DE1792500A1 - Medicines with a laxative effect - Google Patents

Description

Subject of the invention Bind medicament with laxative effect based on a combination of whether flattened diacetyl-bi-β- (p-hydroxyphenyl) -isatin and activated dimethylpolyailoxane are active ingredients, characterized in that the surface-activated Diacetyl bis (p-hydroxyphenyl) isatin from precipitation a polar, non-aqueous, water-miscible solvent and then treating with a aqueous solution of surfactants Prepared in the presence of a finely divided carrier material and the weight ratio of the surface-activated amorphous diacetyl-bia- (p-hydecyphenyl) -isatin to activated dimethylpolybiloxane obtained is within the limits from 1 to 5 to 10 to 40.

The preferred embodiment of the angeldungsgemäöen Medicines are chewable tablets that are used to treat

209812/1719

Constipations of various origins are used. In the Segel, it is sufficient to take a chewable tablet, such as the one in the Example 4 is described about three sagas before Go to bed in order to achieve the desired success of the treatment. In stubborn cases, stop taking it too continued after three days, if necessary under Use of chewable tablets with a stronger combination of active ingredients «.

The result of the use of the appropriate drugs achievable special treatment success is expressed in the Stool evacuations that start after a short period of treatment and are painless and without any other inconvenience. In particular, the abdominal pain and diarrhea-like bowel movements that often occur in the treatment of constipation are avoided when used of the present medicinal products only in very rare cases

observed.

On the one hand, surface-active, amorphous diaoetyl-bie- (p-hydroxyphenyl) -isatin, which is applied to a finely divided silica-based carrier, such as kieselguhr, is used as the active ingredient for the present pharmaceuticals or colloidal silica, applied and converted into a paste using swellable cellulose derivatives

209812/1719. " ³ '"

Diaoetyl ~ bis- (p-hydroxyphenyl) -isatin produced showed that a produced according to the following procedure Product has the most favorable properties. owns:

1 kg crystalline diacetyl bis (p-hydroxyphenyl) - ieatin are dissolved in 9 kg of dimethylformamide. the Clearly filtered solution is loaded with thorough stirring slowly added dropwise to 100 liters of water, Loading 10 g Hi- utes stand, centrifuged the precipitate and washes with water until the wash water is free from dimethylformamide. The precipitation will

in a solution of 3 β TEXAPON-K-12 ^ Irf 1 liter

Stirred water and after 30 minutes of stirring a Suspension of 4 kg of CELLITE superfine superfloss ^

added in 6.4 kg of water and then another 0.6 kg

Tylose-C-300-P added with stirring. You get so

a storable paste of the surface-active,

amorphous active ingredient. I.

As a further active ingredient in the present aromatic drugs activated dimethyl polyailoxane is used, as is present, for example, in the commercially available "Antifoam A? Emulsion" from Dow Corning Corporation «These is obtained with the paste of the surface-activated “amorphous Diaoetyl-bia- (p ~ hydroxyphenyl) -lemtin with the help

209812/1719

Usual auxiliaries and additives and flavor corrections compressed into tablets. However, the production of coated tablets and capsules is also easily possible and is within the scope of the invention.

The laxative effect of the known crystalline diacetylbis (p-hydroxyphenyl) i8atin and medicinal preparations based on this are familiar to the person skilled in the art

Furthermore, the combination of surface-active substances Diacetyl ™ bi3- (p-hydroxyphenyl) -isatin with activated Dimethylpolysiloxane in a weight ratio of 1 to 80 below Addition of a spasmolytic known, through its use unphysiologlsohe gas accumulations in the gastrointestinal tract be eliminated.

From the French drug patent 322 N, drugs based on a dimethylpolysiloxane activated with finely divided silica are described. Elimination of foamy gas accumulations in the digestive tract to modify the addition of sedatives and alkaloids take place.

Use is also made in US Pat. No. 2,934,472 of silica-activated dimethylpolysiloxane * Emulsions for the elimination of postoperative oasis of the oasis

209812/1719 '" ⁵ "

and thereby caused S _c * s HMER known.

Finally, U.S. Patent 2,951,011 Drug based on antacids with the addition of methylpolysiloxane for the treatment of platulence.

However, these drugs, which characterize the state of the art, have no laxative effect.

In contrast, the pharmaceuticals according to the application are those with a pronounced laxative effect. As a surprising effect, it should be noted that the Combination of the surface-activated amorphous diacetyl-bie- (p-hydroxyphenyl) isatin obtained by the specified process with dirnethylpolyeiloxane in the stressed limits of 1 to 5 to 10 to 40 parts by weight causes a synergistic effect

Table 1 shows the effectiveness of crystalline diacetyl-bi- (p-hydroxyphenyl) isatin alone and in combination with activated dimethylpolyelloxime. Further Corresponding information is given for the combination of surface-active, amorphous diacetyl-bie- (p-hydroxyphenyl) -iaatln alt 'activated dimethylpolyeiloxane, from which shows that a lower dose of surface active! ertem amorphous diacetyl-bie- (p-hydroyphenyl) -

209812/1719 " ⁶ "

-isatin in the presence of activated Eimethylpolyailoxan causes a lower failure rate on average »than this» is the case with crystalline material even in the presence of activated dimethylpolyeiloxane.

