US20100216804A1 - Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents - Google Patents
Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents Download PDFInfo
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- US20100216804A1 US20100216804A1 US12/638,297 US63829709A US2010216804A1 US 20100216804 A1 US20100216804 A1 US 20100216804A1 US 63829709 A US63829709 A US 63829709A US 2010216804 A1 US2010216804 A1 US 2010216804A1
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Definitions
- Nanoparticles for the delivery of therapeutic agents have the potential to circumvent many challenges associated with traditional delivery approaches including lack of patient compliance to prescribed therapy, adverse effects, and inferior clinical efficacy due to lack of targeted delivery.
- Important technological advantages of nanoparticles for drug delivery include the ability to deliver water-insoluble and unstable drugs, incorporation of both hydrophobic and hydrophilic therapeutic agents, and ability to utilize various routes of administration. Nanoparticle delivery systems may also facilitate targeted drug delivery and controlled release applications, enhance drug bioavailability at the site of action, reduce dosing frequency, and minimize side effects.
- nanoparticulate systems have been examined for use as drug delivery vehicles, including polymeric micelles, polymers, liposomes, low-density lipoproteins, dendrimers, hydrophilic drug-polymer complexes, and ceramic nanoparticles.
- Typical polymeric materials utilized in polymeric particulate drug delivery systems include polylactic acid (PLA), poly(D,L-glycolide) (PLG), and poly(lactide-co-glycolide) (PLGA).
- PLA and PLGA are listed as Generally Recognized as Safe (GRAS) under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are approved for use in commercially available microparticulate systems, including Decapeptyl®, Parlodel LA®, and Enantone Depot®, as well as in implant devices, such as Zoladex®.
- GRAS Generally Recognized as Safe
- nanoparticle systems such as liposomes
- polymeric nanoparticles developed to date have limited effectiveness, in part because such nanoparticles clear from the body quickly once administered and/or may accumulate in healthy tissue where treatment is not needed. Control of delivery of an active agent, using nanosystems, remains a challenge.
- biocompatible compositions capable of extended delivery of active agents, e.g., anti-neoplastic agents, that provide for prolonged and/or increased plasma drug concentrations in a patient, especially as compared to administration of an active agent alone.
- active agents e.g., anti-neoplastic agents
- a nanoparticle composition in one aspect of the invention, includes a biodegradable and/or biocompatible polymer and a therapeutic agent, wherein the biodegradable and/or biocompatible polymer matrix releases the therapeutic agent at a rate allowing controlled release of the agent over at least about 12 hours, or in some embodiments, at least about 24 hours
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a biocompatible polymer and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 12 hours when the composition is administered to a patient, and an area under the plasma concentration time curve (AUC) that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient.
- AUC area under the plasma concentration time curve
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 6 hours, at least 12 hours, or at least 24 hours or more when the composition is administered to a patient, to provide an area under the plasma concentration time curve (AUC) that is increased by at least 100%, or at least by 150%, over the AUC provided when the therapeutic agent is administered alone to a patient.
- AUC plasma concentration time curve
- disclosed nanoparticles may provide an actual peak plasma concentration (C max ) that is at least 10% higher, or even at least 100% higher, as compared to a C max of said therapeutic agent when administered alone.
- C max peak plasma concentration
- disclosed nanoparticles may provide a volume of distribution when administered to the patient that is less than or equal to about 5 plasma volumes.
- disclosed nanoparticles and/or compositions may decrease the volume of distribution (V z ) by at least 50% as compared to the V z of the patient when the therapeutic agent is administered alone.
- Biocompatible nanoparticle compositions may include long circulating nanoparticles that may further comprise a biocompatible polymer coupled to a targeting moiety, for example, a targeting moiety that is selected from the group consisting of a protein, peptide, antibody, antibody fragment, saccharide, carbohydrate, small molecule, glycan, cytokine, chemokine, nucleotide, lectin, lipid, receptor, steroid, neurotransmitter, cell surface marker, cancer antigen, or glycoprotein antigen.
- a targeting moiety may bind to prostate membrane specific antigen (PMSA).
- a disclosed nanoparticle may include a biocompatible polymer coupled to a targeting moiety, e.g., a nanoparticle may include PLA-PEG-((S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid.
- Disclosed long circulating nanoparticles may include 1 to about 4% by weight, or 2% to about 4% by weight, of a biocompatible polymer coupled to a targeting moiety
- a biocompatible nanoparticle may include a biocompatible polymer such as PLA-PEG.
- a ⁇ -hydroxy polyester-co-polyether may be polylactic acid-co-polyethylene glycol, and/or a ⁇ -hydroxy polyester-co-polyether comprises about 16 kDa polylactic acid and about 5 kDa polyethylene glycol.
- Disclosed long circulating nanoparticles may be about 80 to about 90 weight percent ⁇ -hydroxy polyester-co-polyether.
- disclosed long circulating nanoparticles may further comprise a biodegradable polymer, such as poly(lactic) acid.
- long circulating nanoparticles may have about 40 to about 50 weight percent poly(lactic)acid, and about 40 to about 50 weight percent of ⁇ -hydroxy polyester-co-polyether.
- Compositions that include such biocompatible nanoparticles and a therapeutic agent may provide a peak plasma concentration (C max ) of a therapeutic agent at least 100% higher than the C max of the therapeutic agent when administered alone, and/or the area under the plasma concentration time curve (AUC) may increased by at least 200% over the AUC of the therapeutic agent when administered alone to the patient.
- C max peak plasma concentration
- AUC area under the plasma concentration time curve
- Disclosed nanoparticle compositions may include a therapeutic agent such as one selected from the group consisting of chemotherapeutic agents, diagnostic agents, prophylactic agents, nutraceutical agents, nucleic acids, proteins, peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and combinations thereof, for example, a nanoparticle may include an anti-neoplastic agent such as docetaxel, vincristine, methotrexate, paclitaxel, or sirolimus. Disclosed nanoparticle compositions may further include an aqueous solution of a saccharide.
- a therapeutic agent such as one selected from the group consisting of chemotherapeutic agents, diagnostic agents, prophylactic agents, nutraceutical agents, nucleic acids, proteins, peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and combinations thereof
- a nanoparticle may include an anti-neo
- Also provided herein is a method of treating a solid tumor cancer, comprising administering disclosed nanoparticle composition to a patient (e.g. a mammal or primate) in need thereof.
- a patient e.g. a mammal or primate
- Such methods may provide wherein at least 24 hours after administration, a solid tumor has significant concentration of therapeutic agent.
- Contemplated herein is a method of treating a solid tumor in a mammal in need thereof, comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, a single dose of said composition may provide extended elevated plasma concentrations of said therapeutic agent in the patient for a least one day, (e.g. the peak plasma concentration (C max ) of the therapeutic agent after administration of the composition to the mammal is at least 10% higher than the C max of said therapeutic agent if administered in a non-nanoparticle formulation.)
