DE2445270A1 - STABILIZED Aqueous CATECHINAMINE SOLUTION AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Applicant: SMITH & NEPHEW PHABMACEUTICALS LIMITED

Title;

Stabilized aqueous catecholamine solution and process for its preparation

description

The invention relates to a stabilized aqueous Brenzcatechinamin solution for topical application in living tissue and primarily for the treatment of open-angled glaucoma peeping at which 0.1 - 5 wt $ contains a biologically active Brenzcateohinamins.. Here, catecholamine is to be understood as dihydroxy-phenylalkyl-amine and the solution is used in drop form for eye treatment. In particular, the invention relates to a solution of adrenaline, which is also known under the name epinephrine. The invention also relates to a method for producing said solution.

Adrenaline and similar biologically active catecholamines are known to be useful in the treatment of wide angle glaucoma. Any solution of this substance should instilled into the eye should ideally be nearly neutral to avoid irritation of the surrounding tissues. With simple adrenaline solutions, the adrenaline base tends to increase

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24A5270

at a pH of 7 or more disadvantageously to precipitate, i.e. precipitate. In the case of very acidic solutions, adrenaline is more stable to oxidation; if but the pH is raised close to 7, the adrenaline or similar cateohinamine is easily attacked by oxygen, with further oxidation the red adrenochrome and similar products such as brown melanin progressively form.

Ss has therefore already been proposed (GB-PS 930 452), aqueous adrenaline solutions that are adjusted to a suitable pH value (6.5 - 8.5) are set to produce with sodium hydroxide, these solutions also include sodium bisulphite, boric acid and 8-hydroxyohinoline together with a common anti-glare protective agent. The sodium bisulphite antioxidant reacts disadvantageously with the adrenaline as an inactive derivative; however, the use of boric acid, which is effective as sodium borate, slows down the extent of this undesirable side reaction and aids in the dissolution of the adrenaline, the 8-hydroxyquinoline the sodium bisulphite stabilizes against oxidation.

Such a solution is not particularly stable when stored under anaerobic conditions and also does not have good stability once it is opened for daily use.

Another suggestion (German patent application

2 052 991) is used as a stable antioxidant instead of sodium bisulphite and 8-hydroxyohinoline a mixture of ascorbic acid and a

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50981 kl λ 148

used a water-soluble, pharmacologically acceptable thiol stabilizing agent and noted that a markedly improved resistance to oxidation is achieved. In In practice, the thiolr bond is usually H-JLc β ty 1-1-cysteine and the pH is usually 5 »5 - 8.5» with boric acid always present and sodium hydroxide or Sodium carbonate is used to adjust the pH as required. The stability is not particularly good under anaerobic conditions.

You invention now provides a solution of the type mentioned at the beginning before, which is characterized in that the catecholamine is used in purified form; 0.5-5.0 wt. ^ Of a water-soluble pharmacologically compatible th.iolieoh.en stabilizing agent together with at least one acid or an acidic compound, if the thiolic compound itself is not sufficiently acidic, is present, the Catecholamine is treated for solubility; A base is present to keep the pH in the range of 6.0 - 7.5 bring to; and the solution is free of borate ions.

The invention is based on the finding that, in comparison with the prior art discussed above, improved results can be achieved in terms of stability under anaerobic conditions (i.e. before opening the container) as well as stability under aerobic conditions (after the open) if a combination of two tools is used. These are 1) the use of a purified form

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applicable.

The solution usually contains an antibacterial protective agent so that it will not become contaminated when the bottle is opened for use. They are common antibacterial ones Active ingredients can be used, such as Benzalkonlumolorid and / or quaternary ammonium compounds or biguanidine compounds. Furthermore, the solution often contains a thickening agent which is usually cellulosic in nature. Purely for this purpose Hydroxyethyl cellulose preferred because it is an appealing one results in a clear solution which does not precipitate with HitzesterlllMtlon. A preferred viscosity is 6-7 centipoles, e.g. about 15 cp.

