DE3632222A1 - Compositions of gyrase inhibitors which can be used topically - Google Patents

Abstract

The invention relates to compositions, which can be used topically, of the general formula (I) <IMAGE> in which R<1>, R<2>, R<3>, X and A have the meanings stated in the description, which contain as active ingredients compounds which belong to the group of gyrase inhibitors and have antibacterial activity.

Description

The invention relates to topically applicable preparations, which as an active ingredient in the group of gyrase inhibitors counting antibacterial compounds of the general formula

included in which

R1 for methyl, ethyl, propyl, isopropyl, cyclopropyl, Vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, Amino, methylamino, dimethylamino, ethylamino, Phenyl, 4-fluorophenyl, 2,4-difluorophenyl,  R² for hydrogen, alkyl with 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, R³ for methyl or a cyclic amino group such as

stand in what

R⁴ for hydrogen, alkyl with 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCl₂-S-, CFCl₂-SO₂-, CH₃O-CO-S-, benzyl, 4-aminobenzyl,

R⁵for hydrogen, methyl, R⁶ for hydrogen, alkyl with 1 to 4 carbon atoms, Phenyl, benzyloxymethyl,  R⁷ for hydrogen, amino, methylamino, ethylamino, Aminomethyl, methylaminomethyl, ethylaminomethyl, Dimethylaminomethyl, hydroxy, hydroxymethyl, R⁸ represents hydrogen, methyl, ethyl or chlorine, X for hydrogen, fluorine, chlorine or nitro and A stands for N or C-R⁹, in which R⁹ for hydrogen, halogen such as fluorine or chlorine, Is methyl or nitro,

or

Also together with R¹ a bridge of the structure can form.

The gyrase inhibitors can be applied topically Preparations as such or as a salt with an acid or base can be applied. Also use as Prodrug, for example of esters, is possible.

The gyrase inhibitors are in the form of topical applicable preparations for treatment or prophylaxis of infections, diseases and injuries to the skin including topical burns. Also treatment or prophylaxis lower down or systemic infections is through a topical application of gyrase inhibitors possible.  

The topically applicable preparations according to the invention contain 0.05 to 30, preferably 0.05 to 20% by weight Active ingredient of formula (I).

Particularly preferably contain the invention topically applicable preparations 0.1 to 5% by weight Active ingredient of formula (I).

In particular, ciprofloxacin, norfloxacin, Perfloxacin, Amifloxacin, Pirfloxacin, Ofloxacin and / or Enoxoacin contained in the preparations mentioned.

A. General part

Topical preparations of the invention include Solutions, sprays, lotions, gels, ointments, creams, Powders, powder sprays, pastes, suspensions, emulsions, Foams and sticks that contain the active ingredient of formula I, optionally also contain several active ingredients.

The topical application of the present formula I. also takes the form of plasters, spray plasters, Occlusive dressings, envelopes and controlled delivery systems. The active ingredients in these preparations be contained in dissolved or suspended form.

Ointments contain hydrocarbon gels as the basis, Lipogels, absorption bases, W / O ointment bases, Mixed emulsions or polyethylene glycols.  

Creams contain O / W basics.

Pastes contain an ointment or cream base high proportions of powdery components such as zinc oxide, Talc, starch or titanium dioxide.

Gels contain solvents such as water, ethanol, Isopropanol or propylene glycol and are using of gel formers such as cellulose ethers, alginates, Polyacrylates, bentonite, gelatin, tragacanth, polyvinyl pyrrolidone or polyvinyl alcohol. Also the Use of lipophilic gel bases or microemulsions is possible.

Powders contain powdered additives such as starch, Stearates, silicon dioxide, clay, magnesium carbonate, talc, Cellulose, zinc oxide and especially lactose.

Stabilizers, antioxidants, Preservatives, humectants, moisturizers, Solvents or auxiliaries for improvement of penetration and effectiveness are added.

Examples of penetration enhancers are propylene glycol, Polyethylene glycol, dimethyl sulfoxide, decyl methyl sulfoxide, Azone, N-methyl-pyrrolidone, diethyltoluamide, Ethanol, isopropyl myristate, isopropyl palmitate, Oleic acid and its esters, medium-chain triglycerides, Dimethyl isosorbitol, 2-octyldodecanol, branched chain Fatty acid esters, benzyl alcohol, urea, salicylates and Surfactants.  

B. Adhesive topical preparations

As far as the treatment of animals is concerned it turned out to be advantageous to adhere topically applicable To use preparations and the invention as explained in the following example.

Topical preparations according to the invention which are based both on wet as dry animals can be applied for example, characterized in that they

• a) 0.1-20%, preferably 0.1-5%, of an active ingredient Formula I,
• b) 1-40%, preferably 1-20%, of a water-soluble Gel- or lacquer-forming polymer,
• c) 40-98%, preferably 60-90%, of an organic, water-miscible solvent, the faster evaporates as water and in which Polymer does not dissolve,
• c) 0.1-10%, various additives, e.g. B. plasticizers, Suspending agents, antioxidants, Spreading agents, dyes etc.

contain.

Known per se are known for the preparation of the preparations Polymers or their salts suspended in a solvent, in which they are not soluble. The polymers  swell on the other hand in water to a gel. The active substance is either suspended or dissolved in the solvent. The solvent must be miscible with water and evaporate faster than water. The suspension can add the usual formulation aids be an easy to shake or homogeneous Ensure suspension. A plasticizer additive can may also be desirable to the forming film keep elastic later.

If such a suspension is poured onto a wet animal or sprayed, the polymer swells with the evaporation of the solvent into a gel that becomes a Lacquer or film layer dries out and the active ingredient incorporated. This layer stays on for a long time cling to the coat or skin and is caused by downpours or a dip bath only slowly - gradually - washed off.

The suspension is in about the same ratio Diluted water. Then it's still low viscosity, that Polymer does not yet swell, so that it deals with the can be easily applied to conventional devices. Here too forms after the solvent has evaporated Gel and later a film from, as already described above.

All macromolecular come as gel and film formers Compounds in question that are in the water-miscible, Do not dissolve organic solvents and after mixing swell with water to a gel that after Drying some kind of film there.  

If you follow a classification of macromolucal excipients, such as B. by Keipert et al. in Pharmacy 28, 145-183 (1973), especially ionic ones Macromolecules in their salt form for use. these are including sodium carboxymethyl cellulose, polyacrylic acid, Polymethacrylic acid and its salts, sodium amylopectin semiglycolate, Alginic acid and propylene glycol alginate as sodium salt, arabic gum, xanthan gum and guar gum.

Amphoteric macromolecules such as protein derivatives, e.g. B. gelatin are just as suitable as nonionic polymers e.g. B. methyl cellulose, other cellulose derivatives and soluble Strengths that meet the above requirements.

All water-miscible liquids are solvents suitable that do not solve the macromolecule and evaporate faster than water.

Consider z. B. alkanols such as ethanol and isopropyl alcohol; Ketones such as acetone, methyl ethyl ketone, glycol ether such as ethylene glycol monomethyl ether or ethyl ether.

It can be used in the preparation of the preparations according to the invention one or more of the type described above Solvents are used.

As further aids for such preparations are suitable:

• a) substances which can stabilize the suspension, e.g. B. colloidal silica, montmorillonite u. a.
• b) surfactants (contains emulsifiers and wetting agents), e.g. B.
  • 1. anionic, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monethanolamine z;
  • 2. cationic, such as cetyltrimethylammonium chloride;
  • 3. ampholytic, such as di-Na-N-lauryl- β -iminodipropionate or lecethin;
  • 4. non-ionogenic, e.g. B. polyoxyethylated rizimus oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether.
• c) Stabilizers to prevent the in some Chemical degradation agents such as Antioxidants, e.g. B. tocopherols, butylated hydroxyanisole.
• d) plasticizers for the elasticity of the film formers, e.g. B. glycerin, propylene glycol.

