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Publication numberUS20110052708 A1
Publication typeApplication
Application numberUS 12/713,092
Publication date3 Mar 2011
Filing date25 Feb 2010
Priority date22 Feb 1993
Also published asCN1839806A, CN1839806B, US5439686, US5560933
Publication number12713092, 713092, US 2011/0052708 A1, US 2011/052708 A1, US 20110052708 A1, US 20110052708A1, US 2011052708 A1, US 2011052708A1, US-A1-20110052708, US-A1-2011052708, US2011/0052708A1, US2011/052708A1, US20110052708 A1, US20110052708A1, US2011052708 A1, US2011052708A1
InventorsPatrick Soon-Shiong, Neil P. Desai
Original AssigneePatrick Soon-Shiong, Desai Neil P
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Methods and formulations for the delivery of pharmacologically active agents
US 20110052708 A1
Abstract
In accordance with the present invention, novel formulations have been developed which are much more effective for the delivery of hydrophobic drugs to patients in need thereof than are prior art formulations. Invention formulations are capable of delivering more drug in shorter periods of time, with reduced side effects caused by the pharmaceutical carrier employed for delivery.
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Claims(17)
That which is claimed is:
1. A formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the size of the nanoparticles is in the range of 20-400 nm, and wherein said formulation is characterized by one or more of the following:
wherein said formulation provides a higher concentration of paclitaxel in the cellular compartment than a formulation of paclitaxel with cremophor;
wherein said formulation provides increased intra-cellular availability of paclitaxel relative to a formulation of paclitaxel with cremophor;
wherein said formulation provides a higher concentration maximum (Cmax) for paclitaxel in tumor cells than does a formulation of paclitaxel with cremophor;
wherein said formulation enhances delivery of paclitaxel to a tumor tissue relative to a formulation of paclitaxel with cremophor; and
wherein said formulation enhances delivery of paclitaxel to pancreas, prostate, kidney, lung, heart, bone, or spleen relative to a formulation of paclitaxel with cremophor.
2. The formulation of claim 1, wherein the albumin is human serum albumin.
3. The formulation of claim 1, wherein said formulation enhances delivery of paclitaxel to a tumor tissue relative to a formulation of paclitaxel with cremophor.
4. The formulation of claim 3, wherein said formulation enhances delivery of paclitaxel to pancreas, kidney, lung, heart, bone, or spleen relative to a formulation of paclitaxel with cremophor.
5. A formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the size of the nanoparticles is in the range of 20-400 nm, wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m2 and about 158 mg/m2.
6. The formulation of claim 5, wherein the albumin is human serum albumin.
7. The formulation of claim 5, wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m2 and about 700 mg/m2.
8. The formulation of claim 5, wherein said administration is intravenous administration.
9. A method of administration comprising administering formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the size of the nanoparticles is in the range of 20-400 nm, and wherein said formulation is characterized by one or more of the following:
wherein said formulation provides a higher concentration of paclitaxel in the cellular compartment than a formulation of paclitaxel with cremophor;
wherein said formulation provides increased intra-cellular availability of paclitaxel relative to a formulation of paclitaxel with cremophor;
wherein said formulation provides a higher concentration maximum (Cmax) for paclitaxel in tumor cells than does a formulation of paclitaxel with cremophor;
wherein said formulation enhances delivery of paclitaxel to a tumor tissue relative to a formulation of paclitaxel with cremophor; and
wherein said formulation enhances delivery of paclitaxel to pancreas, prostate, kidney, lung, heart, bone, or spleen relative to a formulation of paclitaxel with cremophor.
10. The method of claim 9, wherein the albumin is human serum albumin.
11. The method of claim 9, wherein said formulation enhances delivery of paclitaxel to a tumor tissue relative to a formulation of paclitaxel with cremophor.
12. The method of claim 11, wherein said formulation enhances delivery of paclitaxel to pancreas, kidney, lung, heart, bone, or spleen relative to a formulation of paclitaxel with cremophor.
13. The method of claim 9, wherein said administration is intravenous administration.
14. A method of administration comprising administering a formulation comprising nanoparticles comprising paclitaxel and albumin which is free of cremophor, wherein the size of the nanoparticles is in the range of 20-400 nm, and upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m2 and about 158 mg/m2.
15. The method of claim 14, wherein the albumin is human serum albumin.
16. The method of claim 14, wherein upon administration of said formulation the area under curve of paclitaxel increases proportionally with the dose of paclitaxel between about 55 mg/m2 and about 700 mg/m2.
17. The method of claim 14, wherein said administration is intravenous administration.
Description
    RELATED APPLICATIONS
  • [0001]
    The present application is a continuation of U.S. Ser. No. 11/240,940, filed Sep. 29, 2005, now pending, which is a continuation of U.S. Ser. No. 10/146,706, filed May 14, 2002, now abandoned, which is a continuation-in-part of U.S. Ser. No. 09/628,388, filed Aug. 1, 2000, now issued U.S. Pat. No. 6,506,405, which is a divisional of U.S. Ser. No. 08/926,155, filed Sep. 9, 1997, now issued as U.S. Pat. No. 6,096,331, which is a continuation-in-part of U.S. Ser. No. 08/720,756, filed Oct. 1, 1996, now issued as U.S. Pat. No. 5,916,596, and U.S. Ser. No. 08/485,448, filed Jun. 7, 1995, now U.S. Pat. No. 5,665,382, which is, in turn, a continuation-in-part of U.S. Ser. No. 08/200,235, filed Feb. 22, 1994, now issued as U.S. Pat. No. 5,498,421, which is, in turn, a continuation-in-part of U.S. Ser. No. 08/023,698, filed Feb. 22, 1993, now issued as U.S. Pat. No. 5,439,686 and U.S. Ser. No. 08/035,150, filed Mar. 26, 1993, now issued as U.S. Pat. No. 5,362,478, the content of each of which are hereby incorporated by reference therein in their entirety.
