolymers that contain other polyester units or imide units, amount in the present invention. in addition to any one of ethylene-2,6-naphthalate units, ary The aqueous ophthalmic composition of the present inven late units, ethylene terephthalate units, propylene units, eth tion has an effect of inhibiting reduction interpenoid concen ylene units, and imide units, which is contained as a main tration over time. Thus, even when a container including a component. In the present invention, for example, a polyeth container body and a container spout periphery made of the ylene terephthalate container means a container in which 25 materials mentioned above is used, the cooling sensation due polyethylene terephthalate is contained in an amount of 50 to terpenoid can be stably maintained for a long period of w/w % or more based on the total weight of the constituent time, and the composition of the present invention can stably materials of the container. exhibit an effect attained by the combination use of specific Of these containers, although a polyethylene terephthalate polyoxythylene castor oil and terpenoid for a long period of container is excellent in view of durability and cost, reduction 30 time. in terpenoid concentration over time can be sometimes Since the aqueous ophthalmic composition of the present observed when the composition is contained in a polyethyl invention can increase the foam disappearance speed, reduce ene terephthalate container. Even when the aqueous oph variation in the drip amount during use, and can be instilled thalmic composition of the present invention is held in a into an eye in a constant amount per use, it is particularly polyethylene terephthalate container, the combination use of 35 preferably used as eye drops containing a pharmacologically specific polyoxyethylene castor oil and terpenoid inhibits active component and/or a biologically active component. reduction in terpenoid concentration over time; thus, the Such eye drops can be used as eye drops for relieving itchy polyethylene terephthalate container can be effectively used. eyes, eye drops for relieving eye strain, and the like. In particular, even in a container having polyethylene tereph From a different viewpoint, the present invention also pro thalate of 75 w/w % or more, and particularly 95 w/w % or 40 vides use of (A) polyoxyethylene castor oil in which the more based on the total weight of the constituent materials of average number of moles of added ethylene oxide is 2 to 12 the container, the container can be effectively used without and (B) terpenoid, for production of an aqueous ophthalmic noticeably reducing the concentration ofterpenoid over time. composition. The structure, constituent materials, etc., of a container From another different viewpoint, the present invention spout periphery Such as a nozzle mounted on a container 45 also provides use of a composition as an aqueous ophthalmic containing the aqueous ophthalmic composition of the composition, the composition comprising (A) polyoxyethyl present invention are not particularly limited. The structure of ene castor oil in which the average number of moles of added the container spout periphery Such as a nozzle may be a ethylene oxide is 2 to 12 and (B) terpenoid typically applicable structure as a spout (e.g., nozzle) of a From still another different viewpoint, the present inven container for ophthalmologic compositions (e.g., container 50 tion provides a composition for use as an aqueous ophthalmic for eye drops), and the nozzle may be integrally or separately composition, the composition comprising (A) polyoxyethyl formed with the container. Examples of the constituent mate ene castor oil in which the average number of moles of added rials of the spout periphery or spout (e.g., noZZle) include ethylene oxide is 2 to 12 and (B) terpenoid. those mentioned in the constituent materials of the plastic 2. Method for Improving Foam Disappearance Speed and containers. 55 Method for Reducing Variation in Drip Amount In particular, to attain further improved flexibility, reason As mentioned above, in the aqueous ophthalmic composi able cost, and/or an effect of reducing variation in the drip tion of the present invention, by using component (A) and amount, a spout containing polyethylene or polypropylene as component (B) in combination, the foam disappearance a constituent material is preferable. However, such materials speed can be improved in the aqueous ophthalmic composi used for a nozzle are likely to cause reduction interpenoid 60 tion and variation in the drip amount during use can be concentration over time. This is presumably because terpe reduced. noid is likely to adsorb to these materials. The aqueous oph Therefore, from a different viewpoint, the present inven thalmic composition of the present invention can inhibit tion provides a method for improving the foam disappearance reduction interpenoid concentration over time by the combi speed in an aqueous ophthalmic composition, the method nation use of specific polyoxyethylene castor oil and terpe 65 comprising adding (A) polyoxyethylene castor oil in which noid, even when the composition is contained in a container the average number of moles of added ethylene oxide is 2 to having a spout that contains polyethylene or polypropyleneas 12 and (B) terpenoid to the aqueous ophthalmic composition. US 9,320,802 B2 15 16 The present invention also provides a method for improv components such as components (A) and (B) from the aque ing the foam disappearance speed in an aqueous ophthalmic ous ophthalmic composition, and can stabilize the properties composition comprising (A) polyoxyethylene castor oil in of the preparation. which the average number of moles of added ethylene oxide Thus, from a different viewpoint, the present invention is 2 to 12, the method comprising adding (B) terpenoid to the provides a method for inhibiting separation of an aqueous aqueous ophthalmic composition. ophthalmic composition, the method comprising adding (A) The present invention further provides a method for reduc polyoxyethylene castor oil in which the average number of ing variation in the drip amount during use of an aqueous moles of added ethylene oxide is 2 to 12 and (B) terpenoid to ophthalmic composition, the method comprising adding (A) the aqueous ophthalmic composition. The present invention polyoxyethylene castor oil in which the average number of 10 also provides a method for inhibiting separation of an aque moles of added ethylene oxide is 2 to 12 mol and (B) terpe ous ophthalmic composition comprising (A) polyoxyethyl noid to the aqueous ophthalmic composition. ene castor oil in which the average number of moles of eth The present invention still further provides a method for ylene oxide is 2 to 12, the method comprising adding (B) improving the foam disappearance speed in an aqueous oph terpenoid to the aqueous ophthalmic composition. The thalmic composition comprising a surfactant other than com 15 present invention further provides a method for inhibiting ponent (A), and a method for