For the use of the topical preparations according to the invention to combat bacterial diseases of the People prefer to come in as application forms  the usual formulations of dermatology and cosmetics into consideration. Particularly worth mentioning are those that follow Do not apply to the skin in contact with water be washed off right away, i.e. those that form the film or water-repellent additives like the ones above included preparations mentioned. Wording of this Kind are z. B. solutions, sprays, lotions, ointments (here both emulsion ointments and suspension ointments and Pens analogous to insect repellent pens).

C. Liquid preparations with spreading agents

The preparations according to the invention, insofar as they are are in liquid form for better distribution Surfaces, especially on the skin, also spreading Oils are added.

Spreading oils include such oily liquids understood that are particularly good on the skin to distribute. They are known as such in cosmetics. According to a proposal by R. Reymer, Pharm. Ind. 32, 577 (1970) they can e.g. B. by their surface tension can be characterized against air, the less afterwards than 30 dynes / cm.

The following substances are particularly suitable as spreading agents considered:

Silicone oils of different viscosities

Fatty acid esters
such as ethyl stearate, di-n-butyl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols C₁₆-C₁₈, isopropyl myristate, isopropyl palmitate, capryl / capric acid ester of saturated fatty alcohols C oleyl ester, C₁oprop oleate, ₁₂-stoleyl, C₁oprop oleate, ₁₂-stoleyl oleate, ₁₂-C₂-stearyl, C₁oprop oleate, ₁₂, Oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as artificial duck pancreas fat, dibutyl phthalate, diisopropyl aidpate, the latter related ester mixtures and others

Triglycerides
such as caprylic / capric acid triglyceride, triglylceride mixtures with plant fatty acids of chain length C₈-C₁₂ or other specially selected natural fatty acids, partial glyceride mixtures of saturated and unsaturated, possibly also hydroxyl-containing fatty acids, monodiglycerides of C₈ / C₁₀ fatty acids and others.

Fatty alcohols
such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as B. oleic acid

The following are particularly suitable spreading oils: Isopropyl myristate, isopropyl palmitate, caprylic / capric acid ester of saturated fatty alcohols of chain length C₁₂-C₁₈, waxy fatty acid esters such as artificial Duckling glandular fat.  

D. plasters

Further topically applicable preparations of the present Invention are medical plasters for dispensing Active ingredients of formula I on the skin over a longer period Period.

The invention accordingly also relates to medical Patch for the administration of an active ingredient of the formula I to the skin, containing a top layer that made up a longitudinally transverse elastic, impregnated with a polymer or coated, preferably textile fabrics, knitted or knitted fabric in particular, a Reservoir layer and a peelable protective layer, wherein the reservoir layer is a polymer consisting of Polyisobutylene and / or its copolymers Contains entrainer and a resin.

Under polymer in the sense of this part of the invention preferably polyisobutylene and / or its copolymers Roger that.

For the purposes of the invention, polyisobutylenes are understood to be polyisobutylenes which, owing to the production process, have a molar mass distribution M _w / M _n of 1.5 to 3.5, preferably 2.0 to 3.0, and a viscosity average of the molar mass - again due to the production process - of 30,000 have up to 4,000,000 g / mol. The viscosity average of the polyisobutylenes to be used according to the invention is preferably 50,000 to 1,000,000 g / mol, particularly preferably 80,000 to 500,000 g / mol. The viscosity agents can be determined in a known manner according to Polymer Handbook, 3, Brandrup and FH Immergut, Wiley & Sons, New York, 1975, chap. IV, p. 35.

These polyisobutylenes have long been known and can e.g. B. according to US-PS 22 03 873 or DE-PS 7 04 038 can be produced with acidic catalysts.

Copolymers of isobutylene in the sense of the invention are those of isobutylene with 0.5 to 5 mol% conjugated Diolefins, preferably those with 4 to 6 carbon atoms, such as B. 1,3-butadiene, piperylene, 2,3-dimethylbutadiene, particularly preferred with isoprene, its molecular weights can be from 30,000 to 200,000 g / mol. These isobutene copolymers are also known. All polyisobutylene homopolymers are particularly preferred with a viscosity average of 80,000 to 500,000 used.

In the context of the invention, entraining agents are oils, Fatty acid esters, triglyerides, alcohols and / or fatty acids Roger that.

Under oils, in the sense of the medical plasters relevant part of the invention, high-boiling, aliphatic, araliphatic and / or aromatic Hydrocarbons understood, preferably paraffin oil, Purcellin oil, Perhydrosqualen- and solutions of microcrystalline Growing in oils, mineral oils, preferred  Oils whose boiling range is between 150 ° C and 400 ° C; furthermore unsaturated hydrocarbons with at least 16 carbon atoms such as B. oligomers of monoolefins such as Tetraisobutylene, pentaisobutylene, hexaisobutylene or also liquid polymers from diene (monoen) - (co) polymers. Examples of liquid polymers conjugated dienes are those from butadiene, isoprene, 1,3-pentadiene, 2,3-dimethylbutadiene, copolymers various dienes as well as liquid copolymers from a conjugated diolefin and small amounts of Monoolefins such as B. butene-1, isobutene, hexene-1, octene-1, Styrene with MW from 400 to 6000, preferably 800 to 3000 and iodine numbers from 200 to 500 and viscosities from 100 to 10,000 cP at 50 ° C.

Liquid polybutadiene polymers are particularly preferred, which are at least 90% 1,4-linked, whose Share of cis double bonds is more than 60% and whose molecular weights are 1000 to 4000.

Oils also include silicone oils of different viscosities, preferably with average molecular weights from 312 to 15,000, particularly preferably polydimethylsiloxanes understood.

Fatty acid esters are understood to mean those which at least 12 carbon atoms, preferably 15 to 46 carbon atoms, particularly preferably 16 to 36 carbon atoms. In particular, this means: ethyl stearate, Hexyl laurate, dipropylene glycol pelargonate,  Palmitic acid cetylester, isopropyl myristate, isopropyl palmitate, Capryl / Capric acid ester of saturated Fatty alcohols of chain length C₁₂-C₁₈, isopropyl stearate, Oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, artificial duckling glandular fat, respectively individually or in a mixture.

Triglycerides are pure or mixed esters of glycerol with fatty acids of chain length C₈-C₁₈ understood, preferably caprylic and / or capric triglycerides.

Fatty acids are saturated or unsaturated Fatty acids, preferably those with 12 to 24 carbon atoms, individually or in a mixture with one another, particularly preferred Oleic acid, understood.

Under oils in the sense of the invention are also Roger that: Sweet almond oil, avocado oil, sesame oil, castor oil, olive oil, Grape seed oil, clove oil, peanut oil, corn oil, hazelnut oil, Jojoba oil, Carthama oil and wheat germ oil, each individually or in a mixture.

Among resins, in the sense of the plasters Part of the invention, rosin, are dehydrated Rosin, glycerol ester of dehydrated rosin, Rosin glycerol ester, hydrogenated rosin, Hydrogenated rosin glycerol ester, pentaerythritol ester of hydrogenated rosin, methyl ester  of hydrogenated rosin, polymerized rosin, Polymerized rosin glycerol esters, terpene resins, Coumarone / inden resins, hydrogenated petroleum resins, rosin modified with maleic anhydride and Rosin derivatives, C₅ petroleum resins and half esters of Styrene / maleic acid copolymers individually or in a mixture understood each other. Be particularly preferred Polyterpene resins from alpha or beta pinene or modified Rosin glycerol ester. These resins may vary depending on the properties required the stickiness and the adhesive strength on the Part where the resulting patch is attached should be, either alone or in combination be used.

