• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Summary The invention describes polymer-based formulation for drug release, especially lamped for macrolide release. The formulation of the invention consists of polymer-based barriers and roofing agents. The invention also describes a method for preparing the formulation. The invention also describes the polymer carrier. The invention also describes a method for preparing the polymer carriers of the invention.
    公开号:SE1330067A1
    申请号:SE1330067
    申请日:2013-06-09
    公开日:2014-12-10
    发明作者:Maria Kempe；Henrik Kempe
    申请人:
    IPC主号:
    专利说明:

    BACKGROUND OF THE INVENTION TECHNICAL FIELD OF THE INVENTION The present invention relates generally to the field of molecule binding and molecule-releasing carriers and formulations and methods for their preparation. More specifically, in one aspect, the invention provides a polymer-based carrier capable of selective / specific binding and controlled / delayed drug delivery. In another aspect, the invention provides methods for preparing polymer-based carriers and formulations capable of selective / specific binding and controlled / delayed drug release.
    Background and Troubleshooting of the Invention Many drugs need to be administered over long periods of time to cure intended diseases or conditions. A non-limiting example of such a drug is erythromycin, which was the first discovered macrolide antibiotic more than 60 years ago. The substance was isolated from soil and found to be a metabolite of Saccharopolyspora erythraea. It has a broader antimicrobial spectrum than 13-lactam antibiotics and is less prone to cause allergic reactions than these. The antibiotic is therefore often used as an alternative to penicillins in patients who are allergic to them. A number of erythromycin derivatives have later been developed for antibiotic purposes. Examples of such macrolides are clarithromycin, azithromycin, telithromycin and cetromycin. In recent decades, macrolides have been noted not only for their antibacterial properties but also for their anti-inflammatory and immunomodulatory effects [Giamarellos-Bourboulis, Int. J. Antimicrob. Agents, 2008, 31, 12; Kanoh & Rubin, Clin. Microbiol. Rev., 2010, 23, 590; Kwiatkowska & Maslinska, Mediators of Inflammation, 2012, 636157]. For example, erythromycin has been shown to reduce the expression of cyclooxygenase-2 in synovial cells in patients with rheumatoid arthritis and to inhibit periprosthetic tissue inflammation in patients with aseptic release [Fumimori et al., J. Rheumatol., 2004, 31, 436; Ren et al., Bone, 2009, 44, 671]. Macrolides have been tested for the treatment of a number of chronic inflammatory diseases, including cardiovascular disease, asthma, cystic fibrosis, diffuse panbronchiolitis, sinusitis, arthritis and Crohn's disease [Parchure et al., Circulation, 2002, 105, 1298; Suzuki et al., Cardiovasc. Ther., 2012, 30, 301; Shinkai et al., Pharmacol. Ther., 2008, 117, 393; Cervin, Acta Otolaryngol., 2001, 121, 83; Gui et al., J. Antimicrob. Chemother., 1997, 39, 393]. Furthermore, immunosuppressive and antiproliferative effects of non-antibiotic macrolides have been utilized in organ transplants and stent implants [Augustine et al., Drugs, 2007, 67, 369; Ruygrok et al., Int. With. J., 2003, 33, 103]. Examples of non-antibiotic macrolides used for this purpose are tacrolimus and sirolimus.
    In view of the above-mentioned conditions, it is undesirable to develop formulations with a two-stomach to release macrolides over required periods of time. Administration of satlana formulations can take place via a number of administration scales, e.g. dermally, transdermally, topically, subcutaneously, intramuscularly, intraperitoneally, orally, enterally, vaginally, rectally, intravenously, intraarterially, nasally, intravitreally, topically, epidurally, intracerebrally or by inhalation. The administration can further be mediated by an implant whose surface is coated with the formulation or by a bone cement containing the formulation. The need for macrolide release formulations has resulted in the development of a variety of formulations, such as microemulsions [Seo et al., J.
