WO2000053226A1

WO2000053226A1 - Compositions for promoting percutaneous absorption

Info

Publication number: WO2000053226A1
Application number: PCT/JP2000/001430
Authority: WO
Inventors: Hitoshi Yamauchi; Noriko Nakajima
Original assignee: Saitama Daiichi Pharmaceutical Co., Ltd.
Priority date: 1999-03-11
Filing date: 2000-03-09
Publication date: 2000-09-14
Also published as: AU2940100A

Abstract

Compositions for promoting percutaneous absorption which comprise the following components: (a) a substance selected from the group consisting of C8-15 fatty acids, C8-16 fatty acid esters, C8-12 higher alcohols and geraniol; and (b) a substance selected from the group consisting of polyhydric alcohols and ethanol; optionally together with (c) benzyl alcohol.

Description

Specification

Transdermal absorption promoting composition

Technical field

The present invention relates to a composition for promoting percutaneous absorption.

Background art

Transdermal Therapeutic System (TTS) has attracted attention as a new dosage form that controls drug delivery to the systemic circulation by absorbing the drug from the skin. However, to date, products such as Flandre Tape S (Toray-Aio Ichisha Co., Ltd. Yamanouchi Pharmaceutical Co., Ltd.) and Nitroderm TTS (Nippon Ciba-Gai Gi Co., Ltd.) have been launched and are being used clinically. The pharmaceutical composition for percutaneous absorption containing the quinazoline derivative as an active ingredient and various proposed such as hydrochloric acid Terra Zosyn (JP-A 10-45597 and JP International Publication W095 / thirty-one thousand one hundred and ninety, International Publication W098 / 37870) _o Disclosure of the invention

An object of the present invention is to provide a composition capable of promoting transdermal absorption of various drugs. The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have been found that fatty acids having 8 to 15 carbon atoms such as capric acid and esters of fatty acids having 8 to 16 carbon atoms such as methyl carboxylate and the like. The combination of this component and a component such as a polyhydric alcohol can significantly enhance the transdermal absorption of the drug, and the addition of benzyl alcohol to the above-mentioned composition further improves the transdermal It has also been found that a composition having an absorption promoting action can be provided. The present invention has been completed based on these findings.

That is, the present invention provides a composition for promoting percutaneous absorption, comprising the following components: (a) One or more substances selected from the group consisting of fatty acids having 8 to 15 carbon atoms, esters of fatty acids having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol ;as well as

(b) to provide a composition containing one or more selected from the group consisting of polyhydric alcohols and ethanol.

According to a preferred embodiment of the present invention, the above composition further comprising benzyl alcohol as the component (c); wherein the fatty acid is cabric acid, caprylic acid, pende lactic acid, lauric acid, myristic acid, and pentadecane The above composition, wherein the ester of the fatty acid is one or more fatty acids selected from the group consisting of acids; the esters of the fatty acids are methyl caprate, ethyl caprylate, isopropyl caprate, methyl caprylate, ethyl caprylate, caprylic acid The above composition is provided which is one or more esters selected from the group consisting of isopropyl, methyl laurate, and ethyl laurate.

Further, according to another preferred embodiment, the above composition, wherein the higher alcohol is one or more higher alcohols selected from the group consisting of octanol, nonanol, decanol, pendanol, and dodecanol. A polyhydric alcohol consisting of propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,4-butanediol, and glycerin The above composition is provided which is one or more polyhydric alcohols selected from the group.

According to a particularly preferred embodiment, a composition for promoting percutaneous absorption, comprising: (a-1) a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms;

(a-2) a higher alcohol having 8 to 12 carbon atoms;

(b-1) ethanol;

(b-2) a polyhydric alcohol; and

(c) benzyl alcohol

(d) water Is provided by the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

The composition of the present invention comprises one or two selected from the group consisting of fatty acids having 8 to 15 carbon atoms, esters of fatty acids having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol. It is characterized by containing at least one kind of substance (component (a)) and at least one kind of substance (component (b)) selected from the group consisting of polyhydric alcohols and ethanol. The composition of a preferred embodiment of the present invention further contains benzyl alcohol (component (c)) in addition to the above components.