- C max peak plasma concentration
- Also provided herein is a method of minimizing unwanted side effects or toxicity of an active agent in a patient, comprising: administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein said composition is capable of delivery a higher plasma concentration of therapeutic agent to the patient as compared to administering the therapeutic agent alone, and wherein upon administering the nanoparticle composition the volume distribution of the active agent in the patient is reduced, as compared to the volume distribution if the therapeutic agent was administered alone.
- a method for modulating the plasma concentration of a therapeutic agent in a patient e.g. a primate (e.g. human) is also provided, comprising: providing a polymeric nanoparticle comprising the therapeutic agent and administering the polymeric nanoparticle to the patient, thereby modulating the plasma concentration of the human patient.
- FIG. 1 is a schematic illustration of a nanoparticle according to one aspect of the present invention.
- FIG. 2 is a block diagram of the emulsion process used in the fabrication of nanoparticles in one aspect of the present invention.
- FIG. 3 depicts the in vitro release of docetaxel from nanoparticles and conventional docetaxel.
- FIG. 4 depicts the pharmacokinetics of docetaxel encapsulated in nanoparticles and conventional docetaxel in rats.
- FIG. 5 depicts the distribution of radioactivity determined in selected tissues of rats after IV administration of nanoparticles containing 14 C-targeting polymer ( ⁇ ), nanoparticles containing 14 C-docetaxel ( ⁇ ), and conventional 14 C -docetaxel ( ⁇ ).
- FIG. 6 depicts docetaxel concentration in tumor tissue after administration of docetaxel encapsulated in nanoparticles or conventional docetaxel to LNCaP tumor bearing SCID mice.
- FIG. 7 depicts the reduction in tumor volume in mice with PSMA-expressing LNCaP xenografts when treated with docetaxel encapsulated in nanoparticles or conventional docetaxel.
- FIG. 8 depicts pharmacokinetics of vincristine encapsulated in disclosed nanoparticles and conventional vincristine in rats.
- FIG. 9 depicts pharmacokinetics of methotrexate encapsulated in disclosed nanoparticles and conventional methotrexate in rats.
- FIG. 10 depicts pharmacokinetics of paclitaxel encapsulated in disclosed nanoparticles and conventional paclitaxel in rats.
- FIG. 11 depicts pharmacokinetics of rapamycin (sirolimus) encapsulated in disclosed nanoparticles and conventional rapamycin in rats.
- FIG. 12 depicts the tumor accumulation of docetaxel in disclosed nanoparticles in a MX-1 mouse breast tumor model.
- FIG. 13 depicts pharmacokinetics of docetaxel in a NHP model using various disclosed nanoparticles.
- the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 40%-60%.
- an “effective amount” or “therapeutically effective amount” of a composition, as used herein, is a predetermined amount calculated to achieve a desired effect.
- long-circulating refers to enhanced stability in the circulatory system of a patient, regardless of biological activity.
- nanophase and “nanosize” refer to a special state of subdivision implying that a particle has an average dimension smaller than about 1000 nm (1000 ⁇ 10 ⁇ 9 m).
- poly(ethylene glycol) or “PEG” and “poly(ethylene oxide)” or “PEO” denote polyethers comprising repeat —CH 2 —CH 2 —O— units.
- PEG and/or PEO can be different polymers depending upon end groups and molecular weights.
- poly(ethylene glycol) and PEG describes either type of polymer.
- ⁇ -hydroxy polyester refers to polymers having monomers based on one or more ⁇ -hydroxy acid, such as poly(lactic) acid, poly(glycolic) acid, poly-lactic-co-glycolic acid, polycaprolactone.
- target refers to the cell type or tissue to which enhanced delivery of the therapeutic agent is desired.
- diseased tissue may be a target for therapy.
- terapéutica agent means a compound utilized to image, impact, treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
- disclosed long-circulating nanoparticles include a therapeutic agent and biodegradable and/or biocompatible polymeric particles, optionally functionalized with targeting moieties.
- the nanoparticles are designed to circulate in a vascular compartment of a patient for an extended period of time, distribute and accumulate at a target, and release the encapsulated therapeutic agent in a controlled manner. These characteristics can result in an increased level of therapeutic agent in the target and a potential reduction in off-target exposure.
- the disclosed nanoparticles remain in circulation longer because, upon administration to a patient (e.g. a mammal, primate (e.g. human)), the disclosed nanoparticles are substantially confined to the vascular compartment of the patient, and are engineered to be cleared very slowly.
- the activity of many therapeutic agents is dependent on their pharmacokinetic behavior. This pharmacokinetic behavior defines the drug concentrations and period of time over which cells are exposed to the drug. For most therapeutics, e.g. anti-neoplastics, longer exposure times are preferred as this results in increased killing of the cancer cells.
- peak plasma concentration, or maximum plasma concentration (C max ) and area under the curve (AUC) are examples.
- AUC is a measure of plasma drug levels over time and provides an indication of the total drug exposure. Generally, plasma concentration and plasma AUC for a therapeutic agent correlate with increased therapeutic efficacy.
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent.
- Such compositions may provide a therapeutic effect for at least 12 hours, at least 24 hours, or at least 36 hours, or 48 hours or more, upon administration to a patient.
- peak plasma concentration (C max ) of the therapeutic agent of such nanoparticles e.g. when the composition is administered to a patient, may be least 10% higher, 20% higher, or about 10% to about 100% higher, or more, than the C max of the same therapeutic agent when administered alone.
- Actual peak plasma concentration of delivered therapeutic agent includes both agent that is released from the nanoparticle (e.g. after administration) and therapeutic agent remaining in any nanoparticle remaining in the plasma, e.g. at a given time.
- disclosed nanoparticles may provide upon administration to a patient, an area under the plasma concentration time curve (AUC), that may be increased by at least 100%, at least 200%, or about 100% to about 500% or more, over the AUC of the therapeutic agent when administered alone to the patient.
- AUC area under the plasma concentration time curve
- a provided composition that includes disclosed nanoparticles may decrease the volume of distribution (V z ) of distributed active agent, upon administration, in a patient by at least 10%, or by at least 20%, or about 10% to about 100%, as compared to the V z of the patient when the therapeutic agent is administered alone.
- a provided nanoparticle composition may provide V z in a patient that is on the same order of magnitude that the of plasma volume and/or a volume of distribution less than about 10 plasma volumes.
- a disclosed nanoparticle composition may provide a Vz that is less than, or about, 2 times the plasma volume, or less than or about 8 plasma volumes.
- a disclosed nanoparticle composition may provide a V z in a patient that is on about the same order of plasma volume, (e.g. about 5 L for an exemplary 70 kg patient), e.g. about a V z that indicates administered nanoparticles are substantially in the patient's plasma and not substantially in other tissues.
