DE2729786A1 - LOCAL ANESTHETICALLY EFFECTIVE SOLUTIONS - Google Patents

Description

The compound 2-amino-3> 5-dibromo-N- (trans-il-hydroxycyclohexyl) -benzylamine (NA-872) and its acid addition salts are described for the first time in the Belgian patent specification 698 2kk peripheral respiratory function in particular called the antipyretic, antitussive and secretolytic effects.

Furthermore, from the Belgian patent specification 827 * »66 the antiulcus effect of 2-amino-3,5-dibromo-N- (trans- i »-hydroxycyclohexyD-benzylamine and its acid addition salts are known.

Surprisingly, it has now been found that solutions, optionally in combination with a fluorescent dye such as fluorescein 2-amino-3,5-dibromo-N- (trans- ¹ J-hydroxy-cyclohexyl) -benzylamine or its physiologically acceptable acid addition salts with inorganic and organic Contain acids, have an excellent short-term local anesthetic effect, as is necessary for short-term eye examinations or for short-term diagnostic or minor therapeutic manipulations on mucous membranes. The maximum duration of action is 20-25 minutes.

The solutions according to the invention are obtained by dissolving 2-amino-3,5-dibromo-N- (trans-i »-hydroxycyclohexyl) benzylamine or its physiologically acceptable acid addition salts with inorganic and organic acids in a suitable aqueous carrier in a concentration of 0 , 5 - Ί i _t but preferably 1.0 - 2.5 % _t, optionally with the addition of a fluorescent dye such as fluorescein.

809883/0238

The locally anesthetically effective solutions according to the invention have for example, as eye drops, have a local anesthetic effect, especially for short-term eye examinations, e.g. in tonometry is desirable. Tonometry, especially The applanation tonometry is used to measure intraocular pressure, especially in the ongoing control of glaucoma patients. The local anesthetics available on the market for short-term eye examinations have too long a duration of action on, which leads to the fact that the effect has not yet subsided when the patient comes out on the street again and thus the possibility is exposed to unnoticed penetration of dust and other foreign bodies between the eyelids and the cornea, causing injuries of the corneal epithelium, in addition, it must be used because of the frequent use in glaucoma patients of the local anesthetics commonly used up to now, allergic reactions can be expected (see therapy week 2j5, 8640 - 86 * 13 (1976)).

Furthermore, the solutions according to the invention are locally anesthetically effective suitable as short-term anesthetics for the mucous membrane, as desired for the area of the mouth or throat. When they are used, there is no annoyance for the patient associated with a longer-acting local anesthetic, namely the impaired taste, the furry feeling or the difficulty swallowing by switching off the swallowing reflex mechanism.

The superior short-term local anesthetic effect of the new Solutions were compared to proxymetacaine (0.5 * strength 2-diethylaminoethyl-3-amino-4-propoxybenzoic acid hydrochloride solution = ^ -Kerakain) tested on rabbits as follows:

The test animals that showed no damage to the corneal epithelium after slit lamp examination and clinically no conjunctival damage Showed inflammation, 2 drops of the corresponding eye drops were applied. The sensitivity of the zen central cornea is one minute after application by touch

809883/0238

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irritation, the entire corneal epithelium and the sensitivity were assessed 5, 10, 15 and 30 minutes after application. The examiner, who assessed the sensitivity and the corneal epithelial status, was not informed about which eye of each animal had been ^{treated with Chibro v} - 'keracaine.

The following table contains the test results found :

809883/0238

co O CO CO 00 CJ ■ ««. O ro to 00

Animal eye medication Elevated anesthesia findings (A) and corneal findings in minutes
after application of the eye drops 5
A HH 10
A HH 15th
A HH 30 minutes
A HH to the right
Left 0.5 % NA 872
Kerakain 1
A HH + O.B.
++ o.B. ο o.B.
++ o.B. ο o.B.
++ o.B. ο o.B.
ο o.B. to the right
Left Kerakain
1.0 % NA 872 ++
++ ++ ++
+ o.B. ++ o.B.
+ o.B. (+) o.B.
(+) o.B. ο o.B.
ο o.B. to the right
Left 2.0 % NA 872
Kerakain ++
++ ++ o.B.
++ + + o.B.
+ + + ο o.B.
+ (♦) ο o.B.
+ ++
++

++ strong anesthesia or significant epithelial changes + significant anesthesia or small epithelial changes (+) anesthesia clearly detectable or hardly noticeable epithelial changes

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ro co

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The new locally anesthetically effective solutions according to the invention (NA 872) thus have a shorter local anesthetic effect than the comparison solution and also have fewer side effects on the epithelium.

