WO2017081606A1 - Procédés de détermination de caractéristiques de nanoparticules polymères comprenant un agent thérapeutique - Google Patents

Procédés de détermination de caractéristiques de nanoparticules polymères comprenant un agent thérapeutique Download PDF

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WO2017081606A1
WO2017081606A1 PCT/IB2016/056716 IB2016056716W WO2017081606A1 WO 2017081606 A1 WO2017081606 A1 WO 2017081606A1 IB 2016056716 W IB2016056716 W IB 2016056716W WO 2017081606 A1 WO2017081606 A1 WO 2017081606A1
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Prior art keywords
nanoparticle
therapeutic agent
acid
hydrophobic
therapeutic
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PCT/IB2016/056716
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English (en)
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Gregory Charles TROIANO
Donald Maxwell PARSONS
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Pfizer Inc.
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Publication of WO2017081606A1 publication Critical patent/WO2017081606A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility

Definitions

  • therapeutics that include an active drug and that are, e.g. , targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not to normal tissue, may reduce the amount of the drug in tissues of the body that are not targeted. This is particularly important when treating a condition such as cancer where it is desirable that a cytotoxic dose of the drug is delivered to cancer cells without killing the surrounding non-cancerous tissue. Effective drug targeting may reduce the undesirable and sometimes life threatening side effects common in anticancer therapy. In addition, such therapeutics may allow drugs to reach certain tissues they would otherwise be unable to reach.
  • Therapeutics that offer controlled release and/or targeted therapy also must be able to deliver an effective amount of drug, which is a known limitation in other nanoparticle delivery systems. For example, it can be a challenge to prepare nanoparticle systems that have an appropriate amount of drug associated with each nanoparticle, while keeping the size of the nanoparticles small enough to have advantageous delivery properties.
  • nanoparticle information such as whether the therapeutic agent is in a substantially homogenous solid solution or is substantially phase separated within a therapeutic nanoparticle such as a polymeric therapeutic nanoparticle.
  • a method of determining the structural features corresponding to the presence of and/or release rate of a therapeutic agent in a therapeutic nanoparticle that includes the therapeutic agent and a hydrophobic counterion comprising: obtaining a Raman spectra of the nanoparticle; comparing the Raman spectra of the nanoparticle to a Raman spectra of at least one of the therapeutic agent alone, the
  • hydrophobic counterion alone, a nanoparticle that does not include the therapeutic agent, and a salt formed from the therapeutic agent and the hydrophobic counterion to determine whether the therapeutic agent and the hydrophobic counterion in therapeutic nanoparticle occur as a salt.
  • a method of determining the structural features of a polymeric nanoparticle having a therapeutic agent and a hydrophobic counterion comprising: determining whether a salt of the therapeutic agent and the hydrophobic counterion exists in the polymeric nanoparticle; optionally determining the stoichiometry of the salt if present; optionally determining the number or presence of one or more of di-salts of the hydrophobic counterion, free therapeutic agent , and free hydrophobic counterion; and optionally determining whether the polymeric nanoparticle is a substantially homogenous solid solution or substantially phase-separated.
  • a contemplated method in an embodiment, includes determining whether a salt of the therapeutic agent and the hydrophobic counterion exists in the polymeric nanoparticle and comprises obtaining a Raman spectra of the nanoparticle and/or determining the number or presence of one or more of di-salts of the hydrophobic counterion, free therapeutic agent , and free hydrophobic counterion comprising obtaining a Raman spectra of the nanoparticle.
  • the method is further directed to, in some embodiments, determining whether the polymeric nanoparticle is a substantially homogenous solid solution or substantially phase-separated may include for example, by obtaining a XRPD analysis.
  • a disclosed method may further comprise correlating the peak intensities of the Raman spectrum with the mole ratios of the therapeutic agent and hydrophobic acid used to prepare the therapeutic nanoparticles and/or further comprise determining the structural components that correlate with therapeutic release rates from nanoparticles.
  • Figure 1 depicts Raman spectra of single components, their mixtures
  • Compound A-pamoate salt placebo nanoparticles, and nanoparticles containing Compound A and pamoic acid.
  • Figure 2 depicts XRPD patterns from the individual nanoparticles components.
