WO2018011040A1 - Microparticules de plga chargées de fluoroquinolone pour le traitement de maladies respiratoires. - Google Patents

Microparticules de plga chargées de fluoroquinolone pour le traitement de maladies respiratoires. Download PDF

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Publication number
WO2018011040A1
WO2018011040A1 PCT/EP2017/066831 EP2017066831W WO2018011040A1 WO 2018011040 A1 WO2018011040 A1 WO 2018011040A1 EP 2017066831 W EP2017066831 W EP 2017066831W WO 2018011040 A1 WO2018011040 A1 WO 2018011040A1
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fluoroquinolone
plga
levofloxacin
loaded
microparticle
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PCT/EP2017/066831
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English (en)
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Jean-Christophe Olivier
Marisa DA COSTA GASPAR
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Universite De Poitiers
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Publication of WO2018011040A1 publication Critical patent/WO2018011040A1/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • This invention relates to PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability, the method of preparation thereof and applications thereof.
  • Fluoroquinolones are known to be used for the treatment of several bacterial infections. Typically, fluoroquinolones are used in the treatment of pulmonary infections.
  • fluoroquinolones with high mucosal permeability are particularly interesting given that they exhibit specific properties and have particular distribution profiles. More particularly, levofloxacin is a highly water soluble fluoroquinolone characterized by a high permeability profile through the broncho-alveolar barrier.
  • fluoroquinolones are administered orally and intravenously.
  • administration routes require high doses of antibiotics and have undesirable side effects.
  • the search for more efficient therapeutic approaches has driven to the development of inhaled fluoroquinolones.
  • such products request relatively frequent administration to deliver the therapeutic dose, fastidious hygienic procedures and are not particularly adapted to fluoroquinolones with high mucosal permeability.
  • the inventors of the present invention have developed a specific combination of PLGA and a fluoroquinolone with high mucosal permeability.
  • the present inventors have discovered that the specificity of this combination, in term of nature of PLGA, PLGA particle size and fluoroquinolone content, highlights interesting properties in terms of lung concentrations, antibacterial efficacy, systemic exposures and toxicity.
  • the present invention provides PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability which enable to improve treatment efficiency and ease of use, and to reduce frequency of administration while reducing systemic toxicity.
  • a first object of the present invention relates to a PLGA microparticle loaded with fluoroquinolone and applications thereof, wherein the size of the PLGA microparticle is comprised between 1 and 10 ⁇ , and the fluoroquinolone content is comprised between 1 and 30 wt. % in relation to the total weight of the loaded microparticle.
  • a second object of the present invention relates to a population of the PLGA microparticle loaded with a fluoroquinolone.
  • a third object of the present invention relates to a composition comprising the population of the PLGA microparticle loaded with a fluoroquinolone and applications thereof.
  • Another object of the present invention relates to a method for producing the PLGA microparticles loaded with a fluoroquinolone.
  • the inventors of the present invention have demonstrated that PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability enable to solve the above mentioned technical problems, i.e. to provide a sustained-release PLGA microsphere dry powder in the form of aerosol, advantageous in terms of treatment efficiency, ease of use and frequency of administration while reducing systemic toxicity.
  • the present inventors have found that the above-mentioned technical problems could be solved with specific PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability.
  • the microparticles of the present invention are specific in term of nature of PLGA, PLGA particle size and fluoroquinolone content.
  • PLGA poly lactic-coglycolic acid
  • PLA poly lactic acid
  • PGA poly glycolic acid
  • fluoroquinolones refers to fluoroquinolones with high mucosal permeability, i.e. fluoroquinolones characterized by a high permeability profile through the broncho-alveolar barrier.
  • microcosal permeability refers to the permeability of the respiratory system mucosa.
  • fluoroquinolone sustained-release refers to the release of the fluoroquinolone at a slow but steady rate over a specific period of time allowing a prolonged-action.
  • Fine Particle Fraction (FPF) refers to the fraction of particles having a diameter equal to or less than 5 ⁇ .
  • pharmaceutically acceptable carrier or excipient refers to a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredient(s) and which is not excessively toxic to the host at the concentration at which it is administered. Said carriers and excipients are selected from the usual excipients known by a person skilled in the art.
  • treatment refers to a method or process that is aimed at (1) slowing down or stopping the progression, aggravation, or deterioration of the symptoms of the disease; (2) bringing about amelioration of the symptoms of the disease; or (3) curing the disease. A treatment may thus be administered after initiation of the disease, for a therapeutic action.
  • the term "effective amount” of the present invention refers to any amount of fluoroquinolone that is sufficient to fulfil its intended purpose(s), e.g. a desired biological or medicinal response in a cell, tissue, system or patient.
  • patient refers to a human or another mammal (e.g., primate, mouse, rat, rabbit, dog, cat, horse, cow, pig, camel, and the like). Preferably, the patient is a human.
  • One object of the present invention is a PLGA microparticle loaded with a fluoroquinolone wherein the size of microparticle is comprised between 1 and 10 ⁇ , and
  • the fluoroquinolone content is comprised between 1 and 30 wt. % in relation to the total weight of the loaded microparticle.
  • PLGA is obtained by the co-polymerization of poly glycolic acid (PGA) and poly lactic acid (PLA).
  • PGA poly glycolic acid
  • PLA poly lactic acid
  • the release of the loaded fluoroquinolone depends on the PLGA properties, in particular on the PLGA ratio of lactide to glycolide (PLA/PGA), the PLGA molecular weight and the PLGA chain size.
  • a PLGA with higher molecular weight exhibits lower degradation rates than a PLGA with lower molecular weight.
  • a PLGA having longer polymer chains requires more time to degrade than a PLGA having smaller polymer chains.
  • the person skilled in the art might choose the PLGA molecular weight, PLGA ratio of lactide to glycolide and PLGA chain size according to the desired sustained release.
  • the ratio of lactide to glycolide is comprised between 95:5 and 40:60, preferably between 85: 15 and 45:55, more preferably between 75:25 and 50:50, more preferably between 70:30 and 50:50, more preferably between 65:35 and 50:50, more preferably between 60:40 and 50:50, and even more preferably between 55:45 and 50:50.