- disclosed nanoparticles may be used as a drug delivery vehicle based on the encapsulation of a therapeutic agent in a polymer matrix with controlled porosity and/or a soluble shell or matrix that upon dissolution releases the therapeutic agent in the immediate vicinity of the targeted area.
- the protection of the therapeutic agent provided by the polymer shell or matrix allows for the delivery of therapeutic agents that are water-insoluble or unstable.
- dissolution kinetics of the polymer can be designed to provide sustained release of therapeutic agents at a target for an extended period of time.
- Disclosed nanoparticles can be used for a variety of applications, such as, without limitation, drug delivery, gene therapy, medical diagnosis, and for medical therapeutics for cancer, pathogen-borne diseases, hormone-related diseases, reaction-by-products associated with organ transplants, and other abnormal cell or tissue growth.
- a patient e.g. a mammal suffering from cancer, e.g. a solid tumor cancer, prostate cancer, breast cancer or lung cancer using e.g., disclosed nanoparticles.
- contemplated diseases that may be treated using disclosed nanoparticles include a broad range of diseases and find limitation only by e.g. the therapeutic agent, the availability of a marker and/or a targeting ligand for the disease.
- a nanoparticle delivery system mitigates against colloidal instability, agglomeration, polydispersity in nanoparticle size and shape, swelling, and leakage of encapsulated materials.
- nanoparticles for delivery of therapeutic agents are provided that exhibit encapsulation efficiency.
- Encapsulation efficiency is affected by factors including, for example, material characteristics of the polymer utilized as the carrier matrix, the chemical and physical properties of the therapeutic agent to be encapsulated, and type of solvents used in the nanoparticle fabrication process.
- polymeric nanoparticles for delivery of therapeutic agents are provided that exhibit particle heterogeneity.
- Conventional polymeric nanoparticle fabrication techniques generally provide multimodal particle size distributions as a result of self-aggregation during nanoprecipitation of both the polymer and the drug molecules.
- Polymeric nanoparticles for delivery of therapeutic agents are provided, in an embodiment, that may reduce or eliminate burst release effects.
- Conventional polymeric nanoparticle carriers frequently exhibit a bimodal drug release pattern with up to about 40-80% or more of the encapsulated drug released during the first several hours. After 24 to 48 hours, drug release is significantly reduced due to the increased diffusion barrier for drug molecules located deep within the polymer matrix.
- poorly encapsulated drug molecules diffuse quickly into solution, which may lead to significant toxicity in vivo.
- the nanoparticles generally have little or no remaining therapeutic efficacy.
- polymeric nanoparticles for delivery of therapeutic agents may evade rapid capture by the reticuloendothelial system (RES), leading to extended circulation time and elevated concentration of the nanoparticles in the blood.
- Rapid capture and elimination is typically caused by the process of opsonization in which opsonin proteins present in the blood serum quickly bind to conventional nanoparticles, allowing macrophages to easily recognize and remove these particulates before they can perform their designed therapeutic function.
- the extent and nature of opsonin adsorption at the surface of nanoparticles and their simultaneous blood clearance depend on the physicochemical properties of the particles, such as size, surface charge, and surface hydrophobicity.
- a nanoparticle composition including a biodegradable and/or biocompatible polymer matrix and a therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix wherein the clearance rate of said therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix is lower than the clearance rate of said therapeutic agent when administered alone.
- methods are provided that mask or camouflage nanoparticles in order to evade uptake by the RES.
- One such method is the engineering of particles in which polyethers, such as poly(ethylene glycol) (PEG) or PEG containing surfactants, are deployed on the surface of nanoparticles.
- PEG poly(ethylene glycol)
- PEG containing surfactants are deployed on the surface of nanoparticles.
- the presence of PEG and/or PEG-containing copolymers, e.g. on the surface of nanoparticles can result in an increase in the blood circulation half-life of the nanoparticles by several orders of magnitude.
- This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.
- FIG. 1 schematically illustrates a nanoparticle according to one aspect of the present invention.
- docetaxel 100 an anti-neoplastic agent approved for the treatment of hormone refractory prostate cancer (HRPC)
- HRPC hormone refractory prostate cancer
- a matrix 110 derived from the biodegradable and/or biocompatible polymers PLA and poly(lactide-b-ethylene glycol) (PLA-PEG).
- the polymer matrix 110 contains a targeting polymer (PLA-PEG-lys(urea)glu) 120 that is end-functionalized (through the 5 amino moiety) with the lysine-urea-glutamate heterodimer (S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid (lys(urea)glu) 130 , a small molecule ligand that selectively binds to PSMA, a clinically relevant prostate cancer cell surface marker.
- a targeting polymer PDA-PEG-lys(urea)glu
- S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid lys(urea)glu
- a small molecule ligand that selectively binds to PSMA, a clinically relevant prostate cancer cell surface marker.
- the nanoparticles may be biologically degraded by, for example, enzymatic activity or cellular machinery into monomers and/or other moieties that cells can either use or excrete.
- the dissolution or degradation rate of the nanoparticles is influenced by the composition of the polymer shell or matrix.
- the half-life of the polymer (the time at which 50% of the polymer is degraded into monomers and/or other nonpolymeric moieties) may be on the order of days, weeks, months, or years, depending on the polymer.
- nanoparticle delivery characteristics such as water uptake, controlled release of therapeutic agent, and polymer degradation kinetics may be optimized through selection of polymer shell or matrix composition.
- Suitable polymers that may form some of the disclosed nanoparticles may include, but are not limited to, biodegradable ⁇ -hydroxy polyesters and biocompatible polyethers.
- exemplary polyesters include, for example, PLA, PLGA, PEG, PEO, PEGylated polymers and copolymers of lactide and glycolide (e.g., PEGylated PLA, PEGylated PGA, PEGylated PLGA), and derivatives thereof.
- suitable polymers include, for example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene inline), 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 combinations and derivatives thereof.
- a polymer matrix may comprise one or more acrylic polymers.
- acrylic polymers include, for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid polyacrylamide) copolymer, aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, polycyanoacrylates, and combinations thereof.
- the matrix may include dextran, acylated dextran, chitosan (e.g., acetylated to various levels), poly(vinyl) alcohol (for example, hydrolyzed to various degrees), and/or alginate, e.g. alginate complexed to bivalent cations such as a calcium alginate complex.
- dextran acylated dextran
- chitosan e.g., acetylated to various levels
- poly(vinyl) alcohol for example, hydrolyzed to various degrees
- alginate e.g. alginate complexed to bivalent cations such as a calcium alginate complex.
- Nanoparticles disclosed herein include one, two, three or more biocompatible and/or biodegradable polymers.
- a contemplated nanoparticle may include about 10 to about 99 weight percent of one or more block co-polymers that include a biodegradable polymer and polyethylene glycol, and about 0 to about 50 weight percent of a biodegradable homopolymer.
- Exemplary therapeutic nanoparticles may include about 40 to about 90 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer or about 40 to about 80 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer.
