WO1998050018A1 - Systeme d'administration de medicaments - Google Patents

Systeme d'administration de medicaments Download PDF

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Publication number
WO1998050018A1
WO1998050018A1 PCT/CA1998/000419 CA9800419W WO9850018A1 WO 1998050018 A1 WO1998050018 A1 WO 1998050018A1 CA 9800419 W CA9800419 W CA 9800419W WO 9850018 A1 WO9850018 A1 WO 9850018A1
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Prior art keywords
drug delivery
microspheres
delivery composition
poly
acid
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PCT/CA1998/000419
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English (en)
Inventor
Xiao Yu Wu
Zhi Liu
Original Assignee
Xiao Yu Wu
Zhi Liu
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Application filed by Xiao Yu Wu, Zhi Liu filed Critical Xiao Yu Wu
Priority to AU72019/98A priority Critical patent/AU7201998A/en
Priority to CA002288876A priority patent/CA2288876A1/fr
Publication of WO1998050018A1 publication Critical patent/WO1998050018A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface

Definitions

  • the present invention relates to a drug dehvery system, and more particularly to a system which enhances dehvery of two or more drugs which act together BACKGROUND OF THE INVENTION
  • Chemotherapy with anti-cancer drugs is usually limited by its chronic cardiotoxicity, immunosuppressive activity, and necrotic reaction at the in j ection site
  • regional therapy e g mtraarte ⁇ al mfusion of anticancer drug mto the arterial leadmg to a tumor
  • high local toxicity is still a problem
  • drug delivery vehicles are formed as aqueous carriers, gels, polymeric material inserts, or particulates mcorporatmg the agent
  • the agent is released over a prolonged length of time The time release of the agent will depend on factors such as the release mechanism of the agent from the drug delivery vehicle (e g erosion or diffusion), the amount of agent in the drug delivery vehicle, the solubility of the drug in the surrounding physiological medium, and m the case of particulate delivery vehicles, the particle size or size distribution of the vehicle
  • a drug delivery system is desired that enhances delivery of the chemotherapeutic agent to the target organ and prevents loss of the agent m the efferent venous dramage from the organ
  • Microspheres and microcapsules (collectively referred to as "microparticles") have been described for delivery of active agents to target organs
  • Chemoembo zation has been reported to be useful in the treatment of moperable liver tumors, pam control of bone lesions, as a preoperative adjuvant for locally invasive tumors, and in the treatment of solid tumors in liver, kidney, breast, lung, and head and neck (T Kato, Microspheres and Regional Cancer Therapy,
  • microspheres prepared using ion-exchange principles were reported to exhibit high doxorubicm loading capacity (>30%), whereas those usmg chemical cross- linkage and physical entrapment approaches, display drug levels less than 15% (N Wilmott and J Daly, Microspheres and Regional Cancer Therapy, CRC Press, Boca Raton (1994)).
  • high loading capacity ion-exchange microspheres were also reported to provide sustained drug release profiles so that the exposure of the tumor to the drug can be ⁇ maximized (Codde et al Anticancer Research. 13(2):539-43 (1993)).
  • DOX treatment with free drug, liposomes or microspheres significantly reduced tumor growth by 56% (P ⁇ 0.001), 51% (P ⁇ 0.01) and 79% (P ⁇ 0.001) respectively. Furthermore, the DOX-microsphere treatment was reported to be significantly better than either of the other DOX treatments (53%, P ⁇ 0.05) or the sham-microsphere treated group (64%, P ⁇ 0.05).
  • MDR multidrug resistance
  • P-gp P-glycoprotein
  • This invention involves the development of a drug delivery composition containing biodegradable nano- or microspheres which are chemically modified with functional groups to introduce ion-exchange properties to the microspheres, and to modulate hydrophobicity, mechanical strength and drug release profiles.
  • the new system similar to a polylactic acid/polyglycolic acid system in terms of mechanical strength and drug release profiles, has much higher loading capacity for ionic chemotherapeutic agents like doxorubicin, vinblastine, verapamil, quinidine etc.. Therefore, once used in targeted cancer chemotherapy, it is more efficient as a drug carrier.
  • MDR multi-drug resistant
  • the present invention relates to a drug delivery composition
  • a drug delivery composition comprising microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer wherein the microspheres have a biodegradable polymer matrix with functional groups which associate with the chemotherapeutic agent and chemosensitizer.
  • the invention also contemplates a method for preparing microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer comprising: (a) obtaining microspheres having a biodegradable polymer matrix with functional groups which associates with a chemotherapeutic agent and chemosensitizer; and
  • the invention also provides a method for treating multidrug resistant tumors in a subject comprising administering to the subject an effective amount of a drug delivery composition comprising microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer wherein the microspheres have a biodegradable polymer matrix with functional groups which associate with the chemotherapeutic agent and chemosensitizer.
  • Figure la is a graph showing the dynamics of verapamil sorption into microspheres through ion exchange with an initial concentration of verapamil at 0.025 mg/ml.
  • Figure lb is a graph showing the effect of the microsphere/drug ratio on the equilibrium level of drug loaded and the yield of drug loading with an initial verapamil concentration of 0.05 mg/ml.
