WO1998036732A2 - Combination preparation for orally administered antibiotics - Google Patents

Abstract

The invention relates to a combination product for the oral administration of antibiotics as an aqueous suspension, comprising a) an active ingredient component in the form of particles coated with a polymeric, permeable coating agent capable of swelling and/or soluble in gastric juice; and b) a syrup base with a pH between 5 and 10 as a second component which is spatially separate from the first component a). The two components are presented in two separate containers packaged in a combined pack in the form of a 'kit of parts'.

Description

 Combination preparation for oral antibiotics

description

The invention relates to a combination preparation in the sense of a "kit-of-parts" for the oral administration of antibiotics as an aqueous suspension containing a coated active ingredient and a syrup base.

Many of the orally administrable antibiotics commercially available today have a limited shelf life in aqueous suspension. They are usually suspended in water as dry powder, for example in the form of granules, shortly before use. Due to the low stability of the active ingredient, for example as a result of hydrolysis or thermolysis, some of these suspensions must also be kept in the refrigerator. These suspensions are not only disadvantageous because of their unsatisfactory stability. It also disturbs the bitter, strange taste that numerous active ingredients from this indication group and their decomposition products have. In pediatrics, sweet juices (syrups) are popular dosage forms for the treatment of acute diseases. Anti-infectives in the form of a syrup are particularly often administered. The reason for the "popularity" of this dosage form lies in the masking of the bitter taste of the active ingredient. Without the addition of sweeteners, many children would not accept liquid dosage forms at all. However, acceptance of the drug by the patient and thus regular intake is an important prerequisite for successful therapy.

The masking of the taste of the poorly tasting antibiotic by the syrup formulation alone represents an unsatisfactory solution to the problem. The stability of the active ingredient in the aqueous suspension remains unsolved.

Filming, coating or coating active ingredient particles, for example active ingredients which are in the form of crystals, agglomerates, granules, pellets or microtablets, is a common method in pharmaceutical technology to improve the stability of the active ingredient in an aqueous environment. The choice of coating agent is adapted to the therapeutic task. Coating with a high permeability polymer, e.g. B .magensaftlöslichem Dimethylaminoethylmethacry- lat methacrylate copolymer of the type Eudragit ^® E (Röhm GmbH Chemical Factory), and a suitable layer thickness, allows drug release in the acidic environment of gastric juice. The rapid release of the active substance is important if infectious conditions are to be treated within a short time immediately after their appearance and rapid onset of action with higher doses is desired. By choosing a coating with a lower permeability, for example acrylic ester-methacrylic acid ester copolymer of the EUDRAGIT ^® NE type, and possibly a greater layer thickness, the release of active ingredient in the stomach can be delayed with a corresponding prolongation of the duration of action. This effect is desirable with a longer therapy duration.

Coated active ingredient particles are also only stable for a limited time in aqueous suspension. The undesired diffusion of the active ingredient into the suspension liquid takes place immediately after the suspension has been prepared. This results in the hydrolytic decomposition of the active ingredient and the significantly increasing deterioration in taste during the period of use of the suspension.

The object of the present invention is to produce pharmaceutical suspensions (dry juices) with acceptable taste properties and sufficient stability for orally administrable antibiotics.

It has surprisingly been found that active ingredient particles coated with a polymeric coating agent of a cationic nature and with a syrup base adjusted to a pH> 5 meet the required stability criteria if the suspension with the coated active ingredient or combination of active ingredients is administered immediately before the first administration manufactures and consumed within the specified therapy duration. The invention relates to a combination preparation for the oral administration of antibiotics as an aqueous suspension containing

a) an active ingredient component in the form of particles which are coated with a polymeric, permeable, swellable and / or gastric juice-soluble coating agent, and

b) a syrup base with a pH between 5 and 10 as the second component spatially separated from the first component a).

In this combination preparation, active ingredient component a) consists of coated active ingredient particles which are combined with component b), the suspending agent, before use. The two components are contained in two separate containers, which are packaged in a common package in the sense of a "kit of parts". The contents of the two containers are combined in a suitable container immediately before use. The two separate containers can be designed so that a single dose can be found in each case. Alternatively, the contents of the two containers can be combined in a storage vessel from which the measured amount of liquid can be removed until the end of the therapy. The storage container can be one of the two containers. The suspension produced in this way is characterized by favorable taste and stability properties. After the suspension has been prepared, the pleasant taste of the liquid and the effectiveness of the active ingredient are retained until the end of therapy. The terms and terms used above and below are defined within the scope of the description of the invention, unless they are self-evident, as follows:

An oral antibiotic is administered as a single active ingredient or as a combination of active ingredients. Suitable active substances are selected from the group of penicillins, cephalosporins, quinolones, aminoglycosides and macrolides and can be combined with another active substance from the substance groups mentioned.

