Transdermal Absorption Preparation

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

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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 composition 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 administration 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

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"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 as the polyol fatty acid ester. ies according to the type and form of the drug, and the [0014] The lauromacrogol of the component (c) is also like, but is usually 0.01-10%, preferably 0.05-5%, and preferably those having excellent mutual solubility with more preferably 0.1-3% of the preparation. propylene glycol of the component (a). Although not 30 [0021] The amount of the composition of the present specifically limited, lauryl ethers with 2-25 mol, prefera- invention to be incorporated when preparing the prepa- bly 2-9 mol ethylene oxide addition are preferable. ration of the present invention varies according to the [0015] With regard to the ratio of the components (a), type and amount of the drug, the form of the preparation, (b), and (c) in the composition of the present invention, and the like, but is usually 1-99.99%, preferably the ratio of the total weight of the component (b) and 35 2-99.9%, and more preferably 5-99% of the preparation. component (c) to the weight of the component (a) is [0022] Various forms that can cause the drug to be 0.01-99, preferably 0.05-25, and more preferably 0.1-9, absorbed by the skin are possible for the preparation of and the weight ratio of the component (c) to the compo- the present invention without any specific limitations. nent (b) is 0.1-10, preferably 0.25-4, and more prefera- Specific examples of the form include ointment, gel, bly 0.5-2. 40 cream, gel-like cream, liquid, lotion, aerosol, liniment, [0016] The composition of the present invention can plaster, poultice, and reservoir-type patch. be produced by sufficiently mixing to homogenize the [0023] The preparation of the present invention can above components (a), (b), and (c) by a conventional be produced by combining the above components (a) method. An excellent transdermal absorption property to (d) with other components for forming the preparation can be obtained by incorporating a drug component to 45 such as a vehicle, an adjuvant, and other optional addi- the resulting composition. tives. [0017] The transdermal absorption preparation of the [0024] For example, when preparing an ointment, an present invention can be prepared by incorporating a ointment base such as petroleum jelly or macrogol, ad- drug as component (d) together with the above compo- juvants such as paraffin, light anhydrous silicic acid, and nents (a), (b), and (c). 50 a surfactant, a stabilizer such as dibutylhydroxytoluene [0018] Although there are no specific limitations to the or sodium edentate, and, as required, a pH adjusting drug used as the component (d) in the preparation of agent and the like are added to the above components the present invention inasmuch as the drug can promote (a) to (d). transdermal absorption when used together with the [0025] When preparing a gel, a lower alcohol such as composition of the present invention, a drug with com- 55 ethyl alcohol or isopropyl alcohol, purified water, a gel- paratively high lipophilic properties is preferable. The ling agent such as carboxyvinyl polymer or ethylcellu- drug with comparatively high lipophilic properties indi- lose, a neutralizer such as triethanolamine, and the like cates the properties of a drug in which a part or all of are added to the above components (a) to (d). To pre-