  • Figure 3 A depicts overlay plot of XRPD patterns nanoparticles containing compound A and pamoic acid.
  • Figure 3B depicts overlay plot of XRPD patterns from nanoparticles containing compound A and pamoic acid
  • Figure 4 depicts an example of background subtraction.
  • Figure 5 depicts the processed data sets from the placebo nanoparticles (RX-
  • RX 1-9060 the PLA-PEG copolymer (RXl-9056) and the nanoparticles containing compound A and pamoic acid (RX 1-9060, RX 1-9061, RX 1-9063, RX 1-9071, RX 1-9072, RX 1-9073, RX 1-9093, RX 1-9094, RX 1-9095, RX 1-9096, and RX 1-9097) were evaluated using a variance component, least squares analysis method. Two components, designated VCl(PLA-PEG) and VC2 (non-crystalline constituent) were returned.
  • VCl(PLA-PEG) and VC2 non-crystalline constituent
  • Figure 6 depicts plots of VC2 coefficients against concentrations of
  • Fif re 7 depicts spectra of RC1 and RC2.
  • Fif lure 8 depicts spectra of RC1 and RC2.
  • Fif lure 9 depicts spectra of RC1 and RC2.
  • Fif lure 10 depicts graph of salt v. amount released.
  • Fif lure 11 depicts graph of salt v. amount released.
  • Fif lure 12 depicts graph of salt v. amount released
  • Fif lure 13 depicts a plot of Raman peak ratios against moles of pamoic acid used to prepare nanoparticle samples.
  • a method of determining the structural features corresponding to the presence of and/or release rate of a therapeutic agent in a therapeutic nanoparticle that includes the therapeutic agent and a hydrophobic counterion comprising: obtaining a Raman spectra of the nanoparticle; comparing the Raman spectra of the nanoparticle to a Raman spectra of at least one of the therapeutic agent alone, the
  • hydrophobic counterion alone, a nanoparticle that does not include the therapeutic agent, and a salt formed from the therapeutic agent and the hydrophobic counterion to determine whether the therapeutic agent and the hydrophobic counterion in therapeutic nanoparticle occur as a salt.
  • a method of determining the structural features of a polymeric nanoparticle having a therapeutic agent and a hydrophobic counterion comprising: determining the presence of a salt of the therapeutic agent and the hydrophobic counterion existing in the polymeric nanoparticle; optionally determining the stoichiometry of the salt if present; optionally determining the number or presence of one or more of di- salts of the hydrophobic counterion, free therapeutic agent , and free hydrophobic counterion; and optionally determining whether the polymeric nanoparticle is a substantially homogenous solid solution or substantially phase-separated.
  • a contemplated method includes, in an embodiment, determining whether a salt of the therapeutic agent and the hydrophobic counterion exists in the polymeric nanoparticle and comprises obtaining a Raman spectra of the nanoparticle and/or determining the number or presence of one or more of di-salts of the hydrophobic counterion, free therapeutic agent , and /orfiree hydrophobic counterion in the nanoparticle.
  • Contemplated methods can include determining whether the polymeric nanoparticle is a substantially homogenous solid solution or substantially phase-separated and may include for example obtaining a XRPD analysis.
  • a disclosed method further comprises, in an embodiment, correlating the peak intensities of the Raman spectrum with the mole ratios of the therapeutic agent and hydrophobic acid used to prepare the therapeutic nanoparticles and/or further comprise determining the structural components that correlate with therapeutic release rates from nanoparticles.