The penicillins or cephalosporins can be combined with a β-lactamase inhibitor, for example clavulanic acid or sulbactam or tazobactam. For example, the active ingredient component can be made of amoxicillin and clavulanic acid (Augmentan ^® ) or. Ampicillin and Sulbactam (Unacid ^® ) or Piperacillin and Tazobactam (Tazobac ^® ) exist.

Further active ingredient components that can be used in the combination preparation according to the invention are penicillins, such as amoxicillin, ampicillin, bacampicillin, nacillin-Na, propicillin-K, phenoxymethylpenicillin-K, flucloxacillin, dicloxacillin, oxacillin, or pivampicil-lin.

Other active ingredient components are cephalosporins, such as cefaclor, cefadroxil, cefalexin, cefamandole, cefatrizine, cefazolin, cefepim, cefetamet, cefradrin, cefazedone, cef- tazidime, cefbuperazone, cefuroxim, cefiximefefone, cefiximefone , Cefotaxim, Cefotetan, Cefotiam, Cefoxitin, Cefmetazol, Cefperazon, Cefpimizol, Cefpiramide, Cefadroxil, Cefpo- doxim, Cefpodoxim-Proxetil, Cefuroxim-Axitil, Cefpodoxim-Proxitil, Cefterefoxitil, Cefterefoxitil, Cefterefoxitil, Cefterefoxamit , Cefuroxim, Cefuroxim-Axetil, Cef rozil, Lafamoxef or Loracarbef.

The active ingredient component can also be selected from the group of aminoglycosides. Examples of these are neomycin sulfate or paromomycin.

Macrolides such as azithromycin, clarithromycin, roxithromycin, josamycin or spiramycin I / II / III can also be used as active ingredient.

Also preferred are rifampicin, such as quinolones / nalixidic acid derivatives (gyrase inhibitors), such as e.g. Ciprofloxacin, Norfloxacin, Cinoxacin, Lomefloxacin, Moxifloxacin, Ofloxacin, Fleroxacin, Enoxacin, Perfloxacin, Trovafloxacin, Geprafloxacin, Sparfloxacin, Tusofloxacin, Enrofloxacin or Pipemidsäure.

Finally, clindamycin or lincomycin can also be used as an active ingredient in the combination preparation according to the invention.

The active substances mentioned, which have a salt-forming group, can, if not already stated, be present as pharmaceutically acceptable salts, for example alkali metal salts (sodium or potassium salts), alkaline earth metal salts (calcium or gastric salts), plasticites, starates, propionates, Choline salts, citrates, embonates, mesila te, sulfates or hydrochloride. The active ingredients can additionally contain half to ten moles of water of crystallization.

In the combination preparation, the active substances mentioned, or their combinations, are present in the dosages prescribed for oral administration.

A suitable permeable, gastric juice-soluble coating agent consists of a film-like material which is permeable to acidic, aqueous systems, such as the contents of the stomach, and is swellable and / or soluble in these liquids.

Suitable are e.g. hydrophilic polyacrylates with an average molecular weight of approx. 1.0 x 10 to 1.0 x 10, consisting of acrylic acid polymers or acrylic acid-methacrylic acid copolymers. The acid groups of the acrylic acid and / or methacrylic acid monomers are partially or completely esterified by Cχ-C4-alkyl groups, especially by methyl and / or ethyl groups, whereby these ester groups can be replaced by hydrophilic groups, especially trimethylammoniumethyl or dimethylaminoethyl.

Preferred polyacrylates are available under the registered trademark EUDRAGIT ^® from Röhm Chemische Fabrik GmbH. EUDRAGIT ^® commercial forms are particularly preferred for rapidly disintegrating film coatings, for example swellable, permeable types based on acrylic acid ester / methacrylic acid ester copolymer, in particular ethyl acrylate / methyl methacrylate ester copolymer, for example gastric juice-soluble types such as EUDRAGIT ^® E. and the swellability can be accelerated or retarded by adding other polymers, such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetate, polyvinyl alcohol, copolymers of methacrylic acid and methacrylic acid esters (Eudragit ^® S / L) aminomethacrylate copolymers (Eudragit ^® RS / RL), and acrylic acid polymers of the Carbopol type (eg Carbopol ^® 934).

