A method of producing composites of antibiotics

 

(57) Abstract:

Proposed: a method of producing composites of antibiotics. The method is characterized by the fact that preparing a mixture of a plastically moldable salt cationic component of Foundation of the antibiotic (aminoglycoside or from a representative group lincosamides, tetracycline) with a specific anionic component without the use of inorganic or organic needlebearing binder, the molding is carried out by extrusion, calendering, extrusion or milling. The invention expands the Arsenal of methods specified destination. 20 C.p. f-crystals, 1 table.

The present invention relates to a method for producing composites of antibiotics that can be used as implants in medicine and veterinary medicine for the treatment of local microbial infections in the hard and soft tissues.

It has long been known that the systemic use of antibiotics is complicated by a number of problems. When systemic use, it is often necessary to enter very large doses of antibiotics in order to reach the infected tissue antimicrobe existing concentrations of antibiotics. Because of this, in particular, in the case of aminoglycoside antibiotics and of antibiotica. Therefore, already decades ago, the idea arose to introduce antibiotics locally input system release or transfer them to the appropriate depot. For local treatment of microbial infections of soft and hard tissues in medicine and veterinary especially important after high initial doses of antibiotics to ensure the release of small amounts of antibiotics in the period of time calculated by days to several weeks, for possible full the killing of microorganisms. First of all, it is crucial for a successful fight with infections of bone tissue. Particularly of interest when such composites, which along with antibiotic action due to their chemical composition, are costopromedio action.

For medical use antibiotic depo-systems require appropriate antibiotics with suitable excipients to form suitable for use and storage of pharmaceutical drugs or implants. Also pharmaceutical drugs and implants are a composite system of active substances and auxiliary substances required for the preparation of the drug. Such preparations may be in the liquid, t is ing require sufficient mechanical strength. Therefore mechanically stable to link active and auxiliary substances. This can be achieved, on the one hand, by chemical curing process excipients and, on the other hand, by pressing plastically moldable excipients, which under the action of pressure to form a composite material.

Depot systems of antibiotics for the treatment of local infections are the subject of numerous publications and patents, of which only some are mentioned here.

Physical fixation of antibiotics using nerenormiruemye polymers are described in several patents, here are just a few. So, Klemm (K. Klemm: Surgical synthetic polymeric material and a method of treatment of osteomyelitis. 13.05.1975, US 3882858) offers treatment of osteomyelitis of the polymer particles from polymethacrylate, polyacrylate and their copolymers, which are loaded with gentamicin or other antibiotics. Klemm describes the application was septopal (K. Klemm, Septopal - a new path for local antibiotic therapy. In T. J. G. Van Rens, F. H. Kayser (Eds.), Local antibiotic treatment of osteomyelitis and soft tissue infections, Excerpta Medica, Amsterdam (1981) 24-31; K. Klemm: Antibiotic pulsating core is polymetacrylate. Heuser and Dingeidein describe the composition based antibiotics and polymethylmethacrylate or polyacrylate, which as additional components added amino acids (D. Heuser, E. Dingeldein: Synthetic antibiotic compositions based on polymers containing amino acids. 04.04.1980, US 4191740; D. Heuser, E. Dingeldein: Synthetic antibiotic compositions based on polymers containing amino acids. 11.11.1980, US 4233287). Further antibiotics, in particular aminoglycoside antibiotics, were also integrated into the bone cement (A. Gross, R. Schaefer, S. Reiss: Composition of bone cement containing gentamicin. 22.11.1977, US 4059684; A. Welch: Antibiotics in acrylic bone cement. An in vitro study. J. Biomed. Mater. Res. 12 (1978) 679; R. A. Elson, A. E. Jephott, D. B. McGechie, D. Vereitas: Acrylic cement loaded with antibiotic. J. Bone Joint Surg, 59B (1977) 200-205). As a binder used in this act polymers formed during curing of the cement.