  • FIELD OF THE INVENTION
  • [0002]
    The present invention relates to novel formulations of pharmacologically active agents and methods for the delivery of such agents to subjects in need thereof.
  • BACKGROUND OF THE INVENTION
  • [0003]
    In the quest for next generation therapies to treat cancer, scientist often discover promising compounds only to find that the molecule is highly insoluble in water, and hence impossible to deliver intravenously. Such was the problem with paclitaxel, an extremely effective anti-tumor agent discovered over a quarter century ago by the Nation Cancer Institute. Despite almost 30 years of effort, the only method currently approved to address this problem of water-insolubility of paclitaxel is the use of a toxic solvent (cremophor) to dissolve the drug, and administer this solvent-paclitaxel mixture over many hours using specialized intra-venous tubing sets to prevent the leaching of plasticizers. This solvent-drug mixture, currently marketed in branded and generic forms, has become the most widely used anti-cancer agent as it has shown activity in breast, lung and ovarian cancer and is undergoing multiple clinical trials exploring its application in combination with other drugs for other solid tumors.
  • [0004]
    The cremophor formulation of paclitaxel is associated with significant side-effects including life-threatening allergic reactions requiring the need for steroid pre-treatment for every patient receiving the drug, and severe infections as a result of lowering of white blood cells requiring the need for expensive blood cell growth factors. Ultimately these toxicities result in dose-limitation of cremophor-based paclitaxel formulations, thus limiting the full potential of the very effective paclitaxel molecule.
  • [0005]
    While the above toxic side effects of cremophor paclitaxel formulations are well known, it has not been widely recognized by scientists in the field that the presence of cremophor creates a more serious impediment to realizing the maximal potential of paclitaxel by entrapping paclitaxel within the hydrophobic cores of cremophor micelles within microdroplets in the blood-stream. The entrapment effect of cremophor is dependent on cremophor concentration. Thus, increasing the doses of cremophor solutions of paclitaxel can potentially worsen the entrapment by raising the concentration of cremophor, leading to higher toxicities but none of the potential benefits of higher doses of paclitaxel, since much of the active molecule is unavailable to the intra-cellular space, where it is needed to act.
  • [0006]
    This entrapment of paclitaxel by cremophor has a profound effect on the intra-cellular availability of the active molecule and hence may have significant clinical implications in terms of clinical outcome. Accordingly, there is a need in the art for new formulations for the delivery of substantially water insoluble pharmacologically active agents, such as paclitaxel, which do not suffer from the drawbacks of cremophor.
  • BRIEF DESCRIPTION OF THE INVENTION
  • [0007]
    In accordance with the present invention, novel formulations have been developed which are much more effective for the delivery of hydrophobic drugs to patients in need thereof than are prior art formulations. Invention formulations are capable of delivering more drug in shorter periods of time, with reduced side effects caused by the pharmaceutical carrier employed for delivery.
  • BRIEF DESCRIPTION OF THE FIGURES
  • [0008]
    FIG. 1 collectively compares the plasma kinetics of radiolabelled paclitaxel when administered to a mouse model as part of a Taxol formulation (closed squares) or as part of in invention formulation (diamonds; ABI-007). FIG. 1A indicates plasma radioactivity measured up to 0.5 hours after administration. FIG. 1B indicates plasma radioactivity measured up to 24 hours after administration. Inspection of the figure reveals that 2-5 fold higher levels of paclitaxel are retained in the plasma up to 3 hours after administration when paclitaxel is administered in a cremophor-based formulation (Taxol). Due to the reduced rate of metabolism for ABI-007, plasma levels of paclitaxel are higher after 8 hours when administered in an invention formulation, relative to a cremophor-based formulation.
  • [0009]
    FIG. 2 compares the partitioning of paclitaxel between red blood cells and plasma when administered to a mouse model as part of a Taxol formulation (closed squares) or as part of in invention formulation (diamonds; ABI-007). Inspection of the figure reveals that the blood/plasma ratio for paclitaxel administered as part of a cremophor-based formulation (Taxol) in the first 3 hours after administration is about 1.5-2, indicating that the majority of paclitaxel is retained in the plasma due to micellar formation with cremophor. In addition, it is seen that paclitaxel in a cremophor-based formulation does not significantly partition into the red blood cells. In contrast, paclitaxel administered as part of an invention formulation readily partitions into the red blood cells.
  • [0010]
    FIG. 3 summarizes tumor/plasma partitioning kinetics of paclitaxel when administered to a mouse model as part of a Taxol formulation (closed squares) or as part of in invention formulation (diamonds; ABI-007). It is seen that the tumor/plasma ratio of paclitaxel increases significantly over the first 3 hours when as part of an invention formulation, as opposed to a Taxol formulation.
  • [0011]
    FIG. 4 compares the response of mammary carcinoma in a mouse model to exposure to ABI-007 or Taxol.
  • [0012]
    FIG. 5 compares the response of ovarian carcinoma in a mouse model to exposure to ABI-007 or Taxol.
  • [0013]
    FIG. 6 compares the response of prostate tumors in a mouse model to exposure to ABI-007 or Taxol.
  • [0014]
    FIG. 7 compares the response of colon tumors in a mouse model to exposure to ABI-007 or Taxol.
  • [0015]
    FIG. 8 compares the response of lung tumors in a mouse model to exposure to ABI-007 or Taxol.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0016]
    In accordance with the present invention, there are provided methods for the delivery of a substantially water insoluble pharmacologically active agent to a subject in need thereof, said method comprising combining said agent with an effective amount of a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, and administering an effective amount of said combination to said subject.