reducing variation in the drip separation of an aqueous ophthalmic composition compris amount during use of the aqueous ophthalmic composition, ing (B) terpenoid, the method comprising adding (A) poly each method comprising adding (A) polyoxyethylene castor oxyethylene castor oil in which the average number of moles oil in which the average number of moles of added ethylene of added ethylene oxide is 2 to 12 to the aqueous ophthalmic oxide is 2 to 12 and (B) terpenoid to the aqueous ophthalmic composition. composition. In the aforementioned methods, the kinds, the contents In these methods, the kinds of component (A) and compo (amounts added), and the ratio of components (A) and (B), the nent (B) to be used, the contents (or amounts added) and the kinds and the contents (amounts added) of components added ratio thereof, the kinds and the contents (amounts added) of other than the above, and the preparation form of the aqueous components added other than the above, the preparation form 25 ophthalmic composition, the kind and the combination of the of the aqueous ophthalmic composition, the kind and the container, the embodiment manner, and the like are the same combination of the container, the embodiment manner, and as in the “1. Aqueous Ophthalmic Composition' section the like, are the same as in the “1. Aqueous Ophthalmic above. Composition' section above. 5. Method for Inhibiting Reduction in Terpenoid Concentra In particular, the methods described above are suitably 30 tion Over Time used when the aqueous ophthalmic composition is used as an As described above, the combination use of components eye drops or a solution for wearing a contact lens. (A) and (B) can inhibit the reduction of the concentration of 3. Method for Enhancing Preservative Efficacy component (B) over time when the aqueous ophthalmic com As described above, the preservative efficacy in the aque position containing these components is held in a container. ous ophthalmic composition can be enhanced by using com 35 This is presumably because the combination use of compo ponent (A) and component (B) in combination. nents (A) and (B) can inhibit the adsorption of component (B) Accordingly, from another viewpoint, the present inven in the aqueous ophthalmic composition to the container, Vola tion provides a method for enhancing preservative efficacy in tilization of component (B) from the container, and the like. an aqueous ophthalmic composition, the method comprising Thus, it is possible to maintain the cooling sensation of the adding (A) polyoxyethylene castor oil in which the average 40 aqueous ophthalmic composition and the effect of the present number of moles of added ethylene oxide is 2 to 12 and (B) invention over a long period of time. terpenoid to the aqueous ophthalmic composition. Therefore, from a different viewpoint, the present inven The present invention also provides a method for enhanc tion provides a method for inhibiting reduction interpenoid ing preservative efficacy in an aqueous ophthalmic composi concentration over time in an aqueous ophthalmic composi tion comprising terpenoid (B), the method comprising adding 45 tion held in a container, the method comprising adding (A) (A) polyoxyethylene castor oil in which the average number polyoxyethylene castor oil in which the average number of of moles of added ethylene oxide is 2 to 12 to the aqueous moles of added ethylene oxide is 2 to 12 and (B) terpenoid to ophthalmic composition. the aqueous ophthalmic composition. In these methods, the kinds of components (A) and (B) to The present invention further provides the above-described be used, the contents (amounts added) and the ratio thereof, 50 method for inhibiting reduction in terpenoid concentration the kinds and the contents (amounts added) of components over time, wherein the container holding the aqueous oph added other than the above, the preparation form of the aque thalmic composition is a polyethylene terephthalate container ous ophthalmic composition, the kind and the combination of on which a polyethylene nozzle is mounted. the container, the embodiment manner, and the like, are the From another different viewpoint, the present invention same as in the “1. Aqueous Ophthalmic Composition' section 55 provides a method for imparting, to an aqueous ophthalmic above. composition containing (B) terpenoid and being held in a In particular, these methods are preferably used when the container, an effect of inhibiting reduction interpenoid con aqueous ophthalmic composition is a multi-dose aqueous centration over time in the aqueous ophthalmic composition, ophthalmic composition, i.e., an aqueous ophthalmic compo the method comprising adding (A)polyoxyethylene castor oil sition used more than one time after the commercial product 60 in which the average number of moles of added ethylene is opened. Examples of such an aqueous ophthalmic compo oxide is 2 to 12 to the aqueous ophthalmic composition. sition include multi-dose eye drops, multi-dose eye washes, The present invention also provides the above-described multi-dose solutions for wearing contact lenses, and multi method for imparting an effect of inhibiting reduction in dose contact lens care products. terpenoid concentration over time to the aqueous ophthalmic 4. Method for Inhibiting Separation 65 composition, wherein the container holding the aqueous oph As described above, the combination use of component (A) thalmic composition is a polyethylene terephthalate container and component (B) can inhibit separation of poorly soluble on which a polyethylene nozzle is mounted. US 9,320,802 B2 17 18 In these methods, the kinds, the contents (amounts added), disappearance speeds were evaluated by measuring the time and the ratio of components (A) and (B) to be used, the kinds required for the foam to completely disappear. The results are and the contents (amounts added) of components added other also shown in Table 1. than the above, the preparation form of the aqueous oph thalmic composition, the kind and the combination of the TABLE 1 container, the embodiment manner, etc., are the same as those in the “1. Aqueous Ophthalmic Composition' section above. Unit (wiv% In particular, these methods are preferably used in eye Comparative Example Example drops and solutions for wearing contact lenses. 