  • Figure lc is a graph showing competitive loading of vinblastine and verapamil.
  • Figure 2a is a graph showing fractional release of verapamil and vinblastine from single-agent-loaded microspheres as a function of time.
  • Figure 2b is a graph showing fractional release of verapamil and vinblastine from dual-agent-loaded microspheres as a function of time.
  • Figure 3 is a photograph of freeze-dried CMDEX microspheres loaded with doxorubicin. Shown by a confocal fluourescent microscope.
  • Figure 4 is a graph showing release of doxorubicin from microspheres into a phosphate buffer solution (pH 7.4) at 37 degrees C, as a function of time.
  • Figure 5 is a graph showing release of verapamil from microspheres in Pluronic F-127 gel into a phosphate buffer solution (pH 7.4) at 37 degrees C, as a function of time.
  • Figure 6 is a graph showing release of verapamil from hydrophobically modified microspheres in corn oil and from unmodified microspheres in corn oil into a phosphate buffer solution (pH 7.4) at 37 degrees C, as a function of time.
  • Figure 7 is a graph showing the release of quinidine from CMDEX microspheres and CMDEX microspheres coated with hydrophobic polymers as a function of time.
  • Figure 8 is a graph showing vinblastine uptake by parent and MDR CHO cells as a function of time.
  • Figure 9 is a graph which depicts the uptake of doxorubicin by multidrug- resistant murine tumor cells in the presence of chemosensitizing agent, verapamil.
  • Figure 10 is an IR spectrum of maleic ester of inulin.
  • Figure 11 is an IR spectrum of inulin.
  • Figure 12 is an IR spectrum of a copolymer of maleic acid ester of inulin and methacrylic acid.
  • the present invention relates to a drug delivery composition
  • a drug delivery composition comprising microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer wherein the microspheres have a biodegradable polymer matrix with functional groups which associate with the chemotherapeutic agent and chemosensitizer.
  • the delivery composition of the invention has many other characteristics which make it particularly advantageous.
  • the microspheres used in the delivery system are bio-degradable and are stable in physiological environments.
  • the microspheres using ion- exchange principles exhibit high loading capacity for various chemotherapeutic agents. This allows an effective dose to be used to produce high levels of local drug concentration with consequent greater therapeutic efficacy.
  • Administration of microspheres with high drug loading also results in less of the matrix material being co-administered to the body, and biological reaction to the matrix material is minimized.
  • the microspheres also permit diffusion of the chemotherapeutic agent and chemosensitizer from the core through the matrix at a predetermined release rate.
  • the microspheres can also be sterilized for use before addition of the chemotherapeutic agents and chemosensitizers avoiding degradation of sensitive therapeutics.
  • the microspheres in the drug delivery composition of the invention comprises a biodegradable polymer matrix.
  • biodegradable polymer matrixes may be comprised of polyesters, such as for examples, poly(hydroybutyric acid), poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co- glycolic acid), poly( ⁇ -caprolactones), poly( ⁇ -caprolactone-co-DL-lactic acid); polyanhydrides, for example, poly(maleic anhydride); polyamides such as for examples albumin, pol(hydroxyalkyl)-L-glutamines, poly( ⁇ -ehtyl-L-glutaminate-co-glutamic acid), poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamic acid ⁇ ; poly(orthoesters); poly(alkyl
  • R 1 is an alkyl group, an alkene or alkyne, aryl, alkoxy, or cycloalkyl, preferably a C ⁇ to C 10 alkyl, preferably R 1 may be methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, propene, butene, cyclohexene, methylcyclopropyl, methylcyclohexyl, cyclobutyl, or O-methyl; R 2 is a carboxy group (-COOH), a sulfonyl group (-S03), or -NR 3 R 4 R 5 wherein R 3 , R 4 , and R 5 are the same or different and represent hydrogen, alkyl, aryl, or cycloalkyl preferably alkyl.
  • R 1 R 3 , R 4 , and R 5 may contain other chemical functional groups such as halogen, hydroxyl, amine, amide, nitro, and thiol.
  • R 1 is methyl and R 2 is a carboxy group i.e. the functional group is carboxymethyl.
  • Ionic chemotherapeutic agents are suitable for use in the delivery composition of the invention i.e. either cationic or anionic agents.
  • ionic agents which may be used in the delivery composition of the invention are alkaloids such as vinblastine and vincristine, antibiotics such as mitomycin C, doxorubicin (adriamycin), daunorubicin, and their derivatives, hormonal agents such as tamoxifen.
  • Other chemosensitzers or G- glycoprotein inhibitors include LY-335979 (Eli Lilly) and GW-918 (Glaxo Wellcome).
  • Ionic chemosensitizers are suitable for use in the delivery composition of the invention.
  • suitable ionic chemosensitizers which may be used in the delivery system of the invention include calcium channel blockers e.g. verapamil, nifedipine, nicardipine, diltiazem, depridil, felodipine, and their derivatives, calmodulin antagonists e.g. trifluoperazine and chlorpromazine, antibiotics and analogs e.g. cefoperazone and ceftriaxone, indole alkaloids e.g. quinidine, quinine, and quinacrine, and the like.
