WO2014053873A1 - Conjugués polymères de promédicaments - Google Patents

Conjugués polymères de promédicaments Download PDF

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Publication number
WO2014053873A1
WO2014053873A1 PCT/IB2012/055239 IB2012055239W WO2014053873A1 WO 2014053873 A1 WO2014053873 A1 WO 2014053873A1 IB 2012055239 W IB2012055239 W IB 2012055239W WO 2014053873 A1 WO2014053873 A1 WO 2014053873A1
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WIPO (PCT)
Prior art keywords
peg
compound
polymeric prodrug
prodrug conjugate
polymer
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PCT/IB2012/055239
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English (en)
Inventor
Jayant KHANDARE
Girish Badrinath Mahajan
Becky Mary Thomas
Prabhu Dutt Mishra
Shafee Mohammed Abdul
Nitin TAYADE
Ram Vishwakarma
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Piramal Enterprises Limited
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Priority to PCT/IB2012/055239 priority Critical patent/WO2014053873A1/fr
Publication of WO2014053873A1 publication Critical patent/WO2014053873A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • 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
    • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a polymeric prodrug conjugate wherein an antibacterial compound (described herein as Compound A) is conjugated with a polyethylene glycol (PEG) polymer.
  • the present invention also relates to a process for the preparation of the polymeric prodrug conjugate.
  • the present invention provides the polymeric prodrug conjugate for use in the prevention or treatment of bacterial infections, particularly caused by the multi drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin resistant Enterococci
  • Compound A a compound which has been reported to be potential clinical candidate for the prevention or treatment of diseases caused by bacteria, particularly the multi drug resistant bacteria such as methicillin- resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin resistant Enterococci
  • the Compound A is disclosed in PCT Published Application WO2007/1 19201 A2 (hereinafter referred to as WO'201 application).
  • WO'201 application also discloses processes for the isolation of the Compound A.
  • the current invention provides a polymeric prodrug conjugate of the Compound A formed by conjugating the Compound A with a poly ethylene glycol (PEG) polymer and the method for its preparation.
  • the present invention relates to a polymeric prodrug conjugate wherein Compound A (as described herein) is conjugated with a polyethylene glycol (PEG) polymer.
  • the present invention also relates to a process for preparation of the polymeric prodrug conjugate wherein Compound A is conjugated with a polyethylene glycol (PEG) polymer.
  • the present invention further relates to the method for the prevention or treatment of bacterial infections comprising administering to a subject in need thereof a therapeutically effective amount of the polymeric prodrug conjugate of the present invention.
  • the present invention further relates to the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer for use in the prevention or treatment of bacterial infections.
  • PEG polyethylene glycol
  • the present invention also relates to use of the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer for the manufacture of a medicament for the prevention or treatment of bacterial infections.
  • the present invention further relates to a formulation which comprises a therapeutically effective amount of the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer and at least one pharmaceutically acceptable excipient.
  • Figure I depicts fluorescence spectra of the unconjugated form of Compound A and the polymeric prodrug conjugate.
  • Figure II depicts bioavailability of the unconjugated form of Compound A and the polymeric prodrug conjugate.
  • Figure III depicts in vivo efficacy of the polymeric prodrug conjugate.
  • Polymers are molecules comprising covalently linked repeating chemical units.
  • Enhanced permeability and retention (EPR) effect is the property by which certain molecules such as liposomes, nanoparticles and macromolecular drugs tend to accumulate in tumor tissue much more than they do in normal tissues.
  • PEGylation is the process of covalent attachment of polyethylene glycol (PEG) polymer chains to another molecule, such as a drug or therapeutic protein.
  • PD100 The dose of a drug or compound (Compound A in the present invention) required to protect 100 % of animals in the study group in the particular experimental condition.
  • Unconjugated form of Compound A Compound A in its free form i.e. not conjugated (or covalently bound) to any polymer.
  • the term "unconjugated form” or “free form” in the context of the Compound A may be used interchangeably.