The permeability of the polymeric coatings can be changed by adding plasticizers. As plasticizers e.g. Triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin, diethyl phthalate, dibutyl phthalate, glyceryl monocaprylate, monoglycerides and acetylated monoglycerides can be used.

The coating of the drug particles takes place in a conventional manner using conventional coating methods (Rowe, RC, Int. J. Pharm. Tech. & Prod. Mfr., _3. (1) 27-32 (1982)) by dispersing or dissolving the coating agent in the desired ratio in a solvent or mixture, for example in methanol, ethyl acetate, ethanol, isopropanol, tert. Butanol, acetone, methylene chloride, chloroform, water, or mixtures thereof. If necessary, auxiliaries such as Mg stearate, stearic acid, talc or can be added to improve the technical implementation of the coating process

Silicon dioxide (Syloid® 244 FP, / Cab-o-sil ^® , / Aerosil ^® 200). The solution or dispersion is applied to the active ingredient in powder form using known methods, such as spray coating in the fluidized bed. sprayed. The processes and devices are known under the names Aeromatic, Freund, Glatt, Wurster or Hüttlin (Kugel-Coater), 'and in the boiler under the names Accela Cota process or dip pipe process (Kala, H., et al, Pharmazie, 3_4 ( 11) 755-765 (1979)). The coated product is then dried or the solvents are removed.

In the case of particularly unstable active ingredients, process conditions must be selected which allow the process temperatures to be reduced and / or the process times to be shortened. This can e.g. by working at reduced atmospheric pressure (Luy, B., et al, Pharm. Ind., 51, 89-94 (1989)) and / or by using conditioned air.

To produce the powder form of the active ingredient to be coated, the usual grinding processes are used, e.g. Grinding in ball mills, pin mills, mortar mills or air jet mills.

The preparation of the suspending agent b) is carried out in manner known per se, which is described, for example for the production of conventional syrup bases (Temperli, M., et al, Pharm. Act. Helv., _3. 9, 741 ff (1964)). In addition, the syrup base is adjusted to a pH between 5 and 10 with a suitable acid or base or a buffer system. All pharmaceutically acceptable acids, bases or salts or their combinations can be used for this, such as amino acids, benzoic acid, citric acid, tartaric acid, succinic acid, malic acid, acetic acid, carbonic acid, hydrochloric acid, phosphoric acid or Ren Na ⁺ , K ⁺ , or Ca ⁺⁺ salts, sodium hydroxide solution, glycylglycine, glycine, diisopropanolamine, tris (hydroxymethyl) amino methane (HCl), ethylenediamine, and triethanolamine (HCl). In addition, the syrup can contain viscosity-influencing substances (for example macrogols), wetting agents, preservatives, antioxidants, colorants, taste correctives (flavors), sugar and / or sweeteners.

The use of dyes can serve to enhance the appearance as well as to label the preparation. Sugar or sugar substitutes, which can serve as a syrup base are, for example, glucose, hydrogenated glucose (Lycasin ^®), sucrose, xylitol, D-xylose, maltose, D-glucose, sorbitol, glycerol, mannitol, dulcitol, maltitol, lactitol, fructose, Dextrose, lactulose or lactose or their combinations. Sweeteners, which may be included to further round off the taste, are saccharin-Na, dulcin, glycyrrhizin, ammonium glycyrrhizinate, neosperperidine dihydrochalcone, neohesperidin-HCl, glycine, stevioside, L-asparagyl-L-phenylalanamethyl ester (aspartyl ^® ), sodium cyclamate or their combinations.

The combination preparation according to the invention has valuable pharmacological properties and can be used for the therapy of infections of various origins for which the active substance or combination of active substances used is suitable.

The following examples illustrate the invention: example 1

Preparation of the syrup solution

70 kg of Karion ^® FP are placed in a stirred tank with a heating jacket. The solution is heated to 40 ° C. Then 3 g saccharin-Na, 50 g sodium dihydrogen phosphate and 950 g disodium hydrogen phosphate are added to the kettle and stirred until a clear solution is obtained. After a clear solution has been obtained, the pH is adjusted to 7.2 using dilute sodium hydroxide solution or hydrochloric acid. Finally, 5 g of raspberry aroma are added to the batch and completely dissolved. The finished syrup solution is filled into brown glass bottles with a screw cap. If appropriate, the solution can be prepared with nitrogen gas.