  • Disclosed methods of determining the structural features of a polymeric nanoparticle having a therapeutic agent and a hydrophobic counterion can include
  • a disclosed method may be used to measure the structural features of a nanoparticle that include about 35 to about 99.75 weight percent, in some embodiments about 50 to about 99.75 weight percent, in some embodiments about 50 to about 99.5 weight percent, in some embodiments about 50 to about 99 weight percent, in some embodiments about 50 to about 98 weight percent, in some embodiments about 50 to about 97 weight percent, in some embodiments about 50 to about 96 weight percent, in some embodiments about 50 to about 95 weight percent, in some embodiments about 50 to about 94 weight percent, in some embodiments about 50 to about 93 weight percent, in some embodiments about 50 to about 92 weight percent, in some embodiments about 50 to about 91 weight percent, in some embodiments about 50 to about 90 weight percent, in some embodiments about 50 to about 85 weight percent, in some embodiments about 60 to about 85 weight percent, in some embodiments about 65 to about 85 weight percent, and in some embodiments about
  • Nanoparticles used in the disclosed methods include about 0.2 to about 35 weight percent, about 0.2 to about 20 weight percent, about 0.2 to about 10 weight percent, about 0.2 to about 5 weight percent, about 0.5 to about 5 weight percent, about 0.75 to about 5 weight percent, about 1 to about 5 weight percent, about 2 to about 5 weight percent, about 3 to about 5 weight percent, about 1 to about 20 weight percent, about 2 to about 20 weight percent, about 5 to about 20 weight percent, about 1 to about 15 weight percent, about 2 to about 15 weight percent, about 3 to about 15 weight percent, about 4 to about 15 weight percent, about 5 to about 15 weight percent, about 1 to about 10 weight percent, about 2 to about 10 weight percent, about 3 to about 10 weight percent, about 4 to about 10 weight percent, about 5 to about 10 weight percent, about 10 to about 30 weight percent, or about 15 to about 25 weight percent of an therapeutic agent, e.g. a chemotherapeutic agent such as a kinase inhibitor or a taxane such as docetaxel.
  • an therapeutic agent
  • nanoparticles used in the disclosed methods comprise a hydrophobic acid and/or are prepared by a process that includes a hydrophobic acid, such as oleic acid, xinafoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, or pamoic acid.
  • a contemplated hydrophobic acid may include a mixture of two or more acids.
  • the hydrophobic acid may comprise a mixture of two substantially hydrophobic acids, in some embodiments a mixture of three substantially hydrophobic acids, in some embodiments a mixture of four substantially hydrophobic acids, or in some embodiments five substantially hydrophobic acids or more.
  • a salt of a hydrophobic acid may be used in a nanoparticlesused in the disclosed methods.
  • the hydrophobic acid present in nanoparticles may have an acid dissociation constant in water (pK a ) of about -5 to about 7, in some embodiments about -3 to about 5, in some embodiments about -3 to about 4, in some embodiments about -3 to about 3.5, in some embodiments about -3 to about 3, in some embodiments about -3 to about 2, in some embodiments about -3 to about 1, in some embodiments about -3 to about 0.5, in some embodiments about -0.5 to about 0.5, in some embodiments about 1 to about 7, in some embodiments about 2 to about 7, in some embodiments about 3 to about 7, in some embodiments about 4 to about 6, in some embodiments about 4 to about 5.5, in some embodiments about 4 to about 5, and in some embodiments about 4.5 to about 5, determined at 25 °C.
  • Such hydrophobic acids may be chosen, at least in part, on the basis of the difference between the pKg of the hydrophobic acid and the pK a of a therapeutic agent.
  • the difference between the pK a of the hydrophobic acid and the pK a of a therapeutic agent may be between about 1 pK a unit and about 15 pKa units, in some embodiments between about 1 pK a unit and about 10 pK a units, in some embodiments between about 1 pK a unit and about 5 pK a units, in some embodiments between about 1 pK a unit and about 3 pK a units, in some embodiments between about 1 pK a unit and about 2 pK a units, in some embodiments between about 2 pK a units and about 15 pK a units, in some embodiments between about 2 pK a units and about 10 pK a units, in some embodiments between about 2 pK a units and about 5 p
  • a contemplated hydrophobic acid may have a phase transition temperature that is advantageous and/or detectable using contemplated methods for example, for improving the properties of the therapeutic nanoparticles.
  • a method of determining the structural features of a polymeric nanoparticle includes a nanoparticle having a targeting ligand, e.g. , a low- molecular weight ligand.
  • the low-molecular weight ligand is conjugated to a polymer
  • the nanoparticle comprises a certain ratio of ligand-conjugated polymer (e.g., PLA-PEG-Ligand) to non-functionalized polymer (e.g., PLA-PEG or PLGA- PEG).
  • a “nanoparticle” refers to any particle having a diameter of less than 1000 nm, e.g. , about 10 nm to about 200 nm.
