WO1989004672A1 - Derives d'antibiotiques de lincosaminide - Google Patents

Derives d'antibiotiques de lincosaminide Download PDF

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Publication number
WO1989004672A1
WO1989004672A1 PCT/US1988/003865 US8803865W WO8904672A1 WO 1989004672 A1 WO1989004672 A1 WO 1989004672A1 US 8803865 W US8803865 W US 8803865W WO 8904672 A1 WO8904672 A1 WO 8904672A1
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Prior art keywords
lincosaminide
radical
pirlimycin
carrier
group
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PCT/US1988/003865
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English (en)
Inventor
Jean Brison
Paul M. Tulkens
Patrick Bottcher
Andree Zenebergh
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The Upjohn Company
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Publication of WO1989004672A1 publication Critical patent/WO1989004672A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • C07H15/16—Lincomycin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment

Definitions

  • This invention relates to new pharmaceutical derivatives of lincosaminide antibiotics. These novel derivatives provide for intercellular delivery of the antibiotic and are particularly useful to treat bovine mastitis.
  • Lincosaminides are antibiotics active against Gram (+) bacteria including clinical isolates of Staphylococcus aureus. Lincosaminides known in the art include lincomycin, clindamycin, pirlimycin and pharmacologically active derivatives of these antibiotics. In bovine mastitis and other diseases, the infecting bacteria accumulate in phagocytes such as polymorphonuclear neutrophil leukocytic cells or macrophages and are not affected by antibiotic treatment because the antibiotic only penetrates the phagocyte very slowly. In order to improve the rate of penetration of lincosaminides in phagocytes, the antibiotic is linked to suitable macromolecular carriers.
  • These cells are particularly susceptible to antibiotic-carrier complexes which enter the phagocytes by endocytosis because phagocytes have high endocytotic activity.
  • This invention allows the antibiotic-carrier complex to penetrate the phagocyte cell and then release the antibiotic in an active form within the cell in order to eradicate the bacteria inside these cells.
  • Information Disclosure Derivatives of lincosaminides are known in the art. Sinkula, et al., Chemical Modification of Clindamycin: Synthesis and Evaluation of Selected Esters, J. Pharm. Sci.. 1106-1111 (1973) disclose a series of 2- and 3- monoesters and some 2,3-dicarbonates of the lincosaminide, clindamycin.
  • U.S. Patent 4,376,765; Medicaments, Their Preparation and Compositions Containing Same discloses new pharmaceutical forms of known drugs wherein the drug is attached to a proteinaceous macro-molecule by a peptide chain spacer arm.
  • Gilbertson and Stryd, Radioimmunoassay for Clindamycin, Clinical Chemistry, 828-831 (1976) discloses a clindamycin bound to a protein by a succinic spacer arm. Summary of the Invention
  • LINCOSAMINIDE-RADICAL-CARRIER wherein LINCOSAMINIDE is an antibiotic lincosaminide; wherein RADICAL is an organic compound attached to a hydroxyl group of the LINCOSAMINIDE by a carboxyl group and attached to the CARRIER by a carboxyl or amino group; and wherein CARRIER is an organic compound capable of transporting or directing said complex to a specific cell type.
  • the present invention relates to derivatives of lincosaminides in which an appropriate radical has been attached to a hydroxyl group of the antibiotic and to a carrier molecule.
  • the radical can be any multifunctional molecular compatible with known pharmaceutical usage provided it meets the following requirements: a) It carries a carboxyl function through which it is attached to the lincosaminide by substitution of one of the hydroxyl functions on the drug; b) It carries a second carboxyl group or an amino group attached to the appropriate carrier having free amino or carboxyl groups using well established condensation reaction methods: and c) It releases the drug in an active form from the lincosaminide-radical-carrier complexes by hydrolysis of the lincosaminide-radical linkage under conditions compatible with the survival of eukaryotic cells.
  • the carrier can be a peptide or a protein which will deliver the drug to cells which possess recognition sites or affinity for such carriers and will internalize the drug in these cells using biological mechanisms that differ from simple diffusion.
  • the present invention includes examples of radicals and carriers which fulfill these three essential conditions. The rate of release of the lincosaminide can be varied according to the pH and to the nature of the radical used.
