CS261014B1 - A method of making sterile or microbially safe ointments and suppositories - Google Patents

Abstract

The solution relates to a method for producing sterile or microbially harmless ointments and suppositories based on an anhydrous lipophilic base, containing neomycin sulfate. The production consists in that neomycin sulfate, preferably with a particle size of the substance of 10 to 40 μm, is dispersed in a part of the molten base, for example in 10 to 20% by weight of the total amount and heated to a temperature of 80 to 100 °C for 50 to 70 min, after cooling to a temperature of 35 to 50 °C, the remaining part of the base with the addition of another active substance or substances is added with constant homogenization, after which the mixture is cooled to room temperature, i.e. 15 to 25 °C, with continued homogenization. The produced suppositories and ointments are fully suitable for medical use and meet the requirements of CsL 3.

Description

The invention relates to a process for the production of sterile or microbial-free ointments and suppositories containing neomycin sulphate, based on an anhydrous lipophilic base.

As is known, neomycin sulfate is an active ingredient of clinically used and mass-produced preparations, particularly skin and eye ointments or suppositories. These preparations are applied for their anti-infectious (antimicrobial) effect and may also contain other antibiotics (zinc-baoitracin, polymyxin B, gramicidin, etc.) or other active substances, for example corticosteroids. A generally desirable property of these compositions is microbiological safety or sterility. Microbiological safety is required because the preparations come into contact with an open wound and it is therefore not desirable that exposed tissue be exposed to a possible secondary infection. The sterility of the ointment and suppository bases can be ensured by suitable technological interventions, for example heat; similarly, the sterility of ointment tubes and heat-sealable suppository films are assured.

In the case of neomycin sulfate, the situation is complicated by the fact that manufacturers of this antibiotic are not always able to ensure its sterile quality; it may occasionally be that the originally sterile substance is contaminated by microbial contamination outside its own spectrum of activity. For this reason, as required by CsL 3, microbiological safety is checked for each substance supply by culturing the sample on masopepton agar at 20 ° C for 3 to 5 days. The most common are contamination by unidentified rod-like microbes. Since any contamination of the neomycin sulfate substance is unacceptable according to the pharmacopoeial criteria, it must be removed or disposed of before further processing of the substance into a dosage form.

Commonly used sterilization methods, however, have proved to be unsuitable or unusable for the contaminated substance of neomycin sulfate. Residues remain after sterilization with ethylene oxide (Ophtalmica, Vol. 1, p. 343, 1975; Wissenschaftliche Verlagsgesellschaft, Stuttgart; LH Sutaria, FH Williams, Pharm. J. 186, 311, 1961; H. Klaushofer, M. Nekola, Pharm. Ind. 34, 359 (1962). Eye ointments emphasize the direct danger of ethylene oxide residues in the eye causing damage (Mc Donald, Kasten, Bull. Parent. Drug, Assoc. 27, 153, 1973). Also gamma-ray sterilization is unsuitable because it reduces the biological activity of neomycin.

Other methods relate to the decontamination of neomycin sulfate in an aqueous solution by heating in the presence of bactericides at a temperature of 98 to 100 ° C for 30 min. It is also possible to filter the aqueous neomycin sulfate solution through a sterile filter (Extra Pharm. Martindale,

28th Ed., Pp. 1 188, 112-f). Since for the application of neomycin sulphate in ointments or suppositories, the presence of even a minimum amount of water is undesirable for the possibility of rapid degradation (loss of efficacy), the aforementioned methods are not applicable in the art for the production of neomycin sulphate ointments and suppositories.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the decontamination of neomycin sulphate in the manufacture of ointments and suppositories which is reliable, technologically undemanding and does not impart foreign, undesirable excipients (e.g. water) to the formulation. in particular microbiological safety (principles of good manufacturing practice as required by the World Health Organization). This task has been solved by finding suitable measures and conditions that could be used in conventional ointment and suppository technology and included harmoniously and non-violently in the sequence of individual manufacturing operations.

These drawbacks are eliminated by a process for the production of sterile or microbially safe ointments and suppositories containing neomycin sulphate by dispersing the active ingredient in an ointment or suppository base, homogenizing and adding another active ingredient according to the invention, which consists in first dispersing neomycin sulphate in less than 1/3 of the total amount of ointment or suppository base at 80 to 100 ° C, the dispersion is maintained at this temperature for 50 to 70 min, after cooling to 35 to 50 ° C, the remaining portion of the ointment base is added while homogenizing containing further active ingredient (s), whereupon the mixture is cooled to 15-25 ° C with continued homogenization.

Suitably, 10-20% by weight of neomycin sulphate is used in the process according to the invention. of a total amount of mask or suppository base and a neomycin sulfate substance having a particle size of 10 to 40 µm.

