CZ49095A3 - Pharmaceutical antimicrobial preparation - 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

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About czx i στ. in particular, the microparticles contained in the microparticles of oligoesters of aliphatic α-hydroxy acids, their copolymers and copolymers with polyhydric alcohols.

BACKGROUND OF THE INVENTION

IP A '

Topical application of antimicrobial agents is undeniable in the therapy and prevention of infections. It is an essential step in the surgical treatment of localized infectious lesions, widespread wounds and traumatic tissues. When administered topically, it is possible to administer a considerably lower dose of antimicrobial agents compared to systemic administration, that is, to the whole organism. 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 the majority of cases indicated for topical application of antimicrobials, it is an attack or contamination of the tissue with a broad spectrum of microbes. In many cases it is not possible to perform microbiological examinations of the material for time reasons. Therefore, it is advantageous to use preparations containing substances with a broad spectrum of activity.

The disadvantage of some broad-spectrum antibiotics is their lower efficacy on some strains or the induced resistance of some strains. In the case of substances with disinfectant action, the main problem is their high toxicity, local irritation, or a negative effect on the processes associated with the repair of damaged tissues.

The solution may be a 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 reduction of individual doses, in disinfectants it is primarily a reduction of toxicity of individual substances with their synergistic effect.

The effect of antimicrobial agents is related to its duration of action.

Two basic measures are used to prolong 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 a polyvinyl pyrrolidone is commonly used. A composition with very low irritability was obtained in a suitable composition. skin / Pat. 3ur., SP 4-43,288]. The polymeric complex can be successfully impregnated with dressings / Pat. US, US 5,051,256] or may be applied to gloves, catheters, and other rubber articles (U.S. Pat. PCT,

A second way to achieve long-term release of antimicrobial agents is to incorporate it into a matrix having suitable miscibility with water or tissue wet. Said PEM postuΛ ¹ were obtained microcapsules containing dimethyl didecylamonium chloride Built into a matrix-ethylene copolymer vinylacetátového- / Pat. PCI, WO 93 02,668]. Chlorhezidinium dicarbonate was incorporated into a mixture of glycerol with natural collagen fibers.

By drying the formed mixture, sponge bodies were obtained for covering wounds or for implantation into tissue (Pat.Dur ,, 562,864).

Silver or phosphorus pentoxide particles or granules have been prepared to dissolve in water at a very low rate for the prevention of wound infection, for the manufacture of catheters and dental replacements. PCI, WO 90 08, 470].

Preferred biomaterials are esters of aliphatic hydroxy acids, especially lactic acid polymers and lactic acid-glycolic acid copolymers. They are non-toxic, with very low irritability, decomposing into non-toxic readily eliminable fumes in the presence of water. Implants for the treatment of peridontal diseases were obtained with a mixture of tetracyclinium chloride, a lactic acid-glycolic acid copolymer and triacetin / Pat. USA, US 5,242,910]. Two weeks base release time. tetracycline was achieved by applying a solution of this compound together with a copolymer of lactic acid with glycolic acid in a physiological solvent. After application of the solution to the gum, the solvent transferred to the surrounding tissue to form an irregular body from a polymer containing tetracycline / Pat. USA, US 4,933,763]. An interesting biocompatibility solution is a microcapsule consisting of a core of a mixture of tetracycline and gelatin and a wall of copolymers of lactic acid with glycolic acid / Pat. Jap. JP 04.35,233

Ί18, 66946 /. Bodies designed to fix bone fractures containing up to 3U% fluoroquinolone in polylactic acid were prepared by melting to 25 ° C and die casting into Pat. USA, US 5,281,419]. 2 ampicillin and an acid copolymer

-m.1 é.gn4_g. Microspheres / Pat were obtained by emulsion method with glycolic acid. PCT, WO 91 13, 595].

SUMMARY OF THE INVENTION

A prolonged-liberation medicinal product characterized by combining two or more antimicrobials dispersed in an oligo-spherical carrier. The formulation has a particulate character and the microparticle size is about 1 µm to 300 µm. The active substances may be from the group of antibiotics, chemotherapeutic agents or disinfectants. The carrier is the oligoesters of aliphatic .alpha.-hydroxy acids, i.e., glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric acid or hydroxycaproic acid, or copolymers thereof, or terpolymers composed of two different hydroxy acids and a polyhydric alcohol such as sorbitol, mannitol, glucose. , erythritol, glycerol, etc. ·

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. The degradation products are completely non-toxic. Advantages or combinations of antimicrobial agents or a greater number thereof are broadening the spectrum of efficacy, reducing toxicity and irritation and potentiating the effect. _f .