  • calcium channel blockers e.g. verapamil, nifedipine, nicardipine, diltiazem, depridil, felodipine, and their derivatives
  • calmodulin antagonists e.g. trifluoperazine and chlorpromazine
  • the biodegradable polymer of the microspheres used in the drug delivery composition of the invention may also have free hydroxyl groups converted to esters. This conversion increases the hydrophobicity of the microspheres. Modification of the free hydroxyl groups results in increased mechanical strength and slows the drug release of the microspheres in the drug composition.
  • the microspheres can also be coated with hydrophobic polymers to further increase hydrophobicity.
  • polymers examples include poly(methyl methacrylate-co-methacrylic acid), polyurethane, chiti ⁇ , poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid),poly( ⁇ -caprolactones), poly( ⁇ -caprolactone-co- DL-lactic acid); polyanhydrides, e.g., poly(maleic anhydride); polyamides, e.g., albumin, pol(hydroxyalkyl)-L-glutamines,poly( ⁇ -ehtyl-L-glutaminate-co-glutamic a cid), poly( L-l eucine-co-L- aspart ic aci d), p oly(proline-co-g lut amic acid); poly(orthoesters) ; and poly(alkyl 2-cyanoacrylates).
  • the microspheres in the drug delivery composition of the invention may also contain inert excipients commonly used to improve the characteristics of the composition.
  • inert excipients such as vegetable oil, arachis oil, coconut oil, maize oil, almond oil, sesame oil, peanut oil, cottonseed oil, Caster oil, corn oil, olive oil; thermal gels such as Pluoronic series; alcohols like benzyl alcohol, ethanol; syrup; esters such as ethyl oleate, isopropyl myristate, glycerol, propylene glycol, liquid macrogols, esters, may be added to improve viscosity, tonicity, biocompatibility, and release profile and the like.
  • the microspheres may also be dispersed in a physiological medium such as saline.
  • a method for preparing microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer comprising: (a) obtaining microspheres having a biodegradable polymer matrix with functional groups which associates with a chemotherapeutic agent and a chemosensitizer; and
  • microspheres having a biodegradable polymer e.g. albumin or dextran, may be prepared using conventional methods or they may be obtained from commercial sources.
  • G-100 and G-200 may be obtained from Pharmacia.
  • the microspheres have a particle size of about 40-200 ⁇ m and a selected pore size range for molecules with molecular weight of 100-600,000 Da.
  • the microspheres are chemically modified to introduce the functional groups.
  • carboxymethylation or sulphonation may be carried out to introduce a carboxymethyl group or a sulfonyl group, respectively.
  • carboxymethylated dextran ion exchange microspheres are prepared by suspending dextran gel (about 2 to 5 grams, preferably 3 grams) in about 40 wt% sodium hydroxide and adding chloroacetic acid (about 10 to 20 grams, preferably 16 grams).
  • Anionic carboxylic groups (1.95 meq/g) may also be introduced by a base-catalyzed • reaction with succinic anhydride.
  • the present inventors have found that drug loading of the chemotherapeutic agent and chemosensitizer is proportional to the extent of functional modification of the polymer matrix. Generally, drug loading increases with increased modification of the microspheres. In an embodiment of the invention, at least 10% of the hydroxyl groups on the polymer matrix are modified to provide for at least 50% loading of the two drugs.
  • Free hydroxyl groups on the prepared microspheres may be converted to esters, or ethers or otherwise blocked, by, for example, introducing fatty groups to OH groups via an ester bond, ether bond,amide bond, imide bond. It is also possible to increase hydrophobicity by introducing hydrophobic polymers by copolymerization or grafting /block copolymerization or introducing cross-linking agents. Such further modification of the free hydroxyl groups results in increased mechanical strength and slows the drug release of the microspheres in the drug composition.
  • the polymer matrix of the microspheres will be modified to a degree to provide an appropriate loading, and release for the particular combination of chemotherapeutic agent and chemosensitizer and to suit a particular therapeutic application.
  • Free flowing drug loaded microspheres may be obtained after incubation of the prepared microspheres in distilled water or a polar organic solvent, such as ethanol or methanol (for hydrophobic drugs such as cyclosporin DMSO may be used), containing the chemotherapeutic agent and chemosensitizer overnight, followed by filtration, washing with distilled water, and freeze-drying. Chromatographic methods may also be used to enhance loading of the chemotherapeutic agent and chemosensitizer.
  • inert excipients commonly used to improve the characteristics of the composition such as thickeners, surfactants etc. may be added to the microspheres to improve viscosity, tonicity, biocompatibility, stability and the like.
  • lubricants, dyestuffs, sweetners, flavouring agents, inert excipients, preservatives etc. may be added to the microspheres to improve and permeability properties.
  • the microspheres may also be dispersed in a physiological medium such as saline.
  • the microspheres may be sterilized e.g. by heat or UV light before addition of the chemotherapeutic agents and chemosensitizers.