1-1 1-1 10 6. Method for Maintaining Cooling Sensation Polyoxyethylene O.3 O.3 As described above, the combination use of components castor oil 10 (A) and (B) in the aqueous ophthalmic composition can main I-menthol O.O3 tain the cooling sensation of the aqueous ophthalmic compo Boric acid O.S O.S sition. Thus, the cooling sensation of the aqueous ophthalmic Borax O.O2 O.O2 15 Glycerin 2.5 2.5 composition when the composition is instilled into the eyes Purified water (mL) Balance Balance can be maintained. pH 7 7 Therefore, from a different viewpoint, the present inven Time required for the foam 16S 15 tion provides a method for maintaining the cooling sensation to completely disappear of an aqueous ophthalmic composition, the method compris (minutes) ing adding (A) polyoxyethylene castor oil in which the aver age number of moles of added ethylene oxide is 2 to 12 and The volume of the foam part of Example 1-1 measured (B) terpenoid to the aqueous ophthalmic composition. immediately after shaking was similar to that of Comparative In these methods, the kinds, the contents (amounts added), Example 1-1. However, after 1 minute, the volume of the and the ratio of components (A) and (B) to be used, the kinds foam part of Example 1-1 was decreased to about one-eighth and the contents (amounts added) of components added other 25 of that of Comparative Example 1-1. Further, as shown in than the above, the preparation form of the aqueous oph Table 1, the time required for the foam to completely disap thalmic composition, the kind and the combination of the pear was 165 minutes in the aqueous ophthalmic composition container, the embodiment manner, etc., are the same as those containing polyoxyethylene castor oil 10 but not containing a in the “1. Aqueous Ophthalmic Composition' section above. terpenoid (menthol) (Comparative Example 1-1), whereas In particular, these methods are preferably used in eye 30 the foam completely disappeared in only 15 minutes in the drops and solutions for wearing contact lenses. aqueous ophthalmic composition containing both polyoxy ethylene castor oil 10 and a terpenoid (menthol) (Example EXAMPLES 1-1). The present invention is described below in more detail 35 Test Example 2 with reference to Test Examples and Examples. However, the scope of the invention is not limited to these Examples. Foam Disappearance Speed Test (2) Test Example 1 As shown in the following Table 2, aqueous ophthalmic 40 compositions containing a Surfactant other than component Foam Disappearance Speed Test (1) (A) (polysorbate 80) (Example 1-2 and Comparative Examples 1-2 to 1-4) were prepared by a standard method. Aqueous ophthalmic compositions having the formula This test used 1-menthol and polysorbate 80 that conform to tions shown in the following Table 1 (Example 1-1 and Com the standard of the Japanese Pharmacopoeia, 15th revision, parative Example 1-1) were prepared by a standard method, 45 and polyoxyethylene castor oil 10 and polyoxyethylene cas and foam disappearance speeds were evaluated using these tor oil 35 that conform to the standard for polyoxyethylene compositions. Specifically, foaming upon shaking and foam castor oil in Japanese Pharmaceutical Excipients 2003 and in disappearance speeds after the elapse of a certain period of which the average number of moles of added ethylene oxide time were evaluated in the aqueous ophthalmic composition is 10 and 35, respectively. containing a surfactant and the aqueous ophthalmic compo 50 Using these aqueous ophthalmic compositions, a foam dis sition containing a terpenoid in addition to Such a Surfactant. appearance speed test was performed in the same manner as First, each of the aqueous ophthalmic compositions shown in Test Example 1. Foam disappearance speeds were evalu in Table 1 (Comparative Example 1-1 and Example 1-1) was ated by measuring the time required for the initial foam to be prepared. This test used 1-menthol that conforms to the stan reduced by half. The results are also shown in Table 2. dard of the Japanese Pharmacopoeia, 15th revision, and poly 55 oxyethylene castor oil 10 that conforms to the standard for polyoxyethylene castor oil in Japanese Pharmaceutical TABLE 2 Excipients 2003 and in which the average number of moles of Unit (wiv% added ethylene oxide is 10. Comparative Comparative Comparative Subsequently, each of the aqueous ophthalmic composi 60 Example Example Example Example tions in an amount of 30 mL was placed in individual 50-mL 1-2 1-3 1-4 1-2 glass centrifuge tubes, and the tubes were shaken 1,500 times using a Recipad Shaker SR-2w (TAITEC). Immediately after I-menthol O.O3 O.O3 O.O3 Polyoxyethylene O.3 O.3 shaking, a foam part and an aqueous solution part were con castor oil 10 firmed by visual observation, and the volume of the foam part 65 Polyoxyethylene O.3 was measured. The tubes were then allowed to stand, the castor oil 35 Volume of the foam part was measured over time, and foam US 9,320,802 B2 19 20 TABLE 2-continued TABLE 3

Unit (wiv% Unit (wiv% Comparative Comparative Comparative Comparative Example Example Example Example 5 Example Example Example Example 1-2 1-3 1-4 1-2 1-5 1-3 1-4 1-5 Polysorbate 80 O.3 O.3 O.3 O.3 Polyoxyethylene O.OS O.OS O.OS O.OS Boric acid O.S O.S O.S O.S castor oil 3 Borax O.O2 O.O2 O.O2 O.O2 I-menthol O.OOS Purified water Balance Balance Balance Balance 10 Geraniol O.OOS (mL) Eucalyptus oil O.OOS pH 7 7 7 7 Polysorbate 80 O.OS O.OS O.OS O.OS Time required 120 450 380 50 Boric acid O.S O.S O.S O.S for the foam to Borax O.O2 O.O2 O.O2 O.O2 be reduced by Purified water (mL) Balance Balance Balance Balance half (minutes) 15 pH 7 7 7 7 Time required for the 120 30 60 70 foam to be reduced Regarding Volumes of the foam part measured immedi by half (minutes) ately after shaking in Example 1-2 and Comparative Examples 1-2 to 1-4, the volumes of the foam part of Com parative Examples 1-3 and 1-4 and Example 1-2 were similar, TABLE 4 although the volume of the foam part of Comparative Example 1-2 was about 30% larger than the volumes of the Unit (wiv% foam part of the other three preparations. As shown in Table Exam- Exam- Exam- Exam- Exam ple ple ple ple ple 2, however, the time required for the foam to be reduced by 25 half was 120 minutes in the aqueous ophthalmic composition 1-6 1-7 1-8 1-9 1-10 containing polyoxyethylene castor oil 10 and polysorbate 80 Polyoxyethylene O.OS O.OS O.OS O.OS O.OS (Comparative Example 1-2), and 450 minutes in the aqueous castor oil 3 ophthalmic composition containing menthol and polysorbate I-menthol O.OOS O.OOS O.O15 Geraniol O.OOS O.O3 80 (Comparative Example 1-3). 30 Eucalyptus oil O.OS O.O3 In contrast, the foam was reduced by half in only 50 min Polysorbate 80 O.OS O.OS O.OS O.OS O.OS Boric acid 0.5 0.5 0.5 0.5 0.5 utes in the aqueous ophthalmic composition containing poly Borax O.O2 O.O2 O.O2 O.O2 O.O2 oxyethylene castor oil 10, menthol, and polysorbate 80 (Ex Purified water (mL) Balance Balance Balance Balance Balance ample 1-2). In the aqueous ophthalmic composition pH 7 7 7 7 7 containing polyoxyethylene castor oil 35 instead of polyoxy 35 Time required for the 60 60 70 1OO 90 ethylene castor oil 10 (Comparative Example 1-4), it took 380 foam to be reduced minutes. by half (minutes) The above results reveal that the combined use of polyoxy ethylene castor oil 10 and a terpenoid also significantly improves the speed at which foam generated in the presence 40 TABLE 5 of another Surfactant (e.g., polysorbate 80) disappears. This Unit (wiv% effect was very small when polyoxyethylene castor oil 35 was used instead of polyoxyethylene castor oil 10. Comparative Example Example Example 45 1-6 1-11 1-12 Test Example 3 Polyoxyethylene castor oil 10 O.OS O.OS O.OS I-menthol O.OOS Geraniol O.OOS Foam Disappearance Speed Test (3) Polysorbate 80 O.OS O.OS O.OS Boric acid O.S O.S O.S 50 Borax O.O2 O.O2 