    Appl. Polym. Sci., 2013, 4277], nanoemulsions [PCT Int. Appl., 2009, WO 2009158687 Al 20091230], niosomer [Vyas et al., Int. J. Phan) Tech Res., 2011, 3, 1714], cyclodextrins [Song et al., Int. J. Nanomedicine, 2011, 6, 3173], compressed tablets [PCT Int. Appl., 2011, WO 2011107750 A2 20110909], cellulose microspheres [Reddy et al., J. Global Pharma Technol., 2010, 2, 133], polymer microspheres [U.S. Pat. Pat. Appl. Publ., 2009, US 20090317478 Al 20091224], crystalline aggregate [Yadav et al., Int. J. PharmTech Res., 2009, 1, 1109-1114], electrospun polymer fibers [U.S. Pat. Pat. Appl. Pub!., 2009, US 20090269392 A1 20091029] and dendrimers [Bosnjakovic et al., Nanomed. Nanotechnol. Biol. Med., 2011, 7, 284]. The present invention has advantages in relation to the above formulations in that the polymer-based carriers of the invention are tailored for molecular types, eg macrolides, by the so-called molecular imprinting method. The process results in the bars obtaining a selectivity directed towards the molecular species and increasing the binding capacity of the molecular species. This provides beneficial properties when using the bars in terms of drug administration. The molecular imprint method is known as a method in which monomers and crosslinkers are polymerized in the presence of an imprint molecule (Oxen called template molecule or print molecule). Crosslinkers are defined here as a crosslinking monomer, that is, monomer capable of creating crosslinked polymers. After the polymerization, the imprint molecules are degraded, leaving voids, containing functionally placed functional groups in space, consisting of monomers and / or crosslinkers, as well as having the shape of casts of the imprint molecule, exposed in the polymeric material. The resulting materials can be compared to synthetic antibodies and receptors capable of selective molecular recognition. The most frequently used method of producing molecularly printed polymeric materials is via so-called bulk polymerization, which results in bulk polymers. These bulk polymers are usually ground into particles after the polymerization. Sfaxic polymer beads with molecular imprints can be prepared directly by various methods, for example dispersion polymerization, precipitation polymerization, suspension polymerization, emulsion polymerization, multistage polymerization and grafting of polymers into spherical spheres. The precipitation polymerization method results in submicron size spherical spheres. Patent application WO 00/41723 describes monodisperse microspheres with molecular imprints produced by precipitation polymerization. The carriers of the present invention differ from these microspheres and other previously described molecular-weighted polymeric materials in that the molecular-weighted polymer-based carriers of the invention have a different geometric space structure design. The carriers of the invention are elongated in space and can be said to be worm-like, snake-like, ted-like, branched and / or nar-like.
    Elongated structures and shapes may be advantageous for applications in the human body as exemplified by the following: Chauhan et al. has shown that elongated nanotubes penetrate tumor cells more easily than spherical particles do [Angew. Chem. Int. Ed., 2011, 50, 11417]. Shrama et al. has shown that the shape of nanoparticles affects the binding to and internalization of macrophages [J. Controlled Release, 2010, 2 147, 408]. Geng et al. has shown that worm-like micelles have ten times longer circulation time in plasma than the corresponding spherical micelles [Nature Nanotechnol. 2007, 2,249]. Gratton et al. has shown that HeLac cells internalize mature nanoparticles more easily than spherical nanoparticles [Proc. Natl. Acad. Sci. USA, 2008, 105, 11613.]. The Molecular-Printed Polymer-Based Bars of the present invention can thus be expected to interact with the body differently than previously known molecular-printed polymer particles.
    Summary of the Invention The present invention provides polymer-based carriers for the selective binding and release of molecules. The bars are characterized in that they have an increased capacity to bind molecules and that this increased capacity is created by the molecular imprint method. The formulations of the invention are also characterized in that they have worm-like, snake-like, tree-like, branched, and / or night-like space structure / shape. The carriers of the invention have been found to be suitable for the binding and release of drugs. The carriers of the invention have been found to be particularly suitable for the binding and release of macrolides. The present invention also provides methods of making these polymer-based bars.
    The present invention further provides formulations for drug administration and methods of making these formulations. The formulations of the invention consist of polymer-based barriers and medicaments. The formulations of the invention are characterized in that bound drugs are released under physiological conditions. In one embodiment, the release takes place over a required period of time.
    Summary description of the drawings Figure 1. Size distribution of bars.
    Figure 2. TEM images of barers.
    Figure 3. Binding of antibiotics to barers.
    Figure 4. Isotherms for binding of erythromycin to bars in (a) PBS and (b) methanol-water (4: 1).
    Figure 5. Cumulative release of erythromycin from formulation.
