Europäisches Patentamt *EP001522316A1* (19) European Patent Office Office européen des brevets (11) EP 1 522 316 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 47/34, A61K 47/10, 13.04.2005 Bulletin 2005/15 A61K 47/14, A61K 9/06, A61K 9/08, A61K 9/12, (21) Application number: 03764126.3 A61K 9/70 (22) Date of filing: 02.07.2003 (86) International application number: PCT/JP2003/008400 (87) International publication number: WO 2004/006960 (22.01.2004 Gazette 2004/04) (84) Designated Contracting States: • OMICHI, Katsuhiro AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Saitama-shi, Saitama 338-0832 (JP) HU IE IT LI LU MC NL PT RO SE SI SK TR • OKADA, Minoru Designated Extension States: Inzai-shi, Chiba 270-1323 (JP) AL LT LV MK • KURAZUMI, Toshiaki Narita-shi, Chiba 286-0011 (JP) (30) Priority: 16.07.2002 JP 2002206565 (74) Representative: Hartz, Nikolai F., Dr. (71) Applicant: SSP Co., Ltd. Wächtershäuser & Hartz Chuo-ku, Tokyo 103-8481 (JP) Patentanwälte Weinstrasse 8 (72) Inventors: 80333 München (DE) • NARUI, Takashi Sakura-shi, Chiba 285-0817 (JP) (54) TRANSDERMAL ABSORPTION PREPARATION (57) A transdermal absorption promotion composi- and transdermal absorption preparation not only exhibit tion comprising the following components (a), (b), and an excellent transdermal absorption promotion effect, (c) and a transdermal absorption preparation compris- but also exhibit superior skin-permeability, even if a drug ing the following components (a), (b), (c), and (d) are having a relatively high lipophilic property and poor disclosed. transdermal absorbability is used, exhibit a favorable feeling of use, and are safe and stable. (a) propylene glycol (b) a polyol fatty acid ester (c) lauromacrogol (d) a drug component The transdermal absorption promotion composition EP 1 522 316 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 522 316 A1 2 Description lent transdermal absorption promotion effect, but also exhibit superior skin-permeability, even if a drug having TECHNICAL FIELD a relatively high lipophilic property and poor transdermal absorbability is used, exhibit a favorable feeling of use, [0001] The present invention relates to a novel 5 and are safe and stable. transdermal absorption promotion composition and a transdermal absorption preparation and, more particu- DISCLOSURE OF THE INVENTION larly, to a transdermal absorption promotion composi- tion that can promote transdermal absorption of a com- [0007] The present inventors have conducted exten- pound having a comparatively high lipophilic physiolog- 10 sive studies to achieve the above object and found that ical activity (a drug), and to a transdermal absorption a transdermal absorption promotion composition con- preparation containing the transdermal absorption pro- taining propylene glycol, a polyol fatty acid ester, and a motion composition and a drug. lauromacrogol remarkably increases permeability of drugs through the skin. The present inventors have fur- BACKGROUND ART 15 ther found that the transdermal absorption preparation prepared by adding a drug to the transdermal absorption [0002] As a method of administering a drug to a pa- promotion composition exhibits remarkably excellent tient, per-oral medication, transdermal medication, transdermal absorptivity of the drug, a favorable feeling medication by injection, and the like can be given. When of use, and stability, and imparts only slight stimulation a drug is orally administered to a patient, some drugs 20 to the skin. These findings have led to the completion of may exhibit decreased bioavailability due to a first-pass the present invention. effect in the liver and other drugs may cause a side re- [0008] Specifically, the present invention provides a action in an alimentary canal. In addition, it may be dif- transdermal absorption promotion composition com- ficult to orally administer a drug to a patient depending prising the following components (a), (b), and (c): on the clinical condition. On the other hand, injection not 25 only may cause pain to the patient, but also requires the (a) propylene glycol, patient to visit a medical institution to receive the med- (b) a polyol fatty acid ester, and ication. In addition, handling of an injection instrument (c) lauromacrogol. is complicated. For these reasons, dermal administra- tion of drugs in place of these methods of administration 30 [0009] The present invention further provides a is attracting attention due to advantages such as simple transdermal absorption preparation comprising the fol- medication and the like. lowing components (a), (b), (c), and (d) : [0003] However, dermal administration has a basic problem of low permeability of a drug due to a barrier (a) propylene glycol, function of the