O.O2 As shown in the following Tables 3 to 5, aqueous oph Purified water (mL) Balance Balance Balance thalmic compositions containing a surfactant other than com pH 7 7 7 ponent (A) (polysorbate 80) (Examples 1-3 to 1-12 and Com Time required for the foam to 70 30 30 parative Examples 1-5 and 1-6) were prepared by a standard be reduced by half (minutes) method. This test used 1-menthol, eucalyptus oil, and 55 polysorbate 80 that conform to the standard of the Japanese Pharmacopoeia, 15th revision, and geraniol that conforms to As is clear from Tables 3 and 4, the time required for the the standard of Japanese Pharmaceutical Excipients 2003. foam to be reduced by half was significantly shortened in the This test also used polyoxyethylene castor oil 3 that conforms aqueous ophthalmic compositions containing polyoxyethyl ene castor oil 3 and containing 1-menthol, geraniol, or euca to the standard for polyoxyethylene castor oil in Japanese 60 Pharmaceutical Excipients 2003 and in which the average lyptus oil, compared to the aqueous ophthalmic composition number of moles of added ethylene oxide is 3. containing only polyoxyethylene castor oil 3 (Comparative Using these aqueous ophthalmic compositions, a foam dis Example 1-5 and Examples 1-3 to 1-10). appearance speed test was performed in the same manner as Similarly, as is clear from Table 5, the time required for the in Test Example 1. Foam disappearance speeds were evalu 65 foam to be reduced by half was significantly shortened in the ated by measuring the time required for the initial foam to be aqueous ophthalmic compositions containing polyoxyethyl reduced by half. The results are also shown in Tables 3 to 5. ene castor oil 10 and containing 1-menthol or geraniol, com US 9,320,802 B2 21 22 pared to the aqueous ophthalmic composition containing only Test Example 5 polyoxyethylenecastor oil 10 (Comparative Example 1-6 and Examples 1-11 and 1-12). Foam Disappearance Speed Test (5) Test Example 4 5 As shown in the following Table 7, aqueous ophthalmic compositions containing a Surfactant other than component Foam Disappearance Speed Test (4) (A) (polysorbate 80) (Examples 1-15 to 1-17 and Compara tive Examples 1-9 and 1-10) were prepared by a standard As shown in the following Table 6, aqueous ophthalmic method. This test used 1-menthol and polysorbate 80 that compositions containing a Surfactant other than component 10 conform to the standard of the Japanese Pharmacopoeia, 15th (A) (polyoxyethylene castor oil 35) (Examples 1-13 and 1-14 revision, and polyoxyethylene castor oil 3 and polyoxyethyl and Comparative Examples 1-7 and 1-8) were prepared by a ene castor oil 10 that conform to the standard for polyoxyeth standard method. In the preparation of the aqueous oph ylene castor oil in Japanese Pharmaceutical Excipients 2003 thalmic compositions, borax was added in an amount Such 15 and in which the average number of moles of added ethylene that the pH of each aqueous ophthalmic composition was 7. oxide is 3 and 10, respectively. This test used d-camphor that conforms to the standard of the Using these aqueous ophthalmic compositions, a foam dis Japanese Pharmacopoeia, 15th revision, and d-borneol that appearance speed test was performed in the same manner as conforms to the standard of Japanese Pharmaceutical Excipi in Test Example 1. Foam disappearance speeds were evalu ents 2003. This test also used polyoxyethylene castor oil 3, ated by measuring the time required for the initial foam to be polyoxyethylene castor oil 10, and polyoxyethylene castor oil reduced by half. The results are also shown in Table 7. 35 that conform to the standard for polyoxyethylenecastor oil in Japanese Pharmaceutical Excipients 2003 and in which the TABLE 7 average number of moles of added ethylene oxide is 3, 10, and Unit (wiv% 35, respectively. 25 Using these aqueous ophthalmic compositions, a foam dis Compar- Compar appearance speed test was performed in the same manner as ative Exam- ative Exam- Exam in Test Example 1 except that the amount of the composition Example ple Example ple ple placed was 20 mL. Foam disappearance speeds were evalu 1-9 1-15 1-10 1-16 1-17 ated by measuring the time required for the initial foam to be 30 Polyoxyethylene O.OS O.OS castor oil 3 reduced by half. The results are also shown in Table 6. Polyoxyethylene O.2 O.2 O.2 castor oil 10 TABLE 6 I-menthol O.1 O.O1 O.1 Polysorbate 80 O.S O.S O.S O.S O.S Unit (wiv% 35 Boric acid O.S O.S O.S O.S O.S Borax O.O2 O.O2 O.O2 O.O2 O.O2 Comparative Comparative Purified water Balance Balance Balance Balance Balance Example Example Example Example (mL) 1-7 1-8 1-13 1-14 pH 7 7 7 7 7 Time required for the 8O 25 430 100 25 Polyoxyethylene O.25 O.25 40 foam to be reduced castor oil 3 by half (minutes) Polyoxyethylene O.25 O.25 castor oil 10 Polyoxyethylene O.25 O.25 O.25 O.25 As is clear from Table 7, the time required for the foam to castor oil 35 d-camphor O.OOS be reduced by half was significantly shortened in the aqueous d-borneo O.OOS 45 ophthalmic compositions containing 1-mentholtogether with Boric acid O.2 O.2 O.2 O.2 polyoxyethylenecastor oil 3 or polyoxyethylenecastor oil 10, Borax C.S. C.S. C.S. C.S. compared to the aqueous ophthalmic compositions contain Purified water Balance Balance Balance Balance pH 7 7 7 7 ing only polyoxyethylene castor oil 3 or polyoxyethylene Time required for the 300 390 160 100 castor oil 10 (Comparative Examples 1-9 and 1-10, and foam to be reduced 50 Examples 1-15 to 1-17). by half (minutes) Test Example 6 As shown in Table 6, the time required for the foam to be Foam Disappearance Speed Test (6) reduced by half was 300 minutes in the formulation contain 55 ing polyoxyethylene castor oil 3 and polyoxyethylene castor As shown in the following Table 8, aqueous ophthalmic oil 35 (Comparative Example 1-7), and 390 minutes in the compositions containing both polyoxyethylene castor oil 3 aqueous ophthalmic composition containing polyoxyethyl and polyoxyethylene castor oil 10 as component (A) and ene castor oil 10 and polyoxyethylene castor oil 35 (Com containing a Surfactant other than component (A) (polysor parative Example 1-8). 60 bate 80) (Examples 1-18 and 1-19) were prepared by a stan On the other hand, the foam was reduced by half in only dard method. This test used 1-menthol and polysorbate 80 160 minutes in the aqueous ophthalmic composition contain that conform to the standard of the Japanese Pharmacopoeia, ing polyoxyethylene castor oil 3, polyoxyethylene castor oil 15th revision, and polyoxyethylene castor oil 3 and polyoxy 35, and camphor (Example 1-13), and in only 100 minutes in ethylene castor oil 10 that conform to the standard for poly the aqueous ophthalmic composition containing polyoxyeth 65 oxyethylene castor oil in Japanese Pharmaceutical Excipients ylene castor oil 10, polyoxyethylene castor oil 35, and 2003 and in which the average number of moles of added borneol (Example 1-14). ethylene oxide is 3 and 10, respectively. US 9,320,802 B2 23 24 Using these aqueous ophthalmic compositions, a foam dis weight. This was repeated 10 times, and variation that appearance speed test was performed in the same manner as occurred among the 10 drips was further calculated as an SD in Test Example 1. Foam disappearance speeds were evalu value (SD value of the drip amount before shaking). ated by measuring the time required for the initial foam to be After the eye drop containers were vigorously shaken up reduced by half. The results are shown in the following Table 5 and down 20 times, they were allowed to stand for 10 minutes. 