As the fatty acid used as the component (a), those having 8 to 15 carbon atoms can be used, but the structure is not particularly limited, and any fatty acid may be used. For example, either a straight-chain or branched-chain fatty acid may be used, and it may have one or more unsaturated bonds. Of these, saturated and linear fatty acids are preferred. For example, force-puric acid, force-prillic acid, pendecanoic acid, lauric acid, myristic acid, or penic acid decanoic acid can be suitably used, and force-puric acid or lauric acid is more preferable.

As the fatty acid ester used as the component (a), an ester composed of a fatty acid having 8 to 16 carbon atoms can be used. The structure of the fatty acid moiety is not particularly limited, and any structure may be used. For example, it may be linear or branched, and may have one or more unsaturated bonds. Preferably, straight-chain saturated fatty acid esters can be used. Although the structure of the ester moiety is not particularly limited, a linear or branched alkyl group having 1 to 6 carbon atoms, or an aralkyl group such as a benzyl group can be used, and preferably 1 to 6 carbon atoms. A single linear or branched alkyl group can be used. Further, an ester composed of a fatty acid having 8 to 16 carbon atoms can be used.More preferably, a fatty acid ester having 8 to 12 carbon atoms is used. More specifically, as a fatty acid ester, For example, methyl caprate, ethyl caprate, isoprate Mouth pill, methyl caprylate, ethyl caprylate, isopropyl caprylate, methyl laurate, or ethyl laurate can be used, and more preferably, methyl cabrate or ethyl caprylate can be used.

As the higher alcohol used as the component (a), a monohydric alcohol having about 8 to 12 carbon atoms can be used. The structure of the higher alcohol is not particularly limited, may be linear or branched, and may contain one or more unsaturated bonds. Preferably, a linear, saturated alcohol can be used. More specifically, for example, oxanol, nonanol, decanol, pendanol, or dodecanol can be used, and nonanol, decanol, or pendanol is more preferably used. be able to. Component (a) may be one or two selected from the group consisting of fatty acids having 8 to 15 carbon atoms, fatty acid esters having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol. More than one kind of substance is selected, but a more preferable combination is

(a-1) a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms,

(a-2) A combination of higher alcohols having 8 to 12 carbon atoms is used.

As the polyhydric alcohol used as the component (b), a dihydric or trihydric alcohol can be used, but the structure is not particularly limited. For example, propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,4-butanediol, or Glycerin or the like can be used, and more preferably, propylene glycol or 1,3-butylene glycol can be used. As the component (b), one or more substances selected from the group consisting of polyhydric alcohols and ethanol are selected. More preferably, (b_l) ethanol and (b-2) polyhydric alcohol are used. A combination with alcohol is used.

The amount of each component in the composition for transdermal absorption of the present invention can be appropriately selected according to conditions such as the kind of the active ingredient and a desired transdermal absorption rate. the amount of component, compound, or a salt thereof, for example, preferred 0.01~15 wt¾ _s Or 0.1 to 80 wt%, preferably 5 to 70 wt%, more preferably 5 to 20 wt%, and 0.5 to 95 wt% of component (b) when the temperature is 0.05 to 10 wt%. , Preferably about 1 to 90 wt. When benzyl alcohol is blended as the component (c), the blending amount is about 0.5 to 20 wt%.

The composition of the present invention may contain water. In order to reduce skin irritation, a water-containing composition may be suitably used. When prepared as a water-containing composition, component (a) should be blended at 0.1 to 10 wt%, preferably 0.5 to 2 wt%, and component (b) should be blended at 0.5 to 60 wt%, preferably l to 45 wt%. Can be. When water is not contained, the content of the component (a) is 0.1 to 80 wt%, preferably 1 to 70 wt °, and more preferably 5 to 20 wt ° /. The component (b) can be blended in an amount of about 10 to 95% by weight, preferably about 20 to 90% by weight. When benzyl alcohol is added as a component (c) to a water-containing or non-aqueous composition, the amount is about 0.5 to 20 wt%.