The formulation may further comprise other substances that are physiologically active

5 'is active in the sense of promoting wound healing. , Immunomodulatory ^! effects, inflammation suppression, or local anesthesia.

DETAILED DESCRIPTION OF THE INVENTION

The novel type formulation comprises at least two preferably combined antimicrobials of bially active agents dissolved or heterogeneously dispersed in an oligoester carrier 2 of a pharmacological group of antibiotics may preferably comprise a combination of penicillin type substances; most preferably oxacillin; acting specifically on gram positive bacteria with chemotherapeutics acting on anaerobic .......

strains of bacteria, preferably metronidazole or ornidszole. Another preferred combination are fluoroquinolone-type agents, preferably ciprofloxacin, in combination with agents having a pronounced effect on anaerobic strains of bacteria, preferably ornidazole.

From group *. Disinfectants are preferably combinations of chlorhexidine with potentiating agents, such as disinfectants from quaternary ammonium bases, preferably cetrimide, or disinfectants from the phenol family, preferably thymol, or disinfectants from the heavy metal family, preferably zinc salts.

The function of the carriers of the above antimicrobial active substances is preferably performed by biodegradable aliphatic o (-hydroxyacid) oligoesters. hydroxycaproic acid, their copolymers in different proportions of building units, optionally from oligomers and oligomeric copolymers of the above-mentioned κ-hydroxy acids with polyhydric alcohols such as glycerol, erythritol, xylitol, sorbitol, mannitol, glucose, galactose. = 10000 is advantageous due to their faster degradation at the site of application allowing the healing of the damaged tissue ad integrum.

The drug substances may dissolve in whole or in part in oligoester carriers, be completely insoluble and dispersed in the form of small crystals or amorphous particles.

Various particulate-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 can range from about 1% (w / w) to about 80% (w / w), more preferably from about 5% (w / w) to about 10% (w / w). 45% (w / w), preferably from 15% (w / w) to 25% (w / w). The antimicrobials may be contained in the oligoester microparticles individually or in a mixture. For microparticles containing one antimicrobial agent particles differing se._druhem ... _________________ 'substance mixed áv'ěrečném mod ^{_ _} sfá'diu pr-shape manufacture -; ---

Medicines having the composition according to the above conditions may be administered orally, parenterally or bpibkýT ^ L ^ s ^^ ^ PrdlTiú apLTkaci ^- have time ^_ ~ 7 to ~ under i'b'era'C'e ^_ ^ 2O hours for parenteral administration to the muscle, skin, articular capsule, vein, cyst, etc., the time of liberation is from 3 days to 6 months. When topically applied to the skin, mucous membrane, injured or surgically exposed tissue, the time of liberation is from several hours to three months.

In the statistical principle of liberation with many applied microparticles there is a low risk of failure. Application of microparticles. different areas of the affected tissue can be treated.

In the case of difficult to access sites, the use of a microparticle by a hollow needle can be chosen, which is a relatively gentle method of administration compared to incision. The microparticles can be applied in a variety of dosage forms, especially powder, suspension and spray.

Examples:

Example 1

The micronized oxacillin sodium (1.0 g) was mixed with ornidazole (1.0 g) and DL-lactic acid copolymer with glycolic acid 85:15 (8.2 g). The copolymer had 6450,

Mp 45 ° C. Moldings of a diameter of 15 µm, a height of 5 mm, were obtained at a pressure of 9.4 MPa. The moldings were milled to a particle size of 260 µm, 37 ° C and a 0.1 mol phosphate buffer. l ^"1 pH 6.8% released 50 contained * '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. The compounds were determined by the HPLC method with spectrophotometric detection.

The powder is intended for topical application after filling into hard gelatine capsules. Example 2 g of oxacillin sodium were mixed with 25 g of ornidazole and 150 g of DL-lactic acid copolymer with central sorbitol molecule M 8650, Γ 47 ° C, to 9.5% in a slip. The mixture was melted at 120 ° C. , the melt extruded into cold liquid paraffin. Cylindrical bodies having a diameter of 2 mm were obtained. The microparticles less than 300 µm were obtained by screening. 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 by spectrophotometry. The microparticles can be administered orally or topically.