  • the ratio of lactide to glycolide is about 50:50.
  • the PLGA weight average molecular weight is higher or equal to 500 Mw and inferior or equal to 240000, 116000, 70000, 40000, 28000, 18000, 15000, 7000 and 4000 Mw.
  • the PLGA weight average molecular weight is comprised between 500 and 240000, preferably between 500 and 116000, more preferably between 500 and 70000, more preferably between 500 and 40000, more preferably between 500 and 28000 and even more preferably between 500 and 15000 Mw.
  • the PLGA weight average molecular weight is comprised between 500 and 240000, preferably between 4000 and 240000, more preferably between 7000 and 116000, more preferably between 7000 and 70000, more preferably between 7000 and 40000, more preferably between 7000 and 28000 and even more preferably between 7000 and 15000 Mw.
  • PLGA microparticles are loaded with a fluoroquinolone with high mucosal permeability.
  • Fluoroquinolones constitute a family of antibiotics which exert antibacterial effect by acting on the bacterial DNA.
  • fluoroquinolones inhibit the DNA gyrase and DNA topoisomerase IV (Karl Drlica. Mechanism of fluoroquinolone action. Current Opinion in Microbiology, Volume 2, Issue 5, 1 October 1999, Pages 504-508).
  • fluoroquinolones with high mucosal permeability are, but not limited to, levofloxacin, ofloxacin, gatifloxacin, moxifloxacin and lomefloxacin.
  • the fluoroquinolone with high mucosal permeability according to the invention is selected from the group consisting of levofloxacin, ofloxacin, gatifloxacin, moxifloxacin and lomefloxacin, and isomers thereof.
  • Levofloxacin and ofloxacin are characterized by a high permeability profile through the broncho-alveolar barrier.
  • the fluoroquinolone is levofloxacin or ofloxacin.
  • the fluoroquinolone is levofloxacin.
  • the size of the PLGA microparticle loaded with a fluoroquinolone is chosen so as to enable a pulmonary administration in aerosol form.
  • the size of the PLGA microparticle loaded with a fluoroquinolone and the fluoroquinolone content are chosen so as to obtain a fluoroquinolone sustained-release of at least 24 hours, preferably of at least 48 hours, and even more preferably of at least 72 hours in vivo and in vitro.
  • the fluoroquinolone initial content represents approximately 10 wt. % in relation to the total weight of the loaded microparticle.
  • at 48 hours approximately 55 % of the initial content of the administered fluoroquinolone has been released, wherein the fluoroquinolone initial content represents approximately 10 wt. % in relation to the total weight of the loaded microparticle.
  • at 72 hours approximately 75 % of the initial content of the administered fluoroquinolone has been released, wherein the fluoroquinolone initial content represents approximately 10 wt. % in relation to the total weight of the loaded microparticle.
  • sustained-release is assessed by a release study in vitro in phosphate-buffered saline, pH 7.4, at 37°C and estimated in vivo through pharmacokinetic modelling of the blood plasma and ELF concentration-versus-time data.
  • phosphate-buffered saline pH 7.4
  • ELF concentration-versus-time data John W. Skoug et al.
  • Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release is assessed by a release study in vitro in phosphate-buffered saline, pH 7.4, at 37°C and estimated in vivo through pharmacokinetic modelling of the blood plasma and ELF concentration-versus-time data.
  • levofloxacin plasma concentrations versus time data are analyzed according to a non-linear mixed effects method with S-ADAPT software (v 1.52) using MC-PEM (Monte- Carlo Parametric Expectation Maximization) estimation algorithm and S-ADAPT TRAN translator (Bulitta JB, Bingolbali A, Shin BS, Landersdorfer CB. Development of a New Pre- and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S- ADAPT. The AAPS Journal. 2011;13(2):201-11).
  • the PLGA microparticle loaded with a fluoroquinolone according to the invention has a content of fluoroquinolone comprised between 1 and 30 wt. , preferably between 5 and 20 wt. , and even more preferably between 5 and 15 wt. % in relation to the total weight of the loaded microparticle.
  • the content of fluoroquinolone is determined by spectrophotometry using an UV- Visible spectrophotometer after dissolution in DMSO using a fluoroquinolone calibration curve.
  • the PLGA microparticle loaded with a fluoroquinolone according to the invention has a size comprised between 1 and 10 ⁇ , preferably between 1 and 7 ⁇ and even more preferably between 1 and 5 ⁇ .
  • the present invention also relates to a sustained-release dry powder formulation comprising PLGA microparticles loaded with a fluoroquinolone according to the invention.
  • the PLGA microparticle loaded with a fluoroquinolone according to the invention is obtained by a double emulsion method.
  • an appropriate amount of fluoroquinolone is dissolved in an organic solvent, preferably dichloromethane or chloroform, and the resulting mixture is added to an oil phase consisting of PLGA (Wi/O).
  • the Wi/O emulsion is added to a continuous phase of an organic solvent, preferably a polyvinylalcohol.
  • Another object of the present invention is a population of the PLGA microparticle loaded with a fluoroquinolone according to the invention which has a size of volume distribution (Dv) comprised between 1 and 10 ⁇ , preferably between 1 and 7 ⁇ and even more preferably between 1 and 5 ⁇ .
  • Dv size of volume distribution
  • volume distribution (Dv) is measured in purified water using laser light diffraction.
  • Another object of the present invention is a composition comprising the population of the PLGA microparticle loaded with a fluoroquinolone according to the invention.
  • the present invention also relates to a composition consisting of the population of the PLGA microparticle loaded with a fluoroquinolone according to the invention
  • Another object of the present invention is the use of the composition according to the invention for aerosol administration.
  • the present invention relates to aerosol administration comprising administering the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention in a subject.
  • Therapeutic uses comprising administering the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention in a subject.
