CA1306677C

CA1306677C - Composition for transdermal therapeutic systems of loop diuretics and a process for its preparation

Info

Publication number: CA1306677C
Application number: CA000538049A
Authority: CA
Inventors: Walter Petri; Bernhard Reul; Max Hropot
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1986-05-27
Filing date: 1987-05-26
Publication date: 1992-08-25
Anticipated expiration: 2009-08-25
Also published as: DK268287A; DK268287D0; JPS62283936A; AU7338587A; KR870010872A; PT84946A; EP0247507B1; PT84946B; DE3767212D1; ZA873771B; EP0247507A2; GR3001558T3; ATE59782T1; DE3617824A1; ES2033258T3; EP0247507A3; IL82639A0

Abstract

Abstract of the disclosure:

A description is given of a composition for transdermal therapeutic systems, which contains as active compound furosemide, piretanide or lemidosul, or a physiologically tolerated salt of these loop diuretics, in a base composed of a fatty acid alkanolamide, or of a fatty acid alkanol-amide mixture, having 8-18 carbon atoms in the fatty acid residue and 2 to 6 carbon atoms and 1 to 3 hydroxyl groups in the alkanolamide residue, and, where appropriate, of a carboxylic ester, or of a carboxylic ester mixture, in each case having 1-22 carbon atoms in the carboxylic acid moiety and 1-22 carbon atoms in the alcohol moiety.

Description

~306677 HOECHST AKTIENGESELLSCHAFT Dr.D/gm HOE 86/F 116 A composition for transdermal therapeutic systems of loop diuretics and a process for its preparation It is worth~hile, to improve patient compliance in the treatment of hypertens;on w;th loop d;uretics, to lower the ini~ial d;uresis and to extend the duration of action of the active compounds, i.e. the profile of act;ve com-psund release from a pharmaceutical form under consider~tion ought to be constant and long-lasting.

Sustained release formulations for oral administra-tion, from which the active compo~nd is released over a prolonged period - say for up ~o 6 hours - have already been descr;bed for the loop diure~ics furosemide and pir-etanide, for example SGerman Offenlegungsschri~ten

2,3b3,218 ~corresponds to US Patent 4,324,779~ and 2,655,3313. It has also already been described that ac-tive compounds incorporated in transdermal therapeuticsystems (TTS) are del;vered for percutaneous absorption in a continuous and sustained manner. Thus, there are descriptions in the literature of a variety of types of systems containing the active compounds nitroglycerine, scopolamine, estradiol or clonidine; they have been on the pharmaceuticals market in many countries for some time~

Experiments ~ith the known bases of thQse systems have sho~n that the bases contained in these TTS systems are unsuitable for the penetration through the living skin of the loop diuretics f~rosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilic acid; German Patent 1~122,541 corres-pond;ng to US Patent 3,058,822), piretanide S4-phenoxy-

3-~1-pyrrolidinyl)-5-sulfomoylbenzoic acid; German Offen-legungsschrift 2,419,970; U5 Patent 4,U10,273) an(1 lemi-dosul (p~oposed INN; 2-aminomethyl-4-(1,1-d;methylethyl)-6-methylsu~onylphenol hydroçhloride; German Offenlegungs-schrift 3~2U8,190 corresponding to US Patent Application ~L
q~

-` ~L3~66'-;'7 No. 472,226). The bases of the systems are either hydro-philic or lipophilic substances, depending on the active compound.

S It has now been found, surprisingly, that the said loop diuretics and their physiologically acceptable salts re-sult in TTS ~ith constant release of act;ve compound ~hen a base composed of a fatty acid alkanolamide, or of a fatty acid alkanola~ide mixture, and, where appropriate, of a carboxylic ester~ or of 3 carboxylic ester mixture, is used, that is to say a base which has very pronounced lipophilic as well as hydrophilic properties. Furthermore, especially when bases in which the fatty acid alkanolamide proportion is greater than the ester proportion are used, the delivery uf active compound lasts distinctly longer than ~ith oral sustained release formulations.