The effect shown above could be achieved using the aesthesiometer according to Cochet and Bonnet on the human eye with drip or, when used as a spray application with the aid of the pump-dosing valve confirmed on the mucous membrane of the mouth or throat. At a concentration of 0.5 to 1 ί NA 872 and the application From 1 to 2 drops per eye, the local anesthetic effect occurs within 30 to 60 seconds, the duration of the effect lasted 15 to 30 minutes, or when applying a double dose NA 872 solution by means of 3-8 strokes of the pump-dosing valve on the Mucous membranes of the mouth and throat in humans were found to be mildly anesthetized in 6 test persons, the duration of which was effective 15 to 25 minutes.

It should also be mentioned here that the substance 2-amino-3,5-dibromo-N- (trans-1-hydroxycyclohexyl) benzylamine and its physiologically acceptable acid addition salts with inorganic and organic acids have a low acute toxicity, for example an LD as the hydrochloride ₅₀ of 2720 mg / kg po in the mouse.

The following examples are intended to explain the invention in more detail:

809883/0238

example 1

Eye drops with 0.5 % 2-amino-3,5-dibromo-N- (trans-II-hydroxycyclohexyl ) benzylamine hydrochloride

Composition:

Active ingredient 0.5 g

Citric acid 0.1 g

Na ₂ HPO ₁₁ χ 2 H ₂ O 0.2 g

Sodium chloride 0.8 g

Alkyl benzyl dimethyl ammonium chloride 0.02 g

high molecular weight methyl cellulose 0.1 g

Aqua dest. ad 100 ml

Manufacturing:

_{Citric acid, active substance, Na 2} HPO ₁ are added to half of the water with gentle heating and stirring. χ 2HpO and sodium chloride dissolved (solution I).

In the other half of the water, while cooling with ice and stirring, alkyl-benzyl-dimethylammonium chloride and methyl cellulose are added dissolved and left to swell overnight (solution II). Solutions I and II are combined and filtered through a membrane filter .

Example 2

Eye drops with 2 % 2-amino-3,5-dibromo-N- (trans- ¹ l-hydroxycyclohexyl) benzylamine hydrochloride

Composition:
Active ingredient
Citric acid
Na ₂ HPO ₁ , χ 2 H ₂ O

Sorbitol

809883/0238

2.0 G 0.1 G 0.2 G 2.0 G

2723786

Polyvinyl alcohol Ι, Ί g

Alkyl benzyl dimethyl ammonium chloride 0.03 g

Aqua dest. ad 100 ml

Manufacture;

In half of the water are heated and weak Stir citric acid, active ingredient and Na-HPO ^ χ 2HpO one after the other dissolved (solution I).

In the other half of the water are at 90 ° C and with stirring Sorbitol, polyvinyl alcohol and alkyl-benzyl-dimethylammonium chloride dissolved, then cooled to room temperature and left to swell overnight (solution II).

Solutions I and II are combined and filtered through a membrane filter.

Example 3

Eye drops with 0.5 % 2-amino-3,5-dibromo-N- (trans- ¹ l-hydroxy cyclohexylj-benzylamine hydrochloride

Composition: Active ingredient 0.5 g

Boric acid 2.5 g

Borax 0.3 g

Alkyl-benzyl-dimethylammonium chloride Ο, ΟΟΊ g Aqua dest. ad 100 ml Manufacturing:

Boric acid is dissolved in water at 60 ° C. After cooling to room temperature, borax, the active substance, is added one after the other and alkyl benzyl dimethyl ammonium chloride. After overnight swelling is filtered through a membrane filter.

809883/0238

1.0 G ο, ι G 0.2 G 0.7 G 0.03 G ο, ι G 100 ml

Example M

Eye drops with 1.0 % 2-amino-3,5-dibromo-N- (trans- * l-hydroxy cyclohexyD-benzylamine hydrochloride

Composition: active substance citric acid Na ₂ HPO ₁ , χ 2 H ₂ O

Sodium chloride

Alky1-benzyl-dimethylammonium chloride high molecular weight methyl cellulose Aqua dest. ad

Manufacture; analogous to the example

Example 5

Eye drops with 2.0 % 2-amino-3,5-dibromo-N- (trans- ¹ » -hydroxy-cyclohexy1) -benzy lamin-hydrochlori d

Composition: active ingredient citric acid Na ₂ HPO ₁ ,

Sorbitol

high molecular weight methyl cellulose

Sodium chloride Phenyl mercury borate Aqua dest. ad

2.0 G 0.05 G 0.5 G 2.0 G ο, ι G 0.3 G 0.001 G 100 ml

809883/0238

Manufacturing:

Solution I is prepared analogously to Example 1.