0.1-2, typically catfish more than 1% by weight of catechol amines are preferred. The necessary degree of purity of the catecholamine is generally such that the free Base and aqueous solutions are colorless in relation to the colored, somewhat contaminated materials that are customary have been used so far. However, this is best expressed by the fact that a typical pyrocateol amine, as described in FIG Invention is used, preferably based on or calculated on per million parts less than 1 part heavy metal the Elsen ion. The best way to do this is to make up the solution by mixing under nitrogen, with is started with the usual crude base, which is then subsequently converted to a colorless one using normal chemical techniques Solution is cleaned with the required degree of purity. The-

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Impurities of

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such as cysteine, their esters and their N-ayl derivatives, or thiol-substituted poly oils. Suitable examples are cysteine, Methylcysteine, N-aoethyl-cysteine, tx-meroapto-acetic acids, ok-mercapto-propionic acid, 1-thiosorbitol and 1-thioglyserine. A preferred compound is N-Acethyl-L-Cysteine as this reacts acidic and can therefore be used in the absence of an additional acidic component that serves the solubility and stability of the catecholamine. The one commonly used Base is ammonium hydroxide.

The acid added is, for example, when it is added, 1-10% by weight of simple hydroxycarboxy acid; preferably an alpha or beta hydroxy acid such as lactic acid, citric acid, malic acid or gluoic acid. The preferred acid is lactic acid, which is used in amounts of, for example, 2/6. In order to be able to keep the solution at higher values of the pH-value range from ⁹ 6-7, ammonium aotate, for example, is present; this Laotat is added, for example, as lactic acid and reacts in situ with excess

In another embodiment, the solution contains a phosphate, for example ammonium dihydrogen phosphate, or a phosphorous acid as the acidic component, usually in amounts of 0.1 to 10 parts by weight and preferably 0.1. 0.5? *. If N-Aoetyl-cysteine is added as the acid component, the phosphate may have a Pufferfunktlon, and are in such a Pail 4 wt. I>, the usual upper limit. In this embodiment of the invention, a restricted pH range of 6-7, preferably

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5098U / 1.1 48

wise tone 6.2 - 6.7 »e.g. 6.5 common.

Ice _Φ very important optional feature of the invention is to add eintn effective amount of one or sehrerer adrenerglscher neuron-blocking agent to the solution, which increases the sensitivity for the pharmakologisohe adrenaline or similar Brenieatechlnaraln. The solution according to the invention is particularly suitable to contain both the pyrenergic leuronamine and the adrenergic leuron-blocking agent, and levels of the latter of 2–056 sizes, preferably 2-7, eg 5 sizes, are preferred if this is the case given, it is possible to work with preferred Brenzoateohin 'concentrations at the lower end of the given range, for example less than $ 1 and possibly down to $ 0.5 or $ 0.25, while still having a reasonable level of effectiveness.

Typical adrenergic neuron-blocking Igentia include Bethanidin, straight §msa @ tte, iaia of the formula

Χ ~ Λ _Μ _ _0Η

/ ^Η

IH ₂

and its salts, and especially its suIfliste, is special preferred.

Although it is possible to block such adrenergic neutrons Agen & ia regardless of the substance su use it is generally preferred when a system of low ionic strength is used. On the other hand is e.g. a substance

5 0 9 8 U / 1 H 8 ~ ⁹ ~

in which e.g. guanethidine is used, hypertonic if one high buffer concentration is present.

Thus it is clear that two specific substances in the sense of Invention are particularly valuable.

The first is an aqueous solution containing 0.1-2 wt. ^ Adrenaline in a purified form described above; from 0.5-2% by weight of I-acetyl-L-cysteine; from 1.0-10% by weight of lactic acid; and enough ammonium hydroxide to make the lactic acid neutralize and obtain a pH value within the range of 6.0 - 7.5. The second preferred according to the invention Mixture is an aqueous solution containing 0.1-2% by weight of purified adrenaline; from 0.5 to 23 * N-aoetyl-L-cysteine; from 0.1-0.5% by weight of ammonium dihydrogen phosphate; enough ammonium hydroxide to maintain a pH of 6.2-6.7; and from 2 - 75 * guanethidine.

