SK22496A3 - Pharmaceutical antimicrobial agent - Google Patents

Abstract

This therapeutic preparation with local effects based on the principle of prolonged liberation, consisting of biodegradable micro-particles from the oligoesters of aliphatic α-hydroxy acids containing a dispersed combination of at least two anti-microbial substances which are continually released into the biological medium for a period of several hours to several months.

Description

Pharmaceutical antimicrobial preparation

Technical field

The invention relates to a pharmaceutical antimicrobial composition comprising a combination of at least two antimicrobial active ingredients contained in carrier microparticles.

BACKGROUND OF THE INVENTION

The topical application of antimicrobials is undeniable in the therapy and prevention of infections. It is an indispensable step in the surgical treatment of localized infectious foci, widespread wounds and traumatized tissues. When administered topically, a significantly lower dose of antimicrobial agents can be administered compared to systemic, i.e., whole-body administration. In doing so, the effect may be higher due to the achievement of high concentrations of the substances in the affected or exposed area.

In most cases indicated for topical application of antimicrobials, it is the attack or contamination of the tissue with a wide range of microbes. In many cases it is not possible to carry out a microbiological examination of the material for time reasons. Therefore, preparations containing substances with a broad spectrum of activity are preferably used.

A disadvantage of some broad-spectrum antibiotics is their lower efficacy on some strains or the induced resistance of some strains. For disinfectants, the main problem is their overall toxicity, local irritation, or a negative effect on the processes associated with the repair of damaged tissues. The solution may be the simultaneous application of a combination of two or more antimicrobials. In the case of antibiotics, this measure achieves a broadening of the spectrum of action and a reduction of individual doses, while in disinfectants, in particular a reduction of the toxicity of individual substances by their synergistic effect.

The effect of antimicrobials is related to their duration of action. Two basic measures are used to increase the release time of antimicrobials or to control the release rate of these substances. The first is the chemical binding of the antimicrobial to the polymeric carrier. In practice, iodine bound by a complex bond to polyvinyl pyrrolidone has a common utility. A composition with very low skin irritation was obtained in a suitable composition (Pat. Eur., EP 448,288). The polymeric complex can be successfully impregnated with dressings (US Pat. US 5,051,256) or applied to gloves, catheters and other rubber articles (Pat. PCT, WO 90 05,551). A second way of achieving long-term release of antimicrobials is by inserting them into a matrix having suitable miscibility with water or tissue wet. Microcapsules containing dimethyl didecylammonium chloride incorporated into a matrix of ethylene vinyl acetate copolymer (Pat. PCT, WO 93 02,668) were obtained by this procedure. Chlorohexidine diglyconate was introduced into a mixture of glycerol with natural collagen fibers. By drying the molded mixture, sponge bodies were obtained for covering wounds or for implantation into tissue (Pat. Eur., EP 562,864). To prevent wound infection, catheters and dental restorations, silver or phosphorus pentoxide particles or granules dissolving in water at a very low rate were prepared. The powder is intended for direct application or for incorporation into polymers (Pat. PCT, WO 90 08,470).

Preferred biomaterials are esters of aliphatic hydroxy acids, in particular lactic acid polymers and lactic acid-glycolic acid copolymers. They are nontoxic substances with very low irritability, decomposing in the presence of water to non-toxic easily eliminated fumes. Implants for the treatment of peridontal disease were obtained from a mixture of tetracyclinium chloride, a lactic acid-glycolic acid copolymer and triacetin (U.S. Pat. No. 5,242,910). A two week release time of the tetracycline base was achieved by applying a solution of this substance together with a lactic acid-glycolic acid copolymer in a physiological solvent. After application of the solution to the gum, the solvent transferred to the surrounding tissue to form an irregular body of a tetracycline-containing polymer (U.S. Pat. US 4,938,763). An interesting biocompatibility solution is a microcapsule consisting of a core of a mixture of tetracycline and gelatin and a wall of a lactic acid-glycolic acid copolymer (Pat. Jap., JP 04 36,233, In: Chem. Abstr. 118, 66946). Bone fracture fixings containing up to 30% fluoroquinolone in polylactic acid were prepared by melting at 250 ° C and die casting. (U.S. Pat. No. 5,281,419). Microspheres were obtained from ampicillin and a lactic acid-glycolic acid copolymer (Pat. PCT, WO 91 13,595).