In the other half of the water, sorbitol, methyl cellulose and phenyl-Hg-borate are dissolved and while stirring with ice

left to swell overnight (solution II).

Solution I and II are combined and passed through a membrane filter filtered.

Example 6

On drop solution with 0.5 - 2.0 % 2-amino-3,5-dibromo-N- (trans- ¹ < hydroxycyclohexyp-benzylamine hydrochloride

Composition: 0.5-2.0 g Active ingredient 0.05 g citric acid 0.1 g Na ₂ HPO _1,. 2 H ₂ O 0.8-0.6 g Sodium chloride 0.02 g Alkyl benzyl dimethyl ammonium chloride 100 ml Aqua dest. ad Manufacturing:

The solution takes place in the order citric acid, active substance, Na ₂ HPO ^, sodium chloride and alkyl-benzyl-dimethylammonium chloride in water. It is then filtered with a membrane filter.

809883/0238

0.5 - 2.0 g G 0.05 G 0.1 G 1.0 G 10.0 G 0.03 ml 100

- 11 -

Example 7

Brushing with 0.5-2.0% 2-amino-3,5-dibromo-N- (trans- ¹ < -hydroxy-cyclohexylj-benzylamine hydrochloride

Composition: Active ingredient citric acid Na ₂ HPO _1,. 2 H ₂ O

Sorbitol

Glycerin

Alky1-benzyl-dimethylairanonium chloride Aqua dest. ad Manufacturing:

The substances are dissolved in the larger amount of water in the following order: active substance, citric acid, Na ₂ HPO ₁₄ , alkylbenzyl-dimethylammonium chloride, sorbitol and glycerine. It is then filtered.

Example 8

Solution for pump metering valve spray with 0.5 - 2.0 % 2-amino-3> 5 " dibromo-N- (trans-M-hydroxycyclonexyl) benzylamine

Composition: Active ingredient 0.5 - 2.0 g

Na ₂ HPO ₁ , 0.2 g

1,2-propylene glycol 7.0 g

Alkyl benzyl dimethyl ammonium chloride 0.03 g Sodium chloride 0.6-0.4 g

Aqua dest. ad 100 ml

809883/0238

Manufacture;

The solution is carried out in the following order in the main amount of water: citric acid, active substance, Na ₂ HPO _1. , Alkyl-benzyldimethylammonium chloride, sodium chloride and propylene glycol. Then it is made up with water and pressure-filtered.

Example 9

Dosing aerosol based on propellant gas with 0.5 - 2.0 % 2-amino-3 »5 -di-bromo-N-Ctrans-M-hydroxycyclohexyD-benzylamine

!Composition:

Active ingredient 0.5 g Sorbitan trioleate 0.5 g Isopropyl myristate 1.5 g Propellant gas mixture (11: 12: 114) ad 100.0 g

! Manufacturing:

Active substance, sorbitan trioleate, isopropyl myristate are ground together in one part of propellant gas 11 in the ball mill. This concentrate is transferred to a cold filling system, ^{cooled to -MO 0} C and filled with the remaining propellant gas mixture and filled into suitable aerosol cans, immediately provided with a suitable metering valve and sealed.

809883/0238

Claims (3)

Patent claims: 1. Local anesthetic solutions containing 2-amino-3,5-dibromo-N-Ctrans-'t-hydroxycyclohexyD-benzylamine or its Acid addition salts. 2. Local anesthetic solutions according to claim 1, characterized in that they contain 2-amino-3,5-dibromo-N- (trans- ^| l-hydroxycyclohexyD-benzylamine or its acid addition salts in a concentration of 0.5-4 % . 3. Local anesthetic eye drops according to claim 1 and 2, characterized in that they are used as a further excipient Contain fluorescent dye such as fluorescein. M. Use of 2-amino-3 »5-dibromo-N- (trans-'l-hydroxycyclohexyl) -benzylamine or its acid addition salts for the preparation of solutions with a local anesthetic effect. 80S883 / 0238