As a more preferred composition,

(a-1) 0.1 to 5 wt% of a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms,

(a-2) 0.1 to 5 wt% of a higher alcohol having 8 to 12 carbon atoms,

(b-1) 0.5 to 60 wt% ethanol

(b-2) 1 to 40 wt% of a polyhydric alcohol,

(c) 0.5 to 20 wt% of benzyl alcohol,

(d) 1-70 wt% water

And a composition comprising:

Since the composition of the present invention has an effect of promoting transdermal absorption of active ingredients of various medicaments, a compound or a salt thereof used as an active ingredient of various medicaments is combined with the composition of the present invention. As a result, a pharmaceutical composition having excellent transdermal absorbability can be produced. The type of the compound or a salt thereof used as an active ingredient of the medicament is not particularly limited.For example, as a free form, a compound having a molecular weight of 500 or less, a compound having a melting point of 300 ° C or less, and / or one or more A compound having a polar group; These salts and the like can be used.

As a compound or a salt thereof used as an active ingredient of a medicament, for example, morphine and a salt thereof (for example, morphine hydrochloride), narcotic analgesics such as fenyu neil, buprenorphine, dihidide quichetorphin; indomethacin, ibuprofen, i Non-steroidal anti-inflammatory drugs such as bufenac, flurbiprofen, aclofenac, diclofenac, mefenamic acid, ketoprofen, fenilbuzone, methyl salicylate, methyl salicylate, and proxycam; cortisone, hydrated cortisone, prednisolone, Steroid anti-inflammatory drugs such as dexamethasone, methasone dipropionate, betamethasone valerate, triamcinolone, and fluocyloacetonide; flumethiazide, polythiazide, and methiclothiazide at the bend opening , Diuretics such as Application Benefits chlormequat thiazides, ventile hydrochloride port thiazides, Hidorokuro port thiazides, blanking main evening two de;

Remedies for dysuria, such as terazosin, prazosin, doxazosin, perapidil, muspidosin, etc .; Hypnotics such as valpital, tiopental, phenobarbiyl, cyclobarbital, etc .; antiepileptic agents such as ethosuximide, sodium pulp oxalate, acetoralamide, meprobamate;

Anti-parkinson agents such as chlorzoxazone and levodopa; antiemetic agents such as Tokubumaram and metoclopramide hydrochloride; hormone agents such as insulin, testosterone, methyltestosterone, progesterone, and estradiol; aspirin, codin, acetoanilide, Analgesics such as aminovirine, antipyrine, puprenorphine, and phenyieneil; sulfa drugs such as sulfamine, sulfamonomethoxin, and sulfamethizole; ditroglycerin, isosorbide dinitrate, erythritol tetranitrate, erythritol, provanyl nitrate, dipyridamole Coronary vasodilators such as papaverine hydrochloride; Azimarin, pindolol, propranolol; antiarrhythmic drugs such as quinidine; caffeine, digoxin, digitoxin, amrinone; cardiotonic agents such as milrinone; calcium such as dicardipine hydrochloride, diltiazem hydrochloride, nivadipine, difedipin, nitredipine, nildipine, nimodipine Antagonists; antihistamines such as diphenhydramine hydrochloride, carbinoxamine, dipheniruraline, fenbenzamine, chlorpheniramine maleate, brompheniramine maleate, diphenylimidazoyl, clemizole; antiallergic agents such as ketotifen fumarate Antihypertensive drugs such as clonidine; Asthma drugs such as allobuterol, salbuyumol, and formoterol; adjuvant drugs for smoking cessation such as nicotine; heparins, argato Examples include, but are not limited to, anti-thrombotic agents such as loban, ticlovidine hydrochloride, and ethyl icosapentate.