  • Polymeric prodrug conjugate Compound A conjugated to the polyethylene glycol (PEG) polymer.
  • subject refers to an animal, particularly a mammal, and more particularly a human.
  • mammal refers to warm-blooded vertebrate animals of the class Mammalian, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and the human.
  • therapeutically effective amount means an amount of the polymeric prodrug conjugate that yields a desired therapeutic response such as, alleviating, treating and/or preventing bacterial infection or the symptoms of localized redness, heat, inflammation and pain associated with or caused by a bacterial infection.
  • formulation comprises a therapeutically effective amount of the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer and at least one pharmaceutically acceptable excipient.
  • PEG polyethylene glycol
  • compositions As used herein, the term “pharmaceutically acceptable excipients” refer to the following types of excipients which may be used in the formulation:
  • solid dose excipients which may be selected from diluents such as hydroxypropyl methyl cellulose, biopolymers, or polycarbohydrates;
  • solution/suspension excipients such as water; solublisers and base sweeteners such as sorbitol, dextrose; water-miscible co-solvents such as propylene glycol, glycerol, ethanol, low molecular weight PEGs and water- immiscible co-solvents such as emulsions/microemulsions using fractionated coconut oils;
  • Multi arm polyethylene glycol As used herein, the term “mutli arm PEG” refers to a branched PEG with branches (also referred to as “arms”) varying from 2 to 8.
  • alkyl refers to alkyl groups having from 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.
  • alkanal refers to alkyl group having an aldehyde (-CHO) functionality. This term is exemplified by groups such as n-butyraldehyde (n- butanal), isobutyaldehyde (isobutanal), propionaldehyde (propanal), acetaldehyde, pentanal, hexanal, heptanal, 2-methyloctanal, 3-methylhexanal and the like.
  • the present invention relates to a polymeric prodrug conjugate wherein the Compound A (as described herein) is conjugated with a polyethylene glycol (PEG) polymer.
  • PEG polyethylene glycol
  • the Compound A is structurally represented by the following formula:
  • the microorganism, which may be used for the production of the Compound A is a strain of Kocuria species (ZMA B-1/ MTCC 5269), herein after referred to as culture no. ZMA B-1 , isolated from a marine sample collected in Palk Bay, Tamil Nadu coast, India. Culture no. ZMA B-1 has been deposited with Microbial Type Culture Collection (MTCC), Institute of Microbial Technology, Sector 39-A, Chandigarh -160 036, India, a World Intellectual Property Organization (WIPO) recognized International Depository Authority (IDA) and has been given the accession number MTCC 5269.
  • MTCC Microbial Type Culture Collection
  • IDA World Intellectual Property Organization
  • the Compound A can be produced by the methods described in the PCT Published Application WO2007/1 19201 .
  • the Compound A can be produced from culture no. ZMA B-1 , comprising the steps of: growing the culture no. ZMA B-1 under submerged aerobic conditions in a nutrient medium containing one or more sources of carbon and one or more sources of nitrogen and optionally nutrient inorganic salts and/or trace elements; isolating the Compound A, from the culture broth; and purifying the Compound A, using purification procedures generally used in the art.
  • the polyethylene glycol (PEG) polymer which is used in the polymeric prodrug conjugate of the present invention, is linear or branched polyethylene glycol (PEG) polymer.
  • PEG as used in the polymeric prodrug conjugate of the present invention is represented by the following general formula:
  • R at each occurrence may be independently selected from hydrogen, alkyl, alkanal, NH 2 , succinimidylcarboxymethyl, succinimidylcarboxypentyl, succinimidylglutarate, succinimidylsuccinate, maleimide, propylamine, ethanthiol, p- nitrophenylcarbonate or a biologically active moiety; and 'n' an integer selected from 05 units to about 50,000 units.
  • R when R is a biologically active moiety, can be selected from TAT peptide, VEGF peptide or Arginine peptide, or bonded through amino acid linkers.