8. Thereafter, the amount (weight) of one drip was measured in the same manner as described above, and variation that TABLE 8 occurred among the 10 drips was calculated as an SD value (SD value of the drip amount after shaking). Unit (wiv% 10 The rate of change in the SD values before and after shak Example 1-18 Example 1-19 ing was determined as the rate of change in variation by the following formula. The results are also shown in Table 9. Rate Polyoxyethylene castor oil 3 O.1 O.OS Polyoxyethylene castor oil 10 O.1 O.1 of change in variation (times)=SD value after shaking/SD I-menthol O.O2 O.O1 value before shaking Polysorbate 80 O.2 O.2 15 Boric acid O.S O.S TABLE 9 Borax O.O2 O.O2 Purified water (mL) Balance Balance Unit (wiv% pH 7 7 Time required for the foam to 25 50 Compar- Compar be reduced by half (minutes) ative ative Exam- Exam- Exam Example Example ple ple ple 2-1 2-2 2-1 2-2 2-3 As shown in Table 8, it was found that the use of 1-menthol Polyoxyethylene O.3 O.S O.3 O.S O.S together with both polyoxyethylene castor oil 3 and polyoxy castor oil 10 ethylene castor oil 10 significantly shortened the time 25 I-menthol O.O3 O.O3 required for the foam to be reduced by half. Geraniol O.O1 Polysorbate 80 O.3 O.3 The above results reveal that when a terpenoid is contained, Polyoxyethylene O.S O.S O.S the speed at which generated foam disappears is significantly hydrogenated improved also in aqueous ophthalmic compositions wherein castor oil 60 polyoxyethylene castor oils in which the average number of 30 Boric acid O.S O.S O.S O.S O.S Borax O.O2 O.O2 O.O2 O.O2 O.O2 moles of added ethylene oxide is 2 to 12 are used in combi Purified water Balance Balance Balance Balance Balance nation. (mL) pH 7 7 7 7 7 Test Example 7 Rate of change in 2.1 times 2.7 times 1.3 1.1 1.7 35 variation (times) times times times Test on Foam Disappearance Speeds and Drip Amounts The SD value of the drip amount after shaking was about twice that before shaking in Comparative Example 2-1, Aqueous ophthalmic compositions shown in the following whereas the SD value of the drip amount after shaking was Table 9 (Examples 2-1 to 2-3 and Comparative Examples 2-1 40 only about 1.3 times that before shaking in Example 2-1. and 2-2) were prepared by a standard method, and foam Specifically, it was found that compared to Comparative disappearance speeds and drip amounts were evaluated. This Example 2-1, the rate of change in variation was significantly test used 1-menthol and polysorbate 80 that conform to the Smaller in Example 2-1, indicating that variation in the drip standard of the Japanese Pharmacopoeia, 15th revision, and amount was inhibited even after shaking. A similar tendency geranioland polyoxyethylene hydrogenated castor oil 60that 45 was also observed from comparison of Comparative Example conform to the standard of Japanese Pharmaceutical Excipi 2-2 with Example 2-2 and Example 2-3. ents 2003. This test also used polyoxyethylene castor oil 10 The above results reveal that according to the aqueous that conforms to the standard for polyoxyethylene castor oil ophthalmic composition of the present invention, which con in Japanese Pharmaceutical Excipients 2003 and in which the tains both polyoxyethylene castor oil 10 and a terpenoid, the average number of moles of added ethylene oxide is 10. 50 drip amount during use is stabilized even when Such a com First, each of the aqueous ophthalmic compositions in an position foams during distribution, due to carrying by the user amount of 6.5 mL was placed in individual 13-mL eye drop or other causes. containers made of polyethylene terephthalate, and each con tainer was equipped with a nozzle made of low-density poly Test Example 8 ethylene to prepare eye drops. Separately, a sheet of filter 55 paper was placed in a measurement container, the measure Separation Inhibition Test ment container was sealed with a lid, and the total weight (initial value) of the sheet offilter paper and the measurement Aqueous ophthalmic compositions shown in the following container was measured. While the nozzle of each eye drop Table 10 (Example 3-1 and Comparative Example 3-1) were container was held horizontal (container turned sideways), 60 prepared by a standard method, and the presence of separa one drip of the aqueous ophthalmic composition was placed tion was evaluated by visual observation. This test used in the measurement container. The measurement container 1-menthol that conforms to the standard of the Japanese Phar was subsequently sealed with the lid. The total weight of the macopoeia, 15th revision, and polyoxyethylene castor oil 10 sheet of filter paper into which the aqueous ophthalmic com that conforms to the standard for polyoxyethylene castor oil position was absorbed and the measurement container was 65 in Japanese Pharmaceutical Excipients 2003 and in which the measured, and the amount (weight) of one drip was deter average number of moles of added ethylene oxide is 10. mined by subtracting the initial value from the measured total Specifically, the state of the aqueous ophthalmic composi US 9,320,802 B2 25 26 tions was confirmed by visual observation immediately after Detailed measurement conditions are as follows. preparation. Subsequently, 1 mL of each aqueous ophthalmic composition was placed in individual Eppendorf tubes and centrifuged at 6000 G for 3 minutes using a centrifuge (MX Measurement conditions 100 TOMY) to separate materials of different specific gravi 5 Temperature 25o C. ties, and the state of the aqueous ophthalmic compositions ND value Auto (10% or 25%) Probe for concentrated solutions was confirmed again by visual observation after centrifuga Measurement time 180 seconds tion. The results are also shown in Table 10. Number of repetition 1 Dust cutting 10 times (upper: 10%, lower: 1,000%) TABLE 10 10 Light Amount Adjustment