The active ingredients of formula 2 can be found in the patches of Invention in an amount of 1 to 30 wt .-%, preferably 2 to 20 wt .-% incorporated into the reservoir layer will. The percentages by weight refer to Total reservoir.

The active ingredients of formula I can additionally Active substances are added or cooling or fragrance-releasing substances, preferably methyl salicylate, Glycol salicylate, salicylic acid, menthol, peppermint oil, Camphor, thymol, acrinol, scopolia extract, chlorpeniramine maleate, Benzyl nicotinate, capsicum extract, nonylvanillylamine, Capsaicin.  

If necessary, the inventive Patches with additives and fillers, e.g. B. anti-aging agents, Antioxidants and reinforcing fillers be transferred.

Known drug delivery systems, such as. B. gels, ointment bases, Patches give about 0.5 to 20% active ingredient free in 7 hours. The inventive described above On the other hand, put plasters up to 70% in 7 hours Active ingredient free with a significantly greater bioavailability (3 to 5 times larger). The invention Systems can be modified by changing the polymer content Entrainer or the resin with regard to their active ingredient release rate set almost arbitrarily will.

As a top layer for the plasters according to the invention became longitudinally and transversely elastic knitted and crocheted used (see e.g. Koch-Satlow, Großes Textlexlexikon, German publishing house Stuttgart 1965).

Knitted fabrics and knitted fabrics are therefore textile fabrics, made up of one or more thread systems Mesh formation on knitting or knitting machines will. There are two categories: Knitted knitted fabrics and knitted fabrics (main characteristic: thread course in the transverse direction, analogous to the weft direction Woven fabrics) and warp knitted fabrics (main characteristic: thread course lengthways, analogous to warp direction at Tissues).  

The usual terminology in the terminology in Knitted fabrics and knitted fabrics refer to the manufacturing process. When knitting, the stitches become one row of stitches trained at the same time (knocked off), while at Knit one stitch at a time. In the There are exceptions, however. Binding technology Kulier knitted fabrics and knitted fabrics do not differ.

In contrast to fabrics, knitted fabrics and knitted fabrics have high elongation and elasticity, especially in the width direction; furthermore they have due to the mesh structure a large pore volume, which means air permeability and Thermal insulation favors. These and other properties can through formation as well as fiber and yarn selection be largely varied.

The knitted fabrics used according to the invention preferably have and knitted fabrics stretch character. To achieve this Stretch character become the usual in textile technology Methods used. (see Koch-Satlow, page 441) or else it will be the same when choosing the basic materials for the knitted and crocheted elastomer fibers or elastomeric yarns used.

In addition to the knitted fabrics and knitted fabrics can be used as a top layer for the plasters according to the invention in general use textile fabrics with a stretch character, d. H. all three-dimensional structures made of natural and synthetic textile fibers such as braids, nonwovens or felts are suitable as a top layer.  

As base material for the top layer come u. a. Fibers and filaments made of polyamide, polyester, polyurethane, Polyamide polyurethane, cotton, rayon and animal Wool for use.

The textile covering layer of the plasters according to the invention is impregnated or coated. For coating and The usual techniques and materials are impregnated used (see also Koch-Satlow, pp. 157 to 159 and p. 616 ff.).

The cover layer is preferably impregnated with polyisobutylene or coated. The molecular weight of the Polyisobutylene preferably <1 000 000 g / mol (viscosity agent).

Coming as a coating and impregnation material prefers the polyisobutylenes in question, which are also in the Reservoir layer are included, but higher molecular weights and have no stickiness.

The release liner of the plaster according to the invention can be made from occlusive, flexible or inflexible materials exist, such as polyethylene, polypropylene, polyethylene terephthalate, Nylon u. known films. As a peel-off film can also metal foils, such as aluminum foil, used alone or laminated with polymers. Even multi-layer films such as laminates made of polyethylene with polyester PE terephthalate and with aluminum steamed, can be used. Other peelable  Slides are a. silicone treated polyester, polyethylene terephthalate with detached silicone groups, treated paper, silicone treated paper, with Polyethylene coated paper and Ä.

E. Gels

The invention preferably also relates to topically applicable ones Preparation in the form of gels. Be under gel understood disperse systems "solid / liquid", in which the disperse phase is no longer freely movable.

Topical preparations of the active ingredients in gel form of the formula I are suitable for the treatment of bacterial Infections of preferred body cavities, in particular the oral cavity. The depot effect, good adhesive properties and a higher bioavailability of the active ingredients enable short-term therapy.

In order to shorten the duration of therapy, you need a certain depot effect and a higher one Bioavailability of the active ingredients. These are especially the Formulations according to the invention are suitable in gel form. If you can without increasing the drug concentration wants to shorten the duration of therapy, one must for an optimal bioavailability of the active substance Take care.

Therefore, especially in the area of the oral mucosa Formulations required on the one hand Apply an adequate amount to the oral mucosa  Have adhesiveness, on the other hand that in the formulation containing active ingredient sufficient, also in Loosened saliva, can release.

It has been found that such formulations of the active ingredients of the formula I which, as a gel former, contains a cellulose ether, especially hydroxypropyl cellulose, sodium alginate or propylene glycol alginate and also the contain usual formulation auxiliaries, optimal Adhesive properties and optimal release of the Active ingredient and thus a shortened duration of therapy reaching antibacterial concentrations of the Enable active ingredient. This will make this effect achieved the bioavailability of the formulations containing active ingredients, by adhering Properties are increased and thereby the drug release can be increased in saliva.

In particular, it has been found that such formulations which in addition to the above gelling agents linear high molecular polysaccharides as stabilizing Gelling agents contain the heat stability of the Formulations and thus the long-term durability essential improve. Formulations without high molecular weight Polysaccharide additives can only be kept up to 30 ° C 30 ° C phase separation occurs after a short time, d. H. the gel structure is irreversibly destroyed. Wording which in addition to the gel formers small amounts of a linear high molecular polysaccharide are stable up to 50 ° C and therefore the The shelf life of such preparations is significantly increased.  

The means thus produced also have other extraordinary ones Characteristics:

The viscosity is hardly affected by temperature fluctuations influenced: the adhesive properties of the formulations are improved.

Active substances that are formulated in this way can, all active ingredients of formula I, in particular Ciprofloxacin and the others mentioned on page 4 Active ingredients. They are in the gels according to the invention preferably in amounts of 0.05 to 30% by weight, preferably 0.05 to 0.5% by weight, in particular 0.1 to 1% by weight, available.

Such macromolecular compounds come as gel formers in question, both in water and in dissolve or swell organic solvents. Cellulose ethers are particularly worth mentioning, of which 2.5 to 17.5% are required.

If you follow an attitude of the macromolecular auxiliary substances, (Keipert et al., Die Pharmazie 28, 145-183 (1973)), so ionic macromolecules come in their salt form for use. These are among others Sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, Alginic acid and propylene glycol alginate as Sodium salt, arabic gum, guar gum.  

Amphoteric macromolecules such as protein derivatives, e.g. B. Gelatins are just as suitable as nonionic polymers, e.g. B. methyl cellulose, hydroxypropyl cellulose and soluble starches that meet the above requirements.

As gelling agents that also have a stabilizing effect long chain linear high molecular polysaccharides with a molecular weight of more than one million in Consider. Such stabilizers are 0.1 to 1.5% needed.

The solvent is water and all with water miscible solvent suitable. Be considered e.g. B. alkanols such as ethanol and isopropyl alcohol, benzyl alcohol, Propylene glycol, u. a.

As a particularly stable gel combination basis such macromolecular compounds found such. B. Hydroxypropyl cellulose (probably molecular weight 2,000,000).

The gels according to the invention preferably contain 2.5 to 35.0% by weight of the spreading agents mentioned under C.  