Education depot-antibiotics using rezorbiruetsa polymers, in particular polyesters-hydroxycarbonic acids, has also been the subject of several publications, of which only some are mentioned. Sampath et al. proposed releasing gentamicin system consisting of poly-L-lactide and gentamicin, which was obtained pressemuh delivery systems of poly (L-lactic acid)/gentamicin. Int. J. Pharmaceutics 78 (1992) 165-174). This system depending on the quantity entered, the powder has a slight slow release of the active substance. In such a system poly-D,L-lactide was used to produce microspheres containing the active substance (R. Bodmeier, J. W. McGinity: Obtaining and evaluating containing medicines poly(D,L-lactide) microspheres obtained by evaporation of the solvent. Pharm. Res. 4 (1987) 465-471). Fries and Schlapp also described microparticles from polylactide, which are covered with a collagen/gentamicin sulfate (W. Friess, M. Schlapp: Improved implants for local delivery of gentamicin. Sixth World Biomaterials Congress Transactions (2000) 1488). These coated microspheres exhibit only a very slight tendency to slow down the release of gentamicin. Schmidt et al. proposed containing gentamicin, rezorbiruetsa moulded products (C. Schmidt, R. Wenz, B. Nies, F. Moll: Releasing in vivo/in vitro antibiotics histochemistry and biodegradable implants gentamicin, based on polymers and copolymers of lactic acid. J. Control. Release 37 (1995) 83-94). These products were obtained by extrusion of mixtures of gentamicin sulfate/poly-L-lactide, gentamicin sulfate/poly-D,L-lactide and gentamicin sulfate/poly-D,L-lactide-co-glycolide. The decree is P CLASS="ptx2">Along with systems based on polymers described numerous inorganic systems with retardism action. Hereinafter briefly referred to only some of the system obtained with calcium sulfate. So, Randolph, and others, have described retardiculous system, which is based on the influence of active substances in a matrix of calcium sulfate (D. A. Randolph, J. L. Negri, T. R. Devine, S. Gitelis: Calcicola matrix controlled release. 15.09.1998, US 5807567). The receipt of such granules of calcium sulfate is carried out on the basis of a mixture of hemihydrate of calcium sulfate, hemihydrate of calcium sulfate, additives and water. Curing is carried out by formation of the dihydrate of calcium sulfate. Turner and others have described the tablets of calcium sulphate that contain tobramycin and should find application in the treatment of medullary defects (T. M. Turner, R. M. Urban, S. Gitelis, A. M. Lawrence-Smith, D. J. Hall: delivery of tobramycin using tablets calcium sulphate for vaccinations large medullary defect: local and systemic effects. Sixth World Biomaterials Congress Transaction (2000) 767). Were also described a similar system release calcium sulphate, but with amikacin sulfate (D. W. Petersen, W. O. Haggard, L. H. Morris, K. C. Richelson, J. E. Parr: Elution amikacin from granules of calcium sulfate. An in vitro study. Si is tibiotics relatively few took into account when receiving depo-preparations. The formation of insoluble salts or chelates of the antibiotics tetracycline type for several decades is well known. So, Folch Vazquez describes obtaining dodecyl sulfate by tetracycline interaction tetracycline hydrochloride with sodium dodecyl sulfate in water (C. Folch Vazquez: Valium tetracycline. 08.02.1966, ES 3309402; C. Folch Vazquez: Derivative of tetracycline. 09.01.1967, NL 6609490). Alternatively, the receiving may be performed on the basis of tetracycline and modellserie acid (C. Folch Vazquez: Valium tetracycline. 08.02.1966, ES 322771). Additionally it was also suggested that the use of sulfamate tetracycline for antibiotic therapy (A. Jurando, J. M. Puigmart: Sulpham tetracycline antibiotic and its derivatives. 27.10.1970, US 3536759; Anonym: Alkylsulfonate tetracycline antibiotic. 16.10.1969, ES 354173; C. Ciuro, A. Jurado street: Stability derivatives of tetracycline. Afinidad 28 (292) 1971, 1333-5). For aminoglycoside antibiotics in principle known a number of sparingly soluble salts. So, for gentamicin describes the obtaining of sparingly soluble salts on the basis of higher fatty acids, arylalkylamines acids, alkyl sulphates and alkyl sulphonates (G. M. Luedemann, M. J. Weinstein: Gentamicin and method of receipt. 16.07.1962, US 3091572). Examples of salts of gentamicina-1-carboxylic acid, euryceros acid and dodecylbenzenesulfonic acid. These salts in many cases are not preferred because they are waxy hydrophobic substances, which makes it difficult for herbal use. Despite this, were synthesized salts of fatty acids gentamicin and atomizing of the free bases or their salts in water at 50-80°C (H.Voege, P. Stadler, H. J. Zeiler, S. Saaman, K. G. Metzger: Vzaimodestviye salt of aminoglycosides and structures that contain them, inhibited the release of substances. 28.12.1982 DE 3248328). These salts antibiotics and fatty acids must be suitable as drugs for injection. Also described receiving dodecyl sulfate gentamicin and its use in ointments, creams (C. Folch Vazquez: Derivative of gentamicin. 29.10.1974, BE 821600). A new direction are insoluble phosphates of aminoglycoside-flavonoids (N. Wahling, E. Dingeldein, R. Kirchiechner, D. Orth, W. Rogalski: Salt phosphates flavonoids of aminoglycoside antibiotics. 13.10.1986, US 4617293). Described salts profirov phosphoric acid derivatives hydroxyflavone, hydroxyflavone, hydroxyflavanone, hydroxyflavone and hydroxyflavone. Especially preferred derivatives of flavanone and flavone. These insoluble salts fibrillary structure (N. Wahling, E. Dingeldein, D. Braun: Applicable in medicine molded mass of collagen, recibira in the body. 22.09.1981, US 4291013). Next, artificial heart valves were soaked these insoluble salts of gentamicin, gentamicin-crabeater (Crobefat) (M. Cimbollek, B. Nies, R. Wenz, J. Kreuter: antibiotic-Impregnated rings artificial heart valve for the treatment and prevention of bacterial endocarditis. Antimicrob. Agents Chemother. 40(6) (1966) 1432-1437). In the mentioned patent is particularly interesting that brought a mixture of soluble sulfate gentamicin and sparingly soluble gentamicin-crorepati. When this goal was to, on the one hand, after making rings heart valves in the body or in the model liquid was achieved by the high initial concentration of gentamicin thanks soluble sulfate gentamicin and, on the other hand, due to the relatively insoluble gentamicin-crorepati was possible release of gentamicin over a long period of time.