- Such poly(lactic) acid-block-poly(ethylene)glycol copolymer may include poly(lactic acid) having a number average molecular weight of about 15 to 20 kDa (or for example about 15 to about 100 kDa, e.g., about 15 to about 80 kDa), and poly(ethylene)glycol having a number average molecular weight of about 2 to about 10 kDa, for example, about 4 to about 6 kDa.
- a disclosed therapeutic nanoparticle may include about 70 to about 90 weight percent PLA-PEG and about 5 to about 25 weight percent active agent (e.g.
- PLA-PEG docetaxel
- PLA ((poly)lactic acid) may have a number average molecular weight of about 5 to about 10 kDa.
- PLGA poly lactic-co-glycolic acid
- PLA-PEG copolymers may include a chemical linker, oligomer, or polymer chain between the PLA and PEG blocks, e.g., may include PLA-linker-PEG.
- disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. about 10 weight percent docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa, e.g. about 87.5% PLA-PEG (16 kDa/5 kDa)), and optionally e.g. a PLA-PEG-lys(urea)-glu (e.g. at 2.5 weight percent).
- active agent e.g. about 10 weight percent docetaxel
- PLA-PEG with e.g. PLA about 16 kDa and PEG about 5 kDa, e.g. about 87.5% PLA-PEG (16 kDa/5 kDa)
- optionally e.g. a PLA-PEG-lys(urea)-glu e.g. at 2.5 weight percent.
- a disclosed nanoparticle which may have slow release properties, may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), (e.g. 43.25% PLA-PEG), about 42 to 45 weight percent PLA (e.g. about 75 kDa) (e.g. 43.25% PLA/75 kDa) and about 10 to 15 weight percent active agent (e.g. docetaxel).
- disclosed nanoparticles may 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, e.g a homopolymer of PLA), or may 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 (glycolic) acid.
- disclosed nanoparticles may include two polymers, e.g. PLA-PEG and PLA, in a weight ratio of about 30:60 to about 60:30, e.g, about 40:60, about 60:40, or about 50:50.
- Such substantially homopolymeric poly(lactic) or poly(lactic)-co-poly(glycolic) acid may have a weight average molecular weight of about 10 to about 130 kDa, for example, about 20 to about 30 kDa, or about 100 to about 130 kDa.
- Such homopolymeric PLA may have a number average molecule weight of about 5 to about 90 kDa, or about 5 to about 12 kDa, about 15 to about 30 kDa, or about 60 to about 90 kDa.
- Exemplary homopolymeric PLA may have a number average molecular weight of about 80 kDa or a weight average molecular weight of about 124 kDa.
- molecular weight of polymers can be related to an inherent viscosity.
- homopolymer PLA may have an inherent viscosity of about 0.2 to about 0.4, e.g. about 0.3; in other embodiments, PLA may have an inherent viscosity of about 0.6 to about 0.8.
- Exemplary PLGA may have a number average molecular weight of about 8 to about 12 kDa.
- modified surface chemistry and/or small particle size of disclosed nanoparticles may contribute to the effectiveness of the nanoparticles in the delivery of a therapeutic agent.
- nanoparticle surface charge may be modified to achieve slow biodegradation and reduce clearance of the nanoparticles.
- porosity of the polymer shell or matrix is optimized to achieve extended and controlled release of the therapeutic agent.
- the nanoparticles may have porosity in the range of about 10 to about 90 percent and/or a pore diameters in the range of about 0.001 to about 0.01 microns.
- the nanoparticles according to some embodiments of the invention may be able to penetrate the altered and often compromised vasculature of tumors via the enhanced permeability and retention (EPR) effect resulting in preferential accumulation of nanoparticles in tumor interstitium.
- EPR enhanced permeability and retention
- therapeutic agents examples include, but are not limited to, chemotherapeutic agents (e.g. anti-cancer agents), diagnostic agents (e.g. contrast agents, radionuclides, and fluorescent, luminescent, and magnetic moieties), prophylactic agents (e.g. vaccines), nutraceutical agents (e.g. vitamins and minerals), nucleic acids (e.g., siRNA, RNAi, and mircoRNA agents), proteins (e.g. antibodies), peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and/or combinations thereof.
- chemotherapeutic agents e.g. anti-cancer agents
- diagnostic agents e.g. contrast agents, radionuclides, and fluorescent, luminescent, and magnetic moieties
- prophylactic agents e.g. vaccines
- nutraceutical agents e.g. vitamins and minerals
- nucleic acids e.g., siRNA, RNAi, and mircoRNA agents
- the active agent or drug may be a therapeutic agent such as an antineoplastic such as a mTor inhibitor (e.g., sirolimus (rapamycin), temsirolimus, or everolimus), vinca alkaloids such as vincristine, a diterpene derivative, a taxane such as paclitaxel (or its derivatives such as DHA-paclitaxel or PG-paxlitaxel), docetaxel, or methatrexate.
- antineoplastic such as a mTor inhibitor (e.g., sirolimus (rapamycin), temsirolimus, or everolimus), vinca alkaloids such as vincristine, a diterpene derivative, a taxane such as paclitaxel (or its derivatives such as DHA-paclitaxel or PG-paxlitaxel), docetaxel, or methatrexate.
- a mTor inhibitor e.g., siroli
- the therapeutic agent to be delivered is an agent useful in the treatment of cancer (e.g., a solid tumor cancer e.g., prostate or breast cancer).
- Such therapeutic agents may include, for example, doxorubicin (adriamycin), gemcitabine (gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere), mitoxantrone, mitoxantrone hydrochloride, aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-I1, 1O-hydroxy-7-ethylcamptothecin (SN38), dacarbazine, S-I capecitabine, ftorafur, 5′de
- contemplated nanoparticles may include more than one therapeutic agent. Such nanoparticles may be useful, for example, in aspects where it is desirable to monitor a targeting moiety as such moiety directs a nanoparticle containing a drug to a particular target in a subject.
- Disclosed nanoparticles may be formed using an emulsion process, e.g. as presented as a block diagram in FIG. 2 .
- an organic polymer/drug solution containing docetaxel, PLA, PLA-PEG, and PLA-PEG-lys(urea)glu dissolved in a co-solvent mixture of ethyl acetate and benzyl alcohol is dispersed in an aqueous solution of sodium cholate, ethyl acetate, and benzyl alcohol to form a coarse emulsion.
- the conditions under which the emulsion process is performed favor the orientation of the PEG and/or PEG-lys(urea)glu polymer chains toward the particle surface.
- an orientation is achieved where the PEG is folded within the nanoparticle polymer shell or matrix.
- a coarse emulsion can be passed through a high pressure homogenizer to reduce the droplet size, forming a fine emulsion.
- the fine emulsion is diluted into an excess volume of a quench solution of cold water containing polysorbate 80.
- the presence of polysorbate 80 serves to remove excess therapeutic agent that has not been encapsulated in the nanoparticle.