  • Disclosed therapeutic nanoparticles include nanoparticles having a diameter of about 60 to about 120 nm, or about 70 to about 120 nm, or about 80 to about 120 nm, or about 90 to about 120 nm, or about 100 to about 120 nm, or about 60 to about 130 nm, or about 70 to about 130 nm, or about 80 to about 130 nm, or about 90 to about 130 nm, or about 100 to about 130 nm, or about 1 10 to about 130 nm, or about 60 to about 140 nm, or about 70 to about 140 nm, or about 80 to about 140 nm, or about 90 to about 140 nm, or about 100 to about 140 nm, or about 1 10 to about 140 nm, or about 60 to about 150 nm, or about 70 to
  • Methods contemplated herein may be applied to any polymeric nanoparticles that include polymers and a therapeutic agent.
  • a therapeutic agent and/or targeting moiety for example, a low-molecular weight ligand
  • a targeting moiety for example, a ligand
  • covalent association is mediated by a linker.
  • methods contemplated herein are applied to any polymeric nanoparticles with a therapeutic agent e.g., associated with the surface of, encapsulated within, surrounded by, and/or dispersed throughout the polymeric
  • matrixPolymers can be natural or unnatural (synthetic) polymers. Polymers can be homopolymers or copolymers comprising two or more monomers. In terms of sequence, copolymers can be random, block, or comprise a combination of random and block sequences. Typically, polymers are organic polymers.
  • the term "polymer,” as used herein, is given its ordinary meaning as used in the art, that is a molecular structure comprising one or more repeat units (monomers), connected by covalent bonds. The repeat units may all be identical, or in some cases, there may be more than one type of repeat unit present within the polymer. In some cases, the polymer can be biologically derived, that is, a biopolymer. Non-limiting examples include peptides or proteins.
  • additional moieties may also be present in the polymer, for example, biological moieties such as those described below. If more than one type of repeat unit is present within the polymer, then the polymer is said to be a "copolymer.” It is to be understood that in any embodiment employing a polymer, the polymer being employed may be a copolymer in some cases.
  • the repeat units forming the copolymer may be arranged in any fashion. For example, the repeat units may be arranged in a random order, in an alternating order, or as a block copolymer comprising one or more regions each comprising a first repeat unit (for example a first block), and one or more regions each comprising a second repeat unit (for example, a second block), etc.
  • Block copolymers may have two (a diblock copolymer), three (a triblock copolymer), or more numbers of distinct blocks.
  • Contemplated methods include detecting featurs of nanoparticles having polymers that may be polyesters, including copolymers comprising lactic acid and glycolic acid units, such as poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide), collectively referred to herein as "PLGA”; and homopolymers comprising glycolic acid units, referred to herein as "PGA,” and lactic acid units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide, collectively referred to herein as "PLA.
  • exemplary polyesters include, for example, polyhydroxyacids; PEGylated polymers and copolymers of lactide and glycolide (e.g. , PEGylated PLA, PEGylated PGA, PEGylated PLGA, and derivatives thereof).
  • PEGylated polymers and copolymers of lactide and glycolide e.g. , PEGylated PLA, PEGylated PGA, PEGylated PLGA, and derivatives thereof.
  • polyesters include, for example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene imine), PEGylated poly(ethylene imine), poly(L-lactide-co-L- lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[a-(4-aminobutyl)-L-glycolic acid], and derivatives thereof, or the nanoparticles may include polymers with one or more acrylic polymers.
  • acrylic polymers include, for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl
  • the acrylic polymer may comprise fully-polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • nanoparticles that can for example comprise a diblock copolymer of PEG and PL(G)A
  • the PEG portion may have a number average molecular weight of about 1,000-20,000, e.g., about 2,000- 20,000, e.g., about 2 to about 10,000
  • the PL(G)A portion may have a number average molecular weight of about 5,000 to about 20,000, or about 5,000-100,000, e.g., about 20,000- 70,000, e.g., about 15,000-50,000, e.g., applied to an exemplary therapeutic nanoparticle that includes about 10 to about 99 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer or poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer, or about 20 to about 80 weight percent, about 40 to about 80 weight percent, or about 30 to about 50 weight percent, or about
  • Exemplary poly(lactic) acid-poly(ethylene)glycol copolymers can include a number average molecular weight of about 15 to about 20 kDa, or about 10 to about 25 kDa of poly(lactic) acid and a number average molecular weight of about 4 to about 6, or about 2kDa to about 10 kDa of poly(ethylene)glycol.