F. powder

Preparations according to the invention which can be used topically in Powdered form contain the active ingredients of formula I and preferably Powder bases such as rice, corn, wheat starch, Talcum, Bolum alba and Bolus rubra, diatomaceous earth, Aerosil, Magnesium oxide, magnesium carbonate, zinc oxide and titanium dioxide.

In general, the following powder raw materials can be used according to the invention are used: Aerosil, aluminum hydroxide, palmitate and stearate, amylum non mucilaginosum, arrowroot, Avicel microcrystalline cellulose, barium sulfate, Bolus, cab-o-sil, calamine, calcium carbonicum praecipitatum, Calcium silicate, stearate and sulfate, Calflo, Dextrans, Ekasil, Flosilite, Glaxie Micron, Gasil, Kaolin, diatomaceous earth, silica D 17, kirusol, Kronos titanium dioxide pigments, Laminarin, Luvokoll, magnesium carbonate, -oxid, -silicate, -stearate and -trisilicate, Magnesol, Marinco, metal soaps, Metasap, milk sugar, NAL, Neosyl, Oracid powder, Ottalume, polyethylene, polyamide powder, Polyester powder, Pontybond 2150, Powdertrol, Quso, rice starch, Santocel C, Sea sorb, silk fibroin, Sicol, Siflox, silica gel, Silin S 100, S-Micron Silica, Starch strontrium sulfate, syloid, talcum cetylatum, talc, Tego metal soaps, Tiotal, Tioxide, titanium dioxide, Titanium stearate, Veegum, Vinylon, Witcarb, zinc carbonate, myristate, oxide and stearate, zirconium carbonate, oxide and silicate.  

Starch, especially rice starch and wheat starch preferred as powder basis for the active ingredients of Formula I used. Etherified starches are also preferred to use.

Powders containing active ingredients are manufactured at solid active ingredients of formula I by mixing the active ingredients in finely divided form with the corresponding Amount of powder base according to the criteria of Mixing powders.

They can also be combined with liquefied propellants fill in aerosol compressed gas packs and as use sprayable powder. There are about 8 to 9 parts by weight Use propellant on 1 part powder.

Liquid or semi-solid active ingredients of the formula I are with a small portion of the basis rubbed intimately and the then dry mass with the rest of the powder foundation mixed. It is also possible to use volatile solvents use as excipients to the active ingredients Apply evenly on the powder base.

G. suspension

Suspensions according to the invention contain the active ingredients of formula I in solid form dispersed in a liquid Phase. The particle size of the dispersed active ingredients lies in the range between 0.1 µm and approximately  100 µm. Depending on the use, the solids content is one suspension according to the invention approximately between 0.5% and 40%. Your basic property should be the slow one Sedimentation of the solid particles and their light Be able to be shaken to avoid incorrect dosing.

Suspensions according to the invention are usually carried out by Rub the solid with a small amount of liquid and gradually dilute to the final volume produced. The dispersant consists of several Liquids (e.g. Mucilago Tylose, Glycerin and Water), the component with the highest viscosity used for rubbing. The final mix can be done mechanically with the help of mixers, homogenizers, Corundum disc mills, bead mills, ultrasound and. a. homogenized will.

The following measures are used to make stable Suspensions according to the invention:

Increasing the wettability of the particles and targeted Flocculation by adding amphiphilic additives and suitable electrolytes.

Increasing the viscosity of the dispersant to reduce it the sedimentation rate.

To lower the interfacial tension solid / liquid As with emulsions, surfactants can be used.  

These are caused by the hydrophobic particles of the disperse Phase so adsorbed that its solvated hydrophilic Molecular parts away from the active ingredient into the dispersant protrude. If ionic surfactants are used, they are obtained the particles in addition to good wetting a sufficient electrostatic charge that the Stabilization of the suspension supports.

Electrolytes such as phosphates, alkali carbonates, citrates, Gallate et al. a., After adsorption on the drug particles are potential determining, lead to a high Zeta potential and thus cause mutual repulsion.

By means of the active ingredients of formula I can be easily can be shaken up again and dosed evenly Prepare suspensions by that by an anionogenic surfactant initially negatively charged hydrophobic particles using a calcium or aluminum salt to flocculate. The forming loose, bulky sediment can be shaken be easily redispersed.

The addition of macromolecular substances like methyl cellulose, Strength, tragacanth and a. causes in addition to the increase in viscosity the formation of sorbate shells around the particles the disperse phase. This in turn complicates the Aggregation.

Gel formers are particularly effective, those of the outer phase impart thixotropic properties. The trained at rest Gel framework prevents sedimentation of the  disperse phase. Under the influence of low shear forces (Shaking) the dispersant is released fluent, and the suspension can be dosed well.

The statements made for aqueous suspensions apply vice versa also for oily suspensions. Here are mostly at Processing of oxophilic (hydrophilic) solids surfactants e.g. B. displayed by the type of metal soaps. But often enough already the proportion of free fatty acids in the oil or a corresponding additive for the lyophilization of zinc oxide or other pharmaceutically used hydrophilic Fabrics. The effect of such a wetting addition is already on appearance z. B. of a zinc oil: While Unwetted zinc oxide accumulates sedimentation and gives a shiny supernatant of pure oil (including when using liquid paraffin), the ZnO particles wetted with fatty acids form, sediment little and the surface Give a matt look.  

H. Emulsions

The topical preparations of the active compounds according to the invention of the formula I can also be in the form of "liquid / liquid" disperse systems are available.

According to "Pharmaceutical Forms", P. H. List, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 1985, page 168 the following points for the production of emulsions consider:

1. Required emulsion type - O / W, W / O, bicoherent system 2. Viscosity - flowable or paintable system 3. Temperature stability- stability in as much as possible wide temperature range, Sterilizability 4. Degree of division - droplet size <1 µm for ordinary emulsions 5. Components - selection of components from therapeutic, physiological, technological and economic establish 6. Concentration ratios - from application-specific establish 7. Devices and batch sizes

Due to the variety of factors, it is not possible to establish generally applicable manufacturing rules. It rather, series of tests are to be carried out, whereby the HLB system, Lin's process for preparing O / W emulsions, the creation of three-component diagrams or the formation of emulsifier gels can be helpful.

Emulsifiers and other auxiliaries for the production of topical preparations according to the invention were described in H.P. Fiedler, Lexicon of auxiliary substances for pharmacy, cosmetics and adjacent areas, Edition Cantor K.G., Aulendorf i. Württ., 1971, especially on pages 185-194 described.

Emulsions of the active ingredients of the formula I can be external Serve application. Externally, both types of emulsion d. H. O / W and W / O emulsions applicable.

Liquid O / W emulsions, often referred to as lotions serve primarily dermatological Purposes. The semi-solid forms are called washable Called ointments; also the semi-solid W / O emulsions, which are called creams. Liquid W / O emulsions for external Application led DAB 6 under the name Liniments.  

I. Solutions

To the topically applicable preparations according to the invention The active ingredients of Formula I include solutions.

The selection of a solvent or solvent mixture for the production of the invention Preparations depend primarily on the nature of the solution Substance or mixture of substances. Beyond that the question matters whether the solvent is whole or partially remains in the finished preparation. In the case of remaining, the solvent must first Line should be physiologically harmless.

For these reasons, drug preparation only comes a relatively small number of liquids as Solvent in question.

By far the most common is water.

Water and therefore all are included as solvents Suitable for water-miscible solvents. In consideration come z. B. alcohols such as ethanol and isopropyl alcohol, Propylene glycol, methyl cellosolve, cellosolve, ester, Morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, Tetrahydrofuran, cyclohexanone etc.

It can in the manufacture of the invention Formulations used one or more solvents will. The following are particularly suitable as solubilizers:  Butyl alcohol, 2-octyl-dodecanol, polyethylene glycols, Phthalates, adipates, propylene glycol, glycerin, di- and Tripropylene glycol, water etc. and others in cosmetics additives used.