Unit (wiv% Homodyne light amount 30,000 cps optimum value Comparative Max 50,000 cps Example Example Min 10,000 cps 3-1 3-1 15 Analysis technique Polyoxyethylene castor oil 10 O.3 O.3 Marquardt (lambda: 1,000, iteration: 1,000) I-menthol O.O3 Boric acid O.S O.S Borax O.O2 O.O2 Propylene glycol 1 1 TABLE 11 Purified water Balance Balance Unit (wiv% Total amount 100 mL. 100 mL. Visual observation before Not separated Not separated Comparative centrifugation Example Example Visual observation after Separated Not separated 3-2 3-2 centrifugation 25 Polyoxyethylene castor oil 10 O.15 O.15 I-menthol O.O2 Both the aqueous ophthalmic compositions were uni Polyoxyethylene hydrogenated O.15 O.15 formly cloudy liquid when the state of the aqueous oph castor oil 60 Boric acid O.S O.S 30 thalmic compositions was confirmed by visual observation Borax O.OS O.OS immediately after preparation (before centrifugation). From Purified water Balance Balance the visual observation of the state of the aqueous ophthalmic compositions after centrifugation, however, it was confirmed Total amount 100 mL. 100 mL. that the aqueous ophthalmic composition of Comparative Example 3-1 had been separated into a transparent aqueous 35 The average particle size of Comparative Example 3-2 was Solution part and a white solid that was assumed to be poly about 1.4 times the average particle size of Example 3-2. This oxyethylene castor oil 10. On the other hand, the aqueous test was performed to measure the particle sizes of micelles in ophthalmic composition of Example 3-1 was uniformly the aqueous ophthalmic compositions in which solubility had cloudy liquid both before and after centrifugation, with no been improved by adding a nonionic Surfactant (polyoxyeth precipitate observed. From this fact, it was confirmed that 40 ylene hydrogenated castor oil 60) in addition to polyoxyeth separation was inhibited and each component was uniformly ylene castor oil 10. Since it is presumed that micelles with present in the aqueous ophthalmic composition of Example Smaller particle sizes are less likely to coalesce, and thus 3-1. separation tends not to occur, it can be said that separation is The above results reveal that despite its relatively low water less likely to occur in Example 3-2 than in Comparative solubility, polyoxyethylene castor oil 10 is Surprisingly less 45 Example 3-2. likely to separate in aqueous ophthalmic compositions when used in combination with 1-menthol, which also has low Test Example 10 water solubility. Test on Reduction in Terpenoid Concentration Over Test Example 9 50 Time Particle Size Measurement Test Aqueous ophthalmic compositions shown in the following Table 12 (Example 4-1 and Comparative Examples 4-1 and Aqueous ophthalmic compositions shown in the following 4-2) were prepared by a standard method. Each of the aque Table 11 (Example 3-2 and Comparative Example 3-2) were 55 ous ophthalmic compositions was placed in individual eye prepared by a standard method, and particle size in each of the drop containers made of polyethylene terephthalate (herein aqueous ophthalmic compositions was measured using a par after referred to as PET) and a test was performed to confirm ticle size measurement device (FPAR-1000 (Otsuka Elec the change in the concentration of menthol. This test used tronics Co., Ltd.)). This test used 1-menthol that conforms to 1-menthol that conforms to the standard of the Japanese Phar the standard of the Japanese Pharmacopoeia, 15th revision, 60 macopoeia, 15th revision, and polyoxyethylene hydroge and polyoxyethylene hydrogenated castor oil 60 that con nated castor oil 60 that conforms to the standard of Japanese forms to the standard of Japanese Pharmaceutical Excipients Pharmaceutical Excipients 2003. This test also used polyoxy 2003. This test also used polyoxyethylene castor oil 10 that ethylene castor oil 10 and polyoxyethylene castor oil 35 that conforms to the standard for polyoxyethylene castor oil in conform to the standard for polyoxyethylene castor oil in Japanese Pharmaceutical Excipients 2003 and in which the 65 Japanese Pharmaceutical Excipients 2003 and in which the average number of moles of added ethylene oxide is 10. The average number of moles of added ethylene oxide is 10 and results are also shown in Table 11. 35, respectively. US 9,320,802 B2 27 28 First, each of the aqueous ophthalmic compositions (EX Test Example 11 ample 4-1 and Comparative Examples 4-1 and 4-2) in an amount of 10 mL was placed in individual 10-mL eye drop Preservative Efficacy Test (1) containers made of PET and each container was equipped and sealed with a nozzle made of low-density polyethylene. Simi 5 Aqueous ophthalmic compositions shown in the following larly, each of the aqueous ophthalmic compositions in an Table 13 (Example 5-1 and Comparative Examples 5-1 to amount of 10 mL was placed in individual 10-mL glass 5-3) were prepared by a standard method, and a preservative ampoules (glass containers) and sealed. The aqueous oph efficacy test was performed for each of the aqueous oph thalmic compositions placed in the glass containers were thalmic compositions. Specifically, Staphylococcus aureus used as controls since they were believed to have almost no 10 (ATCC6538) was inoculated on the surface of a soybean adsorption of menthol and less menthol loss caused by Vola casein digest slant medium and cultured at 33° C. for 24 tilization or the like. hours. The cultured cells were aseptically collected using a platinum loop and Suspended in an appropriate amount of The samples were stored (in a manner Such that the glass sterile physiological saline to prepare a bacterial Suspension containers were placed in an upright position and the eye drop 15 containing viable cells at about 1x10 CFU/mL. The viable containers were placed in an inverted position) at 60° C. for cell count in the Suspension was measured by culturing sepa three days, and then the concentration of menthol in each of rately. Subsequently, the aqueous ophthalmic compositions the aqueous ophthalmic compositions was measured using were filter-sterilized, and each of the aqueous ophthalmic gas chromatography. The amount of menthol loss relative to compositions in an amount of 10 mL was placed in individual the control was calculated by Subtracting the menthol con 15-mL CORNIA conical tubes (PET). The Staphylococcus centration in the eye drop container from the menthol con aureus bacterial Suspension (Suspended in physiological centration in the glass container (control) for each aqueous saline) was inoculated into each of the aqueous ophthalmic ophthalmic composition having the same formulation. The compositions in Such a manner that the viable cell count (final rates of menthol loss in Example 4-1 and Comparative concentration) was about 10 CFU/mL (3 log), and stirred Example 4-2 relative to the amount of menthol loss in Com 25 thoroughly to prepare samples. The samples were stored at parative Example 4-1 were then calculated. The amount of 23° C. for three days while shielded from light. After this menthol loss in Comparative Example 4-1 was defined as 3-day period ended, each of the samples containing viable 100. The results are also shown in Table 12. cells was adjusted to have an adequate concentration for counting, and the viable cell count was determined by a 30 TABLE 12 filtration method using a membrane filter. The viable cell count immediately after inoculation and the viable cell count Unit (wiv% after three days of storage in each sample were compared, and the reduction in viable cell count was calculated as log reduc Comparative Comparative tion. Bacterial culture for counting was performed at 33°C. Example Example Example 35 4-1 4-1 4-2 for three days. This test used 1-menthol that conforms to the standard of the Japanese Pharmacopoeia, 15th revision, and Polyoxyethylene