  • Disclosed nanoparticles optionally include about 1 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid (which does not include PEG), or optionally include about 1 to about 50 weight percent, or about 10 to about 50 weight percent or about 30 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly
  • poly(lactic) or poly(lactic)-co-poly(glycolic) acid may have a number average molecule weight of about 5 to about 15 kDa, or about 5 to about 12 kDa.
  • Exemplary PLA have a number average molecular weight of about 5 to about 10 kDa.
  • Exemplary PLGA have a number average molecular weight of about 8 to about 12 kDa.
  • a therapeutic nanoparticle may, in some embodiments, contain about 10 to about 30 weight percent, in some embodiments about 10 to about 25 weight percent, in some embodiments about 10 to about 20 weight percent, in some embodiments about 10 to about 15 weight percent, in some embodiments about 15 to about 20 weight percent, in some embodiments about 15 to about 25 weight percent, in some embodiments about 20 to about 25 weight percent, in some embodiments about 20 to about 30 weight percent, or in some embodiments about 25 to about 30 weight percent of poly(ethylene)glycol, where the poly(ethylene)glycol may be present as a poly(lactic) acid-poly(ethylene)glycol copolymer, poly(lactic)-co-poly (glycolic) acid-poly(ethylene)glycol copolymer, or poly(ethylene)glycol homopolymer.
  • the polymers of the nanoparticles can be conjugated to a lipid.
  • the polymer can be, for example, a lipid-terminated PEG.
  • n 1, 2, 3, 4, 5, or 6, and wherein R is independently selected from the group consisting of NH 2 , SH, OH, CO 2 H, Ci-6-alkyl that is substituted with NH 2 , SH, OH, or CO 2 H, and phenyl that is substituted with N3 ⁇ 4, SH, OH, or CO 2 H, and wherein R serves as the point of covalent attachment to the nanoparticle (e.g. , -N(H)-PEG, -S-PEG, -O- PEG, or CO 2 -PEG).
  • a therapeutic nanoparticle may include a polymer-drug conjugate.
  • a drug may be conjugated to a disclosed polymer or copolymer (e.g., PLA-PEG), and such a polymer-drug conjugate may form part of a disclosed nanoparticle.
  • a disclosed therapeutic nanoparticle may optionally include about 0.2 to about 30 weight percent of a PLA-PEG or PLGA-PEG, wherein the PEG is functionalized with a drug (e.g., PLA-PEG- Drug).
  • Ethyl acetate, benzyl alcohol, trifluoroacetic acid (TFA), and dimethyl sulfoxide (DMSO) were from EMD Millipore (Billerica, MA, USA).
  • Oleic acid, l-hydroxy-2 -naphthoic acid, cholic acid, deoxycholic acid, dioctyl sulfosuccinate sodium salt (docusate sodium salt), pamoic acid, citric acid, sodium dihydrogen phosphate, di-sodium hydrogen phosphate dihydrate, and phosphate buffered saline (PBS) were purchased from Sigma-Aldrich Ltd. (St. Louis, MO, USA). All reagents were analytical or high-performance liquid chromatography (HPLC) grade and were used without further purification.
  • Nanoparticles were created via a nanoemulsion process using the modified o/w emulsification solvent extraction method as described by J. Hrkach, D. Von Hoff, M.M. Ali, E. Andrianova, J. Auer, T. Campbell, D. De Witt, M. Figa, M. Figueiredo, A. Horhota, S. Low, K. McDonnell, E. Peeke, B. Retnarajan, A. Sabnis, E. Schnipper, J.J. Song, Y.H. Song, J. Summa, D. Tompsett, G. Troiano, T. Van Geen Hoven, J. Wright, P. LoRusso, P.W.
  • This coarse emulsion was subsequently processed by a high-pressure microfludizer (Microfluidics, Inc., Westwood, MA, USA) to form a fine nanoemulsion.
  • the emulsions were quenched by addition into cold water or buffer solutions, resulting in extraction of solvent from the organic phase and hardening of nanoparticles.
  • Subsequent processing included tangential flow filtration, which removes unencapsulated API and processing aids, and addition of sucrose for stabilization and cryopreservation of the nanoparticle suspension.