  • the attachment of the lincosaminide to the radical is performed by condensing a suitable anhydride or mixed anhydride with a suitable lincosaminide in the presence of a tertiary amine, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • a suitable solvent such as dichloromethane.
  • the lincosaminide is preferentially protected on the amino group by reacting the amine with di-t-butyl carbonate and on the hydroxy groups at the 3 and 4 positions by reacting the glycoside with 2,2-dimethoxypropane in the presence of acid in dimethylformamide. After the radical is attached the protecting groups are removed.
  • the radical when the radical is a peptide, an appropriate N-protected peptide is attached to the protected lincosaminide in the presence of dicyclohexylcarbodiimide. After the radical is attached the protecting groups are removed.
  • the methods described above are well known in the art and other known condensation methods could be used to attach the radical to the lincosaminide.
  • the attachment of the lincosaminide-radical to the carrier is performed in two different ways using carbodiimides as coupling agents.
  • the attachment is performed in a mono-phasic reaction mixture using diethylaminopropyl carbodiimide as coupling agent between the carrier and the lincosaminide-radical.
  • the attachment is performed in a biphasic reaction mixture using dicyclohexylcarbodiimide as coupling agent between the carrier and the lincosaminide-radical.
  • DMEM 10% serum is used for the culture of the IR983F myeloma.
  • This medium is prepared by using Dulbecco's Modified Eagle's Medium (Gibco Ltd., Paisley, Scotland, UK; medium no. 074-1600) supplemented with (for one liter) 3.5 g glucose, 100 mg streptomycin, 60 mg penicillin, 50 ml fetal calf serum, 50 ml horse serum and 10 ml of Non-Essential Aminoacids Solution (Gibco Ltd., Paisley, Scotland, UK; solution no. 043-1140).
  • DMEM Hepes is used for the fusion experiments. This medium is a serum-free DMEM medium supplemented with 10 mM Hepes pH 7.2-7.4.
  • PEG solution is made of polyethyleneglycol 4000 (Merck AG, Darmstadt, W. Germany) 62.64% (w/v) in DMEM Hepes medium supplemented with 12.9 ml dimethylsulfoxide.
  • DMEM HAT-serum rich medium is used for the selective growth of the hybridoma cells.
  • This medium is made of DMEM 10% serum medium enriched with 5% fetal calf serum and supplemented with 13.6 mg/l hypoxanthine, 3.88 mg/l thymidine and 0.178 mg/l aminopterine.
  • Buffered EDTA is 1-5% EDTA in 13.2 mM phosphate - 0.7% NaCl adjusted to pH 6.8.
  • Bovine polymorphonuclear neutrophilic leukocytes (PMN) are isolated from cow blood following the procedure of Carlson and Kaneko, Isolation of Leukocytes from Bovine Peripheral Blood, Proc. Soc. Exp. Biol. Med. , 853-856 (1973). Blood (10 volumes) is collected on a solution of buffered EDTA (one volume). After centrifugaation at 1000 g for 15 minutes, the plasma and the buffy coat are discarded. The pellet (containing the erythrocytes and the bulk of the PMN) is resuspended In 5 volumes of distilled water.
  • Isotonicitv is restored after 30 seconds by the addition of one volume of 13.2 mM phosphate buffer pH 6.8-2.7% NaCl per 2 volumes of mixture.
  • Leukocytes are collected by centrifugation at 200 g for 10 minutes. This fraction contains the PMN but is often contaminated with polvmor- phonuclear eosinophilic leukocytes. These are separated from PMN or. a preformed Percoll ® gradient described bv Homepagela et al., Isolation and Partial Characterization of the Plasma Membrane of Purified Bovine Neutrophils, Eur. J. Biochem., 341-346 (1980).
  • Percoll ® (Pharmacia AB, Uppsala, Sweden) in 0.9% NaCl adjusted to pH 7.3 is first centrifuged for 20 minutes at 21,000 rpm. The leukocyte suspension (in PBS) is then deposited on the top of this gradient, which is further centrifuged for 15 minutes at 10,000 rpm. The lowest band corresponding to the PMN (density approximately 1.094) is collected, whereas the eosinophils (equilibrating at density approximately 1.078) are discarded. The PMN's are washed with PBS pH 6.8 to remove the Percoll ® and resuspended in DMEM medium.
  • the IR983F cell line derived from the Lou/C rat strain is used.