  • the agents and chemosensitizers may be sterilized separately avoiding possible degradation of sensitive therapeutics.
  • a time release profile for the drugs can be optimized taking into consideration the amount of drug loaded into the drug delivery composition, the solubility of the drug in the surrounding physiological milieu the affinity of the drug to the microspheres, the hydrophobicity of the microspheres and the coating, and the particle size and size distribution of the microspheres in the composition.
  • the drug delivery composition of the invention exhibits a sustained drug release profile, and it provides a chemosensitization effect in drug resistant cells. Accordingly, the drug delivery system may be used in the treatment of multidrug drug resistant tumor cells. It is expected that the drug delivery compositions will be particularly useful in the treatment of malignancies including multiple myeloma, breast cancers, ovarian cancers, childhook neuroblastoma, leukemia, pancreas carcinomas, liver carcinomas, cervical carcinoma, endometrial carcinomas, and adenocarcinomas of the kidnev and colon.
  • the drug delivery composition may also be used to deliver other combination drug therapies, for examples, AZT and 3TC (anti-AIDS); angiostatin and endostatin (anticancer); Intro-
  • vasoconstrictors e.g.epinephrine
  • anticancer drugs e.g. taxol
  • chemosensitizers e.g. cyclosporins
  • in vitro and in vivo model systems may be used to assess the therapeutic efficacy and system.
  • an in vitro system using multidrug resistant CH R C5 CHO cells may be used to test therapeutic efficacy in multidrug resistant tumors.
  • the present invention contemplates a method for treating multidrug resistant tumors in a subject comprising administering to the subject an effective amount of a drug delivery composition comprising microspheres containing at least one chemotherapeutic agent and at least one chemosensitizer wherein the microspheres have a biodegradable polymer matrix with functional groups which associate with the chemotherapeutic agent and chemosensitizer.
  • the drug delivery compositions may be delivered to a target site through a variety of known routes of administration.
  • a drug delivery composition comprising cross-linked dextran microspheres for use in treating a multidrug resistant tumor may be administered by intratumor injection.
  • Other administration routes include oral deliver for verapamil and other weak acidic or basic drugs; rectal delivery and topical adminstration such as creams for dermal or transdermal application, ophthalmic application, containing drugs such as actibiotics, antifungal agents, anticancer drugs, antiglucoma agents, localanesthetic agents, anti-inflammatory, analgesic agents.
  • the drug delivery compositions of the invention can be intended for administration to humans or animals. Dosages of the chemotherapeutic agent and chemosensitizer incorporated in the drug delivery composition will depend on individual needs, on the desired effect and on the chosen route of administration.
  • the microspheres loaded with chemosensitizers and radiolabeled P-glycoprotein substrates are injected intratumorally, among which sestamibi is preferable because it is not a cytotoxic agent
  • Radio image of the tumor gives the concentration of the radiolabeled chemicals in the tumor
  • the MDR tumors will show low concentration of the chemicals in the absence of chemosensitizers, whereas the non-resistant tumors higher concentration More importantly, m the presence of microsphere-dehvered chemosensitizers, the mcrement of concentration of the radiochemicals will be much higher m the MDR tumors than that in the non-resistant tumors
  • Cross-linked dextran gels (Sephadex G-200) are used to prepare carboxvmethylated dextran ion exchange MS drug carriers
  • 3 g of dextran gel were suspended in 50 ml of 40 wt % sodium hydroxide solution and 16 g of chloracetic acid were then added to this suspension
  • the reaction mixture was gently agitated for 12 hours at room temperature
  • the reaction mixture was washed extensively with distilled water and then freeze dried
  • the content of ion exchange carboxymethyl groups was assayed by acid-base titration method b) Drug Loading and Release Studies
  • Drug loadmg is carried out by mixing drug solutions in distilled water with freeze-d ⁇ ed resins
  • 0 1 g of ion exchange resm was added to 10 ml of 1% verapamil or doxorubicin aqueous solution After overnight incubation, the resm was isolated by either centnfugation or filtration followed bv extensive washmg with distilled water and then lyophilization Unbound drug in the wash was determmed by
  • UV/VIS spectroscopy HP8452A
  • the drug-loaded resms were added to buffer solution directly, or mcorporated mto other pharmaceutical vehicles first, and then added to the buffer solution
  • the pharmaceutical vehicles m clude aqueous system such as thermal gels and hydrocarbon system such as sesame oil, vegetable oil, and corn oil UV/VIS spectroscopy was applied to assay the drug released from the delivery system mto the buffer solution
  • aqueous system such as thermal gels and hydrocarbon system such as sesame oil, vegetable oil, and corn oil
  • UV/VIS spectroscopy was applied to assay the drug released from the delivery system mto the buffer solution
  • more than one compound I e , doxorubicin or vinblastine and verapamil
  • HPLC high performance liquid chromatography
  • Drug loading was calculated from the difference between the amount of drug originally used and that after incubation with the ion exchange microspheres.