Although the invention is primarily aqueous solutions providing according to the above description, it 1st clear that it also extends to a) mt a method of treating a patient suffering from wide-angle glaucoma patients, such solutions are instilled into the eye, and b) a process for the stabilization of an aqueous cateohinamine solution containing 0.1-5 % of a biologically active cateohinamine, the cateohinamine in purified form according to the above description being added to an aqueous solution of 0.5-5% by weight of a water -

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victorious agent and

(if the tlioliseh® contains earner iet), Bas® is added to its dissolving power, in order to bring and wilt .

ttiioliecSiem stable 1-

Oiler iiitter reactive

not even off-IsenseateciLinamiQ in wölbei afterwards a®

B storage, from 6 - 7 _{f kept} free of borate ions.

Di © Erfittäung is below approximately examples auBgelrlcIct _v is given.

miter -Beawgnalfflie auf Aus fIh- Here are all © ropes in weight is about saleres amelrlcklioh.

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Example 2 A mixture is prepared which contains: Adrenaline (purified) 1 »O N-acetyl-cysteine 1.0

ffatrosol 250 M (Hercules) 0.4

Benzalkonlumclorld 0.01 Ammonium lactate 4.0

. Ammonium hydroxide up to pH 6.5

distilled water to 100

The solution is made by taking the N-Acβty1-cysteine, adrenaline, the antibacterial component and the lactate in less than half the required amount of water under one Be dissolved in a nitrogen atmosphere. Then the Natrosol 250 M (a hydroxyethyl cellulose diabetic agent) dissolved in the remaining half te of the water and added, after which the solution is adjusted to the desired pH with ammonium and brought to volume. Samples of this solution are brought to different pH values with ammonium hydroxide set and subjected to a bubble test * Hierau Put 100 ml of the solution in a Dreoheel Plasohe, welohe is placed in a water bath at 25 ° 0 and bubbled with air, which contains water vapor. The end of the test is when the solution is deeply colored.

Results ES Sprudellelt (Ψ * ζ *)

7.5 7

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ne comparable solution that only differs in that it contains 2.0 parts of boric acid instead of 4.0 parts of ammonium lactate, gives the following results:

Alterun «in weeks adrenaline HAG % _ 0.98 Salary* 0.85 0 0.99 0.66 CVJ -, 0.48 4th 0.60 8th 0.46

In another experiment, the previously known product, which uses ascorbic acid and N-acetyl-cysteine, changes its color, if stored at 60 ° C, within four weeks. this does not happen with the solutions described above. It is known that ascorbic acid under anaerobic conditions Can decompose products to a colored breakdown, and this decomposition is accelerated by borate ions; the Products according to the invention are free from this disadvantage.

Solutions which are prepared in this and the following examples are preferably packaged in a catfish, which prevents the entry of oxygen so that the solutions remain colorless during normal storage.

Example 5 A substance similar to that of Example 2, but

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Iatroeel 250 M '
BenBalkonium-Cblövid

7.0

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1
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1 1

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(a) Aerobic Spru & el-Teat

Solution 4 Phosphate (2.0) + Aging (hole " 7.0 Snrudeltelt (Sac) (Adrenaline +
NAC (0.5)) 6.5 15th 0 β, Ο 18th ; - - 4 ^: .. 18th Solution 1 IAC (1.0)) -8th 7.0 (Adrenaline + 6.5 .14 0
2 6.0 23 (b) Ana ^ roblsche tests 4th 23 Solution 1 ■ ■ - - 8, .. ' Salary? Lin- üACi (Adrenaline +
NAC (1, O)) 0.99 0 _s 85 0.97 0.67 0.80 Solution 5 0.64 (Adrenaline +
NAC (1.0) +
Borates (2.0)) 0.99 0.60 0.98
0.85 0.46 0.66 0.48