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical antimicrobial composition comprising a combination of at least two antimicrobial active agents dissolved or heterogeneously dispersed in a carrier, optionally containing other physiologically active healing aids, wherein the carrier is a biodegradable oligoester of aliphatic α-hydroxy acids or a copolymer or terpolymer thereof. α-hydroxy acids and polyhydric alcohol, with an oligoester molecular weight of up to 10 000 and a microparticle size of 1 μπι to 300 μιη.

The aliphatic α-hydroxy acid is selected from the group consisting preferably of glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric acid, or hydroxycaproic acid.

The polyhydric alcohol is selected from the group consisting preferably of glycerol, erythritol, xylitol, sorbitol, mannitol, glucose, or galactose.

The concentration of antimicrobial active agents in the carrier is 1% to 80%, preferably 5% to 45%, even more preferably 15% to 25%.

The liberation time of the ingredients is in the range of several hours to several weeks. After release of the active ingredients, the carrier is completely decomposed. Decomposition products are quite non-toxic. The advantage of combining two or more non-toxic substances is that they extend the spectrum of efficacy, reduce toxicity and irritation and potentiate the effect.

The composition may further comprise other substances that are physiologically active in terms of promoting wound healing, immunomodulatory effects, suppression of inflammation, or local anesthesia.

DETAILED DESCRIPTION OF THE INVENTION

The novel formulation comprises at least two preferably combined antimicrobial active agents dissolved or heterogeneously dispersed in the oligoester carrier. From the pharmacological class of antibiotics, it may advantageously comprise a combination of penicillin type substances; most preferably oxacillin; acting exclusively on gram positive bacteria with chemotherapeutic agents acting on anaerobic strains of bacteria, preferably metronidazole or ornidazole. Another preferred combination is of the fluoroquinolone type, preferably ciprofloxacin, in combination with agents having a pronounced effect on anaerobic strains of bacteria, most preferably ornidazole. Among the disinfectants, the combination of chlorhexidine with potentiating agents such as ammonium base disinfectants, preferably cetrimide, phenol groups, preferably thymol, quaternary or disinfectants from heavy metals, preferably zinc salts, is preferred for this purpose.

The function of the carriers of the above-mentioned antimicrobial active substances is preferably performed by biodegradable oligoesters of aliphatic α-hydroxy acids. Oligoesters are obtained from glycolic acid, various configurations of lactic acid, α-hydroxybutyric acid, α-hydroxyvaleric acid, α-hydroxycaproic acid, their copolymers in different building unit ratios, optionally from oligomers and oligomeric copolymers of the above α-hydroxy acids with polyhydric alcohols such as glycerol, erythritol, xylitol, sorbitol, mannitol, glucose, galactose. The low molecular weight of the oligoesters limited by M _n = 10,000 is advantageous in view of their faster degradation at the site of application allowing the healing of the damaged tissue ad integrum.

The drug substances may dissolve wholly or partially in oligoester carriers, may be completely insoluble and dispersed in the form of small crystals or amorphous particles. Various particle type dosage forms can be prepared from a mixture of antimicrobials and oligoester carriers. Microcapsules can be prepared by coacervation and precipitation, microspheres by liquid or gas dispersion, and microparticles by disintegration.

The concentration of antimicrobials in the oligoester carriers may range from 1% to 80%, preferably from 5% to%, most preferably from 15 to 25%. The antimicrobials may be contained in the oligoester microparticles individually or in a mixture. In the case of microparticles containing one antimicrobial substance, the particles differing in the other substance are mixed at the final stage of the production process.

Medicaments having a composition according to the above conditions may be administered orally, parenterally or topically. For oral administration they have a liberation time of up to 20 hours, for parenteral administration into muscle, subcutaneous tissue, articular capsule, vein, cyst, etc., the liberation period is from 3 days to 6 months. For topical application to skin, mucosa, wounded or surgically exposed tissue, the time of liberation is from a few hours to three months.