  • Fluoroquinolones constitute a family of antibacterial agents. Fluoroquinolones are indicated for the treatment of several bacterial infections. Several bacterial infections include but are not limited to, respiratory infections such as bacterial bronchitis, bronchiolitis, pneumonia, tuberculosis, tonsillitis pharyngitis, otitis and sinusitis, septicaemia, typhoid fever, joint and bone infections, soft tissue and skin infections, gastrointestinal infections and urogenital infections. More particularly, fluoroquinolones are known to have an activity against a wide range of gram-positive and gram- negative organisms.
  • the present inventors have found and demonstrated that the PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability of the present invention enable to improve the fluoroquinolone efficiency against bacterial agents in comparison to free fluoroquinolones. They have also demonstrated that a pulmonary administration of the PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability of the present invention, results in a prolonged release of the fluoroquinolone within the lung and in much higher fluoroquinolone concentrations in pulmonary system, in particular in lung epithelial lining fluid (ELF).
  • ELF lung epithelial lining fluid
  • PLGA microparticles loaded with a fluoroquinolone in term of nature of PLGA, PLGA particle size and fluoroquinolone content enable to reduce the frequency of administrations, to increase anti-infectious treatment efficiency while reducing systemic toxicity.
  • the PLGA microparticles loaded with a fluoroquinolone with high mucosal permeability of the present invention have fluoroquinolone sustained-release of at least 72 hours.
  • Another object of the present invention relates to the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention for use as a medicament.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as active principle, the PLGA microparticles loaded with a fluoroquinolone according to the invention and a pharmaceutically acceptable excipient.
  • Another object of the present invention relates to the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention for use in the treatment of pulmonary infections.
  • pulmonary infections are bacterial bronchitis, bronchiolitis and pneumonia.
  • the present invention also relates to a method for treating a pulmonary infection, comprising administering to a patient an effective amount of the PLGA microparticle loaded with a fluoroquinolone according to the invention, or of the composition according to the invention.
  • pulmonary infections are bacterial bronchitis, bronchiolitis and pneumonia.
  • the present invention also relates to a method for treating a patient having a pulmonary infection.
  • pulmonary infections are bacterial bronchitis, bronchiolitis and pneumonia.
  • the present invention also relates to the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention used in a method for the treatment of a human or an animal.
  • the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention is used for aerosol administration
  • the present invention relates to the PLGA microparticle loaded with a fluoroquinolone according to the invention or the composition according to the invention for aerosol administration destined to the treatment of pulmonary infections.
  • pulmonary infections are bacterial bronchitis, bronchiolitis and pneumonia.
  • Suitable dosage ranges depend upon numerous factors such as the severity of the infection to be treated, the age and health of the subject. Furthermore, the dosage ranges depend on the sustained-release parameter and the fluoroquinolone content.
  • the dosage range of the PLGA microparticle loaded with a fluoroquinolone according to the invention is comprised between 1 and 10 mg/kg daily, preferably between 1 and 5 mg/kg daily, and more preferably between 1 and 2.5 mg/kg daily of body weight.
  • the dosage range of the PLGA microparticle loaded with a fluoroquinolone according to the invention is around 5 mg/kg of body weight every three days.
  • Another object of the present invention relates to a method for producing the PLGA microparticles loaded with a fluoroquinolone according to the invention comprising the step of:
  • step (a) dispersing the water-in-oil (W/O) emulsion obtained in step (a) in an aqueous solution saturated with the fluoroquinolone.
  • a levofloxacin solution is emulsified into a solution of PLGA and levofloxacin in dichloromethane or chloroform.
  • the obtained Wi/0 emulsion is dispersed in a solution W 2 of polyvinylalcohol saturated with levofloxacin in PBS (phosphate buffered saline).
  • PBS phosphate buffered saline
  • the present invention also relates to the PLGA microparticles loaded with a fluoroquinolone obtainable by the method according to the invention.
  • Figure 1 Structural pharmacokinetic model for intravenous or intratracheal administration of levofloxacin solutions and for intratracheal administration of chitosan loaded with levofloxacin or PLGA microsphere powder loaded with levofloxacin, with typical parameter estimates.
  • Vd levofloxacin distribution volume
  • VELF volume of ELF compartment
  • Vp volume of peripheral lung compartment
  • CL levofloxacin total clearance
  • Cldif bidirectional transfer of levofloxacin clearance between plasma and ELF
  • Clout unidirectional transfer of levofloxacin clearance from plasma to ELF
  • Cldist levofloxacin distribution clearance
  • FELF fraction of dose immediately released into the ELF compartment
  • FWeib fraction of dose released according to a Weibull release model
  • a time scale parameter
  • b curve shape parameter, and CV (coefficient of variation), estimable inter-individual variabilities.
  • a pharmacokinetic model was constructed to model levofloxacin concentrations both in plasma and in the lung epithelial lining fluid (ELF).
  • Resomer® RG 502 H (PLGA 50:50, acid terminated) and dimethyl sulfoxide (DMSO) were obtained from Sigma- Aldrich® (France).
  • Rhodoviol 4/125 polyvinylalcohol, degree of hydrolysis of 88%) was purchased from Prolabo (France).
  • Levofloxacin hemihydrate was provided by Tecnimede S.A. (Portugal).
  • Isoflurane (Forene®) was purchased from Abb Vie (France).
  • Acetonitrile of HPLC grade was purchased from Carlo Erba reagents (France).
  • Purified water was produced using a MilliQ Gradient® Plus Millipore system.
  • levofloxacin was dissolved in saline.
  • the final concentration 1.5 - 2 mg/ml was adapted to the rat weights in order to administer a maximum volume of 1 ml through the tail vein and to achieve 5 mg levofloxacin per kg body weight.
  • This dose was calculated to be in the range of the levofloxacin inhalation solution (Aeroquin®) doses administered in the Cystic Fibrosis patients (Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ. Levofloxacin Inhalation Solution (MP- 376) in Patients with Cystic Fibrosis with Pseudomonas aeruginosa. American Journal of Respiratory and Critical Care Medicine, 2011;183(l l): 1510-6).
  • levofloxacin was dissolved in saline at a 20 mg/ml final concentration in order to administer a fixed volume of 100 ⁇ containing a targeted dose close to the intravenous dose (5mg/kg).