- polysorbate 80 may also be adhered or associated with a nanoparticle surfaces. While not wishing to be bound by theory, polysorbate 80 coupled to the nanoparticle surfaces may impact characteristics such as controlled release of therapeutic agent and polymer degradation kinetics.
- Quenching may be performed at least partially at a temperature of about 5° C. or less.
- water used in the quenching may be at a temperature that is less that room temperature (e.g., about 0 to about 10° C., or about 0 to about 5° C.).
- not all of the therapeutic agent e.g., docetaxel
- a drug solubilizer is added to the quenched phase to form a solubilized phase.
- the drug solubilizer may be for example, Tween 80, Tween 20, polyvinyl pyrrolidone, cyclodextran, sodium dodecyl sulfate, or sodium cholate.
- Tween-80 may added to the quenched nanoparticle suspension to solubilize the free drug and prevent the formation of drug crystals.
- a ratio of drug solubilizer to therapeutic agent e.g., docetaxel
- a ratio of drug solubilizer to therapeutic agent is about 100:1 to about 10:1.
- Ethyl acetate and benzyl alcohol are extracted from the organic phase droplets, resulting in formation of a hardened nanoparticle suspension.
- docetaxel or other active agent may be encapsulated at e.g. a loading level of 10% w/w; corresponding to more than 10,000 drug molecules per nanoparticle.
- the nanoparticle suspension is processed using tangential flow ultrafiltration/diafiltration (UF/DF) with cold water to remove processing aids and to concentrate the nanoparticles to a desired value. Residual precursor materials and excess organics present in unwashed nanoparticle suspensions may have a detrimental impact on biomedical applications as well as undesired toxic effects on the physiological system.
- the washed nanoparticle suspension is then passed through a prefilter and at least two sterilizing-grade filters.
- the nanoparticles may be combined with an acceptable carrier to produce a pharmaceutical formulation, according to another aspect of the invention.
- the carrier may be selected based on factors including, but not limited to, the route of administration, the location of the targeted disease tissue, the therapeutic agent being delivered, and/or the time course of delivery of the therapeutic agent.
- a concentrated sucrose solution is aseptically added to the sterile nanoparticle suspension to produce a pharmaceutical formulation.
- the sucrose serves as a cryoprotectant and a tonicity agent.
- the resulting pharmaceutical formulation is a sterile, aqueous, injectable suspension of docetaxel encapsulated in nanoparticles comprised of biocompatible and biodegradable polymers.
- the suspension is assayed for docetaxel content, and may be aseptically diluted to the desired concentration.
- the particle suspension is aseptically filled and sealed in glass vials.
- the bulk drug product suspension is stored frozen at ⁇ 20° C. ⁇ 5° C. prior to filling into vials.
- nanoparticles of the invention may be modified in some embodiments to achieve desired drug-delivery features.
- nanoparticle characteristics such as surface functionality, surface charge, particle size, zeta ( ⁇ ) potential, hydrophobicity, controlled release capability, and ability to control immunogenicity, and the like, may be optimized for the effective delivery of a variety of therapeutic agents.
- the long-circulating nanoparticles produced according to the emulsion process shown in FIG. 2 are well dispersed and unagglomerated, which facilitates conjugation or functionalization of the nanoparticle surfaces with targeting moieties.
- Disclosed nanoparticles may include optional targeting moieties, which may be selected to ensure that the nanoparticles selectively attach to, or otherwise associate with, a selected marker or target.
- disclosed nanoparticles may be functionalized with an amount of targeting moiety effective for the treatment of prostate cancer in a subject (e.g., a low-molecular weight PSMA ligand).
- an amount of targeting moiety effective for the treatment of prostate cancer in a subject e.g., a low-molecular weight PSMA ligand.
- targeting moieties effective for the treatment of prostate cancer in a subject
- the nanoparticles are effective only at targeted sites, which minimizes adverse side effects and improves efficacy.
- Targeted delivery also allows for the administration of a lower dose of therapeutic agent, which may reduce undesirable side effects commonly associated with traditional treatments of disease.
- disclosed nanoparticles may be optimized with a specific density of targeting moieties on the nanoparticle surface, such that e.g., an effective amount of targeting moiety is associated with the nanoparticle for delivery of a therapeutic agent.
- the fraction of the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety may be less than 80% of the total.
- the fraction of the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety is less than about 50% of the total.
- Increased density of the targeting moiety may, in some embodiments, increase target binding (cell binding/target uptake).
- targeting moieties include, for example, proteins, peptides, antibodies, antibody fragments, saccharides, carbohydrates, glycans, cytokines, chemokines, nucleotides, lectins, lipids, receptors, steroids, neurotransmitters and combinations thereof.
- markers that may be useful in embodiments of the invention include, but are not limited to, cell surface markers, a cancer antigen (CA), a glycoprotein antigen, a melanoma associated antigen (MAA), a proteolytic enzyme, an angiogenesis marker, a prostate membrane specific antigen (PMSA), a small cell lung carcinoma antigen (SCLCA), a hormone receptor, a tumor suppressor gene antigen, a cell cycle regulator antigen, a proliferation marker, and a human carcinoma antigen.
- exemplary targeting moieties include:
- a disclosed nanoparticle may include PLA-PEG-targeting moiety, e.g. S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid.
- disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), and about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16 kDa/5 kDa PLA-PEG).
- a disclosed nanoparticle may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa) about 42 to 45 weight percent PLA (e.g. about 75 kDa), about 10 to 15 weight percent active agent (e.g. docetaxel), and about about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16/5 PLA-PEG).
- PLA-PEG with e.g. PLA about 16 kDa and PEG about 5 kDa
- PLA e.g. about 75 kDa
- active agent e.g. docetaxel
- PLA-PEG-lys(urea)glu 16/5 PLA-PEG
- targeting moieties are targeted to an antigen associated with a disease of a patient's immune system or a pathogen-borne condition.
- targeting moieties are targeted to cells present in normal healthy conditions. Such targeting moieties may be directly targeted to a molecule or other target or indirectly targeted to a molecule or other target associated with a biological molecular pathway related to a condition.
- the amount of nanoparticles administered to a patient may vary and may depend on the size, age, and health of the patient, the therapeutic agent to be delivered, the disease being treated, and the location of diseased tissue. Moreover, the dosage may vary depending on the mode of administration.
- the nanoparticles are administered to a subject systemically.
- methods of administration may include, but are not limited to, intravascular injection, intravenous injection, intraperitoneal injection, subcutaneous injection, and intramuscular injection.
- the nanoparticles necessitate only a single or very few treatment sessions to provide effective treatment of disease, which ultimately may facilitate patient compliance.
- administration of the nanoparticles can occur via intravenous infusion once every three weeks.
- a patient e.g. a mammal in need thereof.
