DE1148705B - Agents for the preservation of pharmaceutical and cosmetic preparations - Google Patents

Description

It is known that the low molecular weight and water-soluble phenols disinfect and preserve Have properties. But because they have an unpleasant odor and affect the fabric exert an irritating effect, they can only be used in the rarest of cases to preserve water-containing substances use pharmaceutical or cosmetic preparations. Also the antibacterial properties of Benzyl alcohols have already been described. For example, Gershenfeld reports in Amer. J. Pharm., 1952, Vol. 124, p. 399, on the use of benzyl alcohol in parenteral solutions, wherein a 10% aqueous solution showed good bacteriostatic properties against Staph. aureus, E. coli, Bacillus subtilis, Bacillus mesentericus and Bacillus megatherium. Furthermore, in the French patent 885,966 the use of a number of phenylalkyl and phenylalkenyl alcohols, among others also of p-chloro-benzyl alcohol, as an agent for disinfection, especially against tubercle bacilli.

It has now been found that the p-chloro-phenylethyl alcohol has particularly good preservative and sterilizing properties.

With a ^{0.4 fl} / o aqueous solution at 20.degree. C., bacterial cultures with about 3, 10 ⁶ bacterial cells per 10 cm ³ of Escherichia coli, Pseudomonas aeruginosa, Micrococcus pyogenes var. Aureus and Corynebacterium are achieved within less than 15 minutes Kill diphtheriae completely. With a 0.3 ⁰ / o solution, the same results are observed within 30 minutes to 6 hours. Preservation agents for pharmaceutical and cosmetic preparations

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall

Claimed priority: Switzerland of September 25, 1958 (No. 64 323)

Dr. Peter Speiser, Münchenstein, and Dr. Hans Kaspar Hess, Binningen, Basell.

(Switzerland) have been named as inventors

A 0.2% solution sterilizes suspensions of Escherichia coli and Pseudomonas aeruginosa within 24 hours and reduces the number of living ones

Staph aureus cells by 99.99%. These results and those of analogous experiments with

known disinfectants and preservatives are listed in the following table, where Killing is understood to mean the reduction in the number of living cells as a percentage of the number of bacteria used will.

substance

concentration

Temperature ⁰ C Time of exposure

E. coli

Killing of

Staph. aureus

p-chloro-penhyl-ethyl alcohol

phenol

Benzyl alcohol

ß-phenyl-ethyl alcohol

p-chloro-benzyl

0.4 0.3 0.3 0.2 0.2

1
0.5

1
1

1
1
0.5

0.3

20 20

37 20 37

20 20

20 20

20 20 20

20 <15 minutes 30 minutes 30 minutes 24 hours 2 hours

30 minutes 24 hours

2 hours 24 hours

2 hours 24 hours 24 hours

24 hours

sterile (99.9999) sterile (99.9999)

sterile (99.9999) sterile (99.9999)

99.99 99.99

small amount

99.99

sterile (99.9999) <99.9

sterile (99.9999)

sterile (99.9999)

sterile (99.9999) 99.99 99.99

<99.9 <99.9

approximately

<99.9

sterile (99.9999) <99.9

99.99

309 580/395

The preservative and sterility agent forming the subject of the present invention is Electroneutral and not dissociated in aqueous solution. It is extremely non-toxic, colorless and odorless. It can therefore be used to preserve any medicine or cosmetic. Particularly it is suitable for keeping injection solutions, eye, ear and nose drops sterile, Syrups, jellies and lotions, e.g. B. for cutaneous use.

Another advantage of using the p-chlorophenyl ethyl alcohol as sterile maintenance means is that z. B. Injection solutions, where 0.3 to 0.4% of this compound is added, does not have to be sterilized in an autoclave at 120 ° C, but that a short heating in the flowing steam is enough to kill the spores. This also enables thermolabile injection solutions that cannot be heat-sterilized in the autoclave easy way to get aseptic. Furthermore, the great bactericidal effect of the invention allows substance to be used where a rapid bactericidal effect is not necessary, with amounts of only 0.2% preservatives get by.

The liquid p-chloro-phenyl-ethyl alcohol to be used according to the invention is known and can z. B. according to Journ. May be. Food Agr., Vol. 2, 1951, p. 94, and about the succinic acid half-ester of any traces of water-insoluble impurities that may still be present are cleaned.

The invention is illustrated in the following examples described in more detail. The temperatures are given in degrees Celsius.

Vaccines and Serums Example 1

0.3% p-chlorophenyl ethyl alcohol is dissolved by shaking or stirring, if necessary with gentle heating in physiological saline solution and gives the necessary amounts of Antigenum diphthericum praeciptitatum seu adsorptum Ph.H.V. The vaccine solution obtained can be filled into ampoules in the usual way.

The whooping cough vaccine (Antigenum pertussicum Ph.H.V.) and the tetanus vaccine are used in an analogous manner (Antigenum tetanicum praeciptitatum seu adsorptum Ph.H.V.), poliomyelitis vaccine and serum antidiphthericum Ph.H.V. preserved.