  • Chitosan microspheres crosslinked with genipin and loaded with levofloxacin were prepared by a spray-drying method and characterized by spectrophotometry using a UV-Visible spectrophotometer (Gaspar MC, Sousa JJS, Pais AACC, Cardoso O, Murtinho D, Serra MES et al. Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy. European Journal of Pharmaceutics and Biopharmaceutics, 2015;96:65-75). The drug content was 48.4 + 5.8 wt. and mass median aerodynamic diameter (MMAD) was 5.4 + 0.2 ⁇ . In vitro release studies showed more than 90% release within 15 min in phosphate buffered saline (PBS), pH 7.4 at 37°C.
  • PBS phosphate buffered saline
  • a levofloxacin solution 250 mg/ml, adjusted to pH 6 with hydrochloric acid
  • a levofloxacin solution 250 mg/ml, adjusted to pH 6 with hydrochloric acid
  • a solution of PLGA 300 mg
  • levofloxacin 100 mg
  • dichloromethane a Polytron® PT 3100D homogenizer equipped with a 7 mm homogenizing accessory (Kinematica AG, Switzerland) and set at 30000 rpm for 30 s.
  • the obtained Wi/0 emulsion was dispersed in 7 ml of a solution W 2 of polyvinylalcohol (3% w/v) saturated with levofloxacin (35 mg/ml) in PBS at pH 7.4 under magnetic stirring (400 rpm).
  • the resulting WyO/W 2 emulsion was subjected to three homogenization cycles through a Shirasu porous glass membrane (19.9 ⁇ porosity) under 25 kPa transmembrane pressure using an external pressure-type micro kit emulsification device (SPG Technology, Sadowara, Japan).
  • PLGA microspheres loaded with levofloxacin were then characterized according to their size, aerodynamic properties, drug content, morphology and release profile.
  • the mean size of the volume distribution (Dv) of microspheres was determined in purified water using laser light diffraction (Micro trac® XI 00 particle size analyzer) (Doan TV, Couet W, Olivier JC. Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery. International Journal of Pharmaceutics, 2011;414(l-2): 112-7 - Doan TVP, Olivier JC. Preparation of rifampicin-loaded PLGA microspheres for lung delivery as aerosol by premix membrane homogenization. International Journal of Pharmaceutics, 2009;382(l-2):61-6).
  • Yield (%) was calculated from the recovered mass of freeze-dried microspheres versus the initial weight of levofloxacin (in O and W phases) plus PLGA.
  • microsphere drug content i.e. the amount of levofloxacin (mg) per 100 mg of microspheres (including entrapped levofloxacin) was determined by spectrophotometry at 300 nm using a Varian Cary 50 UV- Visible spectrophotometer after dissolution in DMSO using a levofloxacin calibration curve (0.625 - 10 ⁇ g/ml concentration range in DMSO).
  • MMAD was determined with a Handihaler® Dry Powder Inhaler (DPI) using a Next Generation Impactor (NGI, Copley Ltd., Nottingham, UK), (Gaspar MC, Sousa JJS, Pais AACC, Cardoso O, Murtinho D, Serra MES et al. Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy. European Journal of Pharmaceutics and Biopharmaceutics, 2015;96:65-75). The powder remaining in the capsule and deposited in the inhaler, induction port and all the stages was collected with DMSO (dimethyl sulfoxide) for levofloxacin spectrophotometric determination.
  • DPI Handihaler® Dry Powder Inhaler
  • NPI Next Generation Impactor
  • Gaspar MC Sousa JJS, Pais AACC, Cardoso O, Murtinho D, Serra MES et al. Optimization of levofloxacin-
  • Microspheres were examined by scanning electron microscopy (SEM) using a Jeol JSM 6010 LV electron microscope (Tokyo, Japan) at 15 kV, after gold-sputtering the microspheres in an argon atmosphere.
  • SEM scanning electron microscopy
  • microspheres loaded with levofloxacin were dispersed in 10 ml of PBS, pH 7.4, and incubated at 37 °C under magnetic stirring (600 rpm) (Gaspar MC, Sousa JJS, Pais AACC, Cardoso O, Murtinho D, Serra MES et al. Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy. European Journal of Pharmaceutics and Biopharmaceutics, 2015;96:65-75).
  • the targeted levofloxacin dose was 5 mg per kg body weight.
  • anaesthetized rats were placed on a rodent work stand inclined at an angle of 45° (Tern, Lormont, France) and the tip of the microsprayer or of the powder insufflator was introduced into the rat' s trachea with visualization of the vocal cords using an otoscope (Gagnadoux F, Pape AL, Lemarie E, Lerondel S, Valo I, Leblond V et al. Aerosol delivery of chemotherapy in an orthotopic model of lung cancer. Eur Respir J, 2005;26(4):657-61). After the intravenous or the intratracheal aerosol administrations, rats were returned to individual cages with free access to food and water.
  • rats 3 to 5 per time point were re-anesthetized with inhaled isoflurane for broncho-alveolar lavage (BAL) and blood sampling .
  • BAL broncho-alveolar lavage
  • a polyethylene catheter (0.58 mm i.d. and 0.96 mm o.d.; Harvard, Les Ulis, France) connected to a syringe filled with 1 ml of saline at 37 °C was inserted into the trachea (50 mm deep).
  • BAL samples 300 to 800 ⁇ were immediately collected by aspiration via the same catheter.
  • a blood sample was then collected by cardiac puncture.
  • BAL and blood samples were centrifuged (3500 rpm for 5 min and 3000 rpm for 10 min, respectively, at 4°C) and supernatants stored at -20 °C until levofloxacin and urea assays.
  • conditions for centrifugation were optimized in a preliminary study in order to ensure that all the PLGA microspheres potentially withdrawn during the BAL procedure were sedimented.
  • CELF ELF levofloxacin concentrations
  • Plasma samples 50 ⁇ of plasma were mixed with 200 ⁇ of the ciprofloxacin internal standard solution (0.1 ⁇ g/ml) in acetonitrile. Protein precipitate was separated by centrifugation at 14000 rpm for 15 min and 200 ⁇ of supernatant were collected and vortex- mixed with 400 ⁇ of 0.1 % (v/v) formic acid prior to analysis.