Table 4 also clearly shows the described synergism by comparing the mean effective dose (ED ₅₀ ) of the laxative agent alone with that of its combination with dimethylpafcrsiloxane, which with the aid of Table 2 is all the more remarkable than there Complete ineffectiveness of the activated dimethylpolyslloxane with regard to a laxative effect is shown.

Finally, Table 3 provides a comparison of the laxative effects of a known combination preparation with that of the claimed drugs. It is remarkable that despite the high dosage of the known combination * Preparation, whereby the total dose of active ingredients is higher there is no significant increase in the laxative effect is recognizable.

In theory, it would be conceivable to mile even the most stubborn from Obetix> atlon /% arch increased solicitations of crystalline » Treat dlacetyl-bls ~ (p-hydroxyrphenyl) -i8atln eu.

209812/1719 ~ ^? ~

In practice, however, it has been shown that abdominal pain increases in frequency and severity diarrheal-like bowel movements occur · Bine such treatment is therefore undesirable "

The presently claimed drugs remedy this deficiency by significantly reducing the laxative in itself acting .substance. Because of this and because of the successes shown in the tables, the one with the application requirements Pharmaceuticals achieve technical progress demonstrated

- β 2CS812 / 1719

Table 11 Frequency of the 9 "WhIt

24

in a relationship * DJ? O Si (Ver ff share Tabl really niifh oven ATmI 1— Vn 1? Ions ten di ajcer) pro m pi ette rl-bi OaIm τοη move BOersiert " ■ riV a- (i> -hTdroxv-

KJ J O ω «0 O K » • κ -4

Zueamnitn- diacetyl- activating number of the number of the

Vi -rv-etö-f t eetmane der bie- (p-hy- tea Dimethyl- PatJm- administer- stools in Ter ^{ir B x} chewable tablet droxyphe- polysiloxane parted tablet- 24 hours eager • riipr. Nyl) -iaatin mg / Tablets per tablet accessory

Chewable tablets with crystalline diacetyl-bieip-hydroxyphenyl) -ieatin

10.0

92

82

33

206

135

105

1.5

Chews & blet-

th with

surface

alrtivesif

amorphous di-

acetyl bia

(p-hydroxy

pn0nyl5-iea-

tin

15.0 10.0

138

29

24

789

104

79

1.4 1.7 2.2

5 ro cn

Table 2t

Amount of activated dimethyl polyalloxane administered

Subjects

Increase in the daily amount of stool that is usual for the test person

_gtuhl

_gttQlle

15 mg 17th 0 0 30 mg 17th 0 0 45 mg 18th 0 0 60 mg 16 2 0 75 mg 16 0 1

0 0 0 1

£ DsP activated dimethylpolysiloxane was in the form of chewable tablets Composition according to Example 4, but administered without diacetyl-ble- (hydroxyphenyl) -isatin. These tablets each contained 15 » 30, 45 »60 and 75 mg dimethylpolysiloxane as the only active ingredient.

Table 3 * Comparison of egg laxative effect on 11

obstiplerten persons τοη chewable tablets correspond according to example 4 with a

preparation of the composition pro Tablet:

Surface active diacetyl bis (p-hydroxyphenyl) isatin 0.5 mg

Activated dimethylpolysiloxane 40.0 mg

Mandelic acid benzyl ester 30.0 mg

Medium number of stools' dosage

Torbeob- flatbeob-

SSSSf- ¹ ^ ² - ^Ta «'-« MiSiSf-

worth) worth)

1 tablet 0.9 1.55 2.55 1.27 0.82 according to Beiep.

3x2 tablet- 1.1 1.02 1.15 0.92 0.87 th one
known
Combination preparation

In the attached diagram according to FIG. 1, the divided number of stools per day is shown graphically against the duration of treatment. The dashed line shows the course of treatment with a chewable tablet according to Example 4, while the solid line shows the course of treatment with a known combination preparation

- 11 209812/1719

Table 4: Mutate effective dose (SBc ₀ ) of surfaces

ak ti vem amorp _t hen diacetyl-bis-

isatln (I) and a combination of surface-active "n" orphsm diacetyl-Tjjg-fp hyrophenyl ) -! satin with 56 ma activated dimethyl-polysllpane (II).