  • [0017]
    As readily recognized by those of skill in the art, a wide variety of pharmacologically active agents are contemplated for use in the practice of the present invention. A presently preferred agent contemplated for use herein is paclitaxel.
  • [0018]
    Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention are biocompatible materials such as albumin.
  • [0019]
    Micelle-forming components which are preferably avoided in the practice of the present invention are surface active materials which are commonly used to assist in solubilizing substantially insoluble compounds in aqueous media, such as, for example, cremophor.
  • [0020]
    Invention combination of active agent and pharmaceutically acceptable carrier can be administered in a variety of ways, such as, for example, by oral, intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, intracranial, inhalational, topical, transdermal, rectal, or pessary routes of administration, and the like.
  • [0021]
    In accordance with another embodiment of the present invention, there are provided methods to reduce entrapment of a substantially water insoluble pharmacologically active agent in vehicle employed for delivery thereof, said method comprising combining said agent with a pharmaceutically acceptable carrier which is substantially free of micelle-forming components prior to delivery thereof.
  • [0022]
    Presently preferred pharmaceutically acceptable carriers contemplated for use herein are those having substantially lower affinity for said agent than does the micelle-forming component. Thus, for example, while cremophor has the benefit of aiding in the solubilization of agent, it has the disadvantage of having a substantial affinity for the agent, so that release of the agent from the carrier becomes a limitation on the bioavailability of the agent. In contrast, carriers contemplated herein, such as, for example, albumin, readily release the active agent to the active site and are thus much more effective for treatment of a variety of conditions.
  • [0023]
    In accordance with yet another embodiment of the present invention, there are provided methods to reduce entrapment of a substantially water insoluble pharmacologically active agent in vehicle employed for delivery thereof, said method comprising employing pharmaceutically acceptable carriers which are substantially free of micelle-forming components in aqueous media as the vehicle for delivery of said agent.
  • [0024]
    In accordance with still another embodiment of the present invention, there are provided methods to prolong exposure of a subject to a substantially water insoluble pharmacologically active agent upon administration thereof to a subject in need thereof, said method comprising combining said agent with pharmaceutically acceptable carrier(s) which is (are) substantially free of micelle-forming components prior to delivery thereof.
  • [0025]
    In accordance with a further embodiment of the present invention, there are provided methods to facilitate transport of a substantially water insoluble pharmacologically active agent across cell membranes upon administration thereof to a subject in need thereof, said method comprising combining said agent with pharmaceutically acceptable carrier(s) which is (are) substantially free of micelle-forming components prior to delivery thereof.
  • [0026]
    In accordance with a still further embodiment of the present invention, there are provided methods to facilitate transport of a substantially water insoluble pharmacologically active agent into the cellular compartment upon administration thereof to a subject in need thereof, said method comprising combining said agent with pharmaceutically acceptable carrier(s) which is (are) substantially free of micelle-forming components prior to delivery thereof.
  • [0027]
    In accordance with another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides a higher concentration of said agent in the cellular compartment than a formulation of the same agent with a micelle-forming component.
  • [0028]
    In accordance with yet another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides increased intra-cellular availability of said agent relative to a formulation of the same agent with a micelle-forming component.
  • [0029]
    In accordance with still another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides prolonged activity of said agent relative to a formulation of the same agent with a micelle-forming component.
  • [0030]
    In accordance with a further embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation facilitates delivery of said agent to red blood cells.
  • [0031]
    In accordance with another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation releases a portion of said agent contained therein to the lipid membrane of a cell.
  • [0032]
    In accordance with yet another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides reduced levels of said agent in the bloodstream relative to a formulation of the same agent with a micelle-forming component.
  • [0033]
    In accordance with still another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation delivers said agent to the bloodstream over an extended period of time relative to a formulation of the same agent with a micelle-forming component.
  • [0034]
    In accordance with a further embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein the rate of metabolism of said agent in said formulation is reduced relative to the rate of metabolism of said agent in a formulation with a micelle-forming component.
  • [0035]
    In accordance with another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said agent has a longer half life in said formulation relative to the half life of said agent in a formulation with a micelle-forming component.
  • [0036]
    In accordance with yet another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides a higher red blood cell/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component.
  • [0037]
    In accordance with still another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides a higher tumor/plasma ratio of said agent than does a formulation of the same agent with a micelle-forming component.
  • [0038]
    In accordance with a further embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein the area under the curve for delivery of said agent to a tumor via said formulation is higher than the area under the curve for delivery of said agent to a tumor via a formulation of the same agent with a micelle-forming component.
  • [0039]
    In accordance with a still further embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides a higher concentration maximum (Cmax) for said agent in tumor cells than does a formulation of the same agent with a micelle-forming component.
  • [0040]
    In accordance with another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides a lower concentration maximum (Cmax) for said agent in plasma than does a formulation of the same agent with a micelle-forming component.
  • [0041]
    In accordance with still another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation provides more rapid uptake of said agent by tumor cells than does a formulation of the same agent with a micelle-forming component.
  • [0042]
    In accordance with yet another embodiment of the present invention, there are provided formulations comprising a substantially water insoluble pharmacologically active agent and a pharmaceutically acceptable carrier which is substantially free of micelle-forming components, wherein said formulation enhances delivery of said agent to tissue, relative to a formulation of the same agent with a micelle-forming component.
  • [0043]
    Tissues contemplated for treatment according to the invention include tumors, peritoneal tissue, bladder tissue, lung tissue, and the like.