3 5 EP 1 522 316 A1 6 pare a cream, a higher fatty acid ester such as myristic causing the drug dissolved in propylene glycol to syner- acid ester or palmitic acid ester, a hydrocarbon such as gistically react and exhibit the pharmaceutical action. liquid paraffin, purified water, an emulsifying agent such as polyoxyethylene alkyl ether, and the like are added EXAMPLES to the above components (a) to (d). 5 [0026] To prepare a gel-like cream, a higher fatty acid [0032] The present invention will be described in more ester such as myristic acid ester or palmitic acid ester, detail by examples, which should not be construed as a hydrocarbon such as liquid paraffin, purified water, an limiting the present invention. emulsifying agent such as polyoxyethylene alkyl ether, a gelling agent such as carboxyvinyl polymer, a neutral- 10 Example 1 izer such as diisopropanolamine, and the like are added to the above components (a) to (d). To prepare a liquid [0033] Propylene glycol monocaprylate, polyoxyeth- preparation, a liquid higher fatty acid, a vegetable oil, ylene (2) lauryl ether, and propylene glycol were mixed and the like are added to the above components (a) to at a weight ratio of 1:1:8 to obtain a transdermal absorp- (d). 15 tion promotion composition. One part by weight of lop- [0027] To prepare a lotion, the above components (a) eramide hydrochloride was dissolved in 99 parts by to (d) are dissolved in, emulsified by, or suspended in a weight of the transdermal absorption promotion compo- lower alcohol such as ethyl alcohol or isopropyl alcohol, sition to prepare a homogeneous solution. or a mixture of the lower alcohol and purified water. To prepare a liniment, the above components (a) to (d) are 20 Comparative Example 1 combined with a lower alcohol, a fatty oil, and the like. [0028] An aerosol agent can be prepared by filling an [0034] One part by weight of loperamide hydrochlo- aerosol container with the above-mentioned liquid prep- ride was dissolved in 99 parts by weight of propylene aration, lotion, or liniment, for example, together with an glycol to prepare a homogeneous solution. injection agent such as liquefied petroleum gas. A plas- 25 ter can be prepared by adding the above-mentioned Comparative Example 2 components (a) - (d) to a substrate agent such as an ethylene vinyl acetate agglutinant, a styrene-isoprene- [0035] Propylene glycol monocaprylate and propyl- styrene block copolymer, and the like. A poultice can be ene glycol were mixed at a weight ratio of 1:9 to obtain prepared by adding the above-mentioned components 30 a transdermal absorption promotion composition. One (a) - (d) to an ointment base formed from a partially neu- part by weight of loperamide hydrochloride was dis- tralized polyacrylic acid, sodium polyacrylate, and the solved in 99 parts by weight of the transdermal absorp- like. A reservoir-type patch can be prepared by adding tion promotion composition to prepare a homogeneous the above-mentioned components (a) - (d) to a drug res- solution. ervoir layer formed from a lower alcohol, purified water, 35 water soluble polymer, fatty alcohol, paraffin, silicone, Comparative Example 3 and the like. [0029] One preferable embodiment of the preparation [0036] Polyoxyethylene (2) lauryl ether and propylene of the present invention is a homogeneous solution con- glycol were mixed at a weight ratio of 1:9 to obtain a sisting essentially of the above components (a) to (d). 40 transdermal absorption promotion composition. One Another preferable embodiment of the preparation of part by weight of loperamide hydrochloride was dis- the present invention is an oily ointment or a cream con- solved in 99 parts by weight of the transdermal absorp- taining the above components (a) to (d) and a oily base tion promotion composition to prepare a homogeneous component. solution. [0030] These preparations of the present invention 45 can promote transdermal absorption of the drug com- Test Example 1 ponents contained in the preparations when applied to the skin. The preparations of the present invention can Skin penetration test (1) particularly promote transdermal absorption of drugs with relatively high lipophilic properties which have been 50 [0037] The skin extracted from the back of an HWY/ difficult to be transdermally absorbed in the skin using Slc male rat (age: nine weeks) was applied to a Franz- a conventional absorption preparation. type diffusion cell (application area: 2.83 cm2) in which [0031] Although the detailed mechanism of promoting water at a temperature of 37°C was circulated. 17 ml of transdermal absorption using the composition of the a physiological saline solution was put into the receiver present invention has still to be elucidated, it can be pre- 55 (dermis) side and stirred using a magnetic stirrer. Solu- sumed that the polyol fatty acid ester or lauromacrogol tions of Example 1 and Comparative Examples 1-3, 28 reduce the barrier capability of the skin horny layer, pen- µl each, were respectively applied to the donor (horny etrate into the horny layer, and react with the horny layer, layer) side. The solution in the receiver was extracted