    Detailed Description of the Invention The present invention provides available polymer-based carriers for the selective binding and release of molecules. The bars are suitable for use in the preparation of formulations for drug administration. The formulations are particularly suitable for the release of drugs belonging to the group of macrolides. The formulations consist of polymer-based bars and drugs. The bars are manufactured by the molecular imprint method, which meant that polymerization of crosslinkers and monomers takes place in the presence of imprint molecule. The imprint molecule then functions as a template. Drugs from the macrolide group have been shown to be particularly lamped to serve as templates in the present invention.
    The template molecules are either covalently linked to one or more of the monomeric crosslinkers, or are capable of non-covalent interactions with one or more of the monomers / crosslinkers. The former type of molecular imprint is referred to as covalent molecular imprint. The latter type of molecular imprint is referred to as non-covalent molecular imprint. Examples of macrolides that can be used as templates in the polymerization include, but are not limited to, erythromycin, clarithromycin, azithromycin, telithromycin, cetromycin, dirithromycin, roxithromycin, carbomycin, josamycin, kitasamycin, midecamycin, olecomycin, olecomycin, olecomycin, olecomycin. tacrolimus, pimecrolimus, sirolimus (rapamycin), temsirolimus, everolimus, deforolimus and ridaforolimus.
    The polymer-based carriers of the invention are synthesized by copolymerization of polymerizable crosslinkers and monomers. Normally, the crosslinkers and monomers contain polymerizable groups such as acrylate, methacrylate, vinyl, allyl or epoxide groups. One or more of the crosslinkers and / or monomers may contain a functionality or functional group that may interact covalently or non-covalently with the template molecule. These functionalities / functional groups include, but are not limited to, hydroxyl groups, carboxy groups, carboxylic acid groups, amide groups, ester groups, halogens and amino groups. In one embodiment of the present invention, only monomers and crosslinkers are prepared. In another embodiment, the bars are made from only crosslinkers.
    Examples of crosslinkers used for the synthesis of barers in the present invention include, but are not limited to, divinylbenzene [H 2 C = CH-C 6 H 4 -CH = CH 2], glycerol diglycidyl ether, glycerol dimethacrylate, vinyl sulfone [(H 2 C = CH) 2 SO 2], vinyl acrylate] H2C = CH-C (O) -O-CH = CH2], vinyl methacrylate [H2C = C (CH3) -C (O) -O-CH = C H2], ethylene glycol diacrylate [H2C = CH-C (O) -0 -C H 2 -CH 2 -O- C (O) -CH = CH 21, ethylene glycol dimethacrylate [H 2 C = C (CH 3) -C (O) -O-C H 2 -C H 2 -O-C (O) -C (C H 3 ) = CH21, 1,4-butanediol diacrylate [H2C = CH-C (O) -O- (CH2) 4-O-C (O) -CH = CH2), 1,4-butanediol dimethacrylate [H2C = C (CH3) -C (O) -O- (CH 2) 4 -O-C (O) -C (CH 3) = CH 2), glycerol propoxylate triglycidyl ether, tri (propylene glycol) diacrylate [H 2 C = CH-C (O) - (0 (CH 2)) 3) 3-O-C (O) -CH = CH 2], tri (propylene glycol) dimethacrylate [H 2 C = C (CH 3) -C (O) - (O (CH 2) 3) 3-O-C (O) - C (CH3) = CH2i, poly (ethylene glycol-400) -dialcrylate [H2C = CH-C (O) - (O-CH2-CH2) 9-O-C (O) -CH = CH2], Poly (ethylene glycol400) -dimethacrylate [H2C = C (CH3) -C (O) - (O-CH2-CH2) 9-O-C (O) -C (CH3) = CH21, N, N'-methylenediacrylamide [H2C = CH-C (0) -NH-CH 2 -NH-C (O) -CH = CH 2], N, N'-methylenedimethacrylamide [H2C = C (CH3) -C (O) -NH- CH2-NH-C (O) -C (CH3) = CH21, N, N'-phenylenediacrylamide [H2C = CH -C (O) -NH-C6H4-NH-C (O) -CH = CH2i, N, N'-phenylenedimethacrylamide [H2C = C (CH3) -C (O) -NH-C6H4-NH-C (0) -C (CH3) = CH2i, 3,5- bis (acryloylamido) benzoic acid [H2C = CH-C (O) -NH-C6H3 (CO2H) -NH-C (O) -CH = CH21,3,5- bis (methacryloylamido) benzoic acid [H2C = C (CH3) -C (O) -NH- C6H3 (CO2H) -NH-C (O) -C (CH3) = CH21, N, O-bisacryloyl-L-phenylalaninol [H2C = CH-C (O) -NH-CH (CH2-C6H5) -CH2-O-C (O) -CH = CH21, N, O-bismethacryloyl-L-phenylalaninol [H2C = C (CH3) -C (O) -NH-CH (CH 2 -C 6 H) -CH 2 -O-C (O) -C (CH 3) = CH 2], vinyl acrylate [H 2 C = CH-C (O) -O-CH = CH 2], vinyl methacrylate [H 2 C = C (CH3) -C (O) -O-CH = CH21, trimethylolpropane trivinyl ether [(H2C = CH-O-CH2) 3C (C2H5)], 2,4,6-triallyloxy-1,3,5-triazine, triallyl- 1,3,5-triazine-2,4,6 (1H, 3H, 5H) -trione, tris [2- (acryloyloxy) ethyl] is ocyanurate, di (trimethylolpropane) tetraacrylate R (H2C = CH-C (0 ) -O-CH 2) 2 C (C 2 H 5) -CH 2) 20], di (trimethylolpropane) tetramethacrylate R (H 2 C = C (CH 3) -C (O) -O-CH 2) 2 C (C 2 H) -CH 2) 20], pentaerythritol tetrachrylate [C (CH 2 -O-C (O) -C) H = CH2) 4], pentaerythritol tetramethacrylate [C (CH2-O-C (O) -C (CH3) = CH2) 41, pentaerythritol triacrylate [HO-CH2-C (CH2-O-C (O) -CH = CH2) 3], pentaerythritol trimethacrylate [HO-CH2-C (CH2-O-C (O) -C (CH3) = CH2) 3], trimethylol-propane triacrylate [CH3-CH2-C (CH2-O-C (O) -CH = CH2) 3], trimethylolpropane trimethacrylate [CH3- 4 CH2 — C (CH2-0 — C (O) —C (CH3) —CH2) 3], trimethylolpropane benzoate diacrylateRH2C = CH — C (O) -O— CH2) 2C (C2H) CH2-O-C (O) -C6H], trimethylolpropane benzoate dimethacrylate [(H2C = C (CH3) -C (O) -O— C112) 2C (C21 {5) C112-O-C (0) -C 611] trimethylolpropane allyl ether [H2C = CH — CH2-O — CH2 — C (C2H5) (CH2OH) 2, trimethylolpropane ethoxylate (1E010H) methyl ether diacrylate [H2C = CH — C (O) -O — CH2 — CH2—0- CH2) 2C (C2H) CH2-O-CH2-CH2-O-CH3], trimethylolpropane ethoxylate (1E0 / OH) methyl ether dimethacrylate [H2C-C (CH3) -C (O) -O-CH2-CH2-O-CH2) 2C (C2H ) CH2-0— CH2 — CH2-0 — CH3], trime tylolp rop an e to xylate (1/3 EO / OH) triacrylate RH2C = CH — C (O) -0— (CH2 — CH2-0) 11CH2) 3C-C2H5], trimethylolpropane ethoxylate (1/3 EO / OH) trimethacrylate [(H2C = C (CH3) —C (O) -O— (CH2 — CH2-0), ICH2) 3C — C2H], trimethylolpropane ethoxylate t (7/3 EO / OH) triacrylate RH2C = CH — C (O) -O— (CH2 — CH2-0) „CH2) 3C — C2H5], trimethylolpropane ethoxylate (7/3 EO / OH) trimethacrylate [(H2C = C (CH3) —C (O) -O— (CH2 — CH2-0) 11CH2) 3C — C2H5], trimethylolpropane ethoxylate (14/3 E0 / OH) triacrylate [(H2C = CH — C (O) -O— ( CH2 — CH2-0) 11CH2) 3C — C2H5], trimethylolpropane ethoxylate (14/3 EO / OH) trimethacrylate [(H2C = C (CH3) - C (O) -O— (CH2 — CH2-0), ICH2) 3C —C2H5], trimethylolpropane propoxylate (IP 0 / OH) triacrylate RH2C = CH — C (O) -O— (C3H60) n — CH2) 3C — C2H], trimethylolpropane propoxylate (1PO / OH) trimethacrylate [(H2C = C (CH3) ) —C (O) -O— (C 3 H 60) n —CH 2) 3 C — C 2 H 5], trimethylolpropane propoxylate (2PO / OH) triacrylate RH 2 C = CH — C (O) -O— (C 3 H 6 O) 11 —CH 2) 3C— C2H1, trimethylolpropane propoxylate (2PO / OH) trimethacrylate RH2C — C (CH3) —C (O) -O— (C3H60) 11 —CH2) 3C — C2H5], triolein [CH3— (CH2) 7 —CH = CH— ( CH2) 7— C (O) -O — CH (CH2-0 — C (O) - (CH2) 7 — CH = CH— (CH2) 7 — CH3) 2], trimethylolpropane triglycidyl ether and analogs and derivatives thereof.