J. Ointments, pastes, creams, foams

(According to Ullman, Vol. 18, Pharmaceutical Technology and Pharmacology, P.H. List, 4th edition, Wissenschaftl. Verlagsgesellschaft mbH, Stuttgart).

Ointments are gels of plastic deformability that Active ingredients of formula I dissolved, emulsified or suspended can contain.

They serve the local treatment of diseased skin or Areas of mucous membrane. Again, you can use the function of protective and deck ointments. Contain the ointments Active ingredients of formula I, which are in the lower Penetrate skin layers, penetrate, and there to effect get, so one speaks of penetration ointments. Absorption ointments are those whose Active substances after penetration into the subcutaneous tissue finally get into the bloodstream (percutaneous or transcutaneous absorption).

Ointments are named differently according to their composition, consistency or the place of application:
Unguenta, ointments (English: French: pommades) is either the generic term for this pharmaceutical form or means anhydrous preparations based on various principles.

Cerata is the name for ointments made from a mixture consist of wax and oil.

Creams, creams are ointments with a particularly soft consistency, which contain larger amounts of water.

Glycerola are glycerol-containing preparations of semi-solid Called consistency.

Pastae, pastes are ointments with a high proportion of powder Solids and therefore high consistency.

Oculenta, Unguenta ophthalmica, eye ointments ointments) are soft ointments for application in the Conjunctival sac and on the edges of the eyelids, to those regarding Purity and particle size made special demands will.

Ointment bases, for topically applicable preparations the invention are used are hydrocarbon gels, Lipogels, hydrogels, polyethylene glycol gels and silicone gels.

Vaseline, plastibase, waxes (according to DGF) especially beeswax, Walrat DAB 8, Cetaceum, wool wax  DAB 8. Lanae Cera, oleic acid oleyl ester DAB 8, Oleyli oleas, isopropyl myristate, lard, hardened Peanut oil, glycerol, sorbitol solutions, low molecular weight Polyethylene glycols, colloidal silica, Aerosil, Swelling clays such as bentonite, potash soap, soft soap, Opodeldoc, starch, cellulose derivatives, polyacrylic acid, Polyethylene glycol gels DAB 8, silicone oils.

The topical preparations according to the invention come in Ointment form as solution ointments, emulsion ointments and suspension ointments to use. They preferably contain Antioxidants such as Avenol, Avenex, Conidendrin, Nor-Conidendrin, Nordihydroguajaritsäure, tocopherol, ascorbic acid esters e.g. B. stearate, palmitate, myristate, laurate, 3-butyl-4-hydroxyanisole, hydroquinone, propyl gallate, Citric acid, cis methyl maleic acid, gallic acid ester such as ethyl gallate, propyl gallate, jonol, BHT, tetraoxydimethylbisphenyl (TDBP).

Pastes are highly concentrated suspensions with a yield point for use on the skin or mucous membrane. they contain a large proportion of insoluble powder, the dispersed in a liquid or ointment-like vehicle are.

The powdery ingredients with a maximum grain size 100 µm will gradually increase to the necessary the water bath melted or softened dispersant rubbed into a uniform mass and if possible homogenized with an ointment mill.  

Creams in the sense of the invention are particularly smooth Preparations that contain large amounts of water in the form of Contain oil-in-water or water-in-oil emulsions. The ratio of aqueous to oily phase determines the Viscosity and spreadability of a cream. Suitable Basics depending on the emulsion type are e.g. B. different Lanette types (sodium fatty alcohol sulfate), cetylstearyl alcohol or wool fat, wool wax alcohols etc.

The topical preparations according to the invention can also in the form of foams. Under foams understood disperse systems "gaseous / liquid" (For definitions, terms and production see "Dosage Form Theory", List).

The topical preparations according to the invention show low toxicity a broad antibacterial spectrum against gram-positive and gram-negative germs, in particular against enterobacteriaceae; especially against those who are resistant to various antibiotics, such as B. Penicillins, cephalosporins, aminoglycosides, sulfonamides, Tetracyclines.

These valuable properties enable their use as chemotherapeutic preparations in medicine as well as substances for the preservation of inorganic and organic Materials, especially organic materials of all kinds, e.g. B. polymers, lubricants, paints, Fibers, leather, paper and wood, of food and of Water.  

The preparations according to the invention are very resistant to wide range of microorganisms effective. With their Gram-negative and gram-positive bacteria and can help fights bacteria-like microorganisms as well as through prevents these pathogens caused diseases, improved and / or be cured.

The topicals according to the invention are particularly effective Preparations against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and chemotherapy of local and possibly systemic Infections in human and veterinary medicine, that are caused by these pathogens.

For example, local and / or systemic diseases treated and / or prevented by the following pathogen or by mixtures of the following pathogens caused: Gram-positive cocci, e.g. B. Staphylococci (Staph. aureus, Staph. epidermidis) and streptococci (strept. agalactiae, strept. faecalis, strept. pneumoniae, Strept. pyogenes); gram-negative cocci (Neisseria gonorrhoeae) as well as gram-negative rods such as enterobacteriaceae, e.g. B. Escherichia coli, hemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella; furthermore stickies (Klebs. Pneumoniae, Klebs. Oxytoca), Enterobacter (Ent. aerogenes, ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia, and the genus  Acinetobacter. It also includes antibacterial Spectrum of the genus Pseudomonas (Ps. Aeruginosa, Ps. maltophilia) and strictly anaerobic bacteria such as B. Bacteroides fragilis, representative of the genus Peptococus, Peptostreptococcus and the genus Clostridium; further Mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, e.g. B. Mycobacterium tuberculosis.

The above list of pathogens is only an example and not to be interpreted as restrictive. As diseases, those caused by the pathogens mentioned or mixed infections caused and topically by the invention applicable preparations prevented, improved or can be cured, for example: Infectious diseases in humans such as septic infections, bone and joint infections, Skin infections, postoperative wound infections, abscesses, Phlegmon, wound infections, infected burns, Burns, infections in the mouth, infections after Dental surgery, septic arthritis, mastitis, tonsilitis, Genital infections and eye infections.

In addition to humans, bacterial infections can also be treated in other species. Be exemplary called:

Pig:
Coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalaktiae syndrome, mastitis;

Ruminants (cattle, sheep, goats):
Diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

Horse:
Bronchopneumonia, foal paralysis, puerperal and postpuerperal infections, salmonellosis;

Dog and cat: bronchopneumonia, diarrhea, dermatitis, Otitis, urinary tract infections, prostatitis;

Poultry (chicken, turkey, quail, pigeon, ornamental birds and others):
Mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Bacterial diseases during rearing can also occur and keeping of farmed and ornamental fish are treated, the antibacterial spectrum over the previous mentioned pathogens to other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borellia, Treponema, Nocardia, Rikettsien, Yersinia, expanded.

The present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutical suitable carriers one or more of the invention Contain connections or which consist of one or consist of several active ingredients according to the invention, and Process for the preparation of these preparations.

Pharmaceuticals also belong to the present invention Preparations in dosage units.  

The pharmaceutical preparations listed above can in addition to the compounds of the invention also others contain active pharmaceutical ingredients.

The preparation of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. B. by mixing the active ingredient (s) with the or the carriers.

Examples Adherent topical preparations 1. Example of a pen

composition

1) Ciprofloxacin hydrochloride 0.2 g 2) Beeswax 13.0 g 3) Vaseline 6.0 g 4) Cetyl alcohol 4.0 g 5) Wool wax 3.0 g 6) Isopropyl myristate 9.0 g 7) Castor oil 64.8 g 100 , 0 g

Manufacturing

The substances 2) to 7) are weighed in and at melted approx. 70 ° while stirring. In it will Ciprofloxacin hydrochloride suspended. The melt is cast in appropriate shapes (pens) and cooled to room temperature.  