Example 2

Production of granules with a combination of active ingredients

62.5 kg Amoxicillin x 3H ₂ 0 and 32.813 kg K clavulanate are with 15.0 kg Avicel ^® PH 101 in a Hüttlin-ball coater with TurboJ et means presented. The product temperature is set to 26 ° C, and after reaching the temperature 150 kg of a 15 wt .-% Eudragit ^® E solution are sprayed. The Eudragit ^® E is previously dissolved in a mixture of 80 parts by volume of isopropanol and 20 parts by volume of acetone. The entire process is carried out after nitrogenization of the device. Nitrogen is used to operate the device. After the solution has been sprayed on, the granules are leveled through a 0.8 mm sieve and the residual solvents are removed in a vacuum drying cabinet. The dried granules are mixed with 5 5 kg Syloid 244 FP ^®. Finally, the mixture is portioned into sachets of 11.065 g each.

Example 3

Production of granules with azithromycin

157 kg of azithromycin and 13 kg of talc are placed in a Glat vacuum fluidized bed apparatus with Wurster insert. The atmospheric pressure in the system is reduced to 120 mbar before injecting a 20% by weight Eudragit ^® E solution in acetone. After reaching a process temperature of approx. 24 ° C, a total of 180 kg of this solution is sprayed in. After the spraying process has ended, the pressure in the system is set to 40 mbar and 30 ° C. product temperature in order to dry off the residual solvent.

The dried granulate is passed through a sieve with a mesh size of 1 mm and mixed with 1.1 kg of Aerosil ^® . The finished mixture can be filled in portions in sachets or in brown glass bottles.

Claims

claims 1. Combination preparation for oral administration of antibiotics as an aqueous suspension, containing a) an active ingredient component in the form of particles which are coated with a polymeric, permeable, swellable and / or gastric juice-soluble coating agent, and b) a syrup base with a pH of 5 to 10 as the second component spatially separated from the first component a). 2. Combination preparation according to claim 1, characterized in that the syrup base has a pH of 5.5 to 8.5. 3. Combination preparation according to claim 1 or 2, characterized in that the coating agent is an acrylic acid polymer or an acrylic acid-methacrylic acid copolymer. 4. Combination preparation according to claim 3, characterized in that the acid groups of the Acrylsäurpolyτneren or the acrylic acid-methacrylic acid copolymer are partially or completely esterified by C ₁ -C ₄ alkyl groups, which ester groups can be replaced by hydrophilic groups. 5. Combination preparation according to claim 3, characterized in that the acid groups of the acrylic acid polymer or the acrylic acid-methacrylic acid copolymer are esterified by methyl and / or ethyl groups, these ester groups optionally being replaced by trimethylammoniumethyl and / or dimethylaminoethyl groups. 6. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component is a combination of β-lactam antibiotic and β-lactamase inhibitor. 7. Combination preparation according to claim 6, characterized in that the active ingredient consists of amoxicillin and clavulanic acid or ampicillin and sulbactam or piperacillin and tazobactam. 8. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component is amoxicillin, ampicillin, bacampicillin, nafcillin-Na, propicillin-K, phenoxymethylpenicillin-K, flucloxacillin, dicloxacin- or linivacillin-, oxacillin-pacin 9. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component cefaclor, cefadroxil, cefalexin, cefamandole, cefatrizine, cefazolin, cefepim, cefetamet, cefradrin, cefazedone, ceftazidime, cefbuperazone, cef- menox, cefuroximone Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxim, Cefotetan, Cefotiam, Cefoxitin, Cefmetazol, Cefperazon, Cefpimizol, Cefpiramide, Cefadroxil, Cefixim, Cefpodoxim, Cefpodoxim-Proxetil, Cefuroxim-Axitil, Cefpodoxim-Proxitil, Cefteram Proxitil, Cefteram, Ceftezole, Cefefimimoxin, Cefizoximoxin, Cefizoximoxin, Cefizoximoxin, Cefizoximoxin , Cefprozil, Lafamoxef or Loracarbef. 10. Combination preparation according to claims 1 to 5, characterized in that the active ingredient is neomycin sulfate or paromomycin. 11. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component is azithromycin, clarithromycin, roxithromycin, josamycin or spiramycin I / II / III. 12. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component is ciprofloxacin, norfloxacin, cinoxacin, lomofloxacin, moxifloxacin, ofloxacin, fleroxacin, enoxacin, perfloxacin, tofofloxacin, trovofloxacin, trovafloxacin, trovafloxacin, trovafloxacin, trovafloxacin 13. Combination preparation according to claims 1 to 5, characterized in that the active ingredient component is clindamycin or lincomycin. 14. Use of a syrup base with a pH of 5 to 10, preferably 5.5 to 8.5, as a suspending agent for the preparation of an aqueous suspension of an antibiotic in the form of particles which are coated with a polymer. Ren, permeable, swellable and / or enteric coating agents are coated.