    Example pd. monomers used in the synthesis of the bars of the present invention include, but are not limited to, acid-containing monomers such as (meth) acrylic acid, trifluoro (meth) acrylic acid, itaconic acid, vinyl acetic acid, 4-vinylbenzoic acid, 4-vinylphenylboronic acid, vinylsulfonic acid, and vinylsulfonic acid, ; ester-containing monomers such as vinyl acetate, vinyl propionate, vinyl pivalate, allyl acetate, methyl (meth) acrylate, ethyl (meth) acrylate, propyl (mefiacrylate, butyl (meth) acrylate, pentyl (meth) acrylate, cyclohexyl (meth) acrylate, ) acrylate, is ob ornyl (meth) acrylate, hydroxybutyl (meth) acrylate, vinyl decanoate, vinyl 4-tert-butyl benzoate, and glycidyl (meth) acrylate; amide-containing monomers such as acrylamide, methacrylamide, and N-vinyl acetamide; monomers such as allylamine, 2-aminoethyl methacrylate, 2- (diethylamino) ethyl methacrylate, (ar-vinylbenzyfitrimethylammonium chloride, and 4-aminostyrene; heteroaromatic monomers such as 1-vinylimidazole, 4-vinylpyridine, 2-vinylpyridine, 1-vinylpyridine-1-pyrroline vinyl caprolactam, and N-vinylphthalimide; hydroxyl-containing monomers such as 4-hydroxystyrene, α-vinylbenzyl alcohol, 2-hydroxyethyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 4-hydroxypropyl (meth) acrylate, 5-hydroxypentyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, N-hydroxymethyl (meth) acrylamide, ally alcohol, hydroxyethyl vinyl ether, and allyl -2-hydroxy-2-phenyl ether; vinyl acid halides such as (meth) acryloyl chloride; halide-containing monomers such as vinyl bromide and vinyl chloride; silane-containing monomers such as vinyltrimethylsilane, vinyltrimethoxysilane, and 3-glycidoxypropyltrimethoxysilane; and analogues and derivatives thereof.
    The carrier of the invention is prepared in the presence of one or more solvents. Example pd. solvents include, but are not limited to, acetonitrile, chloroform, dichloromethane, carbon tetrachloride, benzene, tetrahydrofuran, ethyl acetate, acetone, pentane, cyclohexane, n-hexane, cycloheptane, n-heptane, N, N-dimethylformamide (DMF), DMSO), methanol, ethanol, 1-propanol, 2-propanol, diethyl ether, toluene, water, physiological saline solution, PBS and other buffer solutions with regulated pH values and ionic strengths, or mixtures thereof.
    The polymer-based Ware of the present invention is prepared by chain reaction polymerization such as free radical polymerization, anionic polymerization and cationic polymerization. Initiators are included as ingredients in the reagent mixture. Free radical initiators useful in the present invention include Adana which are normally suitable for free radical initiation. These varieties include azo compounds and organic peroxides. Examples of azo compounds include, but are not limited to, 2,2'-azobis (2-methylbutyronitrile), 2,2'-azobis (2-methylpropionitrile), 1,1'-azobis (cyclohexane carbonitrile), phenyl azo-triphenylmethane and 4,4'-azob (4-cyanovaleric acid).