2. Example of a protective ointment

composition

1) ciprofloxacin 0.5 g 2) low molecular weight acrylic resin 5.0 g 3) water demin. 71.5 g 4) ammonia 1.5 g 5) wool wax alcohol 9.0 g 6) Tween 81® 1.0 g 7) liquid paraffin 11.5 g 100.0 g

Manufacturing

a) Heat substances 1, 5, 6, 7 to 65 ° C with stirring.
b) Heat substances 2 and 3 (aqueous phase) to 65 ° C.
c) Work b into a while stirring vigorously.
d) add the ammonia with vigorous stirring and cool to room temperature with stirring.

3. Example of a film-forming concentrate

composition

1) Coprofloxacin 5.0 g 2) Sodium alginate 10.0 g 3) Nonionic emulsifier 2.0 g 4) Colloidal silica 2.0 g 5) Isopropanol ad 100 ml 81.0 g 100.0 g

Manufacturing

Ciprofloxacin is dispersed in 3 and 5 with stirring. 2 and 4 are entered into the dispersion and homogenized.

This suspension is shaken before use and diluted with water 1 + 9. It imagines Gel that after drying an elastic film on the skin, which also lasts for a long time Water contact is liable.

4. Example of a solution

composition

1) Ciprofloxacin or Norfloxacin 0.03 g 2) Poly (methyl vinyl ether / maleic acid monoalkyl ester) 3.0 g 3) Isopropanol 96.97 g 100.0 g

Manufacturing

The solution can be applied to the skin. After drying, an active ingredient is formed Film on the skin.

5. Example of a spray formulation

The solution from Example 4 is used with propane / butane Propellant gas in the ratio 1 + 2 in suitable aerosol cans bottled.  

band Aid Example 1

A 12.5% polyisobutylene solution (M.G. viscosity agent 1 270 000) (in gasoline), is siliconized on Paper applied and a knitted fabric consisting of polyamide polyurethane fibers laminated and in the drying tunnel gradually dried at 70/90/100 ° C (polymer 30 g / m²).

On siliconized paper, one is in petrol / acetone dissolved mixture consisting of

36,000 gpolyisobutylene MG viscosity medium 400,000, 44,928 gparaffin, 9,000 gpolyterpene resin from β- pinene, 10,000 gciprofloxacin or ofloxacin or norfloxacin, 0.072 g of anti-aging agent

applied and gradually in the drying tunnel at 70/90/100 ° C dried (drug delivery system approx. 150 g / m²).

After drying, it was impregnated with polyisobutylene Knitted fabric with stretchchrackers.  

Example 2

A polymer solution was placed on siliconized paper (Gasoline / acetone) consisting of

36,000 g polyisobutylene MG viscosity medium 1,270,000, 44,928 g paraffin thin, 9,000 g polyterpene resin from α- pinene, 10,000 g ciprofloxacin and 0.072 g anti-aging agent

applied and gradually in the drying tunnel at 70/90/100 ° C dried.

After drying, the drug delivery system was included Polyisobutylene (as in Example 1) on coated Laminated stretch material.

The plasters according to the invention have an equally good one Resorption of the active ingredients as conventional with aluminum-polyethylene films coated plasters.

For laminating the active substance depot on the textile Flat structures with a stretch character are u. a. the Methods and materials used in Koch-Satlow, Large textile lexicon.  

Gels Example 1

Ciprofloxacin lactate 0.20 g Benzyl alcohol 3.00 g Hydroxypropyl cellulose (M.G. 1,000,000) 2.50 g Water demineralizedad 100 g

Example 2

Ciprofloxacin acetate 0.20 g Benzyl alcohol 3.00 g Hydroxypropyl cellulose (M.G. 1,000,000) 2.5 g Water demineralizedad 100 g  

Example 3

Norfloxacin hydrochloride 0.20 g Benzyl alcohol 3.00 g Hydroxypropyl cellulose (M.G. 1,000,000) 2.5 g Water demineralizedad 100 g

Example 4

Ofloxacin hydrochloride 0.20 g Benzyl alcohol 3.00 g Hydroxypropyl cellulose (M.G. 60,000) 17.50 g Water demineralizedad 100 g  

Creams Example 1 Cream, O / W

Phase I

Sorbitan monostearate 2.0 g Polyoxyethylene (20) sorbitan monostearate 1.5 g Artificial walnut 3.0 g Cetylstearyl alcohol10.0 g 2-octyldodecanol 13.5 g

Warm to 75 ° C, stir, mix.

Phase II

Ciprofloxacin, norfloxacin or ofloxacin,
Enoxacin, Pefloxacin 1.0 g

add to phase I, stir, suspend.

Phase III

Benzyl alcohol 1.0 g Water, demineralized 68.0 g

Warm to 75 ° C and add to phase II. Intensive mix, slowly stirring further Cool down to room temperature. Homogenize.  

Example 2 Cream, O / W

Phase I

Sorbitan monostearate 1-3 g Polyoxyethylene (20) sorbitan monostearate 0.5-2.5 g Artificial walnut 2-4 g Cetylstearyl alcohol5-15 g Isopropyl myrisate 5-25 g

Warm to 75 ° C, stir, mix.

Phase II

Ciprofloxacin, norfloxacin or Ofloxacin 0.5-1.5 g

add to phase I, stir, suspend.

Phase III

Benzyl alcohol 0.5-1.5 g Water, demineralised quantum. sat.

Warm to 75 ° C and add to phase II. Intensive mix, slowly stirring further to room temperature cooling down. Homogenize.  

Liquid plasters Example 1

Ciprofloxacin 1.0 g Benzyl alcohol5.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isoopropanolad 100 ml

Example 2

Ciprofloxacin 0.1 g Benzyl alcohol5.0 g Isopropyl myristate 6.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isopropanolad 100 ml

Example 3

Ciprofloxacin 1.0 g Benzyl alcohol4.0 g Isopropyl stearate 10.0 g Hydroxypropyl cellulose (M.G. 60,000) 12.0 g Isopropanolad 100 ml  

Example 4

Ciprofloxacin 1.0 g 1,2-propylene glycol 1.0 g Isopropyl myristate 6.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isopropanolad 100 ml

Example 5

Norfloxacin 0.1 g Benzyl alcohol5.0 g Isopropyl myristate 6.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isopropanolad 100 ml

Example 6

Ofloxacin 1.0 g Benzyl alcohol5.0 g Isopropyl myristate 6.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isopropanolad 100 ml  

Example 7

Ciprofloxacin 1.0 g Benzyl alcohol 8.0 g Isopropyl myristate / isopropyl stearate / isopropyl palmitate 1.0 g Hydroxypropyl cellulose (M.G. 60,000) 10.0 g Isopropanolad 100 ml

Example 8

Norfloxacin 1.0 g Benzyl alcohol5.0 g Isopropyl myristate 6.0 g Methyl cellulose 10.0 g Isopropanolad 100 ml

Sprays

The active ingredient solutions prepared according to Examples 1 to 8 or suspensions can also be used as sprays are processed. For this purpose you mix z. B. 60 to 90% drug solution with 20 to 40% of the Common blowing agents, e.g. B. N₂, N₂O, CO₂, propane, Butane, halogenated hydrocarbon, etc.  

Emulsions / creams Example 1 Emulsion, O / W

Phase I

"Glyceryl stearates" (mixture of mono- and
Diglycerides of palmitic and stearic acid) 8.00 g 2-octyldodecanol 10.00 g cetylstearyl alcohol with approx. 12 mol ethylene oxide 1.5 g cetylstearyl alcohol with approx. 30 mol ethylene oxide 1.5 g paraffin, viscous 6.0 g 1,2-propylene glycol 5.00 g caprylic / capric acid triglyceride 6.00 g

The mixture is stirred and melted at 70 ° C.