The task of the invention is to develop a method of producing composites of the antibiotic/antibiotics, which provides a simple commercially available obtaining composites without the need of prinny to be suitable as implants in the field of medicine and veterinary medicine for the treatment of local microbial infections in bone and soft tissues. Further, the method should be suitable not only for special antibiotic, but, on the contrary, must be suitable for a number of antibiotics similar structures.

The invention is based on the surprising fact that known organic sulfates, organic sulfonates, and aliphatic carboxylates of aminoglycoside antibiotics, lincosamide and tetracycline type, which are typically hydrophobic waxy substance, molded plastic and have the properties of a binder. It is shown that the data plastically moldable salt under the action of pressure forming with auxiliary substances durable composite materials. This makes it possible to enter these plastically moldable salt of antibiotics as a binder upon receipt of the composites antibiotics from inorganic materials and, if necessary, organic materials. Additional binders to ensure form stability of the composite are no longer necessary. This allows you to save on price and does not occur possible problems of biocompatibility and reformiruemoi more inorganic and/or organic binder. A particular advantage of the offer according to image the x infection is that after making the composites obtained according to the invention, in the aquatic environment is the dissolution of the binder with the release of antibiotics, and together with the dissolution of the binder, there is a simultaneous decomposition of the composite. This means that together with the release of antibiotic decay of the composite.

The invention is based further on unexpected data that known organic sulfates and organic sulfonates antibiotics aminoglycoside type lincosamides type and tetracycline type can be formed in the presence of inorganic components of the composite and, if necessary, the organic components of the composite under the action of water during molding molded articles of commercially available water-soluble salt forms of antibiotics, such as sulfates, by interaction with water-soluble organic sulfates and sulfonates. Due to such formation in situ plastically moldable salts separate synthesis of salts is no longer necessary. This can save on costly stages of synthesis and purification.

