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(12) United States Patent (10) Patent No.: US 9,320,802 B2 Furumiya Et Al

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(12) United States Patent (10) Patent No.: US 9,320,802 B2 Furumiya Et Al 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.
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