Examples of suitable compounds or salts thereof include therapeutic agents for dysuria, such as terazosin, prazosin, doxazosin, perapidil, dumus mucin, anti-drugs such as diclofenac, indomethacin, ketoprofen, flurbiprofen, and glycol salicylate. Inflammatory drugs; analgesics such as buprenorphine and fenyuyl; hormones such as estradiol and testosterone; asthma drugs such as llobuterol; antihypertensive drugs such as clonidine; angina drugs such as isosorbide dinitrate and nitroglycerin; And smoking cessation aids.

As the active ingredient of the above-mentioned pharmaceutical composition, a hydrate or solvate thereof may be used in addition to the compound or a salt thereof as the above-mentioned active ingredient. When these compounds have one or more asymmetric carbon atoms, they may have a pure form, such as an optical isomer, a stereoisomer such as diastereomer, an arbitrary mixture of stereoisomers, or a racemic isomer. You may use as an active ingredient.

The form of the pharmaceutical composition produced using the composition for promoting percutaneous absorption of the present invention is not particularly limited as long as it is a form suitable as a preparation for percutaneous absorption. For example, common ointments, creams, solutions, lotions, liniments, cataplasms, plasters (blasters), tapes, patches, gels, or reservoirs It can be prepared in the form of an external preparation. In addition, the preparation method of the pharmaceutical composition is not particularly limited, and a preparation method well-known and commonly used by those skilled in the art can be adopted according to the formulation form. In the manufacture of a pharmaceutical composition, one or more pharmaceutical additives can be used, but the necessity and type thereof can be appropriately selected by those skilled in the art according to the type of the pharmaceutical form. It is.

For example, aqueous bases such as macrogol; oily bases such as serine and liquid paraffin; gum arabic, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, polyvinyl Water-soluble polymers such as alcohol and polyvinylpyrrolidone; antioxidants such as erythorbic acid, sodium erysorbate, hydroxyanisole, and sodium sulfite anhydride; preservatives; and coloring agents can be used as additives for the preparation. However, the present invention is not limited to these. It should be noted that these pharmaceutical additives need to be selected so as not to impair the transdermal absorbability of the pharmaceutical composition, but by conducting the skin absorbency test specifically described in the Examples of this specification. It is possible to select the desired pharmaceutical additives.

The composition of the present invention is excellent in transdermal absorbability, but is not only excellent in skin irritation but also excellent. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.

Example 1

The isolated skin of Yucatan micropig is sandwiched between vertical diffusion cells (Franz-type diffusion cells, application area: 0.95 cm ² ) circulating water at 37 ° C, and phosphate buffered saline (pH 7.4) 4 ml was added and stirred with a magnetic stirrer. Apply 200〃1 of each sample to the donor (horny) side, sample the solution in the receiver over time, measure the drug concentration in it by high performance liquid chromatography, and remove the skin. The amount of drug that permeated was determined. Each sample was prepared as a suspension composition by adding terazosin hydrochloride to the components shown in Table 1.

Table 1 shows the results. In Table 1, BA is benzyl alcohol; PG is propylene glycol; BG is 1,3-butylene glycol; S-318 is monoglyceride caprylic acid; IPM is isopropyl myristate; IPA is isopropyl alcohol. The permeation rate indicates the maximum value of the skin permeation rate of the drug per unit area (〃g / cm ² / hr), and the cumulative permeation rate indicates the cumulative permeation rate of the drug per unit area after 48 hours (〃g / cm ² ).