    Commercial products of this type include VAZO 52, VAZO 64, VAZO 67 and VAZO 88 initiators frail DuPont. Examples of peroxides include, but are not limited to, tert-butyl peroxide, cumyl peroxide, acetyl peroxide, benzoyl peroxide, lauroyl peroxide, tert-butyl hydroxy peroxide, and tert-butyl perbenzoate. The peroxidation rate of the peroxides can be increased by the addition of tertiary amines, such as, but not limited to, N, N-dimethylaniline. The rate of initiation of the initiators can also be increased by exposure to an energy wedge, such as ultraviolet straining and / or an elevated temperature for a time sufficient to affect the polymerization. Anionic initiators useful in the present invention include Adana which are normally suitable for anionic initiation. Examples of anionic initiators include, but are not limited to, metal alkyls such as n-butyllithium. Cationic initiators useful in the present invention include those which are normally exemplary of cationic initiation. Examples of cationic initiators include, but are not limited to, sulfuric acid, stannous chloride, boron trifluoride and iodine. In preparing the bar of the invention by polymerization, the conditions are maintained such that nucleation (nucleation) and particle growth promote the formation of elongated structures and shapes. By early aggregation of the cores during the polymerization, the formation of elongated structures is promoted and the formation of discrete spherical particles is avoided.
    In one embodiment of the invention, the bar is extracted after completion of polymerization with solution to remove any residues of reactants and templates. Examples of extraction solutions include, but are not limited to, acetonitrile, chloroform, dichloromethane, carbon tetrachloride, benzene, tetrahydrofuran, ethyl acetate, acetone, pentane, cyclohexane, n-hexane, cycloheptane, n-heptane, N, N-dimethylsulfoxide, dimethylsulfoxide, ethanol, 1-propanol, 2-propanol, diethyl ether, toluene, water, acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, nitric acid, ammonia, sodium hydroxide solution, potassium hydroxide solution, trimethylamine, triethylamine, triethanolamine, pyridine, piperidine and other buffering solutions. regulated pH values and ionic strengths, or mixtures ddrav. In certain embodiments of the invention, extraction may be omitted and the carriers applied directly as a liquid formulation.
    The formulation of the invention is prepared by loading the carrier of the invention with a controlled amount of drug. The charge is caused by incubation with a drug in a suitable incubation solution. The carrier can be charged with one or more lubricants. The drug may be identical to the template, an analog or one with the template arbesididad association. Examples of incubation solution include, but are not limited to, acetonitrile, chlorophone, dichloromethane, carbon tetrachloride, benzene, tetrahydrofuran, ethyl acetate, acetone, pentane, cyclohexane, n-hexane, cycloheptane, n-heptane, N, N-dimethylform , ethanol, 1-propanol, 2-propanol, diethyl ether, toluene, water, physiological saline solution, PBS and other buffer solutions with regulated pH values and ionic strengths, or mixtures thereof.
    The polymer-based formulations of the present invention are suitable for use in a wide range of applications. The formulations of the invention are particularly suitable for use in the medical field for the administration of drugs, including human and veterinary medicine. The formulations were found to be particularly suitable for the administration of drugs belonging to the group of macrolides. The formulations of the invention are adapted to be administered dermally, transdermally, topically, subcutaneously, intramuscularly, intraperitoneally, orally, enterally, vaginally, rectally, intravenously, intraarterially, nasally, intravitreally, topically, epidurally, intracerebrally, via inhalation, via implant, via implant other administration to the body. In certain embodiments, the formulations of the invention may be integrated with other components that facilitate insertion into, or contact with, the body, such as, but not limited to, plastics, catheters, and balloons used in percutaneous coronary interventions. In certain embodiments, the formulations of the invention may be further formulated, for example, by, but not limited to, tablet compression, coating, and entrapment in polymers and micelles.
    Example Example 1: Synthesis of the carrier of the invention Erythromycin (0.367 g, 0.5 mmol) and methacrylic acid (0.344 g, 4 mmol) were dissolved in 4.5 mL of acetonitrile by sonication in an ultrasonic bath. Trimethylolpropane trimethacrylate (1,356 g, 4 mmol) and 2,2'-azobisisobutryonitrile (0.938 g, 5.7 mmol) were added and the mixture was sonicated. The solution was diluted with 35.5 mL of acetonitrile, cooled on ice, and bubbled with nitrogen for 5 minutes. Polymerization is challenged in a water bath at 60 ° C for 8 hours. After the polymerization, the mixture was centrifuged (9500 rpm, 1 hour) and the supernatant was removed. The resulting bars were extracted with methanol-acetic acid (1: 1) by incubation first in an ultrasonic bath for 30 minutes and then on a VXR basic Vibrax shaker table (IKAWerke, Staufen, Germany) at 1000 rpm for 1 hour + 18 hours. Between incubations, the mixture was centrifuged (9500 rpm, 1 hour) and the supernatant was removed. The extraction scheme was then repeated with methanol and water, respectively. Finally, the bars were incubated for one hour with methanol, centrifuged, separated from the supernatant and dried in vacuo overnight. Carriers without molecular imprints were prepared according to the same procedure as described above except that no imprint molecule was added.