  • This myeloma is a non-secreting, 8-azaquanine-resistant cell line adapted to in vitro growth in DMEM 10% serum according to procedures described by DeClercq, et al., Generation of Rat-Rat Hybridomas with the Use of the LOU IR 983 F Non- secreting Fusion Cell Line, Meth. Enzymol., 234-238 (1986).
  • These cells are obtained by peritoneal lavage of outbred Wistar rats, collected and cultivated in 96 well plates (Nunc A/S, Roskilde, Denmark, article no. 167008; 2 X 10 4 cells/well) in DMEM HAT serum rich medium.
  • the myeloma IR983F cells and the dispersed lymphnode cells are centrifuged separately for 5 minutes at 250 g and resuspended in
  • DMEM-Hepes medium IR983F cells and lymphnode cells are then counted and mixed at a ratio of one myeloma cell for 5 lymphnode cells. After centrifugation of the cell mixture, all medium is carefully discarded and one ml PEG solution is added dropwise to 2 X 10 7 cells over 90 seconds with gentle shaking. After 60 seconds of further gentle shaking, 2 ml of DMEM-Hepes is added dropwise over 90 seconds, followed by further progressive addition of 20 ml of the same medium. The suspension is centrifuged for 5 minutes at 180 g and the cells are carefully resuspended in dMEM HAT-serum rich medium ( 10 6 cell/ml).
  • Hybridomas resulting from the fusion of lymphocytes with IR983F cells are cultured in a 10% CO 2 atmosphere one to 3 weeks with change of half the culture medium (0.1 ml) every 3 to 4 days.
  • the culture medium is added to 5.10 6 bovine PMN. After one hour of incubation at 4oC, the PMN are washed with PBS and reincubated for one hour at 4oC with fluorescein-labeled or 3 H-methyl-labeled rabbit anti-rat immunoglobulins. After 3 washings with PBS the PMN are examined by fluorescence microscopy (for cells treated with fluorescent-labeled antibodies), or centrifuged, and their radioactivity measured by scintillation counting (for cells treated with 3 H-labeled antibodies). Hybridomas secreting anti-PMN antibodies are transferred to 24 well plates and further cultured in standard vessels.
  • rat Immunoglobulin Characterization is performed by 2-dimensIon immunodiffusion using specific antisera directed against rat IgG 1 , IgG2a, IgG2b, IgG 2c , IgA, IgM, IgE, and IgD. Only clones secreting IgG types of immunoglobulins are kept for production. The clones selected In this step are propagated by culture in stationary vessels or by injection in the peritoneal cavity of Lou/C rats (with weekly transfer from animal to animal).
  • the monoclonal immunoglobulins secreted in the ascitic fluid or in the culture supernatant are purified by passing the fluids on an immunosorbant column made of insolubilized monoclonal mouse antibodies directed against rat kappa light chain (MARK- 1), Bazin, et al., Purification of Rat Monoclonal Antibodies, 638-652 (1986) .
  • MARK-1 antibodies are obtained from the ascitic fluid of Balb/C mice injected with a mouse hybridoma producing these antibodies and purified on an immunosorbant made of polyclonal Immobilized rat immunoglobulins.
  • pirlimycin-2 '0-hemisuccinate coupled to mannosylated serum albumin upon exposure of the conjugate to aqueous media at 37°C and at different pH.
  • the temperature is increased to 80°C, no further liberation is observed at either pH 5 , 7 or 8 compared to the values observed after 96 hours at 37°C and pH 8.0.
  • the conjugate probably contains approximately 25% of available pirlimycin and 75% of unavailable pirlimycin.
  • pirlimycin-2'0-hemisuccinate is hydrolyzable to approximately 75%, it is unlikely that the pirlimycin which cannot be released from mannosylated serum albumin is not bound to the protein by its succinyl and/or its 2'OH group.
  • Various batches of pirlimycin-2'0-hemisuccinate rat monoclonal immunoglobulin G conjugate are incubated at 37°C and at pH 8. Between one and 6 pirlimycin molecules per molecule of conjugate are released after 96 hours. The nature of compound released is assessed by TLC (after revelation with orcinol/H 2 SO 4 spray versus a TLC standard scale) and mass spectrum (detection of a molecular ion at 410).