- the solid tumor may have significant concentration of therapeutic agent, e.g. may have an increase in tumor drug concentration of at least about 20%, or at least about 30% or more active agent (e.g. docetaxel) as compared to the amount present in a tumor after administration of (e.g. the same dosage) of therapeutic agent alone (e.g. not in a disclosed nanoparticle composition).
- a method of treating a solid tumor in a mammal comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, wherein single dose of said composition provides extended release of said therapeutic agent for a least one day.
- Such methods may provide an actual peak plasma concentration (C max ) of the therapeutic agent after administration of the composition to the mammal that is at least 10% higher, or at least 20% higher or 100% higher or more than the C max of said therapeutic agent if administered in a non-nanoparticle formulation.
- Disclosed methods may provide, upon administration of nanoparticles, an area under the plasma concentration time curve (AUC) in a patient that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient.
- disclosed methods may also, alone or in addition to the above plasma parameters, decrease the volume of distribution (V z ) of the therapeutic agent upon administration by at least 50% as compared to the V z of the patient when the therapeutic agent is administered alone.
- disclosed nanoparticles may, upon administration, provide a higher plasma concentration of therapeutic agent as compared to administering an equivalent dosage of therapeutic agent alone.
- disclosed nanoparticles may circulate substantially in the vascular compartment, and therefore may not contribute significantly to other areas that may cause toxicity or unwanted side effects.
- a suspension of docetaxel encapsulated in nanoparticles fabricated according to the emulsion process depicted in FIG. 2 and Example 12 using 87.5 weight percent PLA-PEG, 10 wt. % docetaxel, and 2.5 wt. percent docetaxel (Formulation A) (all docetaxel nanoparticle formulations used in these Examples were in a composition of 5% nanoparticles, 65% water, and 30% sucrose). was placed in a dialysis cassette and incubated in a reservoir of phosphate buffered saline (PBS) at 37° C. with stirring. Samples of the dialysate were collected and analyzed for docetaxel using reversed phase high performance liquid chromatography (HPLC). For comparison, conventional docetaxel was analyzed under the same procedure.
- PBS phosphate buffered saline
- FIG. 3 presents the in vitro release profile of docetaxel encapsulated in nanoparticles compared to conventional docetaxel. Release of the encapsulated docetaxel from the polymer matrix was essentially linear over the first 24 hours with the remainder gradually released over a period of about 96 hours.
- FIG. 4 and Example Table 2.1 present the observed pharmacokinetic profiles and pharmacokinetic parameters, respectively, of docetaxel encapsulated in nanoparticles and conventional docetaxel.
- Example Table 2.1 further includes data from the preclinical development of TAXOTERE® for comparative reference (Bissery et al. 1995). The results for conventional docetaxel were consistent with those reported in literature (Bissery et al. 1995), indicating docetaxel was rapidly cleared from the blood and distributed to tissues. The peak plasma concentration (C max ) was observed at the first sampling time point for all treatments.
- the C max and AUC of the docetaxel encapsulated in nanoparticles were approximately 100 times higher than that for conventional docetaxel. The difference in the C max may be attributable to having missed the rapid initial tissue distribution phase for conventional docetaxel.
- the data indicate that the docetaxel encapsulated in nanoparticles largely remains in circulation upon injection and is slowly cleared over a 24 hour period. The data further shows that docetaxel is released from the nanoparticles in a controlled manner during the 24 hour period (e.g., rapid burst release is not observed). If the nanoparticles were very quickly cleared from circulation, the large increase in AUC would not be observed. Similarly, if there was rapid burst release of docetaxel from the nanoparticles, the pharmacokinetic profile would be expected to more closely resemble that of conventional docetaxel.
- Blood was drawn at 1, 3, 6, 12, and 24 hours post-dosing and processed to plasma. Immediately following blood collection, the rats were euthanized by CO 2 asphyxiation and tissues were immediately collected, blotted, weighed, and frozen on dry ice. Tissue samples were stored frozen (approximately ⁇ 70° C.) until analysis for radioactivity by liquid scintillation (LS) counting.
- LS liquid scintillation
- the docetaxel encapsulated in nanoparticles was gradually cleared from the plasma, exhibiting an approximate 2-fold decrease in plasma concentration over the 24 hour period studied.
- MPS mononuclear phagocyte system
- this difference in plasma clearance times may be attributed to certain nanoparticle characteristics, including particle size and surface properties (e.g., surface charge and porosity).
- the profiles of the docetaxel encapsulated in nanoparticles wherein the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14 C-labeled and the docetaxel encapsulated in nanoparticles wherein the encapsulated docetaxel was 14 C-labeled would be superimposable.
- Example Tables 3.1, 3.2, and 3.3 present the tissue distribution of radioactivity determined in rats after intravenous (IV) administration of (1) docetaxel encapsulated in nanoparticles in which the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14 C-labeled, (2) docetaxel encapsulated in nanoparticles in which the encapsulated docetaxel was 14 C-labeled, and (3) 14 C-labeled conventional docetaxel, respectively.
- Example FIG. 5 contains the radioactivity concentration curves of the test articles determined in plasma, liver, spleen, and bone marrow.
- the concentration of docetaxel encapsulated in nanoparticles was higher in most tissues than conventional docetaxel.
- concentration of docetaxel derived from the nanoparticles was lower than or approximately the same as the concentration of conventional docetaxel in all of the tissues evaluated, except the spleen.
- the concentration of docetaxel encapsulated in nanoparticles was higher than conventional docetaxel at early timepoints and throughout the 24 hour period in the spleen, the nanoparticles doped with docetaxel were well tolerated at approximately 10 mg/kg docetaxel dose.
- body weight changes and clinical observations in the Sprague-Dawley rats indicate that the docetaxel encapsulated in nanoparticles was tolerated as well as conventional docetaxel through a range of acute doses (5-30 mg/kg docetaxel).
- mice Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 300 mm 3 . At this time, a single intravenous (IV) dose of 50 mg/kg docetaxel was administered as either docetaxel encapsulated in nanoparticles or conventional docetaxel. The test subjects were sacrificed 2 hour or 12 hour post-dose. The tumors from each group were excised and assayed for docetaxel using liquid chromatography-mass spectrometry (LC-MS).
- IV intravenous
- Example Table 4.1 and FIG. 6 The measured docetaxel concentrations in tumors excised from the test subjects dosed with docetaxel encapsulated in nanoparticles or conventional docetaxel are presented in Example Table 4.1 and FIG. 6 .
- the tumor docetaxel concentration in test subjects receiving docetaxel encapsulated in nanoparticles was approximately 7 times higher than in the test subjects receiving conventional docetaxel.
- mice Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 250 mm 3 . Subsequently, the mice were treated every other day (Q2D) for four doses, with an eight day holiday, followed by another four doses at the Q2D schedule.
- Q2D every other day
- Example FIG. 7 Average tumor volumes for each treatment group are shown in Example FIG. 7 .