    Example 2: Characterization of the Bars of the Invention The hydrodynamic particle size distribution of the bars (100 micrograms per ml of water) was determined in the temperature range of 20 to 55 ° C by feeding dynamic light scattering (DLS) with an Ultra Nanotrac particle size analyzer from Microtrac (Montgomeryville, PA). Representative 7 size distribution Found in Figure 1. Size, shape and morphology of dried bars were studied with an FEI Tecnai Spirit Biotwin Transmission Electron Microscope (TEM) (Hillsboro, OR, USA). TEM images are shown in Figure 2. Surface area and porosity were determined by nitrogen gas adsorption with an ASAP 2400 analyzer (Micromeritics Instrument Corporation, Norcross, GA, USA) after degassing at 30 ° C for 2 days.
    Adsorption and desorption isotherms were fed with an 80-point pressure table with a 20-second equilibration interval between feeds. Calculation of surface area and porosity was based on the BrunauerEmmett-Teller (BET) equation. The BET surface area was 157 m2 / g. The mean pore diameter was 16 nm. Total pore volume was 0.62 mL / g Example 3: Binding of antibiotics (erythromycin, penicillin V, tetracycline or chloramphenicol) to barrier Barrier (5 mg) was incubated on a shaker table for 20 hours at room temperature with antibiotic (1 ml, 0.5 mM) in either PBS or methanol-water (4: 1). The incubations are challenged in microcentrifuges and all experiments were done in triplicate. After centrifugation (2 hours, 13000 rpm), the supernatants were analyzed by HPLC on a Waters system consisting of a "Model 600 Multisolvent Delivery Module", a Model 600 pump and a "Model 2487 Dual Wavelength" absorbance detector. An ACE 3 C18 column (150 x 4.6 mm) from Advanced Chromatography Technologies (Aberdeen, Scotland) was used as the stationary phase. The flow rate was 1 ml / min. Erythromycin was eluted with acetonitrile-50 mM sodium phosphate buffer, pH 6.3 (35:65, v / v). Penicillin V was eluted with water-acetonitrile-TFA (700: 300: 1). Tetracycline and chloramphenicol were eluted with water-acetonitrile-TFA (850: 150: 1). Erythromycin was detected at 214 nm Other antibiotics were detected at 260 nm. Absorbance data were collected via a PC with Chromatography Station for Windows software (DataApex, Prague, Czech Republic). Results of the incubation study can be found in Figure 3.
    Example 4: Determination of erythromycin binding isotherms Triplicate samples of barer (5 mg) were incubated with 1 ml of increasing concentrations of erythromycin [0.05-0. mM in PBS or 0.1-2 mM in methanol-water (4: 1)] for 18 hours in micro-centrifuges on a shaking table (1500 rpm). After centrifugation (1 hour, 13000 rpm), the supernatants were analyzed by HPLC as described above. Binding data were adapted to Langmuir isotherm with GraphPad Prism (GraphPad Software, Inc., San Diego, CA, USA). Isotherms are found in Figure 4.