I: ^EI> 5o ^e 30.0 mg / kg, determined after oral administration to 200 hats.

II; ^ED 50 " 5 * 3 mg / kgs based on the surface-active amorphous diacetyl-bis- (p-hydroxyphenyl) -iBatin, ^ after oral administration to 45 rats.

In the attached Pig. 2 the ED ₅₀ is shown graphically.

Example 1: Kau t a b le11 e der 2usi »" »nBnsetzmvt *

Diacetyl bis (p-hydroxyphenyl) isatin "

crystalline

Gelite superfine superfloss milk sugar fylose-C-1000-P Citric acid nairium cyclnmat table salt

(Slycerin

Orange water aroma

talc

Magnesiumateerat

Oeeemt weight 209817/1719

“AD ORIGINAL

Example 2s chewable tablet with

Diacetyl bis (p-hydroxyphenyl) isatin

crystalline> 10.0 ag

rest of the composition as in example 1

Diaetyl bis (p-hydroxyphenyl) isatin
crystalline total weight 5.0 ag Activated dimethylpolysiloxane
("Antifoam AP Emulsion" from Pinna
Dow Corning Corporation) BoIs ^- Di el 4: chewable tablet of the composition i 10.0 » Cslite superfine superfloss finely divided, surface-active,
amorphous diacetyl bis (p-hydroxyphenyl) -
ieatin 2OrO » Lactose activated dirnethylpolysiloxane as above 480.4 " Tylose-C-1000 ~ P Celite superfine superfloss 10.0 " Citric acid Lactose 15.6 ■ Hatriuracyelamate Tylose-C-300-P 4.0 « Table salt Citric acid 1.0. "' Glycerin Sodium eclamate 1.0 " Aroma mandarin oil Table salt 3.0 « water Glycerin 15.0 · Emulsifiers 5.0 » 570.0 ag 2.5 ag 15.0 · 10.0 " 310.9 * 20.0 « 11.0 " 2.8 " 0.7 0.6 "

- 13 -

209812/1719

BAD ORiSINAL

- 13 - ' Orange flavor 1792500 Emulsifiers 5.0 ag water 7.5 ■ Biliconized calcium stearate 12.0 * 2.0 *

Total weight 400.0 mg

Example 5: Sauter tablet of the composition:

finely divided, surface-active « amorphous diacetyl bis (p-hydroxyphenyl) isatin

activated pearethylpolysiloxane as above

Celite superfine superfloss milk sugar Tylose-C-1000-P Citric Acid Hodium Cydamate Table Salt Glycerin Aroma Mandarineno'l Water emulsifiers

Total weight 570.0

5.0 mg 10.0 R. 20.0 n 480.4 N 10.0 It 15.6 Il 4.0 η 1.0 n 1.0 η 3.0 η 15.0 N 5.0 H

- 14 -

209812/1719

finely divided, surface-active,
anorphic diec6tyl-bis- (p-hydroxypheny: 0-
isatin 5.0 ag activated dimethylpolysiloxane as above 30.0 « Gelite superfine superfloss 20.0 " Lactose 474.6 ■ Tylose-C-1000-P 15.0 " Citric acid 16.4 " Sodium cyclamate 4.2 " Table salt 0.9 - Glycerin 0.9 " Curb oil 3.0 ■ ! Emulsifiers 15.0 · water 15.0 "

Total weight 600.0 mg

- patent claims -

- 15 -

203812/1719

< v. ■ ■ '■■

Claims (1)

Claims 1. Medicines based on laxative effects a combination of surface-activated diacetyl bis-Cp-hydroxyphenyl-isatln and activated diaethylpclysiloxane as active ingredients, characterized in that the surface-activated diacetyl-bis- (p-hydroxyphenyl) -icatin by precipitation from a polar non-aqueous with Water-miscible solvent and subsequent treatment with an aqueous solution of surface-active substances Substances in the presence of a finely divided carrier material is prepared and the weight ratio of the surface-active amorphous diacetyl-bis- (p-hydroxyphenyl) -isatin to activated dimethylpolysllozane thus obtained is in the range from 1 to 5 to 10 to 40. 2c medicament according to claim 1, characterized in that a solution of dia2etyl-bis- (p-hydroxyphenyl) -ieatln in Dimethylformamide was added dropwise with stirring in the water and the extracted precipitate by treating with an aqueous solution of a mixture of equal proportions Fatty alcohol sulfonate salt and an alkylbenzenesulfonet salt with the addition of τοη swellable cellulose derivatives and kieselguhr is converted into a fast. - 16 - ? 09812/1719 BATH 3 · Medicines according to speeches 1 and 2, characterized in that the paste-like active ingredient combination with the addition of the usual additives and esseechaokekorrlgentien? «u tablets are pressed. 20391J / 1719 /rf.· Blank page