With the statistical principle of liberation from many applied microparticles, there is a low risk of system failure. By applying the microparticles it is possible to treat various large areas of the affected tissue. In the case of difficult to access sites, it is possible to choose to apply the microparticles with a hollow needle, which is a relatively gentle method of administration compared to incision. The microparticles can be administered in a variety of dosage forms, particularly powder, suspension, and spray.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Micronized oxacillin sodium (1.0 g) was mixed with ornidazole (1.0 g) and DL-lactic acid-glycolic acid copolymer 85:15 (8.2 g). The copolymer had an M _{n of} 6450, a Tg of 45 C. Moldings of 15 mm in diameter, 5 mm in height were obtained at a pressure of 9.4 MPa. The moldings were milled to a particle size of 260 µm. At 37 ° C, a concentration of 0.1 mol was added to the phosphate buffer. 1 ^_1 pH 6.8 contained 50% of the released oxacillin for 3.5 hours, 100% was released in 14 hours. Under the same conditions, 50% ornidazole was released in 6.4 hours, 100% ornidazole in 19 hours. Compounds were determined by HPLC with spectrophotometric detection.

The powder is intended for oral administration after filling into hard gelatine capsules.

Example 2 g of oxacillin sodium were mixed in a mortar with 25 g of ornidazole and 150 g of DL-lactic acid copolymer with central sorbitol molecule M _n 8650, Tg 47 ° C, K 9.5%. The mixture was melted at 120 ° C, the melt extruded into cold liquid paraffin. The bodies obtained were comminuted by grinding. The microparticles were obtained by sieving less than 300 µm. The liberation time of oxacillin sodium at pH 6.8 and 37 ° C was 10 hours, ornidazole liberation time under the same conditions was 19 hours. The substances were determined spectrophotometrically. The microparticles can be administered orally or topically.

Example 3

The micronized base of ciprofloxacin (mean Feret diameter 2 µm) was mixed in an amount of 1.6 g with 4.8 g of poly L-lactic acid, M _n 5790, T _g 49 ^e C, T _m 154 ° C, in a mortar. The mixture was melted at 160 ° C, the solidified melt was crushed in a mortar.

The sieve fraction 20 ^µm to 63 µm was applied intramuscularly to rats. 25 mg of powder suspended in 1 ml of 5% poloxamer 407 was administered. Plasma concentrations exceeded the minimum inhibitory concentrations for 7 days.

Microparticles with ornidazole were prepared in a similar manner. A mixture of 2.1 g ornidazole and 8.4 g poly

DL-lactic _Mn 9,500, _Tg 52 C was melted at 135 ° C After solidification of the melt, the block was comminuted in a mortar and sieved to obtain a fraction of 40 μπι to 80 μη. A suspension of 120 mg powder in poloxamer solution was administered intramuscularly to rats. An effective concentration of ornidazole was found in the blood serum for 4 days.

Particles smaller than 10 μπι interact less with cells of the immune system, especially phagocytic cells - phagocytic cells absorb these particles to some extent and are metabolically stimulated by these particles to produce microbicides. The action of oxacillin in the microparticles was more pronounced than that of ornidazole in the microparticles.

A powder containing both substances can be applied to wound exposed tissue.

Example 4

1.2 g of micronized ciprofloxacin base was mixed with 1.5 g of ornidazole and 32.5 g of a solution of 20% poly DL-lactic acid (Myj 9500, T _g 52 ° C) in ethyl acetate. The mixture was poured onto a Teflon plate and dried under vacuum at 31 ° C. The thin film was crushed in a ball mill. The liberation time of the microparticles less than 160 μιη in 0.05 moles · l ^{-1 of} trometamol buffer pH 7.4 was 49 days for ciprofloxacin and 5 days for ornidazole. The microparticles can be applied to open fractures of long bones.

Example 5

1.0 g of micronized chlorhexidine bromide was treated with 2.1 g of poly L-lactic Mn _of 2250, a Tg of 44 ° C, T _m 128

C. The mixture was cooled and crushed in a mortar. Sieving yielded a fraction of 10 to 63 μπι. Manner similar to the microparticles were obtained from 1.0 g of cetrimide and 4.0 g of a copolymer of lactic acid with glycolic acid in a ratio of structural units 9: 1, Mn _of 5,620, Tg of 48 ° C, T _m 146 ° C After melting at 162 ° C and solidifying the melt, a sieve fraction of 20 to 71 µm was obtained by crushing the solidified melt block in the mortar. The two powders, one containing chlorhexidine bromide, the other containing cetrimide chloride, were mixed and administered intramuscularly to the rabbit. After 30 days, effective concentrations of substances in muscle tissue around the implant were found.

A powder containing two kinds of microparticles differing in antimicrobial may be applied to open bone fractures.