  • the present invention particularly relates to a polymeric prodrug conjugate wherein the Compound A (as described herein) is conjugated with a polyethylene glycol (PEG) polymer.
  • PEG polyethylene glycol
  • the polymeric prodrug conjugate i.e. the PEG conjugate thus formed is a prodrug having an enhanced permeability and retention (EPR) effect. Due to the EPR effect, the prodrug can accumulate significantly into tumor mass and cross the cell membranes by endocytosis to reach intracellular targets.
  • EPR enhanced permeability and retention
  • prodrug is a form of a drug that remains inactive during its delivery to the site of action and is activated by the specific conditions of the targeted site.
  • Prodrug reconversion i.e. its conversion into its active form, occurs in the body inside a specific organ, tissue or cell.
  • the PEG polymer used in the polymeric prodrug conjugate of the present invention has an average molecular weight ranging from 1 ,000 Da to 20,000 Da.
  • the PEG polymer used in the polymeric prodrug conjugate of the present invention is a mono or multi arm PEG.
  • the multi arm PEG may be selected from PEG with 2 arms to 8 arms.
  • the PEG polymer used in the polymeric prodrug conjugate of the present invention is mono methoxy PEG.
  • the PEG polymer used in the polymeric prodrug conjugate of the present invention is in either mono or dicarboxylate form.
  • the linkage bond formed between the Compound A and the PEG polymer may be an ester, an amide, a maleimide, a glutaryl, a carbonate or thiolnitrophenylcarbonate.
  • the present invention relates to a process for preparation of the polymeric prodrug conjugate wherein the Compound A (as described herein) is conjugated with a polyethylene glycol (PEG) polymer; comprising the steps of :
  • step (b) adding a coupling agent and 4-dimethylaminopyridine (DMAP) as a catalyst to the solution obtained in step (a);
  • DMAP 4-dimethylaminopyridine
  • step (c) stirring the solution obtained in step (b) for 24 hours at room temperature;
  • step (d) removing carbodiimide urea from the solution obtained in step (c);
  • step (f) purifying the solution obtained in step (e) to obtain the desired polymeric prodrug conjugate
  • step (g) drying the polymeric prodrug conjugate obtained in step (f) under vacuum.
  • step (d) of the process for the preparation of the polymeric prodrug conjugate the carbodiimide urea is removed by filtration.
  • step (e) of the process for the preparation of the polymeric prodrug conjugate the unreacted Compound A and EDC.HCI are removed by size-exclusion Sephadex columns in a series of G10, G15 and G25 (Gel Filtration Handbook, Gel Filtration Principles and Methods, 18-1022-18).
  • step (f) of the process for the preparation of the polymeric prodrug conjugate purification of the polymeric prodrug conjugate involves dialysis using Spectra/Por membrane (molecular mass cut off is approximately 2,000 Da) in DMF as a solvent.
  • the organic solvent used in step (a) of the process involving conjugate formation is selected from dichloromethane (DCM), dimethylformamide (DMF) or dimethylsulphoxide (DMSO) or a mixture thereof.
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethylsulphoxide
  • step (a) a mixture of anhydrous dimethylformamide (DMF) and anhydrous dichloromethane (DCM) is used.
  • DMAP 4-(dimethylamino) pyridine
  • the conjugate may be purified using Sephadex column G10, G15 and G25.
  • the molar ratio of Compound A to PEG ranges from 1 :0.5 to 1 :3, preferably 1 :1 to 1 : 2.
  • the conjugate may be purified using Spectrapore membranes having cut off of 2,000 Da.
  • PEG polymer used for conjugating with the Compound A is mono methoxy PEG.
  • PEG-PM conjugate As a representative example of the polymeric prodrug conjugate of the present invention referred to herein as PEG-PM conjugate is prepared as depicted in the following scheme:
  • EDC.HCI, DMAP, DMF and DCM used in the above scheme refer to N-(3-dimethylaminopropyl)-N-ethylcarbodiimide HCI, 4-dimethylaminopyridine, dimethylformamide and dichloromethane respectively.