table 1

Specimen components (b) and (d) Permeation rate

1 10% Ke, Laniole 20% BA 70% PG 106.83 810.82

2 10% cuff. Phosphoric acid 90% PG 127.61 2677.08

3 20% Cuff ⁰ Phosphoric acid 80% BG 103.60 1652.34

4 20% cuff. Methyl lylate 20% BA 60¾ PG 119.98 4110.28

5 20% cuff. Methyl lylate Z0% BA 60% BG 114.59 3508.94

6 20% caffle ethyl acrylate 20% BA 60% PG 75.29 2738.44

7 20% cuff. Isofu lylate. Lohi. 20% BA 60% PG 63.53 2082.32

8 20% cuff. Methyl phosphate 20% BA 60% PG 72.63 2460.82

9 20% Methyl laurate 20% BA 60% PG 78.90 2625.68

10 20% Ethyl laurate 20% BA 60% PG 47.92 1543.60

11 10% cuff. Phosphoric acid 20% BA 70% PG 258.96 5114.90

12 20% Cuff ⁰ Phosphoric Acid 20% BA 60% PG 203.59 6294.52

13 20% Pente, 'Canoic acid 20% BA 60% PG 270.00 8434.24

14 5% Lauric acid 20% BA 75% PG 191.28 4886.87

15 20¾ Lauric acid 20% BA 60% PG 232.45 6981.22

16 20% Lauric acid 20% BA 60% BG 52.20 1072.37

17 5% myristic acid 20% BA 75% PG 35.87 833.95

18 5% straight, 20% BA 75% PG 32.79 811.31

19 20% Octanol 20% BA 60% PG 254.79 8408.74

20 20¾ Nonanol 20% BA 60% PG 232.23 7073.45

21 20% Te, Power Knoll 20% BA 60¾ PG 244.84 9070.71

22 20% Pen, 20% BA 60% PG 281.97 9695.19

23 20% Dete, 20% BA 60% PG 157.52 5315.59

24 PG only 0.08 0.30

25 BA only 4.63 84.80

26 20% BA 80% PG 0.65 0.27

27 60% S-318 / 40% PG 13.86 279.83

28 20% Cuff ⁰ Phosphoric acid 80% IPM 0.54 8.67

29 5% cuff ° phosphoric acid 20% BA 75% IPA 6.41 50.15

30 5% c. Lumitic acid 20% BA 75% PG 2.17 31.12 Example 2

A skin permeation test was performed in the same manner as in Example 1 using the extirpated skin of Yucatan micropig. The water-containing composition shown in Table 2 was used as a sample, and the blending amount of terazosin hydrochloride was 5 Wt%. In Table 2, PG is propylene glycol; BG is 1,3-butylene glycol; BA is benzyl alcohol; EtOH is ethanol; GL is 50% glycerin in water Show liquid. The content is shown in wt%, the permeation rate is the maximum value of the skin permeation rate of the drug per unit area (g / cm ² / hr), and the cumulative permeation is the drug per unit area after 48 hours. Indicates the cumulative transmission amount (〃g / cm ² ).

Table 2

Cuff ° cuff. Rilka PG BG BA EtOH Water GL Permeation rate Cumulative permeation amount

1 0.5 15 one 4 20 55.5 one 22.35 645.50

2 1 15 20 59.0 6.26 233.12

3 1 15 4 10 65.0 21.93 651.51

4 1 15 4 20 55.0 27.78 927.23

5 1 5 4 20 65.0 10.58 354.20

6 2 5 20 68.0 12.35 393.16

7 1 15 4 20 55.0 82.68 3231.83

8 1 45 4 20 25.0 36.31 639.76

9 2 15 4 20 54.0 69.80 2192.63

10 1 45 4 20 25.0 36.20 869.23

11 1 5 4 20 65 32.87 989.27

12 1 15 4 20 55.0 75.20 2721.93

13 15 4 20 56.0 0.31 6.71 Example 3

A drug permeation experiment was carried out in the same manner as in Example 1 except that the extirpated skin of a hairless mouse (female) was used instead of the extirpated Yucatan micropig skin. A composition of the present invention is prepared by adding benzyl alcohol and propylene glycol to lauric acid, methyl caprylate, or decanol, and adding a drug (10 wt%) to the composition. A sample was used. The content is shown in wt%, and the permeation rate is the maximum value of the skin permeation rate of the drug per unit area (速度 g / cm ² / hr). Table 3

Example 4

A skin permeation test was performed in the same manner as in Example 1 except that the application of each sample to the donor side was set to 100% and the blending amount of terazosin hydrochloride was set to 1 wt%. In Table 4, PG indicates propylene glycol; BG indicates 1,3-butylene glycol; BA indicates benzyl alcohol; EtOH indicates ethanol. The content is shown in wt%, the permeation rate is the maximum value of the skin permeation rate of the drug per unit area (〃g / cm ² / hr), and the cumulative permeation amount is the drug per unit area after 48 hours. Indicates the cumulative permeation amount (g / cm ² ).