By comparing the results, diü fto di® solution 1 and the solution 5 are reached, @ i © ht aan that the adrenaline + HAC, without any other material, superior anewbe aging properties both because of the adrenaline and the IAC content. So it can be that the Addition of other material the content of metal ions or

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1 , 01 0 , 83 0, 62 -, o _s ο, 40 2445270 NAC % 6th , 7 6th , 5 6, 3 - 6, 2 pH

(Porting of the prev © rg®h © mden

1 1 4th 40 ° C 12th 09 O 26th 1 93 20 ° σ 26th 18th O , 02 1, 77 O , 99 7th 12th 1, 88 , 89 6th , 86 O, 6th 6th , 79 Q, 1, 10 O, 7th 0 , 6 , 5 6, , 5 6, O, 92 6, 6th 6, 7th 8th - 1.09 0.81 ■ ■ - ".

With the one previously described. Such solutions remain bubble tests over 400 hours without discoloration, whereas a neutral one Adrenaline eye drop solution discolored at 16 hours and a previously known adrenaline-borate-Qjfj ^ IAC-0,5 # ascorbic acid system discolored with a similar pH at 192 hours.

Example 7

A substance is produced which contains C, 5% purified adrenaline, 1 ^ NAG, 5 ^ guanethidine sulphate and the ammonia dihydogen phosphate base required for the required pH values.
The following anaerobic alteration data result:

60 ° G 0 2 - 4th 8th 12th Aging (weeks) 0.38
0.92 0.84 0.25
0.8 0.16
0.66 0.10
0.60
-18- Adrenaline i »
NAO $.;: -
• "" -

pH 4.6
S ₉ S 4 ₉ 5
β ₉ β 4.5 4 ₉ β
6.7

4Ο ^Θ σ 12th 26th 20® 0 12th 26th 0.35 0.35 0 _s 38 0.37 0 * 9 0ρ89 0 ₉ 84 0.91 4s> <p 4 ₅ β 4.5 β, β 6 ₉ β 6 ₉ 6

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Mitt © lu © £ t

Time in Miamtea

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Mean pupillary diameter
Average mean error

6.26 O ₉ GS

6.47
0.15

6 _S 83
0.26

6.61) Neutral address-0.17) nalin eye drops BPO

The time test shows that the laetst substance is not conspicuous differs from the neutral adrenaline BPC (P 0.3).

The hypotensive effect is determined by the pressure drop in the treated xanino'henaugeib. Yorhezgslieiide experiments show that substances which contain 1 $ A & r © iaalin, almost maximum Aatvoften "generation, it is therefore 0.25 $ i solutions ltergeetelt _v ii © otherwise with <8n 1? I solutions are identical. "The solutions are compared with 2.5 $ aorenaline bitartrate, according to the usual maximum consensus. The mean maxiaal, observed skin attack in 8 rabbits were as follows

öiänaia

base

0.
Bi

Adrenaline ii

iarirai

Medium (jam Hg)

More humane medium mistake

3.51 0.38

'3 61
0.26

5.13
0.52

One can therefore infer. " & ®J dl © Pkospinat- und Lactat-Substanzen.in in the same way are © wirlEsaee% p © t @ aüifa.

The increase in bypot @ nsiv @ n Guanethidia can be sifted over the Eaninch @ naug® of guanethidine sulphate

Effect of the adrenaline through at best®a sseigen, however with a 5 $ ig © a solution s what the adrenaline

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Claims (1)