  • levofloxacin calibration standards (2 to 400 ng/ml) were prepared in saline.
  • Levofloxacin concentrations were determined in plasma and BAL samples using a validated LC-MS/MS method.
  • the system consisted of a Waters Alliance 2695 separations module equipped with a binary pump and an autosampler thermostatically controlled at 4°C, and of a Waters Micromass® Quattro micro API triple quadrupole tandem mass spectrometer. Reversed-phase chromatography was performed on a Phenomenex JupiterTM C18 300 A column (5.0 ⁇ , 50 x 2.1 mm).
  • the mobile phase was composed of 0.1% (v/v) formic acid in acetonitrile and 0.1% (v/v) formic acid in water (25:75 (v:v)).
  • the flow rate was 0.20 ml/min and the injection volume 20 ⁇ .
  • the mass spectrometer was operated in the positive-ion mode. Ions were analyzed via multiple reaction monitoring (MRM) employing the transition of the [M + 2H] 2+ precursor to the product ions for the analyte and for the internal standard. Transition ions were 362.2 to 318.2 m/z for levofloxacin and 332.2 to 314.2 m/z for the internal standard.
  • MRM multiple reaction monitoring
  • Optimal MS/MS set up parameters were: +3.25 kV ion spray voltage, 600 L/h and 350°C desolvation gas (N 2 ) flow and temperature respectively, 10 L/h cone gas (N 2 ) flow, 120°C source temperature, 25 V cone potential for the analyte and for the internal standard, 20 V collision energy for the analyte and the internal standard, 500 ms dwell time.
  • LLOQ lower limit of quantification
  • urea determination in plasma a photometric detection was applied using a modular automatic analyzer (Roche, France).
  • the urea concentration in BAL samples was evaluated by LC-MS/MS (Gontijo AVL, Brillault J, Gregoire N, Lamarche I, Gobin P, Couet W et al. Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin. Antimicrobial Agents and Chemotherapy. 2014;58(7):3942-9).
  • the structural pharmacokinetic model (Fig. 1) was derived from an initial generic hybrid compartment model, with a mono- compartmental model for the systemic pharmacokinetics and a bi-compartment model for the ELF pharmacokinetics.
  • the model for levofloxacin systemic pharmacokinetics was monocompartmental with a distribution volume (Vd) and a total clearance (CL).
  • the release process of levofloxacin from the intratracheally-aerosolized formulations was divided into two components: a fraction of the dose FELF that was immediately released into the ELF compartment (burst release), and a fraction of the dose FWeib that was released according to a Weibull release model, expressed as a differential equation for pharmacokinetic modeling,
  • the residual variability was estimated with an additive error model on the log scale, back- transformed into a proportional error model on normal scale for both plasma and ELF data.
  • Plasma drug concentrations below the LLOQ were handled using the Beal M3 method (Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001 ;28(5):481-504).
  • the drug content of 10.5 + 1.4 wt.% was considered satisfactory taking into account that highly water soluble drugs, such as levofloxacin, are generally poorly entrapped within the hydrophobic PLGA polymer matrix (Govender T, Stolnik S, Garnett MC, Ilium L, Davis SS, PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug, Journal of Controlled Release.
  • the MMAD was 7.1 + 0.2 ⁇ , and the fine particle fraction (FPF) was 30.2 + 2.3 %.
  • the fact that MMAD was slightly higher than Dv was attributed to microspheres aggregation, as shown by SEM (Fig. 2A).
  • the levofloxacin release (Fig. 3) was characterized by a "burst" release of 40 % of the levofloxacin microspheres content within the first 30 min, followed by a gradual release up to at least 72 h. At 72h, approximately 75% of the drug content was released.
  • Fig. 3 the levofloxacin release
  • the microspheres appeared to be extensively degraded with obvious signs of surface alteration (Fig. 2D) (Diez S, Tros de Ilarduya C. Versatility of biodegradable poly(d,l-lactic-co-gly colic acid) microspheres for plasmid DNA delivery. European Journal of Pharmaceutics and Biopharmaceutics. 2006;63(2): 188-97), while 25% of levofloxacin initial content still remained in the microsphere polymer matrix (not shown).
  • the low molecular weight PLGA 50:50 Resomer® 502H is therefore expected to minimize pulmonary accumulation of polymer after microsphere lung deposition, especially in the case of repeated administrations.
  • a population pharmacokinetic approach was used to characterize mainly the intra-pulmonary pharmacokinetics of levofloxacin after intratracheal aerosolization of the two dry microsphere powder formulations.
  • the study design included the intravenous and intratracheal administrations of a levofloxacin solution in order to get comparators and to improve the modeling output since the population pharmacokinetic approach allows simultaneous analysis of various data sets. It is also the most appropriate modeling procedure when only one data set (i.e. simultaneous plasma and ELF concentrations) can be collected in each individual.
  • the pharmacokinetic model is presented with the pharmacokinetic parameter estimates on Fig. 1. No inter-individual variability could be estimated for CL, Vd and Vp.
  • the selected pharmacokinetic model provided a reasonably good description of the experimental data over time, both in plasma and ELF, after intravenous administration or intratracheal aerosolization with the various formulations, as illustrated on Figure 4. Residual errors of the model were 13% in plasma and 18% and 21% in ELF depending on whether levofloxacin was administered intravenous or intratracheal (all formulations taken together), respectively. The much higher ELF exposure after aerosolization of PLGA microspheres loaded with levofloxacin with high concentrations sustained over time was adequately reported by the model. However, the analysis of the pharmacokinetic study needs to take into account some limitations.
  • ELF concentrations after intratracheal aerosolization of the dry microsphere powder may indeed depend on multiple uncontrolled parameters, including the depot characteristics and the onset of drug release from the microspheres or/and of levofloxacin solubilization within the small volume of the ELF (Fig. 1).
  • the invasive intratracheal aerosolization procedure may induce by itself a transient alteration of the lung physiology which may affect levofloxacin disposition.