  • dual agents e.g., vinblastine and verapamil
  • HPLC Waters
  • the mobile phase consisted of phosphate buffer (ionic strength 0.1
  • Vinblastine and verapamil were separated in a reverse-phase column (Norva-pak C-18,
  • Curve A in Figure la depicts the fraction of remaining verapamil in the solution as a function of time for the microspheres incubated in 0.025 mg/ml verapamil solution. A rapid decrease in the remaining drug is observed in the initial 10 hours followed by a slower change in the subsequent 10 hours. A plateau is reached after 20 hours indicating an equilibrium state. Similar trend is also observed with vinblastine. Therefore, 30 hours of incubation was carried out for all drug loading to ensure completion of the process.
  • Curve B in Figure la shows that the fraction of drug loaded into the microspheres follows a typical first-order sorption kinetics, suggesting that the drug loading is essentially a diffusion-controlled process like drug release.
  • the amount of microspheres relative to drug is an important factor influencing the equilibrium drug content and the yield of drug loading.
  • the yield of drug loading and the equilibrium level of verapamil loaded are plotted in Figure lb against the ratio of the microspheres to the drug (M/D ratio).
  • M/D ratio the ratio of the microspheres to the drug
  • the compromise approach is to control the conditions in the left region, e.g., M/D ratio between 1 and 3. In this case, the drug content reaches ⁇ 30% with the yield of drug loading 40-60%.
  • Figure 2a shows the fractional release of verapamil and vinblastine from individually-loaded microspheres.
  • Figure 2b depicts the release profiles of verapamil and vinblastine from dual-agent-loaded microspheres. Both graphs indicate that the drugs are released for a prolonged period of time and the release rate of verapamil is higher than that of vinblastine.
  • Figure 3 is a confocal fluorescent photograph of doxorubicin-loaded microspheres.
  • Figure 4 illustrates the sustained release of doxorubicin from the 'microspheres into pH 7.4 buffer solution at 37 °C d) Drug release from microspheres in a synthetic thermal gel (Pluronic F-127) An aqueous solution (20-30%) of Pluronic F-127 was prepared at 4 °C. This solution experiences gelation at temperatures higher than 10 °C. Microspheres (Sephadex
  • Microspheres loaded with ionic drug i.e., verapamil or doxorubicin
  • ionic drug i.e., verapamil or doxorubicin
  • the oil phase behaved as a barrier for the ion exchange process required for drug release. Therefore, slower release was obtained.
  • Hydrophilic polysaccharide microspheres e.g., SP C-25
  • hydrophobically-modified product SP C-25/palmitoyl cholride
  • Hydrophobic resins therefore less swellable in water and probably with higher affinity for hydrophobic drugs (such as digoxin, taxol, cyclosporins, nifedipine, cisplatin, pentaerythritoltetranitrate, indomethacin, theophylline, AZT, and cipro) by esterification of the ion exchange resins and /or by coating with hydrophobic polymers without jeopardizing the ion exchange capacity.
  • hydrophobic drugs such as digoxin, taxol, cyclosporins, nifedipine, cisplatin, pentaerythritoltetranitrate, indomethacin, theophylline, AZT, and cipro
  • CMDEX/MS was added to 100 ml of DMSO containing 15 g of acetyl chloride as esterification agent and pyridine as catalyst.
  • Figure 6 illustrates the results of a comparison of the release of verapamil from hydrophobically-modified resin in oil vehicle with that without modification. Much slower release of the drug was realized from the hydrophobically-modified resin.
  • Figure 7 shows the release of quinidine from CMDEX/MS alone (without coating) and CMDEX/MS coated with hydrophobic polymers (with coating). Again, the results demonstrate that surface coating of the microspheres with hydrophobic polymers significantly reduced the drug release rate.
  • Example 2
  • CHO cells originally selected from the parent line for resistance to colchicine (180 times relatively resistant to colchicine and 30 times to vinblastine) are grown in 25 cm2 and 75 cm2 plastic tissue culture flasks in alpha minimal essential medium (a-MEM), containing 10% fetal bovine serum and 0.5% penicillin-streptomycin at 37 °C in an atmosphere of air and 5% C02.
  • a-MEM alpha minimal essential medium
  • EBSS Earle Balanced Salt Solution
  • Drug accumulation by the cells was rapidly stopped by aspirating the media and by washing the cells twice with 2 ml of ice-cold 0.16N NaCl. The cells were then lysed with
  • Figure 8 shows the uptake of vinblastine over time for both parent AuxBl (series 2) and multi-drug resistant CHRC5 CHO cells (series 1). As can be seen from Figure 8 the uptake of vinblastine is greater in the parent cells as compared to the MDR cells. This demonstrates that the CHRC5 CHO cells used in this experiment are in fact multi-drug resistant cells.
  • CHO cells is determined in the presence and absence of chemosensitizers (i.e., 20mM and 50mM cyclosporin A, 50mM quinidine, 50mM verapamil) to verify that the cells are retaining MDR properties. Then CHRC5 cells are used to evaluate the effectiveness of vinblastine and/or verapamil loaded into the microspheres. The amounts of loading are controlled to make sure that final concentrations of vinblastine and/or verapamil are similar to conditions using free agents. Table 2 shows the uptake of vinblastine by the multi drug resistant CHO cells in the presence of immobilized verapamil as compared with free agents and placebo microspheres.