  • the polymer PEG which is used for conjugating with the Compound A to prepare the polymeric prodrug conjugate may be selected from: 1 .
  • X is succinate, glutarate, and carboxy methyl; and m is an integer from 10 to 10,000;
  • n is an integer from 10 to 10,000;
  • X is spacer selected from succinate, glutarate, and carboxymethyl; and Y is selected from maleimide, amine, NHS glutaryl, NHS carboxymethyl, carbonate or an aldehyde; or 4.
  • Carboxyl terminal PEG at one terminal and HCI salt at other end represented by the following formula:
  • the present invention relates to a formulation comprising a therapeutically effective amount of the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer and at least one pharmaceutically acceptable excipient.
  • PEG polyethylene glycol
  • various formulations of the polymeric prodrug conjugate may be prepared, preferably in deionized water, saline, or in a composition of ethanol: 5 % w/w, PEG 300/400:15 % w/w and de-ionized water: 80 % w/w.
  • Compound A constitutes 5 % to 25 % (w/w) of the formulation.
  • the present invention relates to a method for the prevention or treatment of bacterial infections in a subject comprising administering to the subject a therapeutically effective amount of the polymeric prodrug conjugate of the present invention.
  • the present invention relates to the polymeric prodrug conjugate wherein the Compound A is conjugated with a polyethylene glycol (PEG) polymer for use in the prevention or treatment of bacterial infections.
  • PEG polyethylene glycol
  • the polymeric prodrug conjugate wherein the Compound A is conjugated with a PEG polymer exhibits enhanced aqueous solubility over its corresponding free or unconjugated form.
  • the polymeric prodrug conjugate wherein the Compound A is conjugated with a PEG polymer exhibits enhanced bioavailability in plasma over its free or unconjugated form.
  • Compound A conjugated to the PEG polymer is bioavailable and exhibits antibacterial activity for 48 hours in the rat plasma as compared to the unconjugated Compound A which is available and exhibits activity up to 8 hours.
  • the polymeric prodrug conjugate of the present invention has been demonstrated to exhibit antibacterial activity against vancomycin resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) strain E710 wherein the Minimum Inhibitory Concentration (MIC) for MRSA E710 is in range of 0.625-1 .25 ⁇ g/mL.
  • VRE vancomycin resistant Enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • the polymeric prodrug conjugate of the present invention has also been demonstrated to exhibit in vivo efficacy in a murine septicemia model (Balb/C mice).
  • the present invention relates to the use of the polymeric prodrug conjugate wherein Compound A is conjugated with a polyethylene glycol (PEG) polymer for the manufacture of a medicament for the prevention or treatment of bacterial infections.
  • PEG polyethylene glycol
  • the bacterial infections are caused by multi drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin resistant Enterococci
  • the polymeric prodrug conjugate of the present invention can be administered subcutaneously, intramuscularly, intravenously, intraperitoneal ⁇ or by other modes of administration.
  • the method of administration as well as the dosage range which are suitable in a specific case depend on the species to be treated and on the state of the respective condition or disease, and can be optimized using methods known in the art.
  • the daily dose of the polymeric prodrug conjugate in a patient may range from 0.0005 mg to 15 mg per kg.
  • the sponge sample Spirastrella inconstans var. digitata (Dendy) was collected from Palk Bay, Tamil Nadu coast, India, by SCUBA diving, from a depth of three meters.
  • the sponge sample was rinsed in sterile seawater and immediately transferred into sterile polyethene containers.
  • the containers were stored at -20°C and transported by maintaining the temperature below 0°C, to the laboratory for further studies.
  • the sponge samples were stored at less than 0°C and later thawed to room temperature (25 ⁇ 2°C) just before isolation of the culture.
  • the sponge sample was cut aseptically into 2 x 2 cm pieces and suspended in 5 ml. of sterile seawater in a 25 ml. sterilized test tube.