  • Intratracheal or intravenous administration of the levofloxacin solutions resulted in similar experimental levofloxacin concentrations in plasma and ELF (Fig. 4a and 4b) with an elimination half-life of 0.96h.
  • the bioavailability for the intratracheal solution was estimated to be 98%, with a direct release of levofloxacin into the ELF compartment.
  • the distribution between the ELF and plasma compartments was very rapid, with an estimated half-life of transfer between the two compartments lower than 1 min.
  • the estimated levofloxacin passive diffusion clearance Cldif (Fig.
  • the Clout term which improved the modeling reflected the higher ELF levofloxacin concentrations than the levofloxacin unbound plasma concentrations, independently of the route of administration. It is of note that the ELF-to-plasma AUC0.5-t ratio is slightly above 2 when considering unbound concentrations in plasma, which reflected the ratio of the plasma- to-ELF clearances to the ELF-to-plasma clearance, i.e. (Clout+ Cldif)/Cldif.
  • Inhaled microspheres with diameter below 10 ⁇ are likely to be phagocytosed by lung macrophages (Hirota K, Kawamoto T, Nakajima T, Makino K, Terada H. Distribution and deposition of respirable PLGA microspheres in lung alveoli. Colloids and Surfaces B: Biointerfaces. 2013;105:92-7).
  • the levofloxacin release from the PLGA microspheres may be impacted by the microsphere accumulation in intracellular compartments like phagolysosomes characterized by an acidic pH where levofloxacin is more soluble than at pH 7.4.
  • the intratracheal administration of the immediate release chitosan microsphere formulation provided pharmacokinetic profiles comparable to the intravenous or the intratracheal levofloxacin solutions, with the benefits inherent to dry powder formulations.
  • the plasma and ELF experimental concentration profiles versus time were similar for the intravenous and intratracheal levofloxacin solutions and for the intratracheal administration of chitosan microsphere dry powder loaded with levofloxacin, indicating that levofloxacin diffused almost instantaneously through the broncho-alveolar barrier and that the chitosan microspheres released levofloxacin very rapidly, as anticipated from in vitro release studies.
  • the bioavailability for the intratracheal levofloxacin solution and intratracheal chitosan microspheres was estimated to be 98% and 71%, respectively, both with a direct release into the ELF compartment.
  • the ELF-to-unbound plasma AUC ratios were slightly above 2 and may result from an efflux transport.
  • a high ELF-to- unbound plasma AUC concentration ratio (311) was observed and high levofloxacin concentrations were maintained in ELF for at least 72h in consistency with the in vitro release studies.
  • the bioavailability was 92%, with 19% of the dose released immediately (burst release) into the ELF and 73% released slowly into the ELF from a depot compartment, i.e. the PLGA microspheres, according to a Weibull model.
  • the intratracheal administration of PLGA microspheres loaded with levofloxacin resulted in a prolonged release of levofloxacin within the lungs and in much higher levofloxacin concentrations in ELF than in plasma.
  • Such a sustained-release formulation is expected to reduce the frequency of administrations compared to a levofloxacin solution for inhalation, and to increase anti-infectious treatment efficiency while reducing systemic toxicity.
  • these results highlight the benefit of using sustained-release microspheres administered as aerosols to provide and to maintain high pulmonary concentrations of a highly water soluble antibiotic characterized by a high permeability profile through the broncho-alveolar barrier, i.e. levofloxacin.
  • the sustained-release microsphere dry powder aerosol may therefore provide a promising alternative to the solutions or to pure drug dry powders for inhalation in terms of treatment efficiency, ease of use and frequency of administration, which should have a positive impact on the patients' compliance to their treatments.

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Abstract

L'invention porte sur des microparticules de PLGA, chargées de fluoroquinolone, perméable aux muqueuses, leur méthodes de préparation et leurs applications.
PCT/EP2017/066831 2016-07-13 2017-07-05 Microparticules de plga chargées de fluoroquinolone pour le traitement de maladies respiratoires. WO2018011040A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023015851A1 (fr) * 2021-08-10 2023-02-16 山东谷雨春生物科技有限公司 Implant de microsphère d'acétonide de triamcinolone utilisé pour l'injection et son procédé de préparation

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089291A2 (fr) * 2003-04-03 2004-10-21 Au Jessie L-S Particules a charge medicamenteuse ciblant les tumeurs
WO2006125132A2 (fr) * 2005-05-18 2006-11-23 Mpex Pharmaceuticals, Inc. Fluoroquinolones en aerosols et leurs utilisations
US20080124400A1 (en) * 2004-06-24 2008-05-29 Angiotech International Ag Microparticles With High Loadings Of A Bioactive Agent
WO2008157614A2 (fr) * 2007-06-21 2008-12-24 Yale University Administration soutenue de médicament à partir de microparticules polymères biodégradables
US20100209478A1 (en) * 2009-02-12 2010-08-19 Sawhney Amarpreet S Drug delivery through hydrogel plugs
WO2012054498A1 (fr) * 2010-10-18 2012-04-26 Case Western Reserve University Microparticules polymères