castor O.15 polyoxyethylene hydrogenated castor oil 60 that conforms to oil 10 the standard of Japanese Pharmaceutical Excipients 2003. Polyoxyethylene castor O.15 This test also used polyoxyethylene castor oil 10 and poly oil 35 40 Polyoxyethylene O.15 O.3 O.15 oxyethylene castor oil 35 that conform to the standard for hydrogenated castor oil 60 polyoxyethylene castor oil in Japanese Pharmaceutical -menthol O.O2 O.O2 O.O2 Excipients 2003 and in which the average number of moles of Boric acid O.S O.S O.S added ethylene oxide is 10 and 35, respectively. The results Borax O.OS O.OS O.OS are also shown in Table 13. Hydrochloric acid C.S. C.S. C.S. 45 Sodium hydroxide C.S. C.S. C.S. TABLE 13 Purified water Balance Balance Balance Unit (wiv% Total amount 100 mL. 100 mL. 100 mL. Compar- Compar- Compar bH 7.3 7.3 7.3 Exam- ative ative ative Rate of menthol loss relative to 73 1OO 85 50 ple Example Example Example hat of Comparative Example S-1 S-1 S-2 S-3 4-1 defined as 100 -menthol O.O2 O.O2 O.O2 Polyoxyethylene O.15 O.15 When stored in the eye drop container, the aqueous oph castor oil 10 55 Polyoxyethylene O.15 thalmic composition (Example 4-1) containing both poly castor oil 35 oxyethylene castor oil 10 and polyoxyethylene hydrogenated Polyoxyethylene O.15 O.3 O.15 O.15 hydrogenated castor oil 60 as Surfactants had significantly less menthol loss castor oil 60 compared to the aqueous ophthalmic composition (Compara Boric acid O.S O.S O.S O.S Borax O.OS O.OS O.OS O.OS tive Example 4-1) containing only polyoxyethylene hydroge 60 Hydrochloric acid C.S. C.S. C.S. C.S. nated castor oil 60 as a surfactant. When stored in the eye drop Sodium hydroxide C.S. C.S. C.S. C.S. container, the aqueous ophthalmic composition (Compara Purified water Balance Balance Balance Balance tive Example 4-2) containing polyoxyethylene castor oil 35 Total amount 100 mL. 100 mL. 100 mL. 100 mL. instead of polyoxyethylene castor oil 10 did not exhibit the bH 7.3 7.3 7.3 7.3 effect of inhibiting reduction in the menthol concentration 65 Log Reduction 3.1 O.S 1.6 1.8 over time as high as Example 4-1, which contains polyoxy ethylene castor oil 10. US 9,320,802 B2 29 30 Little reduction in viable cell count was observed in Com From the above results, it was confirmed that high preser parative Example 5-1, which contains only menthol. Reduc Vative efficacy against Staphylococcus aureus is exhibited tion in viable cell count was 1.6 log in Comparative Example when a terpenoid is contained together with polyoxyethylene 5-2, which contains only polyoxyethylene castor oil 10. On castor oil in which the average number of moles of added the other hand, Example 5-1, which contains both menthol ethylene oxide is 2 to 12. and polyoxyethylene castor oil 10, had preservative efficacy such that bacteria were killed. Such high preservative efficacy Test Example 13 was not observed in Comparative Example 5-3, which con tains polyoxyethylene castor oil 35 instead of polyoxyethyl ene castor oil 10. 10 Preservative Efficacy Test (3) Test Example 12 Aqueous ophthalmic compositions shown in the following Table 15 (Example 5-4 and Comparative Example 5-6) were Preservative Efficacy Test (2) 15 prepared by a standard method. Using these aqueous oph Aqueous ophthalmic compositions shown in the following thalmic compositions, the viable cell count immediately after Table 14 (Examples 5-2 and 5-3 and Comparative Examples inoculation of Staphylococcus aureus and the viable cell 5-4 and 5-5) were prepared by a standard method. Using these count immediately after inoculation of E. coli were compared aqueous ophthalmic compositions, the viable cell count with the viable cell count after storage in each sample to immediately after inoculation of Staphylococcus aureus and calculate reduction in viable cell count as log reduction in the the viable cell count after seven days of storage in each same manner as in Test Example 11. Bacterial culture for sample were compared to calculate reduction in viable cell counting was performed at 33°C. for three days for Staphy count as log reduction in the same manner as in Test Example lococcus aureus and for seven days for E. coli. This test used 11. Bacterial culture for counting was performed at 33° C. eucalyptus oil that conforms to the standard of the Japanese This test used d-camphor that conforms to the standard of the 25 Pharmacopoeia, 15th revision, and polyoxyethylene hydro Japanese Pharmacopoeia, 15th revision, and geraniol and genated castor oil 60 that conforms to the standard of Japa polyoxyethylene hydrogenated castor oil 60 that conform to nese Pharmaceutical Excipients 2003. This test also used the standard of Japanese Pharmaceutical Excipients 2003. polyoxyethylene castor oil 10 that conforms to the standard This test also used polyoxyethylene castor oil 10 and poly 30 for polyoxyethylene castor oil in Japanese Pharmaceutical oxyethylene castor oil 35 that conform to the standard for Excipients 2003 and in which the average number of moles of polyoxyethylene castor oil in Japanese Pharmaceutical added ethylene oxide is 10. The results are also shown in the Excipients 2003 and in which the average number of moles of following Table 15. added ethylene oxide is 10 and 35, respectively. The results are also shown in Table 14. 35 TABLE 1.5 TABLE 1.4 Unit (wiv%

Unit (wiv% Comparative Example 5-6 Example 5-4 Comparative Comparative 40 Example Example Example Example Polyoxyethylene castor oil 10 O.O2S 5-4 S-2 5-5 S-3 Polyoxyethylene hydrogenated 00.175 O.15 castor oil 60 Polyoxyethylene O.O2S 0.4 Eucalyptus oil O.OO3 O.OO3 castor oil 10 Boric acid O.S O.S Polyoxyethylene 0.4 Borax O.OS O.OS castor oil 35 45 Sodium hydroxide C.S. C.S. Polyoxyethylene 0.175 O.15 O.S O.S Hydrochloric acid C.S. C.S. hydrogenated Purified water C.S. C.S. castor oil 60 pH 7.3 7.3 d-camphor O.OS O.OS Log Staphylococcits 2.5 3.3 Geraniol O.OO3 O.OO3 reduction attreus (3 days) Boric acid O.S O.S O.S O.S 50 E. coli (7 days) O O.3 Borax O.OS O.OS O.OS O.OS Sodium C.S. C.S. C.S. C.S. hydroxide As is clear from Table 15, Example 5-4, which contains Hydrochloric C.S. C.S. C.S. C.S. acid polyoxyethylene castor oil 10 and eucalyptus oil, had signifi Purified water C.S. C.S. C.S. C.S. 55 cant reduction in the number of Staphylococcus aureus com bH 7.3 7.3 7.3 7.3 pared to Comparative Example 5-6, which contains only Log reduction 3.7 4.7 1.9 2.5 eucalyptus oil, indicating high preservative efficacy. In Example 5-4, which contains polyoxyethylene castor oil 10 As is clear from Table 14, Example 5-2, which contains and eucalyptus oil, reduction in the number of E. coli was polyoxyethylene castor oil 10 and geraniol, had significant 60 observed, whereas no effect on the number of E. coli was reduction in the viable cell count compared to Comparative observed in Comparative Example 5-6, which contains only Example 5-4, which contains only geraniol, indicating high eucalyptus oil. preservative efficacy. Further, Example 5-3, which contains The above results reveal that high preservative efficacy is polyoxyethylene castor oil 10 and d-camphor, had