  • the test tube was vortexed for 30 seconds; the seawater was drained out and fresh seawater was added. The same process was repeated three times. Finally, the seawater was drained out and the sponge piece was placed on petri plates containing above mentioned isolation medium [Zobell Marine Broth 2216 (agarified by 1 .5 % agar agar); HiMedia]. The petri plate was incubated at room temperature till growth was observed in the plates. The colonies grown on the plates were isolated on the basis of colony characteristics and streaked on petri plates containing above mentioned isolation medium [Zobell Marine Broth 2216 (agarified by 1 .5 % agar agar); HiMedia]. The isolates were repeatedly sub cultured till pure culture no. ZMA B-1 was obtained. The culture no. ZMA B-1 was thus isolated from amongst the growing microorganisms as a single isolate. Reference Example 2
  • the culture was available on Zobell Marine Broth 2216 (agarified by 1 .5 % agar agar) in 15 mm diameter petriplate. The growth on the petriplate was streaked on Zobell Marine Broth 2216 (agarified by 1 .5 % agar agar) slant. The slant was incubated for 2 days at 25°C. One of the single colonies from the upper portion of the slant bed was transferred to fresh slants. The slants were incubated for 2 days at 25°C. These were then used for shake flask fermentation for the purpose of primary anti-infective screening.
  • test tubes After dissolving the ingredients thoroughly by heating, the resultant solution was distributed in test tubes and sterilized at 121 °C for 30 minutes. The test tubes were cooled and allowed to solidify in a slanting position. The agar slants were streaked with the growth of culture no. ZMA B-1 by a wire loop and incubated at 27- 29°C until a good growth was observed. The well-grown cultures were stored in the refrigerator at 4-8°C.
  • the production of the Compound A in the fermentation broth was determined by testing the bioactivity against Enterococcus faecium R2 (VRE) and/or S. aureus 3066 MRSA strain using the agar well diffusion method.
  • the harvest pH of the culture broth was 7.0-8.0.
  • the culture broth was harvested and the whole broth was used for bioactivity testing, which is indicative of presence of the Compound A in the fermented broth.
  • the production of the Compound A in the fermentation broth was determined by testing the bioactivity against S. aureus 3066 (MRSA strain) and/or Enterococcus faecium R2 (VRE) using the agar well diffusion method.
  • the harvest pH of the culture broth was 7.0-8.0.
  • the culture broth was harvested and the whole broth was used for isolation and purification of the Compound A.
  • Reference Example 7
  • Example 6 The whole broth (240 L) of Example 6 was harvested and extracted using ethyl acetate (240 L) by stirring in a glass vessel. The organic layer was separated using disc stack separator (Alfa-laval, model No. LAPX404) and concentrated to obtain the crude extract (296 g).
  • the crude material obtained was stirred and sonicated for 30 minutes using petroleum ether (3 X 1 L) and filtered to obtain insoluble residue (38 g), which was chromatographed by vacuum liquid chromatography using following method:
  • the insoluble residue (35.5 g) was dissolved in a mixture of methanol and acetonitrile (3:1 , 400 mL) and preadsorbed on to LiChroprep RP-18 [25-40 ⁇ , 40 g] and applied to a fritted filter funnel (G-4 grade; 10 cm x 10.5 cm) packed with LiChroprep RP-18 (25-40 ⁇ ,1 10 g) adsorbent.
  • PEG (0-[2-(3-Succinylamino)ethyl]-0'-methyl-polyethyleneglycol 20,000 Da) was coupled with the Compound A by one-step condensation method wherein the coupling of the PEG takes place at the phenolic hydroxy group of the Compound A.
  • PEG 100 mg, 0.005 mM
  • Compound A 7.5 mg, 0.005 mM
  • DMF dimethylformamide
  • DCM anhydrous dichloromethane
  • the unconjugated Compound A was dissolved in methanol, while the polymeric prodrug conjugate (0.0064 mg/mL) was dissolved in water and fluorescence spectra were recorded with fluorescence max set at 440 nm and the excitation wavelength at 360 nm.