  • chemosensitizers i.e., 20mM and 50mM cyclosporin A, 50mM quinidine, 50mM verapamil
  • Murine breast sarcoma cell line EMT6/P (parent) and the resistant variant EMT6/AR1.0 are used as the model system. The latter was selected by exposure to doxarubicin and overexpression of P-gp. Cells are grown in alpha minimum-essential medium (a-MEM) with 10% fetal bovine serum and 0.1 mg/mL kanamycin.
  • a-MEM alpha minimum-essential medium
  • EMT6/P and EMT6/AR1.0 cells are grown in multiwell plates for 3-4 days, reaching sub-confluence, drug accumulation is initiated by the addition of 0.5 mL a- MEM/30 mM HEPES containing 14C-doxorubicin and 3 H-mannitol (an extracellular marker). After incubation for 0-120 minutes, cellular accumulation is rapidly stopped by aspirating the medium and by washing the cells twice with 1 mL ice-cold 0.9% NaCl. The cells are lysed with 0.5 N NaOH followed by neutralization and then counted in a liquid scintillation counter.
  • Figure 9 depicts the uptake of doxorubicm by the multidrug-resistant murme tumor cells m the presence of chemosensitizmg agent, verapamil, is mcreased more than
  • mice When mouse tumors have reached a size of 0 6-0 9 g, the therapy is initiated Four groups of 6 mice for each of the two tumor types (EMT6/P and EMT6/AR1 0) are used for the therapeutic trials Each treatment involves intratumoral in j ection in a volume of 50-100 mL contammg 10-25 mg chemotherapeutic agent and chemosensitizer Group C serves as control and receives placebo microspheres Group D receives doxorubicin-loaded microsphere, Group V receives verapamil-loaded microsphere, and Group DV receives both doxorubicm- and verapamil-loaded microspheres Tumor growth is monitored daily and the mice are sacrificed when tumors reach an estimated size of 1 5 g (about 6% of body weight) The dosages of doxorubicm and verapamil is determmed from m vitro data and preliminary in vivo experiments
  • Tumor response to therapy is assessed usmg the growth curves and the delay in growth of tumors mdicates therapeutic response
  • Figure 9 shows the FTIR spectrum of maleic half ester of mulm in comparison with that of mulm ( Figure 10) C-O stretchmg band, I e , 1100-1300 cm J m the ester bond is clearly seen m the figure, which is absent m
  • the broad and mtense O-H stretchmg absorption at -3350 cm "1 m mulm is significantly reduced after esterification
  • Copolymerization was carried out m distilled water at 70 °C under nitrogen atmosphere using N,N-methylene bisacrylamide (BIS) as the cross linking agent and potassium persulfate (KPS) as the mitiator
  • BIOS N,N-methylene bisacrylamide
  • KPS potassium persulfate
  • monomer mixture containing maleic half ester of mulm and inhibitor-free methacrylic acid to a total concentration of 1 82 mole 10% BIS was added and then polymerization was initiated by the addition of small amount of concentrated KPS 0 05 mole solution After polymerization for 4 hours, the copolymer was separated and washed several times with distilled water to remove the impurities
  • Figure 11 is the IR spectrum of the copolymer of maleic ester of mulm and methacrylic acid which was synthesized without usmg cross-linking agent It shows absence of olefimc double bond at -1620 cm “1 (refer to Figure 9) mdicatmg that the double bonds of maleic half ester of mulm are mvolved m copolymerization Solubility of the copolymer
  • the degree of swelling of the cross-linked copolymer of maleic half ester of inulin and methacrylic acid was determined by allowing the copolymer sample to equilibrate in distilled, deionized water at room temperature. The mass of the swollen sample was determined by blot-and-weigh technique. Dry copolymer mass was determined by drying the sample at room temperature and then in vacuum at room temperature. The degree of swelling was then calculated by the ratio of the weight of swollen copolymer to that of dry copolymer.
  • microspheres of maleic ester of inulin and methacrylic acid were prepared by suspension polymerization.
  • Aqueous solution of inulin ester, methacrylic acid, and N,N-methylene bisacrylamide was dispersed in oil phase by vigorous stirring.
  • 10 ml of the aqueous solution was added to 100 ml of paraffin oil containing 10% (v/v) nonionic surfactants, e.g., Pluoronic L-62 and Span 80 with a volume ratio of 3:1.
  • the polymerization was initiated at 70 °C under nitrogen atmosphere by addition of potassium persulfate as the initiator.
  • microspheres After polymerization for 6 hours, the microspheres were filtered and washed with distilled water to remove the impurities.
  • the purified microspheres containing ion exchange groups, -COO " were subject to the tests of drug loading and release, in vitro evaluation of drug uptake, and in vivo therapeutic trials using the same methods as for dextran-based microspheres.