CN102302458B (zh) * 2011-09-15 2013-01-09 中国人民解放军军事医学科学院卫生装备研究所 一种左氧氟沙星缓释微球和长效缓释创伤敷料及制备方法
CN102885783B (zh) * 2012-09-26 2014-04-16 复旦大学附属金山医院 一种纳米药物微球

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089291A2 (fr) * 2003-04-03 2004-10-21 Au Jessie L-S Particules a charge medicamenteuse ciblant les tumeurs
US20080124400A1 (en) * 2004-06-24 2008-05-29 Angiotech International Ag Microparticles With High Loadings Of A Bioactive Agent
WO2006125132A2 (fr) * 2005-05-18 2006-11-23 Mpex Pharmaceuticals, Inc. Fluoroquinolones en aerosols et leurs utilisations
WO2008157614A2 (fr) * 2007-06-21 2008-12-24 Yale University Administration soutenue de médicament à partir de microparticules polymères biodégradables
US20100209478A1 (en) * 2009-02-12 2010-08-19 Sawhney Amarpreet S Drug delivery through hydrogel plugs
WO2012054498A1 (fr) * 2010-10-18 2012-04-26 Case Western Reserve University Microparticules polymères
CN102302458B (zh) * 2011-09-15 2013-01-09 中国人民解放军军事医学科学院卫生装备研究所 一种左氧氟沙星缓释微球和长效缓释创伤敷料及制备方法
CN102885783B (zh) * 2012-09-26 2014-04-16 复旦大学附属金山医院 一种纳米药物微球

Non-Patent Citations (48)

* Cited by examiner, † Cited by third party
Title
"EMA. Quinsair - Summary of product characteristics", SCIENCE MEDICINES HEALTH, 2015
ANDERSON JM: "Shive microspheres. Biodegradation and biocompatibility of PLA and PLGA microspheres", ADVANCED DRUG DELIVERY REVIEWS, vol. 28, no. 1, 1997, pages 5 - 24
BEAL SL: "Ways to fit a PK model with some data below the quantification limit", J PHARMACOKINET PHARMACODYN, vol. 28, no. 5, 2001, pages 481 - 504
BRILLAULT J; DE CASTRO WV; COUET W: "Relative Contributions of Active Mediated Transport and Passive Diffusion of Fluoroquinolones with Various Lipophilicities in a Calu-3 Lung Epithelial Cell Model", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 54, no. 1, 2010, pages 543 - 5
BULITTA JB; BINGOLBALI A; SHIN BS; LANDERSDORFER CB: "Development of a New Pre- and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S-ADAPT", THE AAPS JOURNAL., vol. 13, no. 2, 2011, pages 201 - 11
BULITTA JB; BINGOLBALI A; SHIN BS; LANDERSDORFER CB: "Development of a New Pre-and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S-ADAPT", THE AAPS JOURNAL, vol. 13, no. 2, 2011, pages 201 - 11
DIEZ S; TROS DE ILARDUYA C: "Versatility of biodegradable poly(d,l-lactic-co-glycolic acid) microspheres for plasmid DNA delivery", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 63, no. 2, 2006, pages 188 - 97
DOAN TV; COUET W; OLIVIER JC: "Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 414, no. 1-2, 2011, pages 112 - 7
DOAN TV; COUET W; OLIVIER JC: "Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 414, no. 1-2, 2011, pages 112 - 7
DOAN TV; COUET W; OLIVIER JC: "Formulation and in vitro characterization ofinhalable rifampicin-loaded PLGA microspheres for sustained lung delivery", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 414, no. 1-2, 2011, pages 112 - 7
DOAN TVP; GREGOIRE N; LAMARCHE I; GOBIN P; MARCHAND S; COUET W ET AL.: "A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 48, no. 1-2, 2013, pages 223 - 30
DOAN TVP; OLIVIER JC: "Preparation of rifampicin-loaded PLGA microspheres for lung delivery as aerosol by premix membrane homogenization", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 382, no. 1-2, 2009, pages 61 - 6
FABIENNE DANHIERA; EDUARDO ANSORENAA; JOANA M. SILVAA, B; REGIS COCOA; AUDE LE BRETONA; VERONIQUE PREAT: "PLGA-based nanoparticles: An overview of biomedical applications", JOURNAL OF CONTROLLED RELEASE, vol. 161, no. 2, 20 July 2012 (2012-07-20), pages 505 - 522
FENG T; TIAN H; XU C; LIN L; XIE Z; LAM MH-W ET AL.: "Synergistic co-delivery of doxorubicin and paclitaxel by porous PLGA microspheres for pulmonary inhalation treatment", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 88, no. 3, 2014, pages 1086 - 93
FOUNDATION CF. DRUG DEVELOPMENT PIPELINE, 27 October 2015 (2015-10-27)
GAGNADOUX F; PAPE AL; LEMARIE E; LERONDEL S; VALO I; LEBLOND V ET AL.: "Aerosol delivery of chemotherapy in an orthotopic model of lung cancer", EUR RESPIR J, vol. 26, no. 4, 2005, pages 657 - 61
GAGNADOUX F; PAPE AL; LEMARIE E; LERONDEL S; VALO I; LEBLOND V ET AL.: "Aerosol delivery of chemotherapy in an orthotopic model of lung cancer", EUR RESPIR J., vol. 26, no. 4, 2005, pages 657 - 61
GASPAR MC; COUET W; OLIVIER JC; PAIS AACC; SOUSA JJS: "Pseudomonas aeruginosa infection in cystic fibrosis lung disease and new perspectives of treatment: a review", EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, vol. 32, no. 10, 2013, pages 1231 - 52
GASPAR MC; SOUSA JJS; PAIS AACC; CARDOSO O; MURTINHO D; SERRA MES ET AL.: "Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 96, 2015, pages 65 - 75
GASPAR MC; SOUSA JJS; PAIS AACC; CARDOSO O; MURTINHO D; SERRA MES ET AL.: "Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy.", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 96, 2015, pages 65 - 75
GELLER DE: "Aerosol Antibiotics in Cystic Fibrosis", RESPIRATORY CARE, vol. 54, no. 5, 2009, pages 658 - 70
GELLER DE; FLUME PA; STAAB D; FISCHER R; LOUTIT JS; CONRAD DJ: "Levofloxacin Inhalation Solution (MP-376) in Patients with Cystic Fibrosis with Pseudomonas aeruginosa", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 183, no. 11, 2011, pages 1510 - 6
GONTIJO AVL; BRILLAULT J; GREGOIRE N; LAMARCHE I; GOBIN P; COUET W ET AL.: "Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 58, no. 7, 2014, pages 3942 - 9