Thus the invention relates to a composition for a trans-dermal therapeutic system, ~hich composition contains as active compound furosemide, piretanide or lemidosul, or a physiologically tolerated salt of these loop diuretics, in a base composed of a fatty acid alkanolamide, or of a fatty acid alkanolamide mixture, in each case having 8-18 carbon atoms in the fatty acid residue and 2 to 6 carbon atoms and 1 to 3 hydro~yl groups in the alkanolamide resi~
due, and, ~here appropriate, of a carboxylic ester, or of a carboxylic ester mixture~ in each case having 1-22 carbon atoms in the carboxylic acid moiety and 1-22 carbon atoms in the alcohol moiety.
Both ~ater-soluble and sparingly water-soluble salts are suitable as physiologically tulerated salts.

In the statements made hereinbefore and hereinafter, a fatty acid alkanolamide is to be understood to be both a fatty acid monoalkanolamide and a fatty acid dialkanol-amide. The fatty acid residue is saturated or unsaturated.
The fatty acid alkanolamides can also be named as follows:
a) N-alkanoyl-N-alkylaminoalkanols or ~3~6t~

N-alkenoyl-N-alkylaminoalkanols b) N-alkanoyl-N-hydroxyalkylaminoalkanols or N-alkenoyl-N-hydroxyalkylaminoalkanols and c) N-alkanoylaminoalkanols or N-alkenoylaminoalkanols.

The hydroxyl groups are primary, secondary or te~tiary hydroxyl groups. The compositions jccording to the inven-~ion contain, for example, fatty acid alkanolamides of the follo~ing formulae, R representing the residue of the fatty acid:

/ C:L t o Cg~ Alkyl R-~-N~,~

R-~-N~

2 D ~CH2- CH2- OH
R-~-N~
t::H2- ~:H- CH2- OH
~H

H
R- 1~- N~

H H
}L-~N~ 3 ~ ~ 32-O}i : CH2- ~H- CH2- OH; ~ ~ H2- ~
O~I

~I
R~ CH2- OH ~ :
~;; CH2- OH

~3~;677 Suitable carboxylic esters are esters with mono-, di-and trihydric alcohols. The alcohols are primary, second-ary or ter~iary alcohols. The carboxylic acids and alco-hols are saturated or unsaturated~

The esters which are preferably used are those of ali-phatic monocarboxylic acids and aliphatic alcohols.

The base is preferably composed of a fatty acid alkanol-amide such as, for example, fa~ty acid diethanolamide or fatty acid monoisobutanediolamide, and of a carboxyl ester; tne acid residues of the two co~ponents are pref-erably the same. Particularly suitable are capric acid diethanolamide, lauric acid diethanolamide and capric acid monoisobu~anediolanide, and ethyl caprate and hexyl laurate. ~here ester mixtures are used, especially suit-able are mixtures of ethyl caprate and decyl acetate.

The compositions according to the invention can, in addi-tion to the active compound and the base, contain further inert vehicles or customary auxiliaries such as, for ex-ample, water, paraffins, colloidal silica or surface-active substances~

The extent to which delivery of the active compound from the resulting penetration systems is sustained depends on the mixing ratio of fatty acid alkanolamide to carboxy-lic ester. Thus the penetration of the active compound through the skin depends both on this mixing ratio and on the characterist;cs of the skin and the size of the con-tact area.

The compositions according to the invention preferably contain 1 to 50% by weight of active compound, based on the total weight of the composition. The mixing ratio of fatty acid alkanolamide to carboxylic ester in the base is, for exa~ple, 2 to 98 to 98 : 2. The higher the fatty acid alkanolamide proportion, the more sustained is the release.

---" 13~i6'~7 If the composition also conta;ns one or more vehicles or customary auxiliaries, their proport;on is exped;ently 1 to 90~ by ~eight (based on the total weight of the com-position).