significant exhibited against not only Staphylococcus aureus but also E. reduction in the viable cell count compared to Comparative 65 coli when a terpenoid is contained together with polyoxyeth Example 5-5, which contains polyoxyethylene castor oil 35 ylene castor oil in which the average number of moles of and d-camphor, indicating high preservative efficacy. added ethylene oxide is 2 to 12. US 9,320,802 B2 31 32 Test Example 14 TABLE 16-continued Sensory Test Unit (wiv% Comparative Aqueous ophthalmic compositions having the formula Example Example tions shown in Table 16 (Example 6-1 and Comparative 6-1 6-1 Example 6-1) were prepared and evaluated for cooling sen Boric acid 1 1 sation according to a visual analogue scale (VAS). Specifi Borax O.1 O.1 cally, drops of each aqueous ophthalmic composition were Purified water (mL) Balance Balance applied to the eyes of six panelists, and on Subjective symp 10 pH 7.15 7.15 Cooling Immediately after 7.5 6.9 tomassessment sheets, the panelists wrote down the degree of sensation application to cooling sensation that they felt immediately after application SCOe the eyes and 5 minutes after application. The intensity of subjective 5 minutes after 5.4 3.0 symptoms was Subsequently measured in length (cm) based application to on the Subjective symptom assessment sheets, and the length 15 the eyes (cm) was used as cooling sensation score: the length was 0 cm if no cooling was sensed, 5 cm if cooling was sensed, and 10 As shown in Table 16, the cooling sensation scores of both cm if cooling was strongly sensed. The cooling sensation was the compositions were similar immediately after application; evaluated by calculating the average score value of the six however, in the aqueous ophthalmic composition containing panelists immediately after application and the average score polyoxyethylene castor oil 10, cooling sensation was still value of the six panelists 5 minutes after application. The clearly observed 5 minutes after application. results are shown in Table 16. The above results reveal that the aqueous ophthalmic com position of the present invention, which contains both poly TABLE 16 25 oxyethylene castor oil 10 and a terpenoid, has the effect of Unit (wiv% maintaining the cooling sensation of a terpenoid. Comparative Preparation Examples Example Example 6-1 6-1 According to the formulations shown in Tables 17 and 18, Polyoxyethylene castor oil 10 O.OS 30 eye drops (Preparation Examples 1 to 7), eye wash (Prepara I-menthol O.O1 O.O1 Polysorbate 80 0.45 0.5 tion Example 8), solution for wearing a contact lens (Prepa Sodium chloride 0.4 0.4 ration Example 9), and multi-purpose contact lens Solution Potassium chloride O.1 O.1 (Preparation Example 10) are prepared by standard methods. The unit of osmotic pressure is m0sm (milliosmole). TABLE 17 Unit: g/100 mL. Preparation Example

1 2 3 4 5 Polyoxyethylene castor oil O.OSO O400 35 Polyoxyethylene castor oil O.100 O.OSO O.100 OSOO O3SO 10 Polyoxyethylene castor oil 3 OSOO O.O85 I-menthol O.O10 O.040 O.O15 O.O2O d-camphor O.OOS O.O10 d-borneol O.OO3 O.O15 O.OO1 Geraniol O.OOS O.OO3 O.OO1 Neostigmine methylsulfate O.O10 Tetrahydrozoline O.O10 hydrochloride Chlorpheniramine maleate O.O3O O.O15 O.O10 O.O3O Sodium azulene Sulfonate O.O2O Berberine sulfate O.OOS Dipotassium glycyrrhizate O.2SO Pyridoxine hydrochloride O.100 O.100 O.OSO Aminoethylsulfonic acid OSOO Sodium chondroitin sulfate O.100 O.SOO OSOO OSOO Sodium edetate O.O10 O.O10 O.OSO Sodium chloride O4SO Potassium chloride O.08O Boric acid 1...SOO 1800 1.OOO 1...SOO Borax OSOO O.3SO O.OSO O.300 Hydroxyethyl cellulose O.2SO Hydroxypropyl O.2SO methylcellulose Glycerin O.100 Poloxamer 407 O.100 Polysorbate 80 OSOO O.300 OSOO O.200 US 9,320,802 B2 33 34 TABLE 17-continued Unit: g/100 mL. Preparation Example

1 2 3 4 5 Polyoxyethylene hydrogenated O.200 O.SOO castor oil 60 Potassium sorbate O.OSO Dibutylhydroxytoluene O.OO1 Chlorobutanol O.1SO Hydrochloric acid C.S. C.S. C.S. C.S. C.S. Sodium hydroxide C.S. C.S. C.S. C.S. C.S. Purified water C.S. C.S. C.S. C.S. C.S.

Total amount 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. pH 7.OO 7.0 5.8 7.5 7.0 Osmotic pressure 370 300 3OO 360 350

TABLE 1.8 Unit: g/100 mL. Preparation Example

6 7 8 9 10 Polyoxyethylene castor oil OSOO O.200 35 Polyoxyethylene castor oil O.O10 O.O2O O.100 O.OSO O.100 10 Polyoxyethylene castor oil O.100 3 I-menthol O.O3O O.OSO O.OO2 O.O2S O.O10 d-camphor d-borneo Geraniol O.OO2 Dipotassium glycyrrhizate O.O2S Pyridoxine hydrochloride O.O10 Tocopherol acetate O.OOS Aminoethylsulfonic acid O.O2O Sodium chondroitin sulfate O.SOO O.040 Sodium edetate O.004 O.OSO Sodium chloride O400 O.300 O4SO O.700 Potassium chloride O.O8O O.100 O.100 O.OSO Disodium hydrogen O.1SO O.1SO phosphate Sodium dihydrogen O.OSO O.200 phosphate Boric acid 1.OOO 1.100 1200 Borax O.200 O.300 O.300 Hydroxyethyl cellulose O.OSO Hydroxypropyl O.100 O.300 methylcellulose Poloxamer 407 O.OSO Polysorbate 80 Polyoxyethylene O.300 O.300 O.300 hydrogenated castor oil 60 Potassium sorbate O.OSO O.08O Polyhexamethylene O.OOO1 biguanide Ethanol O.100 Hydrochloric acid C.S. C.S. C.S. C.S. C.S. Sodium hydroxide C.S. C.S. C.S. C.S. C.S. Purified water C.S. C.S. C.S. C.S. C.S.

Total amount 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. bH 7.4 7.5 6.2 7.0 7.5 Osmotic pressure 350 360 3OO 350 290

The invention claimed is: number of moles of added ethylene oxide is 2 to 12 and (B) 1. A method for improving a foam disappearance speed in 6s terpenoid to the aqueous ophthalmic composition. an aqueous ophthalmic composition, the method comprising 2. A method for enhancing preservative efficacy in an aque adding (A) polyoxyethylene castor oil in which the average ous ophthalmic composition, the method comprising adding US 9,320,802 B2 35 36 (A) polyoxyethylene castor oil in which the average number of moles of added ethylene oxide is 2 to 12 and (B) terpenoid to the aqueous ophthalmic composition. 3. A method for inhibiting separation of an aqueous oph thalmic composition, the method comprising adding (A) 5 polyoxyethylene castor oil in which the average number of moles of added ethylene oxide is 2 to 12 and (B) terpenoid to the aqueous ophthalmic composition. 4. A method for inhibiting reduction interpenoid concen tration over time in an aqueous ophthalmic composition held 10 in a container, the method comprising adding (A) polyoxy ethylene castor oil in which the average number of moles of added ethylene oxide is 2 to 12 and (B) terpenoid to the aqueous ophthalmic composition. 5. A method for imparting, to an aqueous ophthalmic com 15 position, an effect of maintaining cooling sensation, the method comprising adding (A) polyoxyethylene castor oil in which the average number of moles of added ethylene oxide is 2 to 12 and (B) terpenoid to the aqueous ophthalmic com position. 6. A method for producing an aqueous ophthalmic compo sition comprising adding (A) polyoxyethylene castor oil in which the average number of moles of added ethylene oxide is 2 to 12 and (B) terpenoid to a carrier containing water. k k k k k 25