Table 4

Try Te Cuff Hydrochloride. Re cuff. Lil ϊ,, Kano PG BG BA EtOH Water Application Permeation Lasso ', Methyl phosphate-Amount') Rate Permeation 虽

1 1.0 0.25 one 0.75 20 4 30 44.0 100 11.34 413.54 1.0 0.25 0.75 20 4 30 44.0 100 10.75 410.42

3 1.0 0.5 0.5 20 4 30 44.0 100 11.82 444.26

4 1.0 0.5 0.5 20 1 4 50 24.0 100 13.99 392.64

D 1.0 0.0 0.5 20 4 50 24.0 100 11.06 394.41

6 1.0 0.5 0.75 20 4 30 43.75 100 10.59 330.51

7 1.0 1.0 10 4 40 44.0 100 10.18 354.17

8 ²⁾ 1.0 10 40 48.0 100 3.28 83.16

9 ³⁾ 1.0 10 40 48.0 100 2.57 63.60

10 ⁴⁾ 1.0 10 40 48.0 100 1.20 23.36

1) Application amount (l / cm ² )

2) Contains 1 wt% lauric acid monoglyceride.

3) Contains 1 wt% of oleic acid monoglyceride.

4) Contains 1 wt% of monoglyceride hydroprillate.

Industrial applicability

INDUSTRIAL APPLICABILITY The composition of the present invention has a transdermal absorption promoting effect on various compounds or salts thereof, which are active ingredients of pharmaceuticals, and is therefore useful for producing a pharmaceutical composition having excellent transdermal absorbability. .

Claims

The scope of the claims

1. A composition for promoting transdermal absorption, comprising the following components:

(a) One or more substances selected from the group consisting of fatty acids having 8 to 15 carbon atoms, esters of fatty acids having 8 to 16 carbon atoms, higher alcohols having 8 to 12 carbon atoms, and geraniol ;as well as

(b) A composition comprising one or more selected from the group consisting of polyhydric alcohols and ethanol.

2. The composition according to claim 1, further comprising (c) benzyl alcohol.

3. The claim 1 is a claim wherein the fatty acid is one or more fatty acids selected from the group consisting of hydropric acid, prillic acid, ndenoic acid, lauric acid, myristic acid, and pendecanoic acid. Item 3. The composition according to Item 2 or.

4. The ester of the fatty acid is selected from the group consisting of methyl caprate, ethyl caprylate, isopyl porphyrate, methyl caprylate, ethyl caprylate, isopropyl caprylate, methyl laurate, and ethyl laurate 1 The composition c according to any one of claims 1 to 3, wherein the composition is a kind or two or more kinds of esters.

5. The method according to any one of claims 1 to 4, wherein the higher alcohol is one or more higher alcohols selected from the group consisting of octanol, nonanol, decanol, pendanol, and dodecanol. Item 2. The composition according to Item 1.

6. Whether the polyhydric alcohol is propylene glycol, 1,3-butylene glycol, ethylene glycol, diethylene glycol, 1,3-propylene glycol, triethylene glycol, dipropylene glycol, 1,4-butanediol, or glycerin 6. The composition according to claim 1, which is one or more polyhydric alcohols selected from the group consisting of:

7. A composition for promoting transdermal absorption, comprising the following components:

(& -1) a fatty acid having 8 to 15 carbon atoms or a fatty acid ester having 8 to 16 carbon atoms; (a-2) a higher alcohol having 8 to 12 carbon atoms;

(b-1) ethanol;

(b-2) a polyhydric alcohol; and

(c) benzyl alcohol

(d) water

A composition comprising: