DD258745A5 - METHOD FOR PRODUCING A PRIMYC-CONTAINING AND, IF APPROPRIATE, ONE OR MULTIPLE ANTIBCATERIAL ACTIVE SUBSTANCES CONTAINING COLLOIDAL GRUNDGELS - Google Patents

Abstract

The invention relates to a process for the preparation of a primycin-containing and optionally one or more antibacterial agents containing base gel, which can be processed well to pharmaceutical preparations and the like. With a relatively high primycin content. The process is characterized in that 5-30% Primycin dissolved in 95-70% N-methyl-2-pyrrolidone at a temperature of 50-150C (possibly with stirring), then optionally the thus obtained base gel at a temperature of 35 -40C mixed with an aqueous solution of one or more antibacterial agents and finally cools only Primycin or Primycin and the or the antibacterial agents containing active substances as base gel to room temperature. As antibacterial substances antibiotics can be used.

Description

Field of application of the invention

The invention relates to a process for the preparation of a primycin-containing and optionally one or more antibacterial active substances containing colloidal base gel.

Characteristic of the known state of the art

Primycin is a macrolide antibiotic which has been characterized in the specialist literature (J.Chem.Soc.Perkin I, page 816, 1974) by a single formula by the formula {5- [18- (aD-arabinofuranosyloxy) -2 -butyl-3,7,11,15,19,21,23,25,27-nonahydroxy-4,16,32,34-tetramethyl-1-oxo-oxacyclohexatriakonta-16,32-dien-35-yl] - 4-hydroxyhexyl} guanidinium sulfate. Although the literature has characterized the structure by a single formula, it is a multicomponent antibiotic complex (HU-Pas 2125/84 and 2869/84). Primycin is a natural antibiotic produced by the fungi strain Thermopolyspora galleriensis, the production of which by fermentation is described in HU-PS 153593. Primycin is a broad spectrum antibiotic that is effective against Gram positive bacteria, even against polyresistant human pathogenic strains. Resistance to primycin has not yet developed. With other antibiotics Primycin shows a Synergisrnus (HU-PS 158241). Primycin is successfully used in dermatology, surgery, ophthalmology, urology, gynecology, phthisiology and in the treatment of household and burn injuries. Primycin has proven to be particularly effective in the treatment of acne vulgaris in dermatology.

The therapeutic use of primycin is made very difficult by its extremely poor solubility, it is quite difficult to prepare such drug forms from which the drug is easily releasable. To remedy this problem, a stable heterocolloid containing 0.2% Primycin is formed according to the HU-PS 173708 in an aqueous-alcoholic medium. However, the primycin-containing heterocolloid thus obtained has two fundamental disadvantages; on the one hand, the active substance is no longer biologically accessible after evaporation of the solvent and, on the other hand, the limit of the achievable concentration is only 0.2%. This limits the applicability of the composition, because the known antibiotic preparations used for the treatment of acne vulgaris have an active ingredient content of 1-2%.

Object of the invention

The aim of the invention is to provide a suitable primycin-containing and optionally further. Antibakterielle active ingredients containing base gel from which advantageous properties having pharmaceutical and / or pharmaco-cosmetic preparations can be prepared.

Explanation of the essence of the invention

The invention is based on the surprising finding that primycin preparations containing any pharmaceutical form can be produced with a primycin concentration of 0-30%.

It has surprisingly been found that can be obtained by dissolving primycin in N-methyl-2-pyrrolidone (hereinafter called NMP) a base gel with stable structure, from the various Primycinpräparate with a much higher primycin content than before, ie in the known preparations , can be made. It has been found that if 5-3Og Primycin dissolved in 100 ml of N-methylpyrrolidone-2 at TOO ⁰ C and the solution cools, a stable gel is obtained which is used both directly and as a basis for any conventional preparations (eg Gels, ointments, solutions, etc.) can be used.

The invention thus relates to a process for the preparation of a primycin-containing colloidal base gel, which is characterized in that 5-30% Primycin in 95-70% N-methyl-2-pyrrolidone at a temperature of 50-150 ⁰ C, if desired under Stir, dissolve and then cool the solution to room temperature.

In an advantageous embodiment of this process, 10-20% primycin is dissolved in 90-80% N-methylpyrrolidone-2. The process may preferably be carried out at a temperature of 70-100 ⁰ C.

Optionally, for the preparation of a Primycin in addition to one or more basic antibacterial agents containing the method also be designed so that after dissolving 5-3O ⁰ C Primycin in 95-70% N-methylpyrrolidone-2 at 50-150 ⁰ C. mixing the base gel at 35-40 ⁰ C with an aqueous solution of the one or antibacterial agents and then the mixture is cooled to room temperature. Preferably, 10-60% of a primycin-containing base gel containing 5-30% primycin and 95-70% N-methylpyrrolidone-2, with 90-40% of an aqueous 30-70% solution of an antibacterial agent, preferably an antibiotic , mixed at a temperature of 35-4O ⁰ C and then cooled to room temperature,

Antibacterial pharmaceutical and / or pharmaco-cosmetic preparations can be prepared by mixing a Primycin and other antibacterial agents - especially antibiotics - containing colloidal base gel with conventional carriers, fillers and / or excipients and formulated to pharmaceutical and / or pharmaco-cosmetic preparations ,

The preparations can be completed in conventional forms - such as gels, ointments, solutions sprays or other forms suitable for local application.

It is possible to proceed with advantage by completing the preparation as a gel, ointment, solution, spray, solution for brushing, scattering powder or in the form of another locally applicable pharmaceutical preparation or by application to a sterile gauze sheet in the form of bandages or patches.

N-methylpyrrolidone-2 is a solvent often used in cosmetic preparations, with the beneficial properties - i. low toxicity and unlimited miscibility with water, organic solvents and fats - use is made. These properties make N-methylpyrrolidone-2 particularly suitable for the preparation of pharmaceutical compositions containing primycin, because in the formulation of this gel with the aid of any solvents or excipients, after evaporation or after absorption of the solvent during use, the original gel structure is restored by itself becomes. This promotes primycin penetration into the biological aqueous and lipid phases.

Spontaneous gelation has been studied with various solvents as well as various pharmaceutical agents. The following solvents were used: methanol, ethanol, isopropanol, n-butanol, isobutanol, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, η-hexane, benzine, benzene, toluene, petroleum ether, ether, dimethylformamide, dimethylsulfoxide and isopropylmiristate. It was found that none of the above solvents was suitable for forming a stable gel with primycin.

Although other solvents (eg, ethanolamine, diethanolamine, triethanolamine, dimethylformamide, dimethyl sulfoxide) form a gel with primycin, in the tested concentration range (5-30%), neither pure nor cold, a pure gel is formed, so that these solvents in this Cases were unsuitable for drug production.

Also, gelation between other pharmaceutical agents and N-methylpyrrolidone-2 as a solvent was tested. The following active ingredients were used: gentamycin, doxicyclin, oxolinic acid, nalidixic acid, drotaverine, theophylline, acetylsalicylic acid, papaverine, indomethacin. A stable and transparent gel was not formed in any of the above cases.

Spontaneous gelation, which results in the formation of a stable clear gel, occurs only as a result of the interaction of primycin and N-methylpyrrolidone-2.

The possibility of the formation of two active substances - u.a. of primycin different active ingredients - containing mixed gels was z. Using gentamycin, doxycycline, oxytetracycline, chloramphenicol, etc. It was found that when the solution of primycin formed with N-methylpyrrolidone-2 was added to the tested antibiotics in solid form, no gel formation takes place. On the other hand, when doxicyclin or gentamycin is dissolved in the water and the resulting solution is added to the primycin solution formed with N-methylpyrrolidone-2, gelation begins and two active agents (i.e., Primycin + Doxicycline and Primycin + Gentamycin), respectively, are obtained.

The specific interaction between primycin and N-methyl-pyrrolidone-2 on the one hand the temperature dependence of the solubility (between 0 and 100 ⁰ C by more than two orders of magnitude), and on the other hand the composition of the Primycins be attributed to several components.

The stability and the change in the chemical or microbiological activity of the primycin base gel prepared according to the invention was tested. The used, 20% of primycin-containing base gel was allowed to stand for 5 hours at 100 ⁰ C and stored for one month at room temperature and for one month at + 5 ⁰ C. During storage, neither the structure nor the chemical composition or the microbiological activity of the gel was changed. This means that gelation does not alter the properties of the primycin that are important for pharmaceutical use. The thus formed stable gel form can be used as a basis for the preparation of primycinhaltigen human or veterinary medical preparations. The pharmaceutical preparations thus prepared may contain as active ingredient either only primycin (monotherapy) or combined with other active substances (eg antibiotics, chemotherapeutic agents, epithelializing agents, topical inshetics, etc.).

-J- MO

embodiments

Further details of the present invention can be found in the following examples without limiting the scope of protection to these examples.

example 1 Ground gel with a primycin content of 20%

20.0 g Primycin are dissolved in 80.0 g of N-methyl-2-pyrrolidone at 100 ⁰ C on a water bath. The gelation already begins during the dissolution and is terminated after cooling to room temperature. The basic gel thus obtained can be used for the preparation of various pharmaceutical preparations.

Example 2

Aqueous gel containing 0.5% primycin ·

9.75 g of Avicell RC 581 (FMC Corporation, Philadelphia, USA) is homogenized with 87.75 g of distilled water in small portions at room temperature with constant stirring. The gel thus obtained is further homogenized with 2.5 g of 20% basic gel.

Example 3

1.0% primycin-containing aqueous gel 9.50 g of Avicell RC 581 (FMC Corporation, Philadelphia, USA) are homogenized with 85.5 g of distilled water in small portions at room temperature with constant stirring. The resulting gel is further homogenized with 5.0 g of 20% base gel.

Example 4

1.0% primycin-containing alcoholic gel 5.0 g 20% basic gel are dissolved in 10.0 g of 96% alcohol with gentle heating.

8.5 g of Avicell RC 581 (FMC Corporation, Philadelphia, USA) are homogenized with 76.5 g of distilled water in small portions at room temperature with constant stirring. The gel thus obtained is mixed after further homogenization with the primycin-containing alcoholic solution.

Example 5.

2.0% primycin-containing aqueous gel 9.00 g Ultraamylopectin (SERVA fine biochemistry, Heidelberg, Germany) are homogenized with 81.0 g of distilled water in small portions at room temperature with constant stirring. The resulting gel is homogenized with 10.0 g of 20% basic gel.

Example 6

10.0% primycin-containing aqueous gel 5.00 g of Avicell RC 581 (FMC Corporation, Philadelphia, USA) are homogenized with 45.0 g of distilled water in small portions at room temperature with constant stirring. The resulting gel is further homogenized with 50 g of 20% basic gel. _

Example 7 '

10% primycin-containing alcoholic gel 50.0 g of a 20% basic gel are homogenized with 50.0 g 96% alcohol.

Example 8

Carbowax Ointment Containing 0.5% Primycin 44.50g Carbowax400 (Polyoxethenum 400, USNF), 15.10g Carbowax 1540 (Polyoxethenum 1540, USNF), 21.45g Carbowax 4000 (Polyoxethenum 4000, USNF), 9.75g Glycerin, 1 , 85g alcohol cetylstearilicus and 4.85g sorbitol are melted together on a water bath.

The resulting ointment base is homogenized in small portions with constant stirring with 2.5 g of a 20% base gel.

Example 9

2.5% primycin-containing alcoholic ointment 2.5 g of a 20% basic gel are dissolved in 20.0 g of 96% alcohol with gentle heating.

35.25g Carbowax 400.12g Carbowax 1540.17.05g Carbowax 4000, 7.75g glycerol, 1.55g alcohol cetylstearilicus and 3.80g sorbitol are melted together on a water bath.

The resulting molten ointment base is mixed in small portions with constant stirring with the alcoholic solution of active substance. The ointment is supplemented with Carbowax 400 to 100.00g and cooled with stirring.

example

2% Primycin Carbowax Ointment 38.60g Carbowax 400.13.20g Carbowax 1540.18.70g Carbowax 4000, 8.5g Glycerin, 2.80g Alcohol cetylstearilicus, 4.20 sorbitol and 5.0g Lactyl are melted together on a water bath ,

The molten ointment base thus obtained is homogenized in small portions with continuous stirring with 10.00 g of a 20% basic gel.

Example 11

10.0% Primycin containing alcoholic ointment

50.0 g of a 20% basic gel are homogenized with 20.0 g of 96% alcohol.

13,65g Carbowax400,4,65gCarbowax 1540,6,60gCarbowax4000,3,00g Glycerin, 0,6g Alcohol cetylsterilicus and 1,50g Sorbitol

are melted together on a water bath.

The molten ointment base is homogenized in small portions with constant stirring with the active ingredient-containing gel. The ointment is supplemented with Carbowax 400 to 100.0 g and cooled with stirring.

Example 12

2% Primycin containing solution

10.0 g of a 20% basic gel are dissolved in a mixture of 40.0 g of N-methylpyrrolidone-2 and 50.0 g of alcohol.

Example 13 Ointment containing Primycin and other active substances -

a) Ointment with a housing of primycin + hydrocortisone + nystatin component content (g)

Primycin 20.00

Hydrocortisone 20.00

Nystatin 20.00

N-methylpyrrolidone-2 (NMP) 40.00

20,00g of primycin and 40,00g N-methyl-pyrrolidone-2, a gel is prepared at 70 ⁰ C, which are added at room temperature with constant stirring nystatin, and hydrocortisone. From the obtained, very viscous solution, a gel is formed after standing for 24 hours.

b) Ointment containing 1% Primycin + 1% Hydrocortisone + 1% (3,00,000 IU) Nystatin Component Amount (g) Primycin + Hydrocortisone + Nystatin NMPGel 5.00 Alcohol cetylstearilicus' 10.00 Emulsifier E 2155 (T. Goldschmidt , Essen, Germany) 5.00 distilled water ad 100.00

The alcohol cetylstearilicus and the emulsifier E 2155 (stearyl alcohol polyglycol ether, production company: T. Goldschmidt, Essen, FRG) are melted together on a water bath with stirring at 60-70 ⁰ C. About 80% of the distilled water of the same temperature are added with constant stirring in a thin stream. The resulting gel is further homogenized with the primycin hydrocortisone + nystatin NMP gel as prepared above and made up with distilled water. ,

The resulting ointment can be used to treat bacterial and fungal infections.

Example 14 Preparation for the treatment of human Mastizis Component amount, g (for 100.00 g)

20% primycin NMP base gel 10.0 ×

Glycerin 10.00

Tannin 5.00 "

Basic ointment. 75.00

100.00

Preparation of the basic ointment Component - Quantity, g

Sodium lauryl sulfate 4.00

Distilled water 1.50

Alcohol cetylstearilicus 36.00

Paraffinium quidum "- 20,00

Vaselinum album, 40.00

The sodium lauryl sulfate and the boiled water are mixed with the cetylstearyl alcohol melted on a water bath and heated to about 90 ^° C. The liquid is heated to about 110-120 ⁰ C and stirred vigorously until the strong foaming stops. The cooled liquid is mixed with a molten mixture of liquid paraffin and vaseline and stirred until cool.

40.0 g of the ointment thus obtained are heated on a water bath to about 65-70 ⁰ C. The mixture is-out in a pre-heated mortar, after which a polymer formed from 1.0 g Solitio conservans and 50.0 g of distilled water and heated to about 65-70 ⁰ C with constant stirring mixture is added in a thin stream. The ointment is stirred vigorously until it reaches the gel state and then carefully cooled until it cools down, and it is supplemented with distilled water to 100.0 g.

Ointment containing Primycingrundgel

An amount of tannin as indicated above is suspended in glycerol in a mortar, then homogenized with primycin NMP ground gel. After adding the basic ointment (room temperature), the mixed components are completely homogenised.

Example 15 vanishing cream Component amount, g (for 100.00 g)

Primycin NMP base gel (20%) 5.00

Cetyl alcohol 5.00

Emulsifier E 2155 (T. Goldschmidt, Essen, FRG) 5.00

Alcohol concentralissimus · 5,00

Distilled water ad 100,00

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The Cetylalkoho ^ the emulsifier E 2155 (Stearylaikohol polyglycol ether) and a large part of the distilled water are melted together on a water bath at 60-70 ⁰ C with constant stirring. The primycin NMP base gel is added in portions with constant stirring, then the concentrated alcohol is added and supplemented with distilled water.

Example 16 night cream component

Primycin-NMP base gel (20%) Alcohol cetylstearilicus Stearinum Sodium lauryl sulfate Solutio conservans (Ph. Ed. Vl.) Solitolum Glycerin Distilled water

Quantity, g (for 100.00 g)

5.00 3.15 7.00 0.35 0.70 2.45 30.00 100.00

The components of the cream base are melted under stirring at 60-70 ⁰ C, after which the primycin base gel was added with continued stirring in portions, and the cream is supplemented with distilled water.

Example 17

Primycin-containing litter powder Component Primycin-NMP base gel (20%) Zinc oxide

Quantity (g) 10.00 40.00 50.00

100.00

The zinc oxide is thoroughly mixed with the talc and then sieved through a vial. The powder mixture is homogenized with the Primycin NMP gel and dried at 40 ⁰ C for 24 hours in a drying oven. The dried powder mixture obtained is sieved again (mesh size 0.16 mm) and then homogenized again. A white homogeneous powder mixture is obtained.

Example 18

Primycin-containing litter powder Component Primycin-NMP base gel (20%) N, N-Dimethyl-acetamide Zinc oxide

Quantity, g 10.00 5.00 40.00 45.00

The primycin NMP base gel is dissolved in Ν, Ν-dimethyl-acetamide with heating and the solution is sprayed onto a prepared according to Example 15 zinc oxide-talc powder mixture. The sprayed powder mixture is left to stand in an oven at 4O ⁰ C 24 hours long and sifted the dried powder mixture. (Mesh size 0.16 mm) After homogenization, a white homogeneous powder mixture is obtained.

Example 19 Primycin + gentamycin containing mixed base gel component

Primycin NMP base gel (20%) Gentamycin sulfate Distilled water

Quantity, g (for 100.00 g)

50.00 20.00 30.00

The gentamicin compound is dissolved in distilled water on a water bath at 40 ° C and at this temperature the primycin NMP base gel is added. A water-clear transparent solution is obtained, which solidifies within 24 hours to a glassy transparent gel. The mixed base gel thus obtained contains 10% primycin and 20% gentamycin.

Example 20 Primycin and doxicycline containing mixed base gel component

Primycin NMP base gel (20%) Doxicycline Distilled water

Quantity, g (for 100.00 g)

50.00 20.00 30.00

The doxycycline is dissolved in distilled water on a water bath at 40 ° C, at which temperature the primycin NMP base gel is added. A water-clear transparent solution is obtained, which solidifies at room temperature within 24 hours to a glassy transparent gel. The mixed base gel thus obtained contains 10% primycin and 20% doxycycline.