The invention also relates to a process for the prepar-at;on of the compositions, and to their use ;n transdermal therapeutic systems. The process comprises intimately mixing furosemide, piretanide or lemidosul, or a physio-logically tolerated sal~ of ~hese loop diuret;cs, w;th afatty ac;d alkanolamide, or w;th a fatty acid alkanol-amide m;xture, in each case hav;ng 8 to 18 carbon atoms ;n the fatty acid res;due and 2 to 6 carbon atoms and 1 to 3 hydroxyl groups ;n the alkanolam;de residue and, ~here appropr;ate, w;th a carboxylic ester, or w;th a carboxylic ester m;xture, ;n each case having 1-22 carbon atoms ;n the carboxyl;c acid moiety and 1-22 carbon atoms in the alcohol ~oiety, at temperatures between room temperature and 50C.
~hen preparing the m;xture, ;t ;s poss;ble to suspend or dissolve the act;ve compound ;n the carboxylic ester, or ;n the carboxyl;c ester mixture, to add the fatty acid alkanolamide to the suspension or solutiorl, and then to m;x intimately at temperatures between room temperature and 50C. It is also poss;ble in;tially to mix the said active compounds with the fatty acid alkanolamide at temperatures between room temperature and 50C, and then to add the carboxylic ester or the carboxyl;c ester mixture~ The mixing can be carri~ed~out in, for example, a customary agitator with incorporated homogenizer.
.
:
The compositions acco~ to the invention are solid, semi-solid ~pasty) or liquid and are suitable for use in transdermal therapeutic systems~ Examples of such systems are films or plasters with circular or oval contact areas 0.5 to 25 cm in size or, preferably, plaster packages ~ith pharmaceutical containers~(recess~. A piaster pack-age which is compossd of a casing which is formed of two ~3C~66 ~7 layers and encloses the composit;on, and of an elast;c film which can adhere to the skin is particularly suitable.
Plaster packages of this type are described in, for example, German Offenlegungsschrift 3,204,582. Another embodiment of a suitable plaster package is described in German utility model 840,736. These plaster packages have pharmaceutical containers to receive solid, sem;-solid or liquid composi-tions~ If a semi-solid or liquid composition according to the invention is to be incorporated in a plaster package of this type~ it is advisable to use in addit;on an absorbant textile insert. The active compounds are delivered percu-taneously fro~ the compositions according to the invention in a sustained and continuous manner. The bioavailab;lity of ~he active compound is in some cases better than that after oral ad~inistration. Another advantage comprises the avoidance of passage through the stomach and intestines, so that the new administration form is of significance as a dosage form ~hich is problem-free and suitable for a large group of patients. By reason of the release profile, the compositions according to the invention are suitable not only as diuretics but also for the treatment of high blood pressure. The dosage unit, that is to say one transdermal therapeutic system, preferably contains 5 to 500 mg of ac-tive compound, in particular 5 to 200 mg.
The examples which follow are intended to illustrate the invention. The compositions were obtained by mixing the active compounds with the base in an agitator ~ith incor-porated homogenizer. The transdermal therapeutic systems used ~ere the plaster packages disclosed in German utility model 8,407,036.

The quantities stated in the examples in each case relate to the composition for one dosage unit.

Example 1 Co~position for one dosage unit 5 a) piretanide 20nO mg laur;c acid diethanolamide64.0 mg (N-bis(2-hydroxyethyl)lauramide) hexyl laurate __16.0 mg 100.0 mg b) piretanide 20.0 mg lauric acid diethanolamide24.0 mg hexyl laurate 56.0 mg - 100.0 mg ~hen tested for natriuresis in the hairy rat~ the composi-tion a) tmixing ratio lauric acid diethanolamide: hexyl laurate = 8 : 2) showed in the first 5 hours after percu-taneous administration a moderate natriuretic action ~hich ~as accompanied by a slow rise in the piretanide levels in the blood. Not until the 6-24 h collection period was there pronounced natriuresis, which correlated with the maximum piretanide level in the blood in the sixth hour.
It ~as possible in the abovementioned preparation to alter the time profile of action of the loop diuretic piretanide in the sense of prolonging the action (cf. Tables 1 and 2).

In contrast to composition a), the preparation b) (mixing ratio of lauric acid diethanolamide. hexyl laurate = 3 : 7) showed a strong natriuretic action in the 1-S hour-collection period, ~hich was accompanied by a large rise in the piretanide levels in the blood, the maximum being reached as soon as the fourth hour after administratlon.
Subs@quently the piretanide levels in the blood fell more rapidly than those after administration of a)~ so that the natriuretic action of b) in the 6-24-hour collection p~riod was distinctly weaker than that of a); there was no prolongation of the action of piretanide (cf. Tables ~3~66 ~7 1 and 2). In the case of preparation b) the time profile of the action of piretanide corresponds to the action pro-file after oral administration (piretan;de suspended ;n 2% strength aqueous starch solution) and thus to that of S a typical loop diuretic (cf. Table 3).