Example 6

3.5 g of chlorhexidine nitrate and 1.0 g of benzododecinium bromide were mixed with 40 g of a 15% acetone solution of a lactic acid-glycolic acid copolymer in a building units ratio of 7: 3, 1830, T _{g of} 7.8 ° C. The solvent was partially evaporated at normal temperature and pressure on a Teflon pad and the thin film was dried in a vacuum oven at 250 Pa at 35 ° C. Microparticles were obtained by crushing in a mortar. The sieve fraction 3 was separated from 2 μιη to 90 μιη.

Liberation time in trometamol buffer 0.05 mol. I ^-1 at pH 7.4 was 16 days nitrate, chlorhexidine, the boron benzododecínia 11 days. The powder can be applied to soft tissue injuries, infected peritoneum, or treatment of focal infections in maxillary surgery.

Example 7

The statistical terpolymer of glycolic acid, L-lactic acid, and D-glucose synthesized at a ratio of 0.41: 0.56: 0.03 feed reactants was dissolved in acetone to a 12.5% solution. To 15.5 g of the solution were added 0.30 g of norfloxacin, 0.11 g of zinc gluconate and 0.05 g of nitrate. silver. The acetone was evaporated on a petri dish for 24 hours at normal pressure and 48 hours at a pressure of 550 Pa and a temperature of 25 ° C. The thin film was crushed in a mortar at 5 ° C. Irregular particles of mean diameter 60 μπι were subjected to liberation in trometamol buffer pH 7.3 at 37 ° C. Liberation time of 50% norfloxacin was 20 hours, 90% norfloxacin was released in 145 hours. The presence of zinc and silver ions was demonstrated in the microparticles after 72 hours of liberation.

The powder is suitable for application to burns.

Example 8

The micronized base of fleroxacin 1.0 g was mixed with ornidazole 0.85 g and a glycolic acid statistical terpolymer with DL-lactic acid and mannitol synthesized in a monomer ratio of 4.0: 5.6: 0.4 (w / w) in an amount of 3.2 g. The terpolymer has a value of _Mn 2200, _Mw 3950, _the M »6350, Tg of 20 ° C. The mixture was compressed at 25 ° C in a tablet press with a 15 mm diameter die at 7.6 MPa. Plates of 5.5 mm height were obtained. The compacts were milled in a ball vibratory mill to irregular particles with a mean diameter of 80 μπι. At 37 ^and C is the trometamol buffer, isotonic sodium chloride, at pH 7.3 contained 90% of the released fleroxacínu for 17 hours, 90% of ornidazole for 8 hours.

The powder may be orally administered after filling into capsules.

Example 9

5.25 g of L-lactic acid, D-lactic acid and D-glucose terpolymer prepared in a monomer ratio of 1: 1: 0.7, M _n 2800, were dissolved in 50.0 g of ethyl acetate. 1.3 g of micronized gentamicin base and 2.05 g of triclosan were added to the solution. The system was poured in slowly with stirring to a 0.6% aqueous solution of polyvinyl alcohol _(Mn 1600, 89% dezacetylácie) an overhead paddle stirrer stirred at 20 ° C and a frequency of 950 rpm. After stirring for three hours, microspheres with an average diameter of 55 μπι were formed. Liberation time in blood plasma isotonic and isoacid buffer was gentamicin 22 hours (50%), respectively. 156 hours (90%). The time of triclosan liberation was 56 hours (50%), respectively. 178 hours (90%).

The powder can be applied by pouring into open wounds.

Claims (4)

PATENT CLAIMS A pharmaceutical antimicrobial composition comprising a combination of at least two antimicrobial active agents dissolved or heterogeneously dispersed in a carrier, optionally containing other physiologically active healing enhancing agents, characterized in that the carrier is a biodegradable oligoester of aliphatic α-hydroxy acids or a copolymer or terpolymer thereof two different α-hydroxy acids and a polyhydric alcohol, with an oligoester molecular weight of up to 10000, a microparticle size of 1 μιη to 300 μπι, the concentration of antimicrobial active substances in the carrier being 1% to 80%. The pharmaceutical antimicrobial preparation of claim 1, wherein the aliphatic α-hydroxy acid is selected from the group consisting of glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric acid or hydroxycaproic acid. Pharmaceutical antimicrobial composition according to claim 1, characterized in that the polyhydric alcohol is selected from the group consisting preferably of glycerol, erythritol, xylitol, sorbitol, mannitol, glucose or galactose. Pharmaceutical antimicrobial composition according to claim 1, characterized in that the concentration of antimicrobial agents is preferably 5% to 45%, even more preferably 15% to 25%.