- Treatment with either conventional docetaxel or docetaxel encapsulated in nanoparticles resulted in appreciable reduction in tumor volume.
- Tumor volume reduction was greater in test subjects receiving docetaxel encapsulated in nanoparticles compared to conventional docetaxel.
- Nasal and eye discharges appeared with a pattern that was unrelated to dose level, test article, sex of the animals, or time after dosing, and this clinical sign was considered to be possibly related to docetaxel and/or to stress from the dosing procedure.
- Example Table 6.1 male and female rats dosed with either conventional docetaxel or docetaxel encapsulated in nanoparticles showed generally minor deficits in body weight gain or actual body weight losses that were considered to be due to docetaxel toxicity.
- the no-adverse effect level (NOAEL) of nanoparticles doped with docetaxel in this study was considered to be 7.5 mg/kg.
- rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 14 having vincristine and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or vincristine alone.
- the release profiles are shown in FIG. 8 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with vincristine alone is as follows:
- rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 15 having methotrexate and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or methotrexate alone.
- the release profiles are shown in FIG. 9 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with methotrexate alone is as follows:
- rats were intravenously dosed with 1.0 mg/kg with either nanoparticles prepared as in FIG. 2 having paclitaxel and PLA-PEG (formulation C) and no specific targeting moiety (passively targeted nanoparticles (PTNP); or paclitaxel alone.
- the release profiles are shown in FIG. 10 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with paclitaxel alone is as follows:
- rats were intravenously dosed with 2.0 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 16, having rapamycin and PLA-PEG and no specific targeting moiety (passively targeted nanoparticles (PTNP); or rapamycin alone.
- the release profiles are shown in FIG. 11 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with rapamcyin alone is as follows:
- mice with MX-1 breast tumors were randomized into three groups, receiving docetaxel (3 mice), passively targeted nanoparticles (Formulation A, without a targeting moiety, PTNP), or Formulation A.
- the average tumor mass was 1.7 g (RSD 34%).
- Mice were then injected with 10 mg/kg of the test article, then euthanized 24 hours later and the tumors were removed and analyzed for docetaxel content using LC/MS/MS. Results are depicted in FIG. 12 .
- the percent of injected dose in the tumor was 3% (for docetaxel alone), 30% for PTNP, and 30% Formulation A.
- the dosing day was 1 day and the formulations were administered by 30 minute IV infusion at 25 mg/m 2 docetaxel or 50 mg/m 2 docetaxel (animals were randomized and then dosed with 50 mg/m2 on day 29 and PK, hematology and clinical chemistry were measured for 21 days). At the end of the study, PK, hematology and clinical chemistry collected over a 21 day period were assessed.
- FIG. 12 depicts the results of male (M) and female (F) PNP.
- a comparison of the pharmacokinetics of the nanoparticles of Formulation A (25 mg/m 2 dose) with docetaxel alone is as follows:
- An organic phase is formed composed of a mixture of docetaxel (DTXL) and polymer (homopolymer, co-polymer, and co-polymer with ligand).
- the organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent.
- aqueous phase is composed of a surfactant and some dissolved solvent.
- about 30% solids in the organic phase is used.
- the primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer.
- the rotor/stator yielded a homogeneous milky solution, while the stir bar produced a visibly larger coarse emulsion. It was observed that the stir bar method resulted in significant oil phase droplets adhering to the side of the feed vessel, suggesting that while the coarse emulsion size is not a process parameter critical to quality, it should be made suitably fine in order to prevent yield loss or phase separation. Therefore the rotor stator is used as the standard method of coarse emulsion formation, although a high speed mixer may be suitable at a larger scale.
- the primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer.
- Organic phase was emulsified 5:1 O:W with standard aqueous phase, and multiple discreet passes were performed, quenching a small portion of emulsion after each pass.
- the indicated scale represents the total solids of the formulation.
- FIGS. 8 and 9 depicts the effect of solids concentration on particle size and drug loading; with the exception of the 15-175 series, all batches are placebo. For placebo batches the value for % solids represents the % solids were drug present at the standard 20% w/w.
- Table A summarizes the emulsification process parameters.
- the fine emulsion is then quenched by addition to deionized water at a given temperature under mixing.
- the emulsion is added to a cold aqueous quench under agitation. This serves to extract a significant portion of the oil phase solvents, effectively hardening the nanoparticles for downstream filtration. Chilling the quench significantly improved drug encapsulation.
- the quench:emulsion ratio is approximately 5:1.
- Tween 80 A solution of 35% (wt %) of Tween 80 is added to the quench to achieve approximately 2% Tween 80 overall After the emulsion is quenched a solution of Tween-80 is added which acts as a drug solubilizer, allowing for effective removal of unencapsulated drug during filtration. Table B indicates each of the quench process parameters.
- the temperature must remain cold enough with a dilute enough suspension (low enough concentration of solvents) to remain below the T g of the particles. If the Q:E ratio is not high enough, then the higher concentration of solvent plasticizes the particles and allows for drug leakage. Conversely, colder temperatures allow for high drug encapsulation at low Q:E ratios (to ⁇ 3:1), making it possible to run the process more efficiently.
- the nanoparticles are then isolated through a tangential flow filtration process to concentrate the nanoparticle suspension and buffer exchange the solvents, free drug, and drug solubilizer from the quench solution into water.
- a regenerated cellulose membrane is used with with a molecular weight cutoffs (MWCO) of 300.
- a constant volume diafiltration (DF) is performed to remove the quench solvents, free drug and Tween-80.
- DF constant volume diafiltration
- buffer is added to the retentate vessel at the same rate the filtrate is removed.
- Crossflow rate refers to the rate of the solution flow through the feed channels and across the membrane. This flow provides the force to sweep away molecules that can foul the membrane and restrict filtrate flow.
- the transmembrane pressure is the force that drives the permeable molecules through the membrane.
- the filtered nanoparticle slurry is then thermal cycled to an elevated temperature during workup.
- a small portion typically 5-10% of the encapsulated drug is released from the nanoparticles very quickly after its first exposure to 25° C.
- ‘loosely encapsulated’ drug can be removed and improve the product stability at the expense of a small drop in drug loading.
- the nanoparticle suspension (concentration 50 mg/ml), is passed through a sterilizing grade filter (0.2 ⁇ m absolute).
- Pre-filters are used to protect the sterilizing grade filter in order to use a reasonable filtration area/time for the process. Filtration flow rate is ⁇ 1.3 L/min/m 2 .
- the filtration train is Ertel Alsop Micromedia XL depth filter M953P membrane (0.2 ⁇ m Nominal); Pall SUPRAcap with Seitz EKSP depth filter media (0.1-0.3 ⁇ m Nominal); Pall Life Sciences Supor EKV 0.65/0.2 micron sterilizing grade PES filter. 0.2 m 2 of filtration surface area per kg of nanoparticles for depth filters and 1.3 m 2 of filtration surface area per kg of nanoparticles for the sterilizing grade filters can be used.