  • [0044]
    ABI-007 is a proprietary, cremophor-free, albumin-based paclitaxel nanoparticle, 1/100th the size of a single red blood cell. Based on several Phase I studies, it has been shown that ABI-007 can be administered rapidly without the need for steroid pre-treatment and without the need for G-CSF at a maximum tolerated dose of 300 mg/m2 given every 3 weeks. This is a significantly higher dose than is approved for cremophor-based paclitaxel formulations (Taxol) of 175 mg/m2.
  • [0045]
    In accordance with the present invention, it has been discovered that ABI-007 acts as a novel biologic nano-transporter for hydrophobic drugs such as paclitaxel, with the capabilities of rapidly releasing paclitaxel to the cellular compartment and increasing intra-cellular availability of the active drug, where it is needed in order to have its chemo-therapeutic effect. Furthermore, through the use of the red blood cell as a secondary storage vehicle it has been discovered that in addition to the rapid and increased availability of paclitaxel at the intra-cellullar level, by the recruitment of circulating red blood cells, ABI-007 further provides a significant prolonged activity of the parent molecule with sustained in-vivo release. These novel mechanisms for rapid and increased intra-cellular availabilty of the drug at the tumor site, together with sustained trafficking of the non-metabolized paclitaxel, has potentially significant implications for the clinical outcome in the treatment of solid tumors. Indeed, the pre-clinical and Phase II clinical data presented below supports this notion.
  • [0046]
    By taking advantage of the differences in binding affinities of albumin and the lipid bi-layer of cell membranes for hydrophobic paclitaxel, the drug-bearing albumin nanoparticle (ABI-007) would rapidly release a portion of its hydrophobic paclitaxel cargo to the lipid membrane of a cell.
  • [0047]
    In the vascular compartment, the first cell encountered is the red blood cell. In accordance with the present invention, the red blood cell has been found to rapidly compartmentalize the paclitaxel molecule. Since the red blood cell has no nucleus and hence no microtubulin to which the paclitaxel molecule can bind, nor any degradation machinery within its core, this cell serves as an ideal secondary storage vehicle for the active paclitaxel, accounting in part for the prolonged activity of paclitaxel noted with ABI-007.
  • [0048]
    Following partitioning of a portion of its paclitaxel payload to the circulating red blood cells, the nanoparticle is carried by the blood-stream to the hypervasular tumor, where paclitaxel is rapidly transferred to the tumor cell-membrane, again due to the differences in binding affinity. It has been well established by other groups that the hydrostatic pressure within these tumor cells is abnormally higher than the surrounding interstitium and vascular space. This abnormally high pressure, together with the fact that the vessels associated with tumors are also abnormally leaky, creates a barrier to the delivery of chemotherapeutic agents to the tumor cell. Thus, under these circumstances it is imperative that the hydrophobic paclitaxel be released rapidly to the lipid cell membrane and be bound by the microtubules within the nuclues before the drug is ejected from the tumor. Evidence presented herein indicates that ABI-007 provides that opportunity by the ability to rapidly release the hydrophobic molecule. In contrast, cremophor-based formulations entrap the paclitaxel, limiting the ability of the drug to partition into cells. This difference may have important clinical implications and may account in part for the positive data noted in the Phase II studies of ABI-007 in metastatic breast cancer and the evidence for responses in patients who had previously failed Taxol therapy
  • [0049]
    As the nanoparticle depeletes itself of paclitaxel into the cellular compartment within the first 3-8 hours following infusion, the plasma concentration of paclitaxel diminshes. At this juncture, paclitaxel (still in its active, non-metabolized form) follows the concentration gradient and is now transferred to albumin again, and is again carried to the tumor bed. Thus, a prolonged half-life of paclitaxel has been achieved, with sustained release and ultimately higher tumor concentration of the drug.
  • [0050]
    The invention will now be described in greater detail by reference to the following non-limiting examples.
  • Example 1 Preclinical Studies Confirm the Modulation of Paclitaxel Release by the Protein Nanosphere and Increased Efficacy of Equi-dose of ABI-007 vs Taxol
  • [0051]
    Using radio labeled paclitaxel, the enahanced intra-cellular availability of paclitaxel has been confirmed following injection of ABI-007. In addition, the entrapment of Cremophor-bound paclitaxel has also been confirmed. This difference in findings correlates with in-vivo studies in mice bearing human breast cancer, with the finding that ABI-007 at equi-dose to Taxol, resulted in improved outcomes that these 130 nanometer size particles distributed throughout the body.
  • [0052]
    Thus, human MX-1 mammary tumor fragments were implanted subcutaneously in female athymic mice. Radiolabelled drug was administered when tumors reached about 500 mm3. Tritium-labelled ABI-007 or tritium-labelled Taxol were administered at a dose of 20 mg/kg. Both groups received about 7-10 μCi/mouse of tritium-labelled paclitaxel. Saline was used as the diluent for both drugs. At various time points (5 min, 15 min, 30 min, 1 hr, 3 hr, 8 hr and 24 hr), 4 animals were sacrificed, then blood samples and tumor were recovered for radioactivity assessment.
  • [0053]
    Radioactivity was determined as nCi/ml of whole blood and plasma, and nCi/g of tumor tissue. Results are presented in FIGS. 1, 2 and 3, and are standardized for radioactivity and paclitaxel dose. The data from these studies are also presented in the following tables.