Table 1 Comparison of the piretanide levels (~g/ml) in the blood after percutaneous administration thereof to rats ~n =6) Hour composition a) composition b) 20 mg/rat 20/mg rat 1 0 19.3 + 25.0 2 12.7 + 12.6 63.8 + 57.6

4 40.7 + 19.1 75~5 + 49,0 6 62.8 + 32.2 62.2 + 34.0 8 50.8 ~ 18.9 58.7 ~ 25.8 24 33.7 + 17.9 20.6 + 8.6 28 21.3 + 13.0 0 32 26.8 + 11.3 48 54.7 ~ 29~9 0 "` 13C36677 g c~ oa~ ,~ ~ ~u~ )~
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3~6~';7 Example 2 Composition for one dosage unit a) furosemide Na 5.3 mg capric acid diethanolamide8.0 mg ethyl caprate 72.0 mg 85.3 mg .b) furosemide Na 21.3 mg capric acid diethanolamide8.0 mg ethyl caprate 72.0 mg 101.3 mg Table 4 shows the saluretic action after percutaneous administration of furosemide sodium salt in doses of 5.3 mg.tcomposition a) and 21.3 mg (composition b) per rat. Comparison was with the excretion level after oral administration (furosemide suspended in 2% strength aqueous starch solution) of 5 mg of furosemide per rat tTable 5).

The furosemide TTS formulations showed.a dose-dependent saluretic action after percutaneous administrationO In additior,~ the furosemide levels in the blood revealed distinct dose-dependent concentration differences tcf.
Table 6), which explains the dose-dependent saluretic action.

.~

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~ ~3G'6677 Table 6 Furosemide sodium levels (~g/ml) in the blood after p.c. administration to ha;ry rats (n = 6 composition b) composition a) Hour 21~3 mg/rat 5.3 mg/rat 0.5 0.25 + 0.23 0.25 + 0.14 1 2.18 ~ 3.45 1.20 + 1.31 2 27013 + 28.02 6.62 ~ 4.78 4 89.70 + 27.36 9.17 + 5.56

6 52.05 ~ 19.41 4.68 + 2.60 24 0.95 + 0.60 0.46 + 0.37 48 0.04 + 0.03 0 ~ontrol 0 0 Example 3 furosemide 20.0 mg coconut acid diethanolamide 16.0 mg (= mixture of lauric ac;d diethanolamide, myristic acid diethanolamide and palmitic acid diethanolamide) eicosanol/docosanol esters of elcosenoic/docosenoic acids ~jojoba oil) 64.0 mg 100.0 mg Example 4 furosemide Na ~ 5.3 mg capric~acid monoisobutanediola:mide4.0 mg ethyl caprate : 7ZO0 mg 81.3 mg `` ~3~6~i'Y7 Example 5 furosemide Na 5.3 mg N-ethyl-N-2-hydroxyethylcapramide 4.0 mg ethyl caprate 72.0 mg 81~3 mg Example 6 furosemide ~a 5.3 mg capric acid diethanolamide 8.0 mg ethyl caprate 14.4 mg decyl acetate 57.6 mg 85.3 mg Example 7 -furosemide Na 5.3 mg undecylenic acid diethanolamide4.0 mg ethyl caprate 72.0 mg 81.3 mg Example 8 furosemide Na 5.3 mg capric acid diisopropanolamide 4.0 mg ethyl caprate 72.0 mg 81.3 mg Example 9 , furosemide Na 5.3 m~
: capr;c acid mono-n-propanolamide 4~0 mg ethyl caprate ?2.0 mg 8103 mg 13~ii66'~7 Example 10 furosemide Na 5.3 mg capric acid 2-ethyl-1,3-propanediol-2-amide 4.0 mg ethyl caprate 72.0 mg 81.3 mg Example 11 . _ furosemide Na 5.3 mg isononanoylamino~
trishydroxymethylmethane 4.0 mg ethyl caprate 72.0 mg 81.3 mg Example 12 _ __ furosemide Na 5.3 mg capric acid diethanolamide 4.0 mg 1,2-propanediyl di(caprylate/caprate) 72.0 mg 81.3 mg Example 13 _ furosem;de Na 5.3 mg capric acid diethanolamide 4.0 mg 1~12-dodecaned;yl diacetate 72.0 mg Exa~ple 14 furosemide Na 5.3 mg capric acid diethanolamide 4.0 mg 1,2-hexadecanediyl diacetate ~ 72.0 mg :: :

: ~ :

.
.