  • Figure I shows fluorescence spectra of the unconjugated Compound A indicating the wavelength of maximum absorption at 439.81 nm, while shift of the wavelength of maximum absorption was observed for the polymeric prodrug conjugate at 425.15 nm.
  • the shift in the wavelength of maximum absorption indicates the change in free form of Compound A and formation of the polymeric prodrug conjugate.
  • PEG 300/400 (15 % w/w) and water (80 % w/w)
  • the polymeric prodrug conjugate shows enhanced aqueous solubility as compared to the unconjugated Compound A.
  • the screen is based on growth inhibition of the bacterial strains inoculated into agarified growth media. Qualitative monitoring of the samples was done by agar well diffusion assay, for which Soybean casein digest agar was used as nutrient medium. The results were recorded as zones of inhibition in millimeters (mm). The agar well size was 6 mm in diameter.
  • the unconjugated Compound A and the polymeric prodrug conjugate were dissolved in composition of ethanol abs.: 5 % w/w, PEG 300/400: 15 % w/w and water: 80 % w/w (filtered through 0.45 m filter) for evaluation of MIC and the results are shown in Table 3.
  • Table 3 In vitro efficacy of the unconjugated Compound A and the polymeric prodrug conjugate dissolved in composition of ethanol abs.: 5 % w/w, PEG 300/400: 15 % w/w and water: 80 % w/w
  • the MIC of the polymeric prodrug conjugate is ten times higher than the unconjugated Compound A when dissolved in composition of ethanol abs.: 5 % w/w, PEG 300: 15 % w/w and water: 80 % w/w (filtered through 0.45 m filter).
  • the polymeric prodrug conjugate was incubated with rat (Wistar) plasma for 2 hours (100 ⁇ g mL). The polymeric prodrug conjugate was then tested for its in-vitro efficacy by agar well diffusion assay as described in Example 4. The unconjugated Compound A was treated in the same manner. The activity was monitored up to 48 hours by agar well diffusion assay method. The results are shown in Figure II. Result:
  • the polymeric prodrug conjugate is available in plasma up to 48 hours and also shows antibacterial activity in agar well diffusion assay up to 48 hours as compared to the unconjugated Compound A which is available in plasma and exhibits activity only up to 8 hours.
  • the polymeric prodrug conjugate shows enhanced bioavailability in plasma as compared to the unconjugated Compound A.
  • the animals were infected intraperitoneally with ⁇ 10 s to 10 9 cfu (colony formimg unit) of an overnight grown culture of methicillin resistant Staphylococcus aureus E710 (MRSA), suspended in saline (0.85 % sodium chloride).
  • MRSA methicillin resistant Staphylococcus aureus E710
  • the polymeric prodrug conjugate was dissolved in saline and was administered intravenously at 5 mg/kg and 2.26 mg/kg and the standard antibiotic Linezolid (manufactured by Glenmark Pharma Ltd; Batch no: K2005028) at 25 mg/kg dose, immediately after the infection.
  • the PD 10 o of the polymeric prodrug conjugate is 5 mg/kg.

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Abstract

L'invention concerne un conjugué polymère de promédicament dans lequel un composé antibactérien (appelé composé A) est conjugué avec un polymère polyéthylène glycol (PEG). L'invention concerne également un procédé de préparation du conjugué polymère de promédicament. L'invention permet d'utiliser le conjugué polymère de promédicament pour prévenir ou traiter les infections bactériennes causées, en particulier, par les bactéries résistant à plusieurs médicaments, telles que Staphylococcus aureus résistant à la méthicilline (MRSA) et Enterococci résistant à la vancomycine (VRE).
PCT/IB2012/055239 2012-10-01 2012-10-01 Conjugués polymères de promédicaments WO2014053873A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119201A2 (fr) * 2006-04-18 2007-10-25 Piramal Life Sciences Limited Nouveaux composés antibactériens

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119201A2 (fr) * 2006-04-18 2007-10-25 Piramal Life Sciences Limited Nouveaux composés antibactériens

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