  • Pharmacokinetic Parameters for Whole-Blood, Plasma and Tumor Distribution of 3H-Paclitaxel in ABI-007 vs Taxol
  • [0054]
  • [0000]
    New
    AUC0-inf AUC0-24
    (nCi hr/mL or g) (nCi hr/mL or g) Cmax (nCi/mL or g)
    Blood Plasma Tumor Blood Plasma Tumor Blood Plasma Tumor
    ABI-007 939 1161 5869 ABI-007 656 836 2156 ABI-007 328 473 144
    Taxol 871 1438 3716 Taxol 849 1415 1804 Taxol 752 1427 117
    Ratio 1.08 0.81 1.58 Ratio 0.77 0.59 1.20 Ratio 0.44 0.33 1.23
    TAXOL: high Plasma AUC - paclitaxel is trapped in cremophor micelles
    ABI-007: higher Tumor AUC (exposure), pac distributed into cells/tissues
    ABI-007: Substantially lower Cmax in Plasma, blood Implies rapid distribution into cells and tissues
    ABI-007: higher Tumor Cmax - more effective tumor kill
  • [0000]
    tmax (hours) te (hours) Vdss (mL/kg)
    Blood Plasma Tumor Blood Plasma Tumor Blood Plasma Tumor
    ABI-007 0 0 0.5 ABI-007 17.1 16.1 40.2 ABI-007 6939 5180 NA
    Taxol 0 0 3 Taxol 4.0 3.3 24.1 Taxol 1409 692 NA
    Ratio 4.28 4.88 1.67 Ratio 4.92 7.49
    ABI-007: Substantially lower tumor tmax indicates rapid uptake of paclitaxel into tumor relative to taxol
    ABI-007: Prolonged half life relative to Taxol in blood, plasma and tumor may result in higher antitumor activity
    ABI-007: Substantially higher volume of distribution indicating extrensive distribution into tissues relative to Taxol
  • [0055]
    Further studies demonstrate that after 24 hours, the active ingredient of the parent molecule, paclitaxel, remains present in the bloodstream, at double the concentration of Taxol. In studies comparing radiolabelled paclitaxel in Taxol vs ABI-007, direct measurements reveal increased and prolonged levels of paclitaxel in the tumors of animals receiving ABI-007.
  • Example 2 Toxicity Studies
  • [0056]
    Toxicity was assessed for Taxol, cremophor and ABI-007. ABI-007 was found to be 50-fold less toxic than Taxol, and 30-fold less toxic than the cremophor vehicle alone, as illustrated in the following table:
  • [0000]
    Agent LD50, mg/kg
    Taxol 9.4
    Cremophor 13.7
    ABI-007 448.5
  • Example 3 In vivo Tumor Xenografts
  • [0057]
    Human tumor fragments were implanted subcutaneously in female athymic mice. Treatment was initiated when tumors reached about 150 mm3. The mice received either CONTROL (saline), ABI-007 (4 dose levels: 13.4, 20, 30 and 45 mg/kg) or TAXOL (3 dose levels: 13.4, 20, and 30 mg/kg) administered I.V. daily for 5 days. Saline was used as the diluent for both drugs.
  • [0058]
    Determination of Equitoxic dose or MTD: The Equitoxic dose or MTD for each drug was determined by satisfying one of the following criteria:
      • a) Dose for each drug that resulted in similar body weight loss (≦20%) if no deaths were seen;
      • b) If body weight loss could not be matched, the highest dose at which no deaths were seen;
      • If neither a) nor b) could be satisfied, the lowest dose that resulted in similar death rate.
  • [0062]
    Tumor response to the drugs was compared at the Equitoxic dose or MTD established as above. Results for several different tumor types are presented in FIGS. 4-8.
  • Example 4 Clinical Studies
  • [0063]
    i. Entrappment of Paclitaxel By Cremophor
  • [0064]
    Working independently at Rotterdam Cancer Institute, Dr Alex Sparreboom has reported in a series of pharmacokinetic studies involving patients receiving Taxol that cremophor “causes a profound alteration of paclitaxel accumulation in erythrocytes in a concentration-dependant manner by reducing the free drug fraction available for cellular partitioning.” He has further found that the drug trapping occurs in micelles and that these micelles act as the principal carrier of paclitaxel in the systemic circulation. Since that publication these findings have been independently confirmed by two other groups.
  • [0000]
    ii. Improved Clinical Activity With ABI-007
  • [0065]
    Data from Phase II shows both increased effiacacy in metastatic breast cancer patients. When compared to the published literature of response rates to Taxol, the study results showed a dramatic difference in both response rates and time of response as well as evidence of reduced toxicities associated with ABI-007. Further details can be obtained by reviewing the posters presented at ASCO.
  • [0066]
    Although the present invention has been described in conjunction with the embodiments above, it is to be noted that various changes and modifications are apparent to those who are skilled in the art. Such changes and modifications are to be understood as included within the scope of the present invention defined by the appended claims.