Claims The stabilized aqueous Brenzoatechinamin solution for topical application at 1 ©> @ Μ © ιΐ Qtmsob® nnä primarily for the treatment of open-angled glaucoma with eye ₉ which 0.1 - 5 percent includes ^ a biologically active Brenzeateehinaniins, characterized. - gekennsq Leh net "that the Srenzcatechinamin is used in purified Pom; 0.5 - 5.0 G-ew. i » a water-soluble, pharmacologically compatible thiolacid stabilizing agent susaiaraeE salt of at least one acid or an acidic compound, if the thiolic compound itself is not sufficiently acidic, is present, the pyrocateehlamine being treated with regard to solubility; a base is present to bring the pH in the range 6.0-7 »5; and the solution is free of borate ions. 2. Solution according to claim 1, characterized in that «the acidic compound is a salt. 3. Solution according to claim 1 or 2, characterized in that «the base is an Ammoniuishydroxyd. 4. Solution according to claim 1, 2 or 3, characterized in that it is free from alkali metal ions. 5. Solution according to one of the preceding claims, characterized in that it contains a thickener * such as a —22— 509814/1 U8 2U5270 © is ® © il © inns si iaspsliok © ρ teärngh © Is Ii = 5 to 2, Solution ägjpsmgSa, 1I ₉ te 50 9 84 4 / 1U- »23» Acid lactic acid 1st. 13. Solution according to claim 12, characterized in that ammonium lactate is present, ias is either added as such or is formed by reaction of excess ammonium hydroxide with the milehic acid in the solution. 14 * Solution according to one of the preceding claims, characterized in that the acidic compound is a phosphate or a Phosphat®amr®. 15. Solution according to claim 14, characterized in that the phosphate Ammonlum-Dihydrogen-Phoeph & t is * 16. Solution according to claim 15 dad ur ch! Gekennze ichnet that 0.1-4.0 wt. $ Ammonium phosphate are provided and a pH value in the range of 6-7 is present. 17. Solution according to one of the preceding claims, characterized in that it further contains at least one adrenergic neuron blocking agent. 18. The solution according to claim 17 » characterized in that the adrenergic neuron-blocking agent is present at 2-10% by weight. 19. Solution according to claim 17 or 18, characterized . . "■■" ■■■■ - ■. ■ ■ ^; '"■""" -24- 5098 14/1 UB that the atetnwrglavh · lawmen tilookieread · agent emmnethidin or let a Sails of it. 20. £ $ sung naeli lmsprmeli 1 “ thereby gafc” BJUM j, g lH | aJ. that it contains tob 0, 1 - 2 © ew.jl adrenaline in purified form 0.5 - 2 * 0 «ir.jl!» © etyl-l-Cyiitidii, from 1.0-10 lactic acid and beneficial % Aroz3rA _$ m tie Mileheäure en EitmtralieieifeB and · 1η · ΐι pH-Yurt in ranges from 6.0 - 7.5 a »fiet®ll®n # 21. Ii & eiang naoh Imeffmoli i _f i ^ Im ^ fk gf ^^^ s®i @ to®t . the al® * contains rom 0 $ i - 2 Oifw.fi ateenalin in purified? era, T © n 0.5 - 2 # I-le®tjl-I (-Ojet®i » _f reu 0.1 - 0.5 iaBeni 'tui-> M] lijI] E ^> ogi) m - flioiipliat _i , gtnttgenl iaioniwi xyd, in order to set a pH value la Bertieli fön 6 _$ 2 - 6.7, and ¥ ®n 2 - If * ttwnethidiiu 22. The procedure "% r Hevstelluig ®in # s JMmumg according to one" of the preceding Imeprtehe, because it is indicated that the Bremseateehinaain in purified form is given to the aqueous IiVsvng, w®lohe di® 0.5-5 & ew. ^ Waseerlus - 'borrowed pharaakolegieeli saträglieli ··, thiolatafcilisiertee Igens susajmen Bit mimdeetene which contains an acidic or acidic reacting'ferMmlMBg, if not the Brenseateehinajiin selliet for acidic, wülmreh the L3 «e ability is due to its porridgeiiattelii himiug®Agt will “w len pE” ¥ ert in the areas 6 ₉ Q - 7.5 ku teingen, and that the 509814/1148 The solution is kept free of borate ions. original inspected 5098 147 1148