  • Bovine mammary macrophages are incubated one hour in the presence of pirlimvcin (labeled with 14 C). or N- 3 H-glycyl-pirlimycin- 2'0-hemlsuccinyl-mannosylated bovine serum albumin. Cells are collected, homogenized and the homogenate fractionated by Isopycnlc centrifugation in a sucrose gradient following the techniques used by Canonico, et al., J. Reticuloendoth. Soc., 115-138 (1979) and Renard, et al., Antimicrob. Agents Chemother., 410-416 (1987).
  • N- 3 H-glycyl-pirlimycin-2'0-hemisuccinyl-mannosylated bovine serum albumin is largely recovered in fractions enriched in the lysosomal enzyme N-acetyl-beta-hexosaminidase.
  • N-acetyl-beta-hexosaminidase N-acetyl-beta-hexosaminidase.
  • N- 3 H-glycyl-pirlimycin is used for coupling to serum albumin rather than pirlimycin to allow for detection of the drug. Since it is unlikely that addition of a glycyl moiety to the coupled pirlimycin should markedly modify the behavior of the whole conjugate, the behavior of N- 3 H-glycyl-pirlimycin-2'0-hemisuccinyl-mannosylated bovine serum albumin describes the potential fate of pirlimycin-2'0-hemisuccInyl-mannosylated bovine serum albumin.
  • the chemical complexes claimed in this invention can be used and administered in practicing the method claimed in this invention. Derivatives of the chemical complexes claimed in this Invention which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent complex in properties such as formulation, stability, patient acceptance and bioavailability are included within the scope of this Invention.
  • N- t-butyloxycarbonyl-3',4'-0-isopropylidene-pirlimycin-2'0- hemisuccinate (200 mg) is dissolved in 25% trifluoroacetic acid in methylene chloride and stirred for 30 minutes at room temperature. The completeness of the reaction is checked by TLC of the reaction mixture in butanol: acetic acid:water (8:1:1). Evaporation under reduced pressure yields a syrup which is submitted to a chromatography on silica gel column (Lobar Lichroprep Si 60 MERCK) eluted with butanol: acetic acid:water (8:1:1). After lyophilization of the eluate, a white powder is obtained.
  • the following compounds can be attached to pirlimycin starting with the appropriate anhydride: glutaryl, 2,2-dimethyIglutaryl, 3,3-dimethyl- glutaryl, 3-ethyl-3-methyIgiutaryI, 2-phenylglutaryl, 3,3-tetramethy leneglutaryl, phtalyl, 3-nitrophtalyl, isatoyl, N-methylisatoyl, 1,2-cyclohexanoyl, dimethylmaleyl, maleyl and citraconyl.
  • the following compounds can be attached to pirlimycin through condensation of the appropriately N-protected amino acid or peptide and N-t-butyloxycarbonyl-pirlimycin-3',4'-0-isopropylidene in the presence of DCC followed by removal of the protecting groups with 25% trifluoroacetic acid in dichloromethane: glycyl, alanyl, leucyl, phenylalanyl, glycylalalanyl, undecanoyl, succinylglycyl, and glycylvalylleucylalanylphenylalanylglycyl.
  • the reaction mixture is dialyzed at 4°C for 8 hours against 3 mM phosphate buffer pH 7.4, and then 3 times 8 hours against distilled water.
  • the undialyzed fraction is lyophilized and stored at -20°C. According to the procedures described in Example 5, pirlimycin 2'0-hemisuccinate rat monoclonal immunoglobulin G conjugate is prepared.
  • Example 6 Mannosylated pirlimycin-2'0-hemisuccinate bovine serum albumin conjugate N-t-butyloxycarbonyl-3'-4'-0-isopropylidene-pirlimycin-2'0-hemisuccinate (100 mg) is solubilized in 600 ul dimethylformamide (DMF) and the mixture is cooled at 0°C. Dicyclohexylcarbodiimide (36.26 mg; DCC, Merck AG, Darmstadt, W. Germany) is added to the mixture under stirring while the temperature is strictly maintained at 0°C. After exactly 3 minutes.
  • DMF dimethylformamide
  • N-hydroxysuccinimide (21.28 mg, Merck AG, in 0.2 ml DMF) is added dropwise to the reaction mixture and the reaction is allowed to proceed at 4°C for 24 hours, this time beine necessary for formin ⁇ a derivative capable of reacting with the free amino groups of the carrier.