GONTIJO AVL; BRILLAULT J; GREGOIRE N; LAMARCHE I; GOBIN P; COUET W ET AL.: "Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY., vol. 58, no. 7, 2014, pages 3942 - 9
GOVENDER T; STOLNIK S; GARNETT MC; ILIUM L; DAVIS SS: "PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug", JOURNAL OF CONTROLLED RELEASE, vol. 57, no. 2, 1999, pages 171 - 85
GOVENDER T; STOLNIK S; GARNETT MC; ILIUM L; DAVIS SS: "PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug", JOURNAL OF CONTROLLED RELEASE., vol. 57, no. 2, 1999, pages 171 - 85
HIRENKUMAR K. MAKADIAL; STEVEN J. SIEGEL: "Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier", POLYMERS (BASEL)., vol. 3, no. 3, 1 September 2011 (2011-09-01), pages 1377 - 1397
HIROTA K; KAWAMOTO T; NAKAJIMA T; MAKINO K; TERADA H: "Distribution and deposition of respirable PLGA microspheres in lung alveoli", COLLOIDS AND SURFACES B: BIOINTERFACES, vol. 105, 2013, pages 92 - 7
HOPPENTOCHT M; HAGEDOORN P; FRIJLINK HW; DE BOER AH: "Developments and strategies for inhaled antibiotic drugs in tuberculosis therapy: A critical evaluation", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 86, no. 1, 2014, pages 23 - 30
HURTADO FK; WEBER B; DERENDORF H; HOCHHAUS G; DALLA COSTA T: "Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 58, no. 2, 2014, pages 678 - 86
JOHN W. SKOUG ET AL., QUALITATIVE EVALUATION OF THE MECHANISM OF RELEASE OF MATRIX SUSTAINED RELEASE DOSAGE FORMS BY MEASUREMENT OF POLYMER RELEASE
KARL DRLICA, MECHANISM OF FLUOROQUINOLONE ACTION. CURRENT OPINION IN MICROBIOLOGY, vol. 2, no. 5, 1 October 1999 (1999-10-01), pages 504 - 508
KARL DRLICA: "Mechanism of fluoroquinolone action", CURRENT OPINION IN MICROBIOLOGY, vol. 2, no. 5, 1 October 1999 (1999-10-01), pages 504 - 508
KING P; LOMOVSKAYA O; GRIFFITH DC; BURNS JL; DUDLEY MN: "In Vitro Pharmacodynamics of Levofloxacin and Other Aerosolized Antibiotics under Multiple Conditions Relevant to Chronic Pulmonary Infection in Cystic Fibrosis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY., vol. 54, no. 1, 2010, pages 143 - 8
KIRKBY S; NOVAK K; MCCOY K. AZTREONAM, CORE EVIDENCE, vol. 6, 2011, pages 59 - 66
KOEPPE MO; CRISTOFOLETTI R; FERNANDES EF; STORPIRTIS S; JUNGINGER HE; KOPP S ET AL.: "Biowaiver monographs for immediate release solid oral dosage forms: levofloxacin", J PHARM SCI., vol. 100, no. 5, 2011, pages 1628 - 36
MARCHAND S; GOBIN P; BRILLAULT J; BAPTISTA S; ADIER C; OLIVIER J-C ET AL.: "Aerosol Therapy with Colistin Methanesulfonate: a Biopharmaceutical Issue Illustrated in Rats", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 54, no. 9, 2010, pages 3702 - 7
RAMAZANI F; CHEN W; VAN NOSTRUM CF; STORM G; KIESSLING F; LAMMERS T ET AL.: "Formulation and characterization of microspheres loaded with imatinib for sustained delivery", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 482, no. 1-2, 2015, pages 123 - 30
SAELIM N; SUKSAWAENG K; CHUPAN J; TECHATANAWAT I: "Biopharmaceutics classification system (BCS)-based biowaiver for immediate release solid oral dosage forms of moxifloxacin hydrochloride (moxiflox GPO) manufactured by the government pharmaceutical organization (GPO", ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2015
SAELIM N; SUKSAWAENG K; CHUPAN J; TECHATANAWAT I: "Biopharmaceutics classification system (BCS)-based biowaiver for immediate release solid oral dosage forms of moxifloxacin hydrochloride (moxiflox GPO) manufactured by the government pharmaceutical organization (GPO)", ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2015
SAH E; SAH H: "Recent Trends in Preparation of Poly(lactide-co-glycolide) Nanoparticles by Mixing Polymeric Organic Solution with Antisolvent", JOURNAL OF NANOMATERIALS, 2015, pages 22
SAWICKI GS; SIGNOROVITCH JE; ZHANG J; LATREMOUILLE-VIAU D; VON WARTBURG M; WU EQ ET AL.: "Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution", PEDIATRIC PULMONOLOGY., vol. 47, no. 1, 2012, pages 44 - 52
SERAI C; BARCIA-MACAY M; MINGEOT-LECLERCQ MP; TULKENS PM; VAN BAMBEKE F.: "Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 55, no. 4, 2005, pages 511 - 7
SERAL C; BARCIA-MACAY M; MINGEOT-LECLERCQ MP; TULKENS PM; VAN BAMBEKE F: "Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 55, no. 4, 2005, pages 511 - 7
SHEN J; BURGESS DJ: "Accelerated in vitro release testing methods for extended release parenteral dosage forms", THE JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 64, no. 7, 2012, pages 986 - 96
STOCKMANN C; SHERWIN CMT; AMPOFO K; SPIGARELLI MG: "Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis", THERAPEUTIC ADVANCES IN RESPIRATORY DISEASE, vol. 8, no. 1, 2014, pages 13 - 21
TRAINI D; YOUNG PM: "Delivery of antibiotics to the respiratory tract: an update", EXPERT OPINION ON DRUG DELIVERY., vol. 6, no. 9, 2009, pages 897 - 905
ZIMMERMANN ES; LAUREANO JV; DOS SANTOS CN; SCHMIDT S; LAGISHETTY CV; DE CASTRO WV ET AL.: "A simultaneous semi-mechanistic population analysis of levofloxacin in plasma, lung and prostrate to describe the influence of efflux transporters on drug distribution following intravenous and intratracheal administration", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2015

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023015851A1 (fr) * 2021-08-10 2023-02-16 山东谷雨春生物科技有限公司 Implant de microsphère d'acétonide de triamcinolone utilisé pour l'injection et son procédé de préparation

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