Phase II

Water, demineralised58.00 g

Phase III

Ciprofloxacin 1.00 g suspended in benzyl alcohol 3.00 g

Phase II, which is heated to 75 ° C., is heated to 70 ° C. Phase I added with stirring. You slowly let go Cool to 40 ° C., add phase III and leave with stirring Cool down to room temperature. The raw emulsion is at 20 to Homogenized 25 ° C in the high pressure homogenizer. Examples 2 and 3 are processed in an analogous manner.  

Example 2 Emulsion, O / W

Ciprofloxacin 1.00 g "glyceryl stearate" mixture of mono- and
Diglycerides of palmitic and stearic acid8.00 g Diglycerides of palmitic and stearic acid9.00 g of cetylstearyl alcohol with approx. 12 moles of ethylene oxide 3.00 g of 2-octyldodecanol 10.00 g of paraffin, viscous 5.00 g of benzyl alcohol 5.00 g of water demineralizedad 100 ml

Example 3 Emulsion, O / W

Norfloxacin 1.00 g "glyceryl sterate" mixture of mono- and
Diglycerides of palmitic and stearic acid9.00 g cetylstearyl alcohol with approx. 12 mol ethylene oxide 3.00 g 2-octyldodecanol 10.00 g benzyl alcohol 5.00 g isopropyl myristate 5.00 g water demineralisedad 100 ml

Example 4 Cream, soft consistency O / W

Ciprofloxacin, norfloxacin, ofloxacin 1.00 g "glyceryl sterate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g cetyl palmitate 4.00 g cetyl stearyl alcohol with approx. 12 mol ethylene oxide 1.00 g cetyl stearyl alcohol with approx. 30 mol ethylene oxide 1.00 g isopropyl myristate / isopropyl palmitate /
Isopropyl stearate mixture 5.00 g Weakly crosslinked polyacrylic acid from
extremely high MG0.50 g sodium hydroxide 45% ig0.11 g glycerol3.00 g benzyl alcohol3.00 g water demineralizedad 100 ml

Example 5 Cream, soft consistency O / W

Ciprofloxacin, norfloxacin, ofloxacin 1.00 g "glyceryl sterate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g cetyl palmitate 4.00 g cetyl stearyl alcohol with approx. 12 mol ethylene oxide 1.00 g cetyl stearyl alcohol with approx. 30 mol ethylene oxide 1.00 g isopropyl myristate / isopropyl palmitate,
Isopropyl stearate mixture 5.00 g Weakly crosslinked polyacrylic acid from
extremely high MG0.50 g sodium hydroxide 45% ig0.11 g glycerol3.00 g benzyl alcohol3.00 g water demineralizedad 100 ml

Example 6 Cream, soft consistency O / W

Norfloxacin, ofloxacin 1.00 g "Glycerylsterate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g stearic acid 4.00 g cetyl palmitate 4.00 g cetylstearyl alcohol with approx. 12 mol ethylene oxide 1.00 g cetylstearyl alcohol with approx. 30 mol ethylene oxide 1.00 g isopropyl myristate / isopropyl palmitate,
Isopropyl stearate mixture 5.00 g Weakly crosslinked polyacrylic acid from
extremely high MG0.50 g sodium hydroxide 45% ig0.11 g glycerol3.00 g benzyl alcohol3.00 g water demineralizedad 100 ml

Example 7 Emulsion, non-greasy O / W

Phase I

Oleic acid decyl ester 2.50 g Isopropyl myristate 2.50 g Paraffin, low viscosity 4.00 g Polyethylene stearate0.90 g Sorbitan and glycerin fatty acid esters 0.60 g

The mixture is stirred at 70 ° C. for 10 minutes and melted.

Phase II

Water, demineralized 50.00 g Allantoin0.10 g

Carbopol slime

Alcohol, denatured 10.00 g Carbopol 934 (weakly cross-linked polyacrylic acid) 0.70 g Water, demineralized 22.945 g

It is dispersed with Turrax, allowed to swell for 2 hours and then neutralized with 0.155 g 45% sodium hydroxide solution.

Phase I, which is 70 ° C warm, is added to phase II at 75 ° C while stirring and cool to 45 ° C. At 45 ° C Stir in Carbopol slime and cool further down to 40 ° C. Add 1.00 g collagen at 40 ° C and cool to 25 ° C. Incorporate 1.0 g ciprofloxacin in 3.0 g benzyl alcohol and add to phases I and II.

The raw emulsion is then stirred at 20 ° C. homogenized up to 25 ° C in a high pressure homogenizer.

Examples 8, 9, 10, 11 processed.  

Example 8 Emulsion, non-greasy O / W

Ciprofloxacin0.10 g oleic acid decyl ester2.50 g isopropyl myristate2.50 g paraffin, low viscosity 4.00 g polyethylene stearate0.90 g sorbitan and glycerol fatty acid ester 0.60 g allantoin 0.155 g weakly crosslinked polyacrylic acid from
extremely high molecular weight 0.70 g collagen 1.00 g benzyl alcohol 3.00 g ethanol 10.00 g water, demineralized to 100 ml

Example 9 Emulsion, non-greasy O / W

Norfloxacin0.15 g oleic acid decyl ester2.50 g isopropyl myristate2.50 g paraffin, low viscosity 4.00 g polyethylene stearate0.90 g sorbitan and glycerol fatty acid ester0.60 g allantoin0.10 g Weakly crosslinked polyacrylic acid from
extremely high molecular weight 0.70 g sodium hydroxide 45% ig 0.155 g collagen 1.00 g benzyl alcohol 3.00 g ethanol 10.00 g water, demineralized to 100 ml

Example 10 Emulsion, non-greasy O / W

Ofloxacin0.10 g oleic acid decyl ester2.50 g isopropyl myristate2.50 g paraffin, low viscosity 4.00 g polyethylene stearate0.90 g sorbitan and glycerol fatty acid ester 0.60 g allantoin0.10 g sodium hydroxide 45% ig0.155 g weakly crosslinked polyacrylic acid from
extremely high molecular weight 0.70 g collagen 1.00 g benzyl alcohol 3.00 g ethanol 10.00 g perfume oil 0.60 g water, demineralized to 100 ml

Example 11 Emulsion, non-greasy O / W

Ciprofloxacin0.05 g oleic acid decyl ester2.50 g isopropyl myristate2.50 g paraffin, low viscosity 4.00 g polyethylene stearate0.90 g sorbitan and glycerol fatty acid ester0.60 g allantoin0.10 g sodium hydroxide 45% ig0.155 g weakly crosslinked polyacrylic acid from
extremely high molecular weight 0.70 g collagen 1.00 g benzyl alcohol 3.00 g ethanol 10.00 g water, demineralized to 100 ml

Example 12 Emulsion, non-greasy O / W

Ciprofloxacin0.10 g "Glycerylstearate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g cetyl palmitate 4.00 g cetyl stearyl alcohol with approx. 12 mol ethylene oxide 1.00 g cetyl stearyl alcohol with approx. 30 mol ethylene oxide 1.00 g isopropyl myristate / isopropyl palmitate,
Isopropyl stearate mixture 5.00 g Weakly crosslinked polyacrylic acid from
extremely high molecular weight0.50 g sodium hydroxide 45% ig0.11 g glycerol3.00 g benzyl alcohol3.00 g water demineralizedad 100 ml

Example 13 Cream, soft consistency O / W

Ofloxacin 0.05 g "glyceryl stearate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g cetyl palmitate 4.00 g cetyl stearyl alcohol with approx. 12 mol ethylene oxide 1.00 g cetyl stearyl alcohol with approx. 30 mol ethylene oxide 1.00 g isopropyl myristate / isopropyl palmitate,
Isopropyl stearate mixture 5.00 g Weakly crosslinked polyacrylic acid from
extremely high molecular weight0.50 g sodium hydroxide 45% ig0.11 g glycerol3.00 g benzyl alcohol3.00 g water demineralizedad 100 ml

Example 14 Cream, soft consistency O / W

Norfloxacin, Pefloxacin 1.00 g "Glycerylstearate" mixture of mono- and
Diglycerides of palmitic and stearic acid 4.00 g Na stearate 16.00 g Cetylstearyl alcohol with approx. 12 moles of ethylene oxide 3.00 g Benzyl alcohol 3.50 g 2-octyldodecanol 2.50 g Isopropyl coconut fatty acid 2.50 g (isopropyl myristate / isopropyl palmitate,
Isopropyl stearate mixture)
Paraffin, low viscosity 3.00 g water demineralisedad 100 ml

Gels Example 1

Phase I

Ofloxacin 1.00 g in isopropanol 40.00 g to solve; subsequently Polyol fatty acid ester 4.00 g Benzyl alcohol 3.00 g Diisopropyl adipate 4.00 g stir in and dissolve.