Example 21 Preparation for the treatment of mastitis in the lactation period. Component quantity, g {for 100.00 g)

Primycin and gentamicin-containing mixed base gel · 10.00

Emulsifier E2209 (T Goldschmidt, Essen, FRG) 5.00

Prokain hydrochloride 1.60

Distilled water ad 100,00

To the aqueous procaine hydrochloride solution is added the emulsifying agent E 2209 (cetyl alcohol polyglycol ether) and thereafter, with constant stirring, the primycin-gentamycin-containing mixed base gel. A paste-like preparation suitable for the treatment of mastitis is obtained, which is suitable for use in the lactation period.

Example 22 A preparation for the treatment of mastitis in the dry period

component , Quantity, g (for 100.00 g) Primycin and gentamycin containing mixed base gel 10.00 Tagat R-40 (T. Goldschmidt, Essen, FRG) 5.00 Ung. simplex 35,00 glycerin 50,00 Composition of Unguentum simplex (Ph. Hg. Vl) component Quantity, g (for 100.00 g) Lanalcolum 6.00 Alcohol cetylstearilicus 3.00 Vaselinum album ophthalmicum 12,00 Vaselinum album 79,00

Ung.simplex and Tagat R-40 are added to the glycerol, after which the primycin and gentamycin-containing mixed base gel is added with constant stirring.

A paste-like preparation suitable for the treatment of mastites is obtained.

Example 23 A preparation for the treatment of mastitis in the dry period Component amount, g (for 100.00 g)

Primycin and gentamicin containing mixed base gel 10.00

Emulsifier E 2209 (T. Goldschmidt, Essen, FRG) 5.00

Ung. simplex '30,00

Oleum helianthi 55,00

The emulsifier E 2209 (cetyl alcohol polyglycol ether) is melted on a water bath and homogenized with the Unguentum simplex. The primycin and gentamycin-containing gel is uniformly homogenized in the cold, after which the sunflower oil is added in portions.

Example 24 A preparation for the treatment of mastitis in the dry period Component amount, g (for 100.00 g)

Primycin and doxicycline containing mixed base gel 10.00

Tagat R-40 (T. Goldschmidt, Essen, FRG) 5.00

Ung. simplex 35,00

Glycerin 50.00

The Unguentum simplex and Tagat R-40 are added to the glycerin, after which the Primycin and Doxicyclin containing mixed base gel is added with constant stirring.

A preparation suitable for the treatment of mastitis is obtained.

Claims (5)

- 1 - ZÜÜ / 4b claims; 1. A process for the preparation of a primycin-containing and optionally one or more antibacterial agents containing colloidal base gel, characterized in that 5-30% and primycin in 95-70% N-methyl-2-pyrrolidone at a temperature of 50-150 ⁰ C, optionally with stirring, then, if appropriate, the base gel thus obtained at a temperature of 35-40 ⁰ C mixed with an aqueous solution of one or more antibacterial agents and finally the only primycin or Primycin and the or the antibacterial agents as active substances containing base gel cools to room temperature. 2. The method according to claim 1, characterized in that one dissolves 10-20% Primycin in 90-80% N-methyl-2-pyrrolidone for the preparation of a primycin-containing base gel. 3. The method according to claim 1 and 2, characterized in that dissolving the Primycin in N-methylpyrrolidone-2 at a temperature between 70 and 100 ⁰ C. 4. The method according to claim 1-3, characterized in that for the preparation of a Primycin and another antibacterial active ingredient, preferably in the form of an antibiotic, containing colloidal base gel 10-60% of a primycin-containing colloidal base gel containing 5-30% Primycin and 95 Contains -70% N-methylpyrrolidone-2, with 90-40% of an aqueous 30-70% solution of an antibacterial agent, preferably an antibiotic, at a temperature of 35-4O ⁰ C mixed and then cooled to room temperature. 5. The method according to claim 4, characterized in that 50% of a primycin containing only as the active ingredient colloidal base gel mixed with 50% of a 40% aqueous solution of an antibiotic at 40 ⁰ C.