4 7 EP 1 522 316 A1 8 over time to determine the concentration of loperamide added to prepare an ointment. hydrochloride using high performance liquid chromatography. The amount of the loperamide hydrochloride that Test Example 2 penetrated the rat skin was calculated. [0038] The relationship between the amounts of ac- 5 Skin penetration test (2) cumulated loperamide hydrochloride extracted from solutions of Example 1 and Comparative Examples 1-3 [0043] The skin extracted from the back of an HWY/ that penetrated the rat skin and the time elapsed is S1c male rat (age: nine weeks) was applied to a Franz- shown in Figure 1. As clear from Figure 1, the solution type diffusion cell (application area: 2.83 cm2) in which of Example 1 which contains propylene glycol, propyl- 10 water at a temperature of 37°C was circulated. 17 ml of ene glycol monocaprylate, and polyoxyethylene (2) lau- a physiological saline solution was put into the receiver ryl ether was confirmed to exhibit higher skin permea- (dermis) side and stirred using a magnetic stirrer. Oint- bility than the solution of Comparative Example 1 con- ments of Example 2 and Comparative Examples 4-6, 28 taining only propylene glycol, the solution of Compara- mg each, were respectively applied to the donor (horny tive Example 2 containing propylene glycol and propyl- 15 layer) side. The solution in the receiver was extracted ene glycol monocaprylate, and the solution of Compar- over time to determine the concentration of lidocaine us- ative Example 3 containing propylene glycol and poly- ing high performance liquid chromatography. The oxyethylene (2) lauryl ether. amount of the lidocaine that penetrated the rat skin was calculated. Example 2 20 [0044] The relationship between the amounts of accumulated drug that penetrated the rat skin from the [0039] One part by weight of lidocaine was dissolved ointments of Example 2 and Comparative Examples 4-6 in 10 parts by weight of propylene glycol. 4 parts by and the time elapsed is shown in Figure 2. As clear from weight of propylene glycol monocaprylate, 4 parts by Figure 2, the solution of Example 2 which contains pro- weight of polyoxyethylene (2) lauryl ether, 5 parts by 25 pylene glycol, propylene glycol monocaprylate, and weight of sorbitan sesquioleate, and 4 parts by weight polyoxyethylene (2) lauryl ether was confirmed to exhibit of paraffin were added to and dissolved in the solution. higher skin permeability than the solution of Compara- Then, 1.5 parts by weight of light anhydrous silicate and tive Example 4 containing only propylene glycol, the so- 70.5 parts by weight of white petroleum jelly were added lution of Comparative Example 5 containing propylene to prepare an ointment. 30 glycol and propylene glycol monocaprylate, and the solution of Comparative Example 6 containing propylene Comparative Example 4 glycol and polyoxyethylene (2) lauryl ether.

[0040] One part by weight of lidocaine was dissolved INDUSTRIAL APPLICABILITY in 10 parts by weight of propylene glycol. 4 parts by 35 weight of sorbitan sesquioleate and 3 parts by weight of [0045] The transdermal absorption promotion compo- paraffin were added to and dissolved in the solution. sition of the present invention and the transdermal ab- Then, 82 parts by weight of white petroleum jelly was sorption preparation containing the composition and a added to prepare an ointment. drug component not only exhibit a transdermal absorp- 40 tion promotion effect, but also exhibit superior skin-per- Comparative Example 5 meability, even if a drug having a relatively high lipophilic property and poor transdermal absorbability is used, ex- [0041] One part by weight of lidocaine was dissolved hibit a favorable feeling of use, and are safe and stable. in 10 parts by weight of propylene glycol. 3.5 parts by [0046] Therefore, the transdermal absorption promo- weight of propylene glycol monocaprylate, 4 parts by 45 tion composition of the present invention and the weight of sorbitan sesquioleate, and 3 parts by weight transdermal absorption preparation containing the com- of paraffin were added to and dissolved in the solution. position and a drug component are useful for transder- Then, 78.5 parts by weight of white petroleum jelly was mally administering various drugs to patients. added to prepare an ointment. 50 Comparative Example 6 Claims

[0042] One part by weight of lidocaine was dissolved 1. A transdermal absorption promotion composition in 10 parts by weight of propylene glycol. 4 parts by comprising the following components (a), (b), and weight of polyoxyethylene (2) lauryl ether, 4 parts by 55 (c): weight of sorbitan sesquioleate, and 3 parts by weight of paraffin were added to and dissolved in the solution. (a) propylene glycol, Then, 78 parts by weight of white petroleum jelly was (b) a polyol fatty acid ester, and

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2. The transdermal absorption promotion composition according to claim 1, wherein the components (b) and (c) are mutually soluble with the component (a). 5

3. The transdermal absorption promotion composition according to claim 1 or claim 2, wherein the ratio of the total weight of the component (b) and component (c) to the weight of the component (a) is 10 0.01-99 and the weight ratio of the component (c) to the component (b) is 0.1-10.

4. A transdermal absorption preparation comprising the following components (a), (b), (c), and (d): 15

(a) propylene glycol, (b) a polyol fatty acid ester, (c) lauromacrogol, and (d) a drug component. 20

5. The transdermal absorption preparation according to claim 4, wherein the component (d) is a drug with comparatively high lipophilic properties. 25 6. The transdermal absorption preparation according to claim 4 or claim 5, wherein the preparation is in the form of an ointment, gel, cream, gel-like cream, liquid, lotion, aerosol, liniment, plaster, poultice, or reservoir-type patch. 30

7. A homogeneous liquid preparation basically comprising the components (a) to (d).

8. An oily ointment or oily cream preparation compris- 35 ing the components (a) to (d) and an oily base.

9. A method of promoting transdermal absorption of a drug in a transdermal absorption preparation comprising applying the transdermal absorption prepa- 40 ration of claim 4 or claim 5 to the skin.

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