Example 3

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

A sieve fraction of 20 µm to 63 µm was administered intramuscularly to rats. 25 mg of powder suspended in 1 ml of a 5% (w / w) polyethylene oxide / polypropylene block copolymer, 12600, 70 $ (w / w) POB, was administered. Plasma concentrations of ciprofloxacin exceeded the minimum inhibitory concentration for 7 days.

Ornidazole microparticles were prepared in a similar manner. A mixture of 2.1 g ornidazole and 8.4 g of poly-DL-lactic __95OO M _n, 52 ° C was melted at 135 ° C. After solidification of the melt "was ^- b'io'k ro ~ Z; drobn'ěn-in-t-conferencing and sift-dioxolan-d-m-by-a-la-t-Skan-fr-akceí- 40 jum to 80 jum. A suspension of 120 mg of powder in poloxamer solution was administered intramuscularly to rats. An ornidazole concentration was found in the blood serum for 4 days.

Particle size. less than 10 µm to a lesser extent by the cells of the immune system, in particular with phagocytic cells - the phagocytic cells absorb these particles to some extent and are metabolically stimulated by these particles to produce microbicidal effects. 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 the tissue. exposed by injury.

Example 4

Micronized ciprofloxacin base in an amount of ^-!, 2 g, was mixed with 1.5 g ornidazole and 32.5 g of a 20% solution of poly-lactic LL (9500 M T 52 ° C) in ethyl acetate.

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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 preferred ratchet time of the microparticles is less than 160 µm in 0.05 mol. tromethamol 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 mixed with 2.1 g of L-lactic acid 2250, Tg 44 ° C, T _m 123. ° C. The mixture was melted at 142 ° C, the melt cooled and crushed in a friction. Sieving gave a fraction of 10 to 63 µm. In a similar manner, microparticles were obtained from 1.0 g of cetriumide chloride and 4.0 g of a lactic acid-glycolic acid copolymer in a building units ratio of 9: 1, 5620, 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 grinding the solidified melt block in the friction. The two powders, one containing chlorhexidine bromide, the other containing cetrimide chloride, were mixed and administered intramuscularly to rabbits. 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 chlorhexidine nitrate and 1.0 g benzododecromide bromide **.

40 g of a 15% acetone solution of a lactic acid-glycolic acid copolymer in a building unit ratio of 7: 3, 1830, 7.8 ° C was mixed. The solvent was partially.

evaporate at normal temperature, under pressure on a Teflon pad, and the thin film is dried in a vacuum oven at 250 Pa at 35 ° C. Microparticles were obtained by grinding in the friction. A sieve fraction of 32 µm to 90 µm was separated. ₄ , ',,

Liberation time in trometamol buffer 0.05 mol. pH 7.4 was 16 days for chlorhexidine nitrate and 11 days for benzododecinium bromide. The powder can be applied to soft tissue injury, infected peritoneum or treatment. * foci of infection in maxillofacial surgery.

- Example 7

The micronized base of fleroxacin was added in an amount of 0.85 g ornidazole in an amount of 0.85 g and a statistical terpolymer of glycolic acid 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 the value 2200, M-395 • _{Ο _Ξ μ} ^ _6 5O -, _ t 2 O ^ C -Mixtures-by-la-Liso-V-ana-pr.i_25_5l .__ WZ ^x g in a tablet press with a diameter of 15 µm at a pressure of 7.6 MPa. Plates of 5.5 mm height were obtained. The pellets were resolved in a spherical vibrating mill to irregular particles with a mean diameter of 80. At 37 °, 90% of the contained fleroxacin crnidazole was released into the trometamol buffer and isotonized in 8 hours.

sodium at pH 7.3 in 17 hours, 90%

The powder may be topically applied after filling into capsules.

Example 8

5.25 g of L-lactic acid, D-lactic acid and D-glucose terpolymer prepared in a monomer ratio of 1: 1: 0.7, 2800, were dissolved in 50.0 g of ethyl acetate.