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US4534899 *7 Mar 198313 Aug 1985Lipid Specialties, Inc.Synthetic phospholipid compounds
US5059699 *28 Aug 199022 Oct 1991Virginia Tech Intellectual Properties, Inc.Water soluble derivatives of taxol
US5362478 *26 Mar 19938 Nov 1994Vivorx Pharmaceuticals, Inc.Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell
US5399363 *1 Jul 199221 Mar 1995Eastman Kodak CompanySurface modified anticancer nanoparticles
US5407683 *1 Oct 199218 Apr 1995Research Corporation Technologies, Inc.Pharmaceutical solutions and emulsions containing taxol
US5415869 *12 Nov 199316 May 1995The Research Foundation Of State University Of New YorkTaxol formulation
US5424073 *14 Oct 199313 Jun 1995Georgetown UniversityLiposome encapsulated taxol and a method of using the same
US5439686 *22 Feb 19938 Aug 1995Vivorx Pharmaceuticals, Inc.Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US5440056 *9 Mar 19948 Aug 1995Abbott Laboratories9-deoxotaxane compounds
US5498421 *22 Feb 199412 Mar 1996Vivorx Pharmaceuticals, Inc.Composition useful for in vivo delivery of biologics and methods employing same
US5505932 *6 Jun 19959 Apr 1996Vivorx Pharmaceuticals, Inc.Method for the preparation of fluorocarbon-containing polymeric shells for medical imaging
US5508021 *19 Oct 199416 Apr 1996Vivorx Pharmaceuticals, Inc.Non-fluorinated polymeric shells for medical imaging
US5512268 *6 Jun 199530 Apr 1996Vivorx Pharmaceuticals, Inc.Polymeric shells for medical imaging prepared from synthetic polymers, and methods for the use thereof
US5560933 *29 Mar 19951 Oct 1996Vivorx Pharmaceuticals, Inc.Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US5565478 *14 Mar 199415 Oct 1996The United States Of America As Represented By The Department Of Health & Human ServicesCombination therapy using signal transduction inhibitors with paclitaxel and other taxane analogs
US5567434 *7 Jun 199522 Oct 1996The Regents Of The University Of CaliforniaPreparation of liposome and lipid complex compositions
US5616330 *19 Jul 19941 Apr 1997Hemagen/PfcStable oil-in-water emulsions incorporating a taxine (taxol) and method of making same
US5616608 *18 Apr 19961 Apr 1997The United States Of America As Represented By The Department Of Health And Human ServicesMethod of treating atherosclerosis or restenosis using microtubule stabilizing agent
US5626862 *2 Aug 19946 May 1997Massachusetts Institute Of TechnologyControlled local delivery of chemotherapeutic agents for treating solid tumors
US5626867 *16 Mar 19936 May 1997Max-Planck Gesellschaft Zur Forderung Der Wissenschaften E.V.Liposomes with a negative excess charge
US5635207 *7 Jun 19953 Jun 1997Vivorx Pharmaceuticals, Inc.Methods for the preparation of blood substitutes for in vivo delivery
US5639473 *7 Jun 199517 Jun 1997Vivorx Pharmaceuticals, Inc.Methods for the preparation of nucleic acids for in vivo delivery
US5648090 *26 May 199515 Jul 1997Georgetown UniversityLiposome encapsulated toxol and a method of using the same
US5650156 *7 Jun 199522 Jul 1997Vivorx Pharmaceuticals, Inc.Methods for in vivo delivery of nutriceuticals and compositions useful therefor
US5651986 *14 Jun 199629 Jul 1997Massachusetts Institute Of TechnologyControlled local delivery of chemotherapeutic agents for treating solid tumors
US5665382 *7 Jun 19959 Sep 1997Vivorx Pharmaceuticals, Inc.Methods for the preparation of pharmaceutically active agents for in vivo delivery
US5665383 *7 Jun 19959 Sep 1997Vivorx Pharmaceuticals, Inc.Methods for the preparation of immunostimulating agents for in vivo delivery
US5670536 *25 Apr 199523 Sep 1997Rhone-Poulenc Rorer S.A.Pharmaceutical composition based on taxoids
US5681846 *17 Mar 199528 Oct 1997Board Of Regents, The University Of Texas SystemExtended stability formulations for paclitaxel
US5716981 *7 Jun 199510 Feb 1998Angiogenesis Technologies, Inc.Anti-angiogenic compositions and methods of use
US5725804 *6 Jun 199510 Mar 1998Hemosphere, Inc.Non-crosslinked protein particles for therapeutic and diagnostic use
US5731334 *27 Oct 199524 Mar 1998The Scripps Research InstituteMethod for treating cancer using taxoid onium salt prodrugs
US5733925 *28 Oct 199631 Mar 1998Neorx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US5756537 *8 Nov 199626 May 1998Parkash S. Gill, M.D., Inc.Regime for paclitaxel in Kaposi's sarcoma patients
US5766635 *5 Jun 199516 Jun 1998Rhone-Poulenc Rorer S.A.Process for preparing nanoparticles
US5795909 *22 May 199618 Aug 1998Neuromedica, Inc.DHA-pharmaceutical agent conjugates of taxanes
US5811447 *25 May 199522 Sep 1998Neorx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US5886026 *7 Jun 199523 Mar 1999Angiotech Pharmaceuticals Inc.Anti-angiogenic compositions and methods of use
US5916596 *1 Oct 199629 Jun 1999Vivorx Pharmaceuticals, Inc.Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5928669 *15 Jun 199827 Jul 1999Danbiosyst Uk LimitedLymphatic delivery methods
US5945033 *12 Nov 199631 Aug 1999Hemosphere, Inc.Method for making non-crosslinked protein particles for therapeutic and diagnostic use
US6051600 *27 Feb 199718 Apr 2000Mayhew; EricLiposomal hydrolysis-promoting hydrophobic taxane derivatives
US6066668 *6 Jan 199923 May 2000Bionumerik Pharmaceuticals, Inc.Formulations and methods of reducing toxicity of antineoplastic agents
US6074659 *10 Jul 199813 Jun 2000Noerx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US6090925 *19 Aug 199618 Jul 2000Epic Therapeutics, Inc.Macromolecular microparticles and methods of production and use
US6096331 *9 Sep 19971 Aug 2000Vivorx Pharmaceuticals, Inc.Methods and compositions useful for administration of chemotherapeutic agents
US6107332 *12 Feb 199922 Aug 2000The Liposome Company, Inc.Hydrolysis-promoting hydrophobic taxane derivatives
US6120805 *31 May 199519 Sep 2000Rhone-Poulenc Rorer SaMicrospheres, process for their preparation and their use
US6179817 *28 Jan 199930 Jan 2001Boston Scientific CorporationHybrid coating for medical devices