~ ~3Q66~7 Example 15 furosemide Na 5.3 mg capric acid diethanolamide 4.0 mg diethylene glycol dicaprate 72.0_mg 81.3 mg Example 16 ~, furosemide Na 5.3 mg capric acid diethanolamide 4.0 mg triethylene glycoL dilaurate ?2.0 mg 81.3 mg Example 17 furosemide Na 5.3 mg capric acid diethanolamide 4.0 mg dipropylene g~ycol monopropionate monomyr;styl ether 72.0 mg 81.3 mg Example 18 ___ furosemide 20.0 mg oleic acid diethanolamide 16.0 mg ethyl oleate 64.0 mg 100.0 mg Table 7 ~hich follows shows the saluret;c action following psrcutaneous administration of furosemide or furosemide sodium salt~from compositions specif;ed in Examples 3 to 18 per rat: ~

-~ ~L306~'77 ~ 0 ~ ~ 0 0 ~ D Ln ~ ~ ~ ~ ~
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13(~66 ~7 EYa=ple 19 furosemide Na 21.3 mg capric acid diethanolamide 4.0 mg ethyl caprate 70~0 mg mono/dioleates of propanetriol1.D mg ~ater 97.3 mg Table 8 which follows summarizes the blood levels, urine levels and saluretic action for the composition specified in Example 19:

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition for transdermal therapeutic sys-tems, which contains as active compound furosemide, piretanide or lemidosul, or a physiologically tolerated salt of these loop diuretics, in a base composed of a fatty acid alkanolamide, or of a fatty acid alkanolamide mixture, in each case having 8-18 carbon atoms in the fatty acid residue and 2 to 6 carbon atoms and 1 to 3 hydroxyl groups in the alkanolamide residue, and which may also contain a carboxylic ester, or of a carboxylic ester mixture, in each case having 1-22 carbon atoms in the carboxylic acid moiety and 1-22 carbon atoms in the alcohol moiety.

2. A composition as claimed in claim 1, wherein the base is composed of a fatty acid dialkanolamide having 8-12 carbon atoms in the fatty acid residue and 2 to 3 carbon atoms in the alkanol residue, and which may also contain a fatty acid ester, or of a fatty acid ester mixture, in each case having a total of 6 to 30 carbon atoms.

3. A composition as claimed in claim 1, wherein the ester proportion amounts to a maximum of 98% by weight based on the total weight of the composition.

b. A composition as claimed in claim 1, wherein the base is composed of a fatty acid alkanolamide and of a carboxylic ester.

5. A composition as claimed in claim 1, wherein the base is composed of a fatty acid diethanolamide and of a carboxylic ester or carboxylic ester mixture.

6. A composition as claimed in claim 1, wherein the base is composed of capric acid diethanolamide and ethyl caprate.

7. A composition as claimed in claim 1, wherein the base is composed of lauric acid diethanolamide and hexyl laurate.

8. A composition as claimed in claim 1, which contains 1 to 50 % by weight of active compound based on the total weight of the composition.

9. A composition as claimed in claim 1, which also contains inert vehicles and customary auxiliaries.

10. A process for the preparation of a composition as claimed in claim 1, which comprises intimately mixing furosemide, piretanide or lemidosul, or a physiologically tolerated salt of these loop diuretics, with a fatty acid alkanolamide, or with a fatty acid alkanolamide mixture, in each case having 8 to 18 carbon atoms in the fatty acid residue and 2 to 6 carbon atoms and 1 to 3 hydroxyl groups in the alkanolamide residue and which may also comprise intimately mixing with a carboxylic ester, or with a carboxylic ester mixture, in each case having 1-22 carbon atoms in the carboxylic acid moiety and 1-22 carbon atoms in the alcohol moiety, at temperatures between room temperature and 50°C.

11. A composition as claimed in claim 1 for use in a transdermal therapeutic system.

12. The use of a composition as claimed in claim 1 in a transdermal therapeutic system.