  • aliquots (0.05 ml) of this mixture are added every 5 minutes to a solution of bovine serum albumin (BSA fraction V, Sigma Chem.,
  • Mannosylation of the conjuga-te is performed by a method adapted from Kataoka, et al., Synthetic Neoglycoproteins: A Class of Reagents for Detection of Sugar Recognizing Substances, J. Histochem. Cytochem., 1091-1098 (1984).
  • p-Aminophenyl-mannose (0.37 mmol; Sigma Chemical Co,., St. Louis, Mo.) is dissolved In 10 ml of 0.1 M hydrochloric acid and 0.01 M KBr in ice-cold water.
  • Sodium nitrite 0.6 mmol, Merck AG, Darmstadt, W.
  • distilled water is added dropwise under stirring to form the diazonium salt of the derivatized sugar.
  • the solution is stirred for 30 minutes and is thereafter added dropwise to 10 mg of an ice-cold solution of pirlimycin-2'0- hemisuccinate-bovine serum albumin conjugate (0.37 mmol in 0.01 M borate buffer pH 9.0) under constant stirring.
  • the reaction Is allowed to proceed at 0°C, for 3 hours, the pH being maintained at 9.0 by suitable addition of 0.5 M NaOH.
  • the neoglycoprotein is dialyzed at 4°C against 0.15 M sodium chloride for 8 hours, and then 3 times 8 hours against distilled water.
  • the product is purified by chromatography on Sephadex ® G25 column eiuted with 0.1 M ammonium acetate buffer pH 7.
  • the fractions containing the conjugate are identified by monitoring the O.D. at 280 run, collected, lyophilized and stored at -20°C.
  • the total amount of mannose and pirlimycin conjugated to the albumin is assessed by colorimetric assay, using the orcinol/sulfonic acid method (Francois, et al., 1962). Total protein concentration is measured by the method of Lowry, et al. (1951).
  • Pirlimycin-2 'O-hemisuccinate mannosylated bovine serum albumin conjugate pirlimycin-2'0-hemisuccinate-monoclonal-immunoglobulin conjugate
  • 3 H-glycyl pirlimycin-2'0-hemisuccinate mannosylated bovine serum albumin 3 H-glycyl-pirlimycin-2'0-hemisuccinate monoclonal immunoglobulin G conjugate are obtained with typical pirlimycin (or ⁇ H-glycyl-pirlimycin) to protein ratios indicated below.
  • Pirlimycin (or 3 H-glycyl- Type of pirlimycin)-protein
  • Example 7 Mastitis ointment
  • An ointment for the treatment of mastitis in dairy cattle is prepared from the following types and amounts of ingredients:
  • Pirlimycin-mannosylated serum albumin and methylprednisolone acetate are milled with the light liquid petrolatum until finely divided and uniformly dispersed.
  • the chlorobutanol, polysorbate 80, peanut oil gel and white petrolatum are heated to 120°F to form a melt and the liquid petrolatum dispersion stirred in. With continued stirring, the dispersion is allowed to cool (and congeal) to room temperature and is filled into disposable mastitis syringes in 10 gm doses.
  • Example 8 Mastitis Ointment
  • a 10 ml dose of an ointment for the treatment of mastitis in dairy cattle is prepared from the following types and amounts of ingredients:
  • Pirlimycin-mannosylated serum albumin 1.5 g 2% glycerol monostearate in gelled peanut oil 10 ml Chlorobutanol 50 mg
  • the chlorobutanol and peanut oil are heated to form a melt (about 120°F) and Pirlimycin-mannosylated serum albumin is stirred in.
  • the dispersion is allowed to cool to room temperature and is filled into a mastitis syringe.
  • a 10 ml dose of an ointment for the treatment of mastitis in dairy cattle is prepared from the following types and amounts of ingredients: Pirlimycin-mannosylated serum albumin 1.5 g
  • a 10 ml dose of an ointment for the treatment of mastitis in dairy cattle is prepared from the following types and amounts of ingredients:
  • Pirlimycin-mannosylated serum albumin 1.5 g
  • the benzyl alcohol, citric acid, sodium carboxymethylcellulose and water are mixed to form a gel.
  • the pH is adjusted with the sodium hydroxide solution and Pirlimycin-mannosylated serum albumin is stirred into the gel until uniformly dispersed and the gel is filled into a mastitis syringe.