US6197051 *11 Feb 19996 Mar 2001Boston Scientific CorporationPolycarbonate-polyurethane dispersions for thromobo-resistant coatings
US6197349 *6 Nov 19976 Mar 2001Knoll AktiengesellschaftParticles with modified physicochemical properties, their preparation and uses
US6268390 *22 Dec 199931 Jul 2001Neorx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US6306421 *31 Mar 199723 Oct 2001Neorx CorporationTherapeutic inhibitor of vascular smooth muscle cells
US6432928 *2 Nov 199513 Aug 2002Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.Complexes and their compositions
US6441025 *30 Mar 199827 Aug 2002Pg-Txl Company, L.P.Water soluble paclitaxel derivatives
US6458373 *5 Jan 19981 Oct 2002Sonus Pharmaceuticals, Inc.Emulsion vehicle for poorly soluble drugs
US6506405 *1 Aug 200014 Jan 2003American Bioscience, Inc.Methods and formulations of cremophor-free taxanes
US6528067 *7 Dec 19994 Mar 2003American Bioscience, Inc.Total nutrient admixtures as stable multicomponent liquids or dry powders and methods for the preparation thereof
US6537579 *19 May 200025 Mar 2003American Bioscience, Inc.Compositions and methods for administration of pharmacologically active compounds
US6565842 *7 Jun 199520 May 2003American Bioscience, Inc.Crosslinkable polypeptide compositions
US6610735 *10 Apr 200126 Aug 2003Baker Norton Pharmaceuticals, Inc.Method, compositions and kits for increasing the oral bioavailability of pharmaceutical agents
US6743826 *27 Apr 19991 Jun 2004Human RtPharmaceutical compositions containing plasma protein
US6749868 *21 May 199915 Jun 2004American Bioscience, Inc.Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US6753006 *31 Jul 200022 Jun 2004American Bioscience, Inc.Paclitaxel-containing formulations
US6759431 *20 Aug 20016 Jul 2004Angiotech Pharmaceuticals, Inc.Compositions and methods for treating or preventing diseases of body passageways
US7238369 *8 Aug 20053 Jul 2007The Regents Of The University Of CaliforniaCationic liposome delivery of taxanes to angiogenic blood vessels
US7332568 *17 Feb 200619 Feb 2008Abraxis Bioscience, Inc.Q3 SPARC deletion mutant and uses thereof
US7758891 *12 Dec 200820 Jul 2010Abraxis Bioscience, LlcCombinations and modes of administration of therapeutic agents and combination therapy
US7771751 *30 Aug 200610 Aug 2010Abraxis Bioscience, LlcCompositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents
US7780984 *20 Jul 200724 Aug 2010Abraxis Bioscience, LlcMethods and compositions for treating proliferative diseases
US7820788 *26 Oct 200626 Oct 2010Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US7923536 *12 Apr 201012 Apr 2011Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US7981445 *11 Mar 200919 Jul 2011Abraxis Bioscience, LlcCompositions and methods for preparation of poorly water soluble drugs with increased stability
US20030087985 *19 Jul 20018 May 2003Hubbell Jeffrey A.Gels for encapsulation of biological materials
US20030199425 *2 May 200123 Oct 2003Desai Neil P.Compositions and methods for treatment of hyperplasia
US20050004002 *9 Dec 20036 Jan 2005American Bioscience, Inc.Compositions and methods of delivery of pharmacological agents
US20060073175 *29 Sep 20056 Apr 2006American Bioscience, Inc.Methods and formulations for delivery of pharmacologically active agents
US20070082838 *30 Aug 200612 Apr 2007Abraxis Bioscience, Inc.Compositions and methods for preparation of poorly water soluble drugs with increased stability
US20070087022 *12 Sep 200619 Apr 2007Abraxis Bioscience, Inc.Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20070093547 *12 Sep 200626 Apr 2007Desai Neil PNovel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20070116774 *6 Oct 200624 May 2007Abraxis Bioscience, Inc.Methods and compositions for treating proliferative diseases
US20070117133 *14 Nov 200624 May 2007Abraxis Bioscience, Inc.Sparc and methods of use thereof
US20070117744 *30 Aug 200624 May 2007Desai Neil PCompositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents
US20070129448 *26 Oct 20067 Jun 2007Abraxis Bioscience, Inc.Compositions and methods of delivery of pharmacological agents
US20070166388 *6 Nov 200619 Jul 2007Desai Neil PCombinations and modes of administration of therapeutic agents and combination therapy
US20080063724 *20 Jul 200713 Mar 2008Desai Neil PMethods and compostions for treating proliferative diseases
US20080161382 *3 Aug 20073 Jul 2008Neil DesaiNovel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20090263483 *10 Apr 200922 Oct 2009Desai Neil PNanoparticle formulations and uses thereof
US20100035800 *28 May 200911 Feb 2010Desai Neil PNovel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20100048499 *14 Dec 200725 Feb 2010Desai Neil PBreast cancer therapy based on hormone receptor status with nanoparticles comprising taxane
US20100112077 *6 Nov 20076 May 2010Abraxis Bioscience, LlcNanoparticles of paclitaxel and albumin in combination with bevacizumab against cancer
US20100166869 *5 May 20081 Jul 2010Desai Neil PMethods and compositions for treating pulmonary hypertension
US20100183728 *7 Mar 200822 Jul 2010Desai Neil PNanoparticle comprising rapamycin and albumin as anticancer agent
US20100215751 *2 Jun 200826 Aug 2010Desai Neil PMethods and compositions for treating recurrent cancer
US20110118342 *17 Jun 201019 May 2011Tapas DeCompositions and methods for preparation of poorly water soluble drugs with increased stability
US20110151012 *25 Jun 201023 Jun 2011Desai Neil PCompositions comprising poorly water soluble pharmaceutical agents and antimicrobial agents
US20110165256 *8 Jul 20107 Jul 2011Desai Neil PCompositions and methods for treatment of hyperplasia
US20110196026 *2 Sep 201011 Aug 2011Abraxis Bioscience, Inc.Compositions and methods for preparation of poorly water soluble drugs with increased stability
Non-Patent Citations
Reference
1 *Fan et al. "Formulation Optimization of Paclitaxel Carried by Paginated Emulsions based on Artificial Neural Network," in Pharmaceutical Research, Vol. 21, No. 9, September 2004 discloses injectable paclitaxel carried by Paginated emulsions.