The process according to the invention is very simple and is logically placed at the beginning of the production process. The melting of the individual components of the lipophilic base takes place first with part of the total amount, at the experimentally found optimal temperature and for the optimum time, with simultaneous decontamination of neomycin sulfate, which is dispersed at once in this part of the base. Although at this stage the production cycle is somewhat prolonged, this prolongation is in many ways overcome by the fact that the resulting product, i.e. ointment or suppository, is reliably guaranteed for microbial safety.

In the following stages, the production process is then terminated according to the usual regulation for the particular product without any extraordinary interventions.

worked out

As the results of the trials of the inventive process have shown, the optimum temperature and time to achieve the desired effect is about 90 ° C and 1 h, which is the temperature and time at which neomycin remains sufficiently stable and any contamination present is reliably destroyed. Heating at a higher temperature for a shorter time or vice versa at a lower temperature for a longer time is possible, but neither useful nor necessary, both for the risk of decomposition of the active substance and for unnecessary energy consumption and prolonging the production time.

Table 1 shows the effect of temperature and duration of decontamination on the biological activity of neomycin sulfate dispersed in an ointment base.

Table 1

Temperature las in min

Biological efficacy in

70 101.0

70 101.0

60 100.9

65 100.8

100 60 101.3

The results are within the limits of the permitted standard with an overload of 15% by weight of neomycin sulphate. above the declared quantity. This exaggeration is used in the production of neomycin-containing dermal preparations according to standard long-standing manufacturing practice.

The results of the microbiological inspection of the formulations prepared according to the invention are shown in Table 2 (temperature 90 ° C, time 1 h). The control was performed according to the GsL 3 method described above.

Table2

Formulation by Number of Batches Tested The number of matching batches of the example

13 13

3 3

5 5

6 6

The measures of the method according to the invention have proved to be very effective, capable of eliminating the occasionally inadmissible contamination of the neomycin sulfate substance, e.g., gram-negative bars, as mentioned above; they allow processing of such substances of neomycin sulphate, which would have to be suspended or eliminated from production due to a control test.

Further details of the process according to the invention are given in the following examples, which are illustrative but not limiting. The amounts of the individual components are given in percent by weight.

Example 1

Eye ointment

Ingredients:

Lanolin

Liquid Paraffin Neomycin Sulphate Zlnk-bacitracin White Vaseline

10.00

10.00

0.38

0.55 and 100.00

Workflow:

Neomycin sulphate with a particle size of 10 to 40 µm is suspended in 1/5 to 1/10 of the total amount of molten ointment base at 90 ° C with stirring, and the mixture is stirred at that temperature for 1 h. to a temperature of 40 ° C and the remainder of the base to which zinc bacitracin is premixed is added and homogenized with slow cooling to room temperature (15-25 ° C).

Example 2

Eye ointment II

Ingredients:

Lanolin

Neutycin Sulfate Zinc Bacitracin Hydrocortisone Acetate White Vaseline

12.00 8.00 0.38 0.55 0.50 ad 100.00

Workflow:

As in Example 1; the hydrocortisone acetate is mixed with the zinc bacitracin into the remainder of the base.

Example 3

Skin ointment

Ingredients:

Lanolin 23,00 Cetyl alcohol 2,00 White wax 2,00 Ceresin white 2,50

Neomycin sulphate

Zinc bacitracin

Vaseline white

Workflow as in Example 1.

Example 4

Veterinary vaginal suppositories

Ingredients:

Karbachol

Neomycin sulphate

Zinc bacitracin

Diethylstilbestrol

Suppository base (glycerol ester with lauric and stearic acid)

0.38

0.55 to 100.00

0.07

16.42

6.57

0.45 to 100.00

Workflow: as in Example 1; the homogenized mixture of all components is made into a suppository.

All ointments and suppositories prepared according to Examples 1 to 4 according to the method of the invention were sterile or microbially safe and fully complied with the requirements of the Cs 3.

Claims (3)

A process for the production of sterile or microbially safe ointments and suppositories based on an anhydrous lipophilic base, containing neomycin sulphate, dispersing the active ingredient in an ointment or suppository base, and after adding the other active ingredient by homogenization, characterized in that the neomycin sulphate is first dispersed in less than 1/3 of the total amount of the camouflage base or suppository base at a temperature of 80 to 100 ° C, the dispersion is maintained at this temperature for 50 to 70 minutes, after cooling to 35 to 50 ° C, the remainder is added a mask or suppository base containing the further active substance or substances, whereupon the mixture is cooled to a temperature of 15 to 25 ° C while continuing to homogenize. 2. A process according to claim 1, wherein from about 10% to about 20% by weight is used to disperse neomycin sulfate. of the total amount of mask or suppository base. 3. A process according to claim 1 or 2, characterized in that a neomycin sulfate substance having a particle size of 10 to 40 .mu.m is used.