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Abstract

Cette invention concerne une nouvelle forme pharmaceutique d'un médicament ayant la formule: lincosaminide-radical-porteur, dans laquelle ''lincosaminide'' représente un lincosaminide antibiotique, ''radical'' représente un radical lié par l'intermédiaire d'une fonction carboxylique au groupe hydroxyle de l'antibiotique avec un autre groupe fonctionnel susceptible de permettre la fixation du complexe ''lincosaminide-radical'' sur un porteur; et ''porteur'' représente un peptide, une protéine, ou une autre macromolécule avec un ou des groupes aminocarboxyle libres et permettant au complexe ''lincosaminide-radical-porteur'' de se lier de manière spécifique aux cellules. Le complexe ''lincosaminide-radical-porteur'' est utile pour traiter des infections bactériennes et est particulièrement utile pour traiter la mastite bovine.
PCT/US1988/003865 1987-11-20 1988-11-07 Derives d'antibiotiques de lincosaminide WO1989004672A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0638583A1 (fr) * 1993-08-13 1995-02-15 Hoechst Aktiengesellschaft Aminosucre substances actives, un procédé pour leur préparation, et leur utilisation comme médicaments
EP0679083A1 (fr) * 1992-12-21 1995-11-02 Ophidian Pharmaceuticals, Inc. Prevention et traitement de la septicemie
US7164011B2 (en) 2002-08-15 2007-01-16 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7199105B2 (en) 2002-08-15 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7199106B2 (en) 2003-06-17 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antimicrobial activity
US7256177B2 (en) 2003-06-17 2007-08-14 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7361743B2 (en) 2004-02-11 2008-04-22 Pfizer Inc Lincomycin derivatives possessing antibacterial activity
CN106074384A (zh) * 2016-08-08 2016-11-09 甘肃新天马制药股份有限公司 一种吡利霉素胶束制剂及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4376765A (en) * 1980-03-31 1983-03-15 Institut International De Pathologie Cellulaire Et Moleculaire Medicaments, their preparation and compositions containing same
EP0176429A1 (fr) * 1984-09-14 1986-04-02 Institut Pasteur Compositions et procédé pour protéger les lymphocytes T contre l'agent étiologique des lymphadénopathies et du syndrome d'immunodépression acquise
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4376765A (en) * 1980-03-31 1983-03-15 Institut International De Pathologie Cellulaire Et Moleculaire Medicaments, their preparation and compositions containing same
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
EP0176429A1 (fr) * 1984-09-14 1986-04-02 Institut Pasteur Compositions et procédé pour protéger les lymphocytes T contre l'agent étiologique des lymphadénopathies et du syndrome d'immunodépression acquise

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 95, 1981, No. 10, 7 September 1981, (Columbus, Ohio, US), RESEARCH PRODUCTS REHOVOT LTD., "Antibiotic Formulation Containing Clindamycin for the Treatment of Bovine Mastitis", page 342, Abstract 86323d; & ISRAELI 53072, 30 January 1981, Appl. 6 Oct. 1977. *
CLINICAL CHEMISTRY, Vol. 22, No. 6, 1976, T.J. GILBERTSON et al., "Radioimmunoassay for Clindamycin", pages 828-831. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0679083A1 (fr) * 1992-12-21 1995-11-02 Ophidian Pharmaceuticals, Inc. Prevention et traitement de la septicemie
EP0679083A4 (fr) * 1992-12-21 1999-03-24 Ophidian Pharm Inc Prevention et traitement de la septicemie.
EP0638583A1 (fr) * 1993-08-13 1995-02-15 Hoechst Aktiengesellschaft Aminosucre substances actives, un procédé pour leur préparation, et leur utilisation comme médicaments
US7164011B2 (en) 2002-08-15 2007-01-16 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7199105B2 (en) 2002-08-15 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7199106B2 (en) 2003-06-17 2007-04-03 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antimicrobial activity
US7256177B2 (en) 2003-06-17 2007-08-14 Vicuron Pharmaceuticals, Inc. Lincomycin derivatives possessing antibacterial activity
US7361743B2 (en) 2004-02-11 2008-04-22 Pfizer Inc Lincomycin derivatives possessing antibacterial activity
CN106074384A (zh) * 2016-08-08 2016-11-09 甘肃新天马制药股份有限公司 一种吡利霉素胶束制剂及其制备方法

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