  • the mouse tumors were grown using the method described in Example 4. When the tumors reached a size of 0.6-0.9 g, 50-100 mL of microsphere suspension was injected into the tumor. Typically, 50 mL of the suspension containing 10 mg/ ⁇ L microspheres loaded with 60% doxorubicin was administered. The mice were sacrificed at various time intervals (e.g., 3 hours, 1 day, and 3 days) and the tumors were taken and immersed in liquid nitrogen and then in formaline to fix the texture of the tissue. The tumors were cut into thin slices which were then subject to confocal fluorescence imaging. The fluorescent image of doxorubicin was obtained using confocal fluorescent microscopy (MRC 600) with an excitation wavelength of 488 nm and an emission wavelength longer than 515 nm.
  • MRC 600 confocal fluorescent microscopy
  • the tumors containg the microspheres were still releasing doxorubicin.
  • CMDEX/MS beads Placebo - blank CMDEX/MS beads (1% wt./v) were added into transport medium, 50mM verapamil or 20mM Cys A. 2. CMDEX/MS beads (1% wt./v) loaded with verapamil.
  • CMDEX/MS beads (1% wt./v) loaded with vinblastine.
  • CMDEX/MS beads (1% wt./v) loaded with vinblastine and verapamil.

Abstract

Composition permettant d'administrer des médicaments, qui comprend des microsphères contenant au moins un agent chimiothérapique et au moins un agent chimiosensibilisant, et dans laquelle les microsphères comportent une matrice polymère biodégradable renfermant des groupes fonctionnels qui s'associent à l'agent chimiothérapique et à l'agent chimiosensibilisant.
PCT/CA1998/000419 1997-05-06 1998-05-06 Systeme d'administration de medicaments WO1998050018A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
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WO2000078287A1 (fr) * 1999-05-18 2000-12-28 Istituto Biochimico Pavese Pharma S.P.A. Produits d'addition polymeres a base de polysaccharides naturels antibiotiques
EP1383516A1 (fr) * 2001-03-27 2004-01-28 Pro-Pharmaceuticals, Inc. Co-administration d'un polysaccharide avec un agent chimiotherapeutique permettant le traitement du cancer
WO2004087094A2 (fr) * 2003-04-02 2004-10-14 Celator Pharmaceuticals, Inc. Compositions pour traiter la resistance aux medicaments
EP1662874A2 (fr) * 2003-09-08 2006-06-07 Pro-Pharmaceuticals, Inc. Co-administration de polysaccharide avec un agent chimiotherapeutique pour le traitement du cancer
EP2153824A1 (fr) * 2004-09-27 2010-02-17 Sigmoid Pharma Limited Formules multi-particules sans soudure
EP2301556A1 (fr) * 2001-03-27 2011-03-30 Pro-Pharmaceuticals, Inc. Co-administration d'un polysaccharide avec un agent chimiotherapeutique dans le traitement du cancer
US8911777B2 (en) 2007-04-04 2014-12-16 Sigmoid Pharma Limited Pharmaceutical composition of tacrolimus
US8951570B2 (en) 2007-04-26 2015-02-10 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US9220681B2 (en) 2012-07-05 2015-12-29 Sigmoid Pharma Limited Formulations
US9278070B2 (en) 2009-05-18 2016-03-08 Sigmoid Pharma Limited Composition comprising oil drops
WO2017011588A1 (fr) * 2015-07-14 2017-01-19 Research Institute At Nationwide Children's Hospital Nouvelle formulation pour l'élimination de pathogènes cariogènes et opportunistes dans la cavité buccale
US9821024B2 (en) 2010-11-25 2017-11-21 Sigmoid Pharma Limited Immunomodulatory compositions
US9878036B2 (en) 2009-08-12 2018-01-30 Sigmoid Pharma Limited Immunomodulatory compositions comprising a polymer matrix and an oil phase
US10434138B2 (en) 2013-11-08 2019-10-08 Sublimity Therapeutics Limited Formulations
CN111093628A (zh) * 2017-09-28 2020-05-01 阿尔法西格玛有限公司 治疗胃食管反流的口服组合物
US10993987B2 (en) 2014-11-07 2021-05-04 Sublimity Therapeutics Limited Compositions comprising Cyclosporin
US11452748B2 (en) 2014-03-06 2022-09-27 Research Institute at Nation Children's Hospital Probiotic formulations and methods for use
US11690892B2 (en) 2015-10-14 2023-07-04 Research Institute At Nationwide Children's Hospital HU specific interfering agents

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Publication number Priority date Publication date Assignee Title
WO2000078287A1 (fr) * 1999-05-18 2000-12-28 Istituto Biochimico Pavese Pharma S.P.A. Produits d'addition polymeres a base de polysaccharides naturels antibiotiques
US6821959B1 (en) 1999-05-18 2004-11-23 Istituto Biochimico Pavese Pharma S.P.A Antibiotic-natural polysaccharide polymer adducts