50

Injection solutions

Example 2

Ascorbic acid 11 g

Sodium bicarbonate 5 g

Sodium chloride 2 g

p-chloro-phenyl-ethyl alcohol 0.3 g

Distilled water up to 100 cm ⁸

The freshly distilled water is heated to the boil for 10 minutes and the p-chloro-phenyl-ethyl alcohol is dissolved in the still hot solution. The mixture is allowed to cool while carbon dioxide is passed through, ^{the ascorbic acid and the common salt are dissolved in 80 to 90 cm 3 of} this water and, after complete dissolution, sodium bicarbonate is gradually added. After the evolution of gas has ceased and the bicarbonate has completely dissolved, water, which has been prepared according to the method given above, is made up to exactly 100 cm ³ . This solution is nitrated immediately through a glass filter slide, filled into ampoules in an atmosphere of carbon dioxide and sterilized by heating in free-flowing steam for 30 minutes.

1, 2 or 3% strength morphine solutions can be prepared in a corresponding manner.

Example 3

Amylocaine chlorohydrate 1.0 g

Sodium chloride 0.65 g

V ₁₀ / n hydrochloric acid 0.8 cm ³

p-chloro-phenyl-ethyl alcohol 0.4 g

Distilled water ad 100 cm ³

The p-chloro-phenyl-ethyl alcohol is dissolved in the freshly distilled warm water by stirring or shaking and, after cooling, the common salt and the amylocaine are added. It is acidified with hydrochloric acid, made up to 100 cm ³ with distilled water and the solution is poured into ampoules. These are sterilized in free-flowing steam for 30 minutes.

Example 4

p-chloro-phenyl-ethyl alcohol is added to 0.4% with a little methyl cellulose and to achieve the Isotonic required amount of table salt (0.75%) and a little water-containing sodium phosphate (0.3%) in Water dissolved by vigorous stirring. It is sterilized at 120 ° for 20 minutes, suspended under Aseptic conditions microcrystals of deoxycorticosterone acetate with the addition of a small amount of wetting agents and ampouled.

If you take testosterone isobutyrate, oestradiol monobenzoate instead of deoxycorticosterone acetate or progesterone, crystal ampoules of the corresponding steroid hormones are obtained.

Example 5

Insulin crist. B.P 0.2g

(= 4000 I.U.)

Glucose 5.0 g

Lactic acid 0.12 g

1 / n sodium hydroxide solution q. See ad 3.2 to 3.5 p-chloro-phenyl-ethyl alcohol 0.3 g

Water ad 100 cm ³

The p-chloro-phenyl-ethyl alcohol is dissolved with warming in sterile water, adds glucose, dissolves lactic acid and insulin after cooling and adds the caustic soda. It is nitrated through a bacteria-proof filter and filled into ampoules.

jelly
Example 6

Pectin 1.0 g

Tragacanth 2.5 to 1.9 g

Glycerin 15 g

Borax 0.7 g

Boric acid 0.5 g

p-chloro-phenyl-ethyl alcohol ... 0.2 g

Water 8Oi

35

Borax, boric acid and p-chloro-phenyl-ethyl alcohol are dissolved in 80 cm ^{3 of} water with warming and vigorous stirring. On the other hand, tragacanth and pectin are rubbed with glycerine and the buffered solution of p-chlorophenyl ethyl alcohol is added to the mixture obtained.

lotion

Example 7

Calamine (zinc oxide with approx

0.5% ferric oxide) 15.0 g

Zinc oxide 5.0 g

Bentonite 3.0 g

Sodium citrate 0.5 g

Glycerine 5 cm ³

p-chloro-phenyl-ethyl alcohol 0.3 g

Distilled water ad 100 cm ³

Calamine, zinc oxide and bentonite are rubbed with a solution of sodium citrate and p-chloro-phenylethyl alcohol, prepared by vigorous stirring or shaking, in about 70 cm ^{3 of} water. The glycerine is added and the volume is made up to 100 cm ³ with water.

eye drop
Example 8

In 11 sterile water or 11 sterile, isotonic saline solution, which can be buffered in the usual way, dissolve 2 cm ^{3 of} p-chloro-phenyl-ethyl alcohol while warming and shaking well. Man

ίο gives 20 g of atropine sulfate or 13 g of ephedrine hydrochloride or 30 g pilocarpine hydrochloride or 1 g zinc sulfate in one under aseptic conditions 1-1 volumetric flask and fills up to the 1-1 mark with the solution prepared above. The solutions obtained in this way are filled into sterile eye dropper bottles.

Claims (1)

PATENT CLAIM: Use of p-chloro-phenyl-ethyl alcohol, ao preferably in a concentration of 0.2 up to 0.4%, as a preservative for pharmaceutical or cosmetic preparations containing water.