According to the invention plastically moldable salt, which consists of, at melenik and tetracycline antibiotics and at least one anionic component from the group of aliphatic carboxylates, of alkyl sulphates, arylsulfatase, alkylarylsulfonates, cycloalkylation, alkylcyclohexanes, alkylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, arylsulfonate, alkylarylsulfonates, alkyl sulphonates, 2-sulfonates of fatty acids, arylsulfonate, alkylarylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, alkylsulfates, cycloalkylation, alkylsulfonates, cycloalkylcarbonyl, arildisulfuri, alkylarylsulfonates, aristidoideae and alkylarylsulfonates, is used as a binder for fixing the inorganic components of the composites and/or, if necessary, the organic components of the composites and, if necessary, when the adulteration of water for molding a composite material, in particular, by pressing, extrusion, rolling, calendering and milling.

The following forms of execution were implemented.

Further according to the invention as anionic components from the group of alkyl sulphates, in particular, are used dodecyl sulphate, tetradecanamide, hexadecylsulfate, octadecylsilyl and docosanol.

According to the invention as bioaccumulation and octadecylsilane.

According to the invention as well as the anionic component is used aliphatic carboxylate, which contains from 12 to 30 carbon atoms.

According to the invention as an anionic component from the group of aliphatic carboxylates are encouraged to use palmitate, stearate, beginilah.

According to the invention plastically moldable salt is synthesized before the molding process.

According to the invention plastically moldable salt is formed during molding of the composite by adding water to the mixture of the inorganic component of the composite, if necessary, the organic components of the composite, one or more members of the aminoglycoside and/or lincosamide, and/or tetracycline antibiotics, which are present in sulfate, cleaners containing hydrochloride, hydrobromide and phosphate form, and one or more representatives of alkyl sulphates, arylsulfatase, alkylarylsulfonates, cycloalkylation, alkylcyclohexanes, alkylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, arylsulfonate, alkylarylsulfonates, alkyl sulphonates, 2-sulfonates of fatty acids, arylsulfonate, alkylarylsulfonates, ticlea, igloukalivaniju, arildisulfuri, alkylarylsulfonates, aristidoideae and alkylarylsulfonates, which are in the form of a sodium salt and/or potassium salt and/or ammonium salts and/or salts of trialkylamine, and/or salts of dialkylamino, and/or salts of monoalkylamines, and/or salts of triarylamine, and/or salts of girilambone, and/or salts of arylamine, and/or salts of alkyldiphenylamine, and/or salts of dialkylacrylamide, and/or salts of tricyclodecane, and/or salts of dicyclohexylamine, and/or salts of minocyclinee, and/or salts of alkyldiethanolamine, and/or salts of dialkylacrylamide.

According to the invention the alkyl sulphates, arylaliphatic, alkylarylsulfonate, cycloalkylcarbonyl and alkylcyclohexanes are polufinale sulphuric acid.

According to the invention as well as preferred alkyl sulphates of sodium dodecylsulfate, tetradecanamide sodium, hexadecylsulfate sodium and octadecylsilyl sodium.

According to the invention as preferred alkyl sulphonates dodecylsulfonate sodium, hexadecylsulfate sodium and octadecylsilane sodium.

Further according to the invention as alkylsulfonate especially predpochtite osadnik antibiotics are alcomicin, amicacin, amikacin, apramycin, bekanamycin, betamicin, butirosin, distamycin, dibekacin, dihydrostreptomycin, lambanein, fertilizin And, fertilizin In, framycetin, gentamicin, chikishimiz, Hemomycin, vibramycin, hygromycin, kanamycin, kasugamycin, lividomycin, miniseminars, neomycin, netilmicin, paromomycin, perculatin, puromycin And, ribostamycin, rimoldi, ristocetin, ristomycin, shamisen, sizomitsin, sorbitan, spectinomycin, streptomycin, tobramycin, tunicamycin, verdammten.

According to the invention from the group lincosamide of preferred antibiotics clindamycin and lincomycin.