1.3 g of micronized gentamycin base and 2.05 S of triclosan were added to the solution. The system was slowly poured into 0.6¾ aqueous polyvinyl alcohol (M 2) solution with stirring

16000, 89¾ desacetylation) mixed with a pendulum stirrer at 20 ° C and 950 rpm. After three

hours of stirring, microspheres of an average diameter of 55 .mu.m were formed. Liberation time in blood plasma isotonic and isoacid buffer was 22 hours (50 µm) and gentamycin base, respectively. 156 hours (90. Triclosan liberation time was 56 hours (50 and 178 hours, respectively).

The powder can be applied by pouring into open wounds.

Example 9 clay

A statistical terpolymer of glycolic acid, L-lactic acid and D-glucose synthesized at a ratio of the input reactants of 0.4 ^L · 0.56: 0.03 (wt) was dissolved in acetone to a 12.5 ¾ 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 silver nitrate. Acetone was evaporated on a petri dish for 24 hours at normal pressure and 48 hours at 550 Pa. and a temperature of 25 ° C. The thin film was comminuted at 5 ° C in the friction. Irregular particles of mean diameter 60 µm were subjected to liberation in trometamol buffer pH 7.3 at 37 ° C. * Liberation time 50% was 20 hours,% 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.

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Example 10

To test the antimicrobial efficacy of the preparation, 8 small laboratory pigs (minipasses) of an average weight of 28 kg were used. On each side of the back of each of the experimental animals were special surgical and aseptic-

----------------- ký púgobe _m _ _Z m for the děny- -4 ~ ..- cuts délky- 5- cul. ». "depths.-! .5 .. cm. _

The same as 1-no-kullan-1-yl-same-1-lactobutyrate with the addition of mg microparticles from the L-lactic acid terpolymer itself, D- milk and glucose. In a fourth section, the microparticles of Example 8 were applied in an amount of 40 mg-mixed with 100 mg of mannitol and -10 mg of polyethylene glycol copolymer with polyglycol glycol, M 12600, 70% polyethylene glycol.

At time intervals of 1 day, 2 days, 3 days, 5 days and 14 days, the incisions as model wounds were uncovered and swabs were collected from the inside and surface of the incisions using sterile cotton swabs. The swabs were cultured by conventional microbiological procedures and the results were read the following day.

It was found and confirmed that in two minipigs the model wounds were sterile two days after the application of Example 8. In 6 pigs, the model wounds were sterile on the third day after the application of Example 8. Wounds inoculated and untreated and wounds with oligoester carrier alone

------- -were massively-i-nicked for * all Ί 4 day ^_ evaluation period?

- Example 11

Female Wistar rats weighing from 180 g to 200 g were treated with 30 mg of the microparticles of Example 8 and 30 mg of the L-lactic acid, D-lactic acid, and glucose carrier microparticles alone from the carrier. After 3, 7 and 14 days histological '(r ........... ”' ........... - - · .......... was performed "- · - · '...... - - sampling of the tissue. preparations were made with focus on visualization of connective tissue further fibrous-tissue and cellular components. It has been used impregnation technique ^modulation! i * etikulárního ligament.

It has been shown that both the carrier microparticles and the microparticles of Example 8 do not cause skin, subcutaneous tissue in the tissues. , nor in skeletal muscle negative reaction, different from change after mere mechanical intervention. The histopathological changes present are mainly due to the regenerative effort of the organism

W 7 of the test animal to remove necrotic tissue resulting from / scalpel injury and subsequent sutures.

Claims (1)

PATENT CLAIMS A pharmaceutical antimicrobial composition comprising a combination of r at least two antimicrobials dissolved. or heterogeneously dispersed in the carrier concentration and V- from ^{1¾, R'S} thmoth 80% <hmoU \ ^ optionally containing further physiologically active substances promoting wound, characterized in that the carrier consists of biodegradable oligoester -al-if-at-íckých- "Α-hydroxyacids ΓΓη or a copolymer thereof consisting of high alpha-hydroxy acids in. selected from the group consisting of glycolic, lactic, hydroxybutyric, hydroxyvaloric, hydroxycaporic and polyhydric alcohol selected from the group consisting of ► glycerol, erythritol, xylitol, sorbitol, mannitol, glucose, galactose having an oligoester carrier molecular weight of up to 10,000, having a microparticle size of from 1pm to 300µm. ’Wd