    Example 5: Charging the bars with erythromycin Molecular imprint bars (7.5 mg / ml) were incubated with erythromycin [1 mM in PBS or 7 mM in methanol water (4: 1, v / v)] on a shaking table (1500 rpm) for 20 hours. at room temperature. After incubation, the tubes were centrifuged with the mixtures (9500 rpm, 1 hour). The supernatants were analyzed by HPLC as described above to determine the free concentrations of erythromycin. The amount of erythromycin bound to the nanobars was calculated. The charge efficiency was 87% (charge in PBS) and 29% (charge in methanol-water), respectively. Example 6: Release of erythromycin from the bars Drug release under "zinc conditions" was initiated by immersion of a Spectra / Pordialysis membrane (MW cut off 6-8 kDa, width 10 mm, 0 6. 4 mm), containing 50 mg of erythromycin-loaded bars and 500 mL of PBS. The experiments are challenged at room temperature and the solutions are stirred with a magnetic stirrer. Triple samples (10 ml) were taken from the buffer solutions at regular intervals and replaced with fresh PBS. The samples were lyophilized to dryness, dissolved in 0.5-1 ml of water and analyzed by HPLC as described above. The released amounts of erythromycin were calculated and the data were adapted to the following kinetic models: the zero order equation, the first order equation and the Higuchi equation. Bast fit is obtained with the Higuchi equation. Release profiles are found in Figure 5. 9
    权利要求:
    Claims (2)
    [1]
    1. producing according to claims 6-7 a polymer-based bar according to claims 1-
    [2]
    2. Prepare the polymer-based carrier for drug release by incubation with drug-containing solution, the drug being associated with the carrier 1
    类似技术:
    公开号 | 公开日 | 专利标题
    EP1765894B1|2012-03-28|Novel temperature and ph sensitive copolymers
    He et al.2009|Hyaluronic acid coated poly | nanoparticles as anticancer drug carriers
    Chouhan et al.2009|Real time in vitro studies of doxorubicin release from PHEMA nanoparticles
    TWI306869B|2009-03-01|Amphiphilic block copolymers and nano particles comprising the same
    Wang et al.2012|Preparation and characterization of pH-sensitive hydrogel for drug delivery system
    Fares et al.2011|Inulin and poly | grafted inulin for dissolution enhancement and preliminary controlled release of poorly water-soluble Irbesartan drug
    ES2391691T3|2012-11-29|Graft copolymers as drug delivery systems
    CA2818873C|2019-08-06|Stealth polymeric particles for delivery of bioactive or diagnostic agents
    Sabaa et al.2019|Encapsulation of bovine serum albumin within novel xanthan gum based hydrogel for protein delivery
    Sheybani et al.2015|Mesoporous molecularly imprinted polymer nanoparticles as a sustained release system of azithromycin
    CN102432783B|2013-05-08|PH response/hydrophobic group random copolymerization polymer, and preparation method and application thereof
    Du et al.2019|Degradable pH and redox dual responsive nanoparticles for efficient covalent drug delivery
    SE1330067A1|2014-12-10|Carriers for the binding and release of molecules and their method of preparation
    US20130190409A1|2013-07-25|Drug delivery vehicles, methods of manufacture, and methods of use thereof
    KR20090080883A|2009-07-27|Temperature-Sensitive Nanocarriers
    CA2545877C|2013-03-12|Biodegradable colloidal particles for pulmonary applications in particular
    Priya Dasan et al.2012|Polymer blend microspheres for controlled drug release: the techniques for preparation and characterization: a review article
    Nikfarjam et al.2014|Preparation of pH-sensitive nanoparticles with core-shell-corona morphology as an oral drug carrier
    JP2018131585A|2018-08-23|Molecular imprinted polymer, method for producing the same and method for separating objective substance using the molecular imprinted polymer
    Vatankhah et al.2020|Seed's morphology-induced core-shell composite particles by seeded emulsion polymerization for drug delivery
    Andonova et al.2014|Indomethacin loading and in vitro release properties from vinyl acetate homo-and co-polymer nanoparticles, coated with polyzwitterion and carbopol® shells
    Cao et al.2016|GSH-responsive polymeric micelles based on the thio–ene reaction for controlled drug release
    CN108641092B|2021-06-18|Preparation method of supramolecular polymer composite micelle based on hydrogen bond
    Rafique et al.2021|Designing gelatin-based swellable hydrogels system for controlled delivery of salbutamol sulphate: characterization and toxicity evaluation
    Gosecka et al.2014|Mechanism of particle formation in radical emulsion copolymerization of styrene with α-tert-butoxy-ω-vinylbenzyl-polyglycidol macromonomer
    同族专利:
    公开号 | 公开日
    SE537943C2|2015-12-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CN109254062A|2018-11-05|2019-01-22|济南大学|A kind of preparation method and application of macrolide antibiotics molecular engram electrochemical sensor|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    SE1330067A|SE537943C2|2013-06-09|2013-06-09|Carriers for the binding and release of macrolides and their method of preparation|SE1330067A| SE537943C2|2013-06-09|2013-06-09|Carriers for the binding and release of macrolides and their method of preparation|
    [返回顶部]