- the nanoparticle preparation protocol described in Example 12 was modified to produce slow release nanoparticles.
- a batch of nanoparticles was produced that incorporated a 50:50 ratio of 100 DL 7E PLA (see Table 1) with the 16/5 PLA-PEG copolymer.
- the addition of high molecular weight PLA is thought to decrease drug diffusion by increasing crystallinity, raising the glass transition temperature, or reducing drug solubility in the polymer.
- Nanoparticle batches were prepared using the general procedure of Example 12, with 80% (w/w) Polymer-PEG or Polymer-PEG with homopolymer PLA at 40% (w/w) each, with a batch of % total solids of 5%, 15% and 30%. Solvents used were: 21% benzyl alcohol and 79% ethyl acetate (w/w). For each 2 gram batch size, 400 mg of drug was used and 1.6 g of 16-5 Polymer-PEG or 0.8 g of 16-5 Polymer-PEG+0.8 g of 10 kDa PLA (homopolymer) was used.
- the organic phase (drug and polymer) is prepared in 2 g batches: To 20 mL scintillation vial add drug and polymer(s). The mass of solvents needed at % solids concentration is:: 5% solids: 7.98 g benzyl alcohol+30.02 g ethyl acetate; 30% solids: 0.98 g benzyl alcohol+3.69 g ethyl acetate
- An aqueous solution is prepared with 0.5% sodium cholate, 2% benzyl alcohol, and 4% ethyl acetate in water. Add to the bottle 7.5 g sodium cholate, 1402.5 g of DI water, 30 g of benzyl alcohol and 60 g of ethyl acetate, and mix on stir plate until dissolved.
- a ratio of aqueous phase to oil phase is 5:1.
- the organic phase is poured into the aqueous solution and homogenized using IKA for 10 seconds at room temperature to form course emulsion.
- the solution is fed through the homogenizer (110S) at 9 Kpsi (45 psi on gauge) for 2 discreet passes to form nanoemulsion.
- the emulsion is poured into quench (D.I. water) at ⁇ 5° C. while stirring on stir plate. Ratio of quench to emulsion is 8:1. 35% (w/w) Tween 80 is added in water to quench at ratio of 25:1 Tween 80 to drug.
- the nanoparticles are concentrated through TFF and the quench is concentrated on TFF with 500 kDa Pall cassette (2 membrane) to ⁇ 100 mL. Diafiltering is used using ⁇ 20 diavolumes (2 liters) of cold DI water, and the volume is brought down to minimal volume then collect final slurry, ⁇ 100 mL.
- the solids concentration of unfiltered final slurry is determined by the using tared 20 mL scintillation vial and adding 4 mL final slurry and dry under vacuum on lyo/oven and the weight of nanoparticles in the 4 mL of slurry dried down is determined.
- Concentrated sucrose (0.666 g/g) is added to final slurry sample to attain 10% sucrose.
- Solids concentration of 0.45 um filtered final slurry was determined by filtering about 5 mL of final slurry sample before addition of sucrose through 0.45 ⁇ m syringe filter; to tared 20 mL scintillation vial add 4 mL of filtered sample and dry under vacuum on lyo/oven.
- the remaining sample of unfiltered final slurry was frozen with sucrose.
- Composition Components by Wt.(%) mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/Vincristine 95/5 mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 46/46/8 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 47/47/6
- Drug was dissolved in the inner aqueous phase consisting of water with 1-arginine or NaOH used for solubilizing the drug.
- the polymer (16-5 PLA-PEG) was dissolved in the oil phase organic solvent system, such as dichloromethane (DCM) at 20% solid concentration.
- the outer aqueous phase consisted mainly of water with 1% sodium cholate (SC) as surfactant, unless noted otherwise.
- the w/o emulsion was prepared by adding the inner aqueous phase into the oil phase under rotor stator homogenization or sonication (using Branson Digital Sonifier) at a w/o ratio of 1:10.
- the coarse w/o/w emulsion was also prepared by adding the w/o emulsion into an outer aqueous phase under either rotor stator homogenization or sonication at o/w ratio of 1:10.
- the fine w/o/w emulsion was then prepared by processing the coarse emulsion through a Microfluidics high pressure homogenizer (M110S pneumatic) at 45000 psi with a 100 ⁇ m Z-interaction chamber.
- M110S pneumatic Microfluidics high pressure homogenizer
- the fine emulsion was then quenched into cold DI water at 10:1 quench:emulsion ratio.
- Polysorbate 80 (Tween 80) was then added as a process solubilizer to solubilize the unencapsulated drug. No drug precipitation was observed at a drug:Tween 80 ratio of 1:200.
- the batch was then processed with ultrafiltration followed by diafiltration to remove solvents, unencapsulated drug and solubilizer. The particle size measurements were performed by Brookhaven DLS and/or Horiba laser diffraction. To determine drug load, slurry samples were analyzed by HPLC and solid concentration analysis. The slurry retains were then diluted with sucrose to 10% before freezing. All ratios listed are on a w/w basis, unless specified otherwise.
- both the inner w/o and outer w/o/w emulsions were formed by rotor stator homogenization followed by 2 passes at 45 k psi using a high pressure homogenizer.
- the nanoparticle suspension was quenched in cold DI water followed by ultrafiltration/diafiltration work-up. HPLC and PSD analysis was used to determine that the drug load stayed at 0.38% for 131 nm particles.
- the emulsion process for all three batches remained similar. The highest drug load was obtained for the 16/5 PLA-PEG batch at 2.23% while the drug load was 0.2% and 0.04% for other batches.
- An organic phase is formed composed of a mixture of sirolimus and polymer (homopolymer, co-polymer, and co-polymer with ligand).
- the organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent.
- aqueous phase is composed of a surfactant and some dissolved solvent.
- the primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer.
- the primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer. The process is continued as in Example 12.
- Rapamycin (sirolimus) formulations are representative Rapamycin (sirolimus) formulations:
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EP2379064A2 (en) | 2011-10-26 |
EP2379064B1 (en) | 2020-02-26 |
US9308179B2 (en) | 2016-04-12 |
ES2776126T3 (es) | 2020-07-29 |
EA201100765A1 (ru) | 2012-04-30 |
JP2015143268A (ja) | 2015-08-06 |
WO2010075072A2 (en) | 2010-07-01 |
US20130034608A1 (en) | 2013-02-07 |
WO2010075072A3 (en) | 2010-10-14 |
US20110217377A1 (en) | 2011-09-08 |
US20140093579A1 (en) | 2014-04-03 |
US9198874B2 (en) | 2015-12-01 |
JP2019142924A (ja) | 2019-08-29 |
JP2012512175A (ja) | 2012-05-31 |
US20160045608A1 (en) | 2016-02-18 |
JP2017165780A (ja) | 2017-09-21 |
EP2379064A4 (en) | 2012-06-20 |
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