EP1383516A1 (fr) * 2001-03-27 2004-01-28 Pro-Pharmaceuticals, Inc. Co-administration d'un polysaccharide avec un agent chimiotherapeutique permettant le traitement du cancer
EP2301556A1 (fr) * 2001-03-27 2011-03-30 Pro-Pharmaceuticals, Inc. Co-administration d'un polysaccharide avec un agent chimiotherapeutique dans le traitement du cancer
EP1383516A4 (fr) * 2001-03-27 2007-08-01 Pro Pharmaceuticals Inc Co-administration d'un polysaccharide avec un agent chimiotherapeutique permettant le traitement du cancer
JP2006525236A (ja) * 2003-04-02 2006-11-09 セレーター ファーマスーティカルズ、インク． 薬剤耐性の治療組成物
WO2004087094A3 (fr) * 2003-04-02 2004-11-25 Celator Technologies Inc Compositions pour traiter la resistance aux medicaments
AU2004226888B2 (en) * 2003-04-02 2009-09-10 Celator Pharmaceuticals, Inc. Nano-sized vehicles transporting a therapeutic agent and at least one drug resistance modulator for the treatment of multi drug resistance
WO2004087094A2 (fr) * 2003-04-02 2004-10-14 Celator Pharmaceuticals, Inc. Compositions pour traiter la resistance aux medicaments
EP1662874A2 (fr) * 2003-09-08 2006-06-07 Pro-Pharmaceuticals, Inc. Co-administration de polysaccharide avec un agent chimiotherapeutique pour le traitement du cancer
EP1662874A4 (fr) * 2003-09-08 2012-08-01 Pro Pharmaceuticals Inc Co-administration de polysaccharide avec un agent chimiotherapeutique pour le traitement du cancer
EP2153824A1 (fr) * 2004-09-27 2010-02-17 Sigmoid Pharma Limited Formules multi-particules sans soudure
EP2156826A1 (fr) * 2004-09-27 2010-02-24 Sigmoid Pharma Limited Formules multi-particules comprenant deux principes actives
US9387179B2 (en) 2007-04-04 2016-07-12 Sigmoid Pharma Limited Pharmaceutical cyclosporin compositions
US9675558B2 (en) 2007-04-04 2017-06-13 Sigmoid Pharma Limited Pharmaceutical cyclosporin compositions
US9114071B2 (en) 2007-04-04 2015-08-25 Sigmoid Pharma Limited Oral pharmaceutical composition
US10434140B2 (en) 2007-04-04 2019-10-08 Sublimity Therapeutics Limited Pharmaceutical cyclosporin compositions
US10434139B2 (en) 2007-04-04 2019-10-08 Sublimity Therapeutics Limited Oral pharmaceutical composition
US8911777B2 (en) 2007-04-04 2014-12-16 Sigmoid Pharma Limited Pharmaceutical composition of tacrolimus
US9844513B2 (en) 2007-04-04 2017-12-19 Sigmoid Pharma Limited Oral pharmaceutical composition
US9585844B2 (en) 2007-04-04 2017-03-07 Sigmoid Pharma Limited Oral pharmaceutical composition
US8951570B2 (en) 2007-04-26 2015-02-10 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US9402788B2 (en) 2007-04-26 2016-08-02 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US9999651B2 (en) 2009-05-18 2018-06-19 Sigmoid Pharma Limited Composition comprising oil drops
US9278070B2 (en) 2009-05-18 2016-03-08 Sigmoid Pharma Limited Composition comprising oil drops
US9878036B2 (en) 2009-08-12 2018-01-30 Sigmoid Pharma Limited Immunomodulatory compositions comprising a polymer matrix and an oil phase
US9821024B2 (en) 2010-11-25 2017-11-21 Sigmoid Pharma Limited Immunomodulatory compositions
US9950051B2 (en) 2012-07-05 2018-04-24 Sigmoid Pharma Limited Formulations
US9220681B2 (en) 2012-07-05 2015-12-29 Sigmoid Pharma Limited Formulations
US10434138B2 (en) 2013-11-08 2019-10-08 Sublimity Therapeutics Limited Formulations
US11452748B2 (en) 2014-03-06 2022-09-27 Research Institute at Nation Children's Hospital Probiotic formulations and methods for use
US10993987B2 (en) 2014-11-07 2021-05-04 Sublimity Therapeutics Limited Compositions comprising Cyclosporin
WO2017011588A1 (fr) * 2015-07-14 2017-01-19 Research Institute At Nationwide Children's Hospital Nouvelle formulation pour l'élimination de pathogènes cariogènes et opportunistes dans la cavité buccale
US20190388309A1 (en) * 2015-07-14 2019-12-26 Research Institute At Nationwide Children's Hospital Novel formulation for the elimination of cariogenic and opportunistic pathogens within the oral cavity
US11484479B2 (en) 2015-07-14 2022-11-01 Research Institute At Nationwide Children's Hospital Formulation for the elimination of cariogenic and opportunistic pathogens within the oral cavity
US11690892B2 (en) 2015-10-14 2023-07-04 Research Institute At Nationwide Children's Hospital HU specific interfering agents
CN111093628A (zh) * 2017-09-28 2020-05-01 阿尔法西格玛有限公司 治疗胃食管反流的口服组合物
CN111093628B (zh) * 2017-09-28 2023-11-17 阿尔法西格玛有限公司 治疗胃食管反流的口服组合物

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