Phase II

Place 46.10 g Carbopol 9401.50 g in demineralized water while stirring, swell for approx. 2 h
leave and with
Neutralize NaOH 45% 0.40 g,

Phase I, in portions, slowly with stirring in phase II incorporate.

Examples 8 and 9 are carried out in an analogous manner.  

Example 2

Ciprofloxacin 1.00 g Polyol fatty acid ester 4.00 g Isopropyl myristate 4.00 g Benzyl alcohol 1.00 g Isopropanol 45.00 g Carbopol 9401.50 g NaOH 45% ig 0.40 g Water, demineralized 43.10 g

Example 3

Ofloxacin 1.00 g Polyol fatty acid ester 4.00 g Coconut fatty acid isopropyl ester 4.00 g Benzyl alcohol 5.00 g Isopropanol 45.00 g Carbopol 9401.50 g NaOH 45% ig 0.40 g Water, demineralized 39.10 g  

Fatty ointment Example 1

Ciprofloxacin 1.00 g Wool wax alcohols 5.00 g Vaseline white 100 g

powder Example 1

Ciprofloxacin hydrochloride 0.1 g Lactosead 100 g

Shake mixture

Ciprofloxacin 1.0 g Lanette N 3.0 g Zinc oxide 18.0 g Talc 18.0 g Glycerin 85% 18.0 g Ethanol 96% 13.2 g Demineralized water 28.8 g

Ciprofloxacin, zinc oxide and talc are in a solution of the other auxiliaries suspended.  

paste

Ciprofloxacin 10.0 g Wheat starch 20.0 g Zinc oxide 20.0 g White Vaseline 50.0 g

The solids are dried at 40 ° C for 4 hours, sieved, suspended in the melted petroleum jelly and stirred cold.

Polyethylene glycol ointment

Ciprofloxacin0.50 g Polyethylene glycol 30049.75 g Polyethylene glycol 150049.75 g

Ciprofloxacin is in the melt of the polyethylene glycols suspended. Then it is stirred cold.

Fatty ointment

Ciprofloxacin microfine 1.00 g p-Hydroxybenzoic acid methyl ester 0.07 g Propyl p-hydroxybenzoate 0.03 g Paraffin viscous 15.00 g Wool wax alcohol ointment83.90 g

Ciprofloxacin is in the melted fat phase registered. It is then cooled with stirring.  

powder

Ciprofloxacin, sodium salt 0.01 g Rice starch not swellable99.99 g

W / O ointment

Ciprofloxacin 2.00 g Protegin X22.00 g Beeswax 3.00 g Isopropyl myristate 1.50 g Medium chain triglycerides 1.50 g Mixture of alkyl branched fatty acid esters 2.00 g Glycerin 3.00 g Demineralized water 65.00 g

Claims (11)

1. Topically applicable preparations containing 0.05 to 30% by weight of antibacterially active compounds of the general formula in which R¹ for methyl, ethyl, propyl, isopropyl, cyclopropyl, vinyl, 2-hydroxyethyl, 2-fluoroethyl, methoxy, amino, methylamino, dimethylamino, ethylamino, phenyl, 4-fluorophenyl, 2,4-difluorophenyl, R² for hydrogen, alkyl with 1 up to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, R³ for methyl or a cyclic amino group such as stand in whichR⁴ represents hydrogen, alkyl having 1 to 4 carbon atoms, 2-hydroxyethyl, allyl, propargyl, 2-oxopropyl, 3-oxobutyl, phenacyl, formyl, CFCl₂-S-, CFCl₂-SO₂-, CH₃O-CO-S-, benzyl , 4-aminobenzyl, R⁵ represents hydrogen, methyl, R⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, benzyloxymethyl, R⁷ represents hydrogen, amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, hydroxy, hydroxymethyl, R⁸ represents hydrogen, methyl, ethyl or chlorine, X represents hydrogen, fluorine, chlorine or nitro and A represents N or C-R⁹, in which R⁹ represents hydrogen, halogen such as fluorine or chlorine, methyl or nitro, or together with R¹ also a bridge of the structure can form. 2. Topically applicable preparations containing 0.05 to 39% by weight ciprofloxarin, norfloxacin, pefloxacin, Amifloxacin, pirfloxacin, ofloxacin and / or Enoxacin. 3. Topically applicable preparations in the form of solutions, Sprays, lotions, gels, ointments, creams, powders, Powder sprays, pastes, suspensions, emulsions, Foams, pens, plasters, spray plasters, Occlusive dressings, envelopes and controlled delivery systems, containing 0.05 to 30 wt .-% of one or several active substances according to claim 1. 4. Topically applicable preparations according to claims 1 to 3, characterized in that they

• a) 0.1-20%, preferably 0.1-5%, of an active ingredient of the formula I according to claim 1,
• b) 1-40%, preferably 1-20%, of a water-soluble gel or lacquer-forming polymer,
• c) 40-98%, preferably 60-90%, of an organic, water-miscible solvent which evaporates faster than water and in which the polymer does not dissolve,
• d) 0.1-10% by weight of various additives, e.g. B. plasticizers, suspending agents, antioxidants, spreading agents, dyes etc.

contain. 5. Topically applicable preparations according to the claims 1 to 4, containing one or more spreading agents. 6. Topically applicable preparations in the form of Plasters containing a top layer consisting of a longitudinally transverse elastic, impregnated with a polymer or coated, preferably textile Fabric, especially knitted or crocheted consists of a reservoir layer that is 0.05 to Contains 30% by weight of the active compounds according to claim 1, and a peelable protective layer, the Reservoir layer a polymer consisting of polyisobutylene and / or its copolymers, an entrainer and contains a resin.   7. Topically applicable preparations in gel form, the 0.05 up to 30% by weight of the active compounds according to claim 1 and as Gelling agent cellulose ether, polyacrylic acid, polymethacrylic acid, Sodium alginate or propylene glycol alginate, Sodium amylopectin semiglycolate, Alginic acid, arabic gum, gluar gum as well optionally linear high molecular polysaccharides included as stabilizing gelling agents. 8. Topically applicable preparations in the form of suspensions, containing 0.05 to 30 wt .-% of the active ingredients according to claim 1 in particle sizes from 0.1 µm to 100 µm and a solids content between 0.5 to 40%. 9. Topically applicable preparations in the form of emulsions, containing 0.05 to 30 wt .-% of the active ingredients according to claim 1. 10. Topically applicable preparations in the form of Solutions containing 0.05 to 30 wt .-% of Active ingredients according to claim 1 and a solvent the group consisting of ethanol, isopropyl alcohol, Propylene glycol, methyl cellulose, cellulose, esters, Morpholine, dioxane, DMF, DMSO, tetrahydrofuran, Water or cyclohexanone and optionally one Solution broker.