According to the invention from the group of tetracycline antibiotics is the preferred tetracycline, chlortetracycline, oxytetracycline, demethylchlortetracycline, metatsiklina, doxycycline, rolitetracycline and minocycline.

According to the invention as well as the inorganic component of the composite preferably is calcium carbonate, magnesium carbonate, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium sulfate, hemihydrate calcium sulphate, dihydrate calcium sulphate, tricalcium phosphate, tetracalcium, calcium phosphate, hydrogen phosphate dihydrate calcium, hydroc is but the invention of the inorganic components of the composites used in the form of powders and/or granules.

Further according to the invention as the organic component of the composite are preferably used starch, cellulose, chitin, chitosan, gelatin, collagen, polymethacrylates, polyacrylates, polyvinyl alcohol, polyvinyl chloride, grades and polytetrafluoroethylene, and mixtures thereof.

According to the invention as the organic component are readily water-soluble antibiotics.

According to the invention, the mass fraction plastically moldable salts in the composites ranged from 0.1 to 98 weight percent.

According to the invention composites are molded into molded products, granulates and powders.

According to the invention composites are plastically mouldable.

Also according to the invention compounds are preferably in the form of pastes. While composites can stretch and implement in infected areas of hard tissues.

Further according to the invention, the composite is applied as a coating on reserverose and preservere implant.

The object of the present invention in more detail is clarified by the following examples 1-2.

Obtaining compositions antibiotic

Example 1

G the ATA calcium sulphate (Fluka) by milling. Every 200 mg of this mixture was pressed under a pressure of 5 tons for two minutes in a stable molded articles in the form of washers with a diameter of 13 mm

Example 2

Preparing a mixture of 25 mg of gentamicin sulfate (700 U/mg, Fluka), 48 mg of pentakisdodecilsulfat gentamicin and 1427 mg calcium hydrogen phosphate (Fluka) by milling. Every 200 mg of this mixture was pressed under a pressure of 5 tons for two minutes in a stable molded articles in the form of washers with a diameter of 13 mm

Study of the release of antibiotics

Obtained in examples 1 and 2 molded products were made in physiological salt solution and kept at a temperature of 37°C for twelve days, to determine the slow release of antibiotics. Sampling was made after 1, 3, 6, 9 and 12 days. Determining the amount of antibiotics was performed using the agar-diffusion test using Bacillus subtilis ATCC 6633 as the test organism (the results are shown in the table).

1. A method of producing composites of antibiotics, characterized in that preparing a mixture of a plastically moldable salt consisting of at least one cationic component protonated base-antibiotic the frame component from the group of aliphatic carboxylates, of alkyl sulphates, arylsulfatase, alkylarylsulfonates, cycloalkylation, alkylcyclohexanes, alkylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, arylsulfonate, alkylarylsulfonates, alkyl sulphonates, 2-sulfonates of fatty acids, arylsulfonate, alkylarylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, alkylsulfates, cycloalkylation, alkylsulfonates, cycloalkylcarbonyl, arildisulfuri, alkylarylsulfonates, aristidoideae and alkylarylsulfonates and inorganic and/or organic components of the composite without the use of inorganic or organic needlebearing binder by milling and pressed under pressure.

2. A method of producing composites of antibiotics on p. 1, characterized in that the molding is carried out by pressing, and/or extrusion and/or rolling and/or calendering, and/or grinding.

3. A method of producing composites of antibiotics in one of the paragraphs.1 and 2, characterized in that as anionic components from the group of alkyl sulphates, preferably using dodecyl sulphate, tetradecanamide, hexadecylsulfate, octadecylsilyl and docosanol is the number of anionic components from the group of alkyl sulphonates use dodecylsulfonate, hexadecylsulfate and octadecylsilane.

5. A method of producing composites of antibiotics in one of the paragraphs.1 and 2, characterized in that as anionic components are preferably used aliphatic carboxylates containing 12-30 carbon atoms.

6. A method of producing composites of antibiotics in one of the paragraphs.1 and 2, characterized in that as anionic components from the group of aliphatic carboxylates use palmitate, stearate, beginilah.

7. A method of producing composites of antibiotics in one of the paragraphs.1-6, characterized in that the plastically moldable salt synthesized before the molding process.