2 *Felix Kratz, "Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles," in Journal of controlled Release, 132, (2008), 171-183.
3 *Gradishar et al. ("Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel compared with polyethylated Castor Oil-Based Paclitaxel in Women With Breast Cancer," in Journal of clinical oncology, vol. 23, no. 31, November 1 2005).
4 *Suri et al. (Nanotechnology-based drug delivery systems," in Journal of Occupational Medicine and Toxicology, Dec. 2007).
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US83141561 Mar 201120 Nov 2012Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US87353946 May 200927 May 2014Abraxis Bioscience, LlcCombinations and modes of administration of therapeutic agents and combination therapy
US884677111 Oct 201230 Sep 2014Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US885326012 Sep 20067 Oct 2014Abraxis Bioscience, LlcFormulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US89117867 Mar 200816 Dec 2014Abraxis Bioscience, LlcNanoparticle comprising rapamycin and albumin as anticancer agent
US89270192 Jun 20086 Jan 2015Abraxis Bioscience, LlcMethods and compositions for treating recurrent cancer
US899939627 Feb 20137 Apr 2015Abraxis Bioscience, LlcBreast cancer therapy based on hormone receptor status with nanoparticles comprising taxane
US901251826 Feb 201321 Apr 2015Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US901251926 Feb 201321 Apr 2015Abraxis Bioscience, LlcCompositions and methods of delivery of pharmacological agents
US910154314 Aug 201211 Aug 2015Abraxis Bioscience, LlcCombinations and modes of administration of therapeutic agents and combination therapy
US91494558 Mar 20136 Oct 2015Abraxis Bioscience, LlcMethods of treating melanoma
US930818029 Feb 201212 Apr 2016Abraxis Bioscience, LlcCompositions and methods for preparation of poorly water soluble drugs with increased stability
US937049425 Mar 201121 Jun 2016Abraxis Bioscience, LlcMethods for treating hepatocellular carcinoma
US939331828 Mar 201119 Jul 2016Abraxis Bioscience, LlcMethods of treating cancer
US939907120 May 201126 Jul 2016Abraxis Bioscience, LlcMethods of treatment of pancreatic cancer
US93990721 Mar 201326 Jul 2016Abraxis Bioscience, LlcMethods of treatment of pancreatic cancer
US944600326 Feb 201420 Sep 2016Abraxis Bioscience, LlcPrion free nanoparticle compositions and methods of making thereof
US956128827 Feb 20137 Feb 2017Abraxis Bioscience, LlcCombinations and modes of administration of therapeutic agents and combination therapy
US958596013 Dec 20127 Mar 2017Abraxis Bioscience, LlcUse of polymeric excipients for lyophilization or freezing of particles
US95974091 Mar 201321 Mar 2017Abraxis Bioscience, LlcMethods of treating cancer
US967557814 Dec 200713 Jun 2017Abraxis Bioscience, LlcBreast cancer therapy based on hormone receptor status with nanoparticles comprising taxane
US972432325 Feb 20158 Aug 2017Abraxis Bioscience, LlcBreast cancer therapy based on hormone receptor status with nanoparticles comprising taxane
US20030199425 *2 May 200123 Oct 2003Desai Neil P.Compositions and methods for treatment of hyperplasia
US20070087022 *12 Sep 200619 Apr 2007Abraxis Bioscience, Inc.Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20070093547 *12 Sep 200626 Apr 2007Desai Neil PNovel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
US20090263483 *10 Apr 200922 Oct 2009Desai Neil PNanoparticle formulations and uses thereof
US20090304805 *6 May 200910 Dec 2009Desai Neil PCombinations and modes of administration of therapeutic agents and combination therapy
US20100048499 *14 Dec 200725 Feb 2010Desai Neil PBreast cancer therapy based on hormone receptor status with nanoparticles comprising taxane
US20100166869 *5 May 20081 Jul 2010Desai Neil PMethods and compositions for treating pulmonary hypertension
US20100183728 *7 Mar 200822 Jul 2010Desai Neil PNanoparticle comprising rapamycin and albumin as anticancer agent
US20100215751 *2 Jun 200826 Aug 2010Desai Neil PMethods and compositions for treating recurrent cancer
US20110052706 *24 Aug 20103 Mar 2011Nordmark Arzeimittel GmbH & Co. KGPancreatine pellets and method of producing same
US20110118342 *17 Jun 201019 May 2011Tapas DeCompositions and methods for preparation of poorly water soluble drugs with increased stability
US20110165256 *8 Jul 20107 Jul 2011Desai Neil PCompositions and methods for treatment of hyperplasia
Classifications
U.S. Classification424/491, 977/773, 514/449, 977/915, 977/906
International ClassificationA23L33/00, A61K9/51, A61K9/50, A61K9/00, A61K47/48, A61P35/00, A61K31/337, A61K49/22, A61K9/14, A61K49/18
Cooperative ClassificationA61K47/6925, A61K47/6927, A61K49/0002, A61K9/5138, A61K9/5146, A61K49/222, A61K49/226, A23L33/40, A61K9/0026, A61K9/5052, A61K49/223, A61K9/5169, B82Y5/00, A61K9/5161
European ClassificationA61K49/22P12, A61K9/51H6D, A61K9/51H6B, A61K9/51H6F, A61K9/00M5F, A61K49/22P, B82Y5/00, A23L1/29F, A61K9/51H6H, A61K9/50H6H, A61K49/22P4, A61K47/48W8D, A61K49/00F, A61K47/48W8E
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