  • cholic acid has relatively low solubility in the organic phase (EA/BA)
  • the cholic acid formulations were created by dissolving sodium cholate in the aqueous phase while using TFA to solubilize the API in the organic phase.
  • Dioctylsulfosuccinic acid was prepared by two-immiscible liquid phase extraction method using dioctyl sodium sulfosuccinate. Briefly, sodium dioctylsulfosuccinate was dissolved in BA, and then concentrated hydrochloric acid solution and water were added to acidify the solution.
  • pamoic acid formulations were created using DMSO as a cosolvent in the organic phase and TFA as a drug solubilizer.
  • Hydrophobic counterions having various acidity, molecular weight, shape/bulkiness, and lipophilicity were characterized for pKa, Log P, and Log D7.5 and incorporated into Compound A nanoparticles for characterization of release rate.
  • the physicochemical properties of the representative counterions measured by SiriusT3.
  • the x-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and 44 mA. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line.
  • the Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics.
  • the inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °2 ⁇ or less.
  • the axial divergence of the X-ray beam is controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths.
  • Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 70 °2 ⁇ using a continuous scan of 2 °2 ⁇ per minute with an effective step size of 0.04 °2 ⁇ . Each sample was spun at 50 rpm during data collection.
  • FT Fourier transform
  • Raman spectra were acquired on a Nicolet model 6700 spectrometer interfaced to a Nexus Raman accessory module.
  • the instrument is configured with a Nd:YAG laser operating at 1024 nm, a CaF2 beam splitter, and a indium gallium arsenide detector.
  • OMNIC 8.1 software was used for control of data acquisition and processing of the spectra. Samples were packed into 3-inch glass NMR tubes for analysis. Each spectrum consisted of 512 scans at 2 cm-1 resolution.
  • the Omnic 8.2 software package (Thermo -Nicolet) was used to acquire, process, and evaluate the spectral data.
  • FIG. 2 There are no detectable crystalline components visible in any of the patterns from the nanoparticles containing Compound A and pamoic acid. Instead, only the PLA-PEG copolymer pattern is seen. The concentrations of compound A and pamoic acid are high enough to expect to see peaks in the patterns if either of those components were present in crystalline form. The conclusion is that those components are in non-crystalline form in the nanoparticles. See Figures 2, 3A and 3B. In order to carry out chemometric analyses, each data set (XRPD pattern) was processed by subtraction of instrumental background contribution and normalization to a common intensity scale. An example of background subtraction is shown in FIG. 4.
  • the numbers in Table 2 are the coefficients assigned to each component that minimize the difference between measured and calculated patterns. Since positive, real components were used the sum of the coefficients for each data set is approximately 1. The coefficients may be multiplied by 100 to yield approximate percentages. Note that the PLA- PEG copolymer and placebo data sets are described only by RC 1. Similarly, the compound A pamoate data sets are described only by the measured, processed data set from that salt. RC2 can be considered a non-crystalline component that is different from the type of compound A pamoate that exists in the standard sample provided.

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Abstract

La présente invention concerne de manière générale des procédés de détermination de caractéristiques structurales correspondant à la vitesse de libération d'un agent thérapeutique dans une nanoparticule thérapeutique. De telles nanoparticules peuvent comprendre l'agent thérapeutique. En particulier, l'invention concerne un procédé de détermination des caractéristiques structurales correspondant à la vitesse de libération d'un agent thérapeutique dans une nanoparticule thérapeutique qui comprend l'agent thérapeutique et un contre-ion hydrophobe, consistant à : obtenir des spectres Raman de la nanoparticule ; comparer le spectre Raman de la nanoparticule à un spectre Raman de l'agent thérapeutique seul, du contre-ion hydrophobe seul, d'une nanoparticule qui ne comprend pas l'agent thérapeutique, et/ou d'un sel formé de l'agent thérapeutique et du contre-ion hydrophobe pour déterminer si l'agent thérapeutique et le contre-ion hydrophobe sont présents sous la forme d'un sel dans la nanoparticule thérapeutique.
PCT/IB2016/056716 2015-11-10 2016-11-08 Procédés de détermination de caractéristiques de nanoparticules polymères comprenant un agent thérapeutique WO2017081606A1 (fr)

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