horny layer on the skin surface against 35 (b) a polyol fatty acid ester, absorption of the drug. In particular, drugs having a large (c) lauromacrogol, and molecular weight or having high water solubility are said (d) a drug component. to exhibit low permeability through the skin. [0004] For these reasons, it is essential for effective BRIEF DESCRIPTION OF THE DRAWINGS dermal medication of drugs to promote dermal absorp- 40 tion of the drugs in some manner. As a method for solv- [0010] ing this problem, use of Azone (1-dodecylazacyclohep- tan-2-on), menthol, pyrrolidone, or terpens independ- Figure 1 is a drawing showing the relationship be- ently or in combination of two or more as transdermal tween the amounts of accumulated loperamide hy- penetration enhancers has been studied. 45 drochloride extracted from solutions of Example 1 [0005] However, these transdermal penetration en- and Comparative Examples 1-3 which penetrated hancers do not exhibit a sufficient effect and are not nec- the rat skin and the time elapsed. essarily effective for all drugs. Some transdermal pen- Figure 2 is a drawing showing the relationship be- etration enhancers that exhibit some effect of dermal ab- tween the accumulated amounts of the drug ex- sorption promotion present a disagreeable odor, are 50 tracted from ointments of Example 2 and Compar- sticky, exhibit an unfavorable feeling of use, and strongly ative Examples 4-6 which penetrated the rat skin stimulate the skin. Other transdermal penetration en- and the time elapsed. hancers are unstable themselves or impair the stability of a drug. BEST MODE FOR CARRYING OUT THE INVENTION [0006] An object of the present invention is to over- 55 come the above problems and provide a transdermal [0011] The amount of propylene glycol used in the absorption promotion composition and transdermal ab- transdermal absorption promotion composition of the sorption preparation that can not only exhibit an excel- present invention (hereinafter referred to simply as 2 3 EP 1 522 316 A1 4 "composition of the present invention") as the compo- the drug incorporated in the preparation is dissolved in nent (a) is usually 1-99 wt%, preferably 4-95 wt%, and propylene glycol of the component (a). Such a drug is particularly preferably 10-90 wt% ("wt%" is hereinafter appropriately selected from among conventionally indicated as "%"). known drugs or novel synthetic, half-synthetic, or ex- [0012] The polyol fatty acid ester used as the compo- 5 tracted drugs. nent (b) in the present invention composition may be an [0019] Examples of such a drug include, but are not ester of a polyol and a fatty acid. The ester may be either limited to, steroid anti-inflammation agents such as a monoester or a diester. As the polyol forming the polyol prednisolone and hydrocortisone, non-steroid anti-in- fatty acid ester, ethylene glycol, propylene glycol, buty- flammation agents such as indomethacin and di- lene glycol, glycerol, sorbitan, tetra glycerol, and the like 10 clofenac, as well as their ester derivatives, antihista- can be given. As the fatty acid, saturated fatty acids such mines such as a diphenhydramine, central-nerve ago- as caprylic acid, capric acid, octanoic acid, isooctanoic nists such as isoprenaline hydrochloride, hormones acid, lauric acid, myristic acid, palmitic acid, and the like such as estradiol, hypotensors such as furosemide, car- can be given. As specific examples of the polyol fatty diotonics such as digitoxin, anti- arrhythmic agents such acid, ethylene glycol monocaprylate, ethylene glycol 15 as disopyramide phosphate, coronary vasodilators such monoisooctanate, propylene glycol monocaprylate, pro- as tolazoline hydrochloride, local anesthetics such as pylene glycol dicaprylate, propylene glycol dicaprate, lidocaine, painkillers such as acetaminophen, muscle glycerol monocaprylate, solbitan monocaprylate, tet- relaxants such as suxamethonium chloride, antifungals raglycerol monocaprylate, and the like can be given. such as clotrimazole, anti-cancer drugs such as fluor- These are used either individually or in combination of 20 ouracil, urination problem improvers such as tamsulosin two or more. hydrochloride, anti-epileptic drugs such as diazepam, [0013] The component (b) is preferably a compound anti-Parkinson's disease agents such as bromocriptine with excellent mutual solubility with propylene glycol of mesilate, non-smoking adjuvants such as nicotine, vita- the component (a), for example, ethylene glycol mono- mins, and prostaglandins. caprylate, ethylene glycol monoisooctanoate, or the 25 [0020] The amount of the component (d) to be incor- like. Propylene glycol monocaprylate is particularly pref- porated into the preparation of the present invention var- erable