8. A method of producing composites of antibiotics on p. 1, characterized in that the plastically moldable salt formed during the molding of the composite by adding water to the mixture of the inorganic component of the composite, if necessary, the organic component of the composite, one or more members of the aminoglycoside and/or lincosamide, and/or tetracycline antibiotics, which are sulfate, cleaners containing hydrochloride, hydrobromide and phosphate form, and one or more representatives of alkyl sulphates, arylsulfatase, alkylarylsulfonates, arylsulfonate, alkylarylsulfonates, alkyl sulphonates, 2-sulfonates of fatty acids, arylsulfonate, alkylarylsulfonates, cycloalkylcarbonyl, alkylcyclobutanones, alkylsulfates, cycloalkylation, alkylsulfonates, cycloalkylcarbonyl, arildisulfuri, alkylarylsulfonates, alkylthiomethyl and alkylarylsulfonates, which are in the form of a sodium salt and/or potassium salt and/or ammonium salts and/or salts of trialkylamine, and/or salts of dialkylamino, and/or salts of monoalkylamines, and/or salts of triarylamine, and/or salts of girilambone, and/or salts of arylamine, and/or salts of alkyldiphenylamine, and/or salts of dialkylacrylamide, and/or salts of tricyclodecane, and/or salts of dicyclohexylamine, and/or salts of minocyclinee, and/or salts of alkyldiethanolamine, and/or salts of dialkylacrylamide.

9. A method of producing composites of antibiotics in one of the paragraphs.1, 2 or 8, characterized in that the alkyl sulphates, arylaliphatic, alkylarylsulfonate, cycloalkylcarbonyl and alkylcyclohexanes are polufinale sulphuric acid.

10. A method of producing composites of antibiotics in one of the paragraphs.1, 2, 8 or 9, characterized in that as alkyls that sodium.

11. A method of producing composites of antibiotics in one of the paragraphs.1 and 2, or 8, characterized in that as alkylsulfonate use dodecylsulfonate sodium, hexadecylsulfate sodium and octadecylsilane sodium.

12. A method of producing composites of antibiotics in one of the paragraphs.1, 2 or 8, characterized in that as alkylarylsulfonate preferably used dodecylbenzenesulfonate sodium.

13. A method of producing composites of antibiotics in one of the paragraphs.1-12, characterized in that the inorganic component of the composite use calcium carbonate, magnesium carbonate, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium sulfate, hemihydrate calcium sulphate, dihydrate calcium sulphate, tricalcium phosphate, tetracalcium, calcium phosphate, dihydrate calcium hydrogen phosphate, hydroxyapatite, fluorapatite, rezorbiruetsa glass, rezorbiruetsa glass-ceramic, and mixtures thereof.

14. A method of producing composites of antibiotics in one of the paragraphs.1-13, characterized in that the inorganic components of the composite used in the form of powders and/or granules.

15. A method of producing composites of antibiotics in one of the paragraphs.1-14, characterized in that kachestvo, collagen, polymethacrylates, polyacrylates, polyvinyl alcohol, polyvinyl chloride, grades, polytetrafluoroethylene, beeswax, Carnauba wax, triglycerides and mixtures thereof.

16. A method of producing composites of antibiotics in one of the paragraphs.1-15, characterized in that, if necessary, as an organic component of the composite use of readily soluble in water antibiotics.

17. A method of producing composites of antibiotics in one of the paragraphs.1-16, characterized in that the mass fraction of plastically moldable salt in composites is 0.1 to 98 wt.%.

18. A method of producing composites of antibiotics in one of the paragraphs.1-17, characterized in that the composites formed into molded products, granulates and powders.

19. A method of producing composites of antibiotics in one of the paragraphs.1-18, characterized in that the composites are plastically mouldable.

20. A method of producing composites of antibiotics in one of the paragraphs.1-17 or 19, characterized in that the composites used in the form of pastes.

21. A method of producing composites of antibiotics in one of the paragraphs.1-20, characterized in that the polymers suitable for coating rezorbiruetsa and nerenormiruemye implants.



 

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