Classifications

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  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
  • A61M5/178—Syringes
  • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
• • A—HUMAN NECESSITIES
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  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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  • A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
• • A—HUMAN NECESSITIES
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  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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  • A61M5/284—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle comprising means for injection of two or more media, e.g. by mixing
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
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  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
  • A61M5/178—Syringes
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Definitions

• the application further pertains to methods of treating an individual comprising subcutaneously administering a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
• rapamycin The mammalian target of rapamycin (mTOR) is a protein kinase known to regulate various cellular processes including cell survival, proliferation, stress, and metabolism. Many inhibitors of mTOR, including rapamycin, are effective in treating various disorders including certain cancers. Many mTOR inhibitors, such as rapamycin, are known to be poorly water soluble, thus requiring excipients such as surfactants and solvents. These excipients can cause irritation, inflammation, and reduced efficacy, particularly when administered parenteraliy, such as subcutaneously.
• the present application provides methods of treating a disease in an individual comprising subcutaneously administering to the individual a pharmaceutical composition comprising nanoparticles comprising an rnTOR inhibitor and an albumin, wherein the amount of the mTOR inhibitor m the pharmaceutical composition is at a dose of about 0.1 mg/m 2 to about 10 mg/m 2 for each administration. In some embodiments, the amount of the mTOR inhibitor in the pharmaceutical composition is at a dose of about 1 mg/m 2 to about 10 mg/m 2 for each administration. In some embodiments, the amount of the rnTOR inhibitor in the pharmaceutical composition is at a dose of about 5 mg/m 2 .
• the pharmaceutical composition further comprises a saccharide.
• the pharmaceutical composition is administered once per week or less. In some embodiments, the pharmaceutical composition is administered once per week. In some embodiments, the pharmaceutical composition is administered twice every three weeks.
• the disease is a cancer. In some embodiments according to any one of the methods described herein, the disease is a mitochondrial disease.
• the individual is a human.
• the present application also provides methods of delivering an effective amount of an mTOR inhibitor to a target tissue of an individual comprising subcutaneously administering a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
• the mTOR inhibitor is rapamycin.
• the pharmaceutical composition further comprises a saccharide.
• the pharmaceutical composition is at a dose of about 0.1 mg/m 2 to about 10 mg/m 2 .
• the target tissue is a brain tissue of the individual.
• the average diameter of the nanoparticles in the pharmaceutical composition is no greater than about 120 nm.
• the nanoparticles comprise the mTOR inhibitor coated with the albumin.
• the albumin is human albumin.
• the mTOR inhibitor is a limus drug.
• the mTOR inhibitor is rapamycin.
• the present application also provides pharmaceutical compositions suitable for subcutaneous administration to an individual comprising: a) nanoparticles comprising an mTOR inhibitor and an albumin, and b) a saccharide.
• the saccharide is selected from the group consisting of alginate, a starch, lactose, pul!ulan, hyaluronic acid, chitosan, glucose, galactose, mannose, N-acetyl glucosamine, sucrose, N-acetyl-D- galactosamine, maltose, or trehalose.
• the saccharide is sucrose.
• the saccharide is trehalose.
• the concentration of mTOR inhibitor in the pharmaceutical composition is at least about 5 mg/ml. In some embodiments, the concentration of mTOR inhibitor m the pharmaceutical composition is at least about 50 mg/ml. In some embodiments, the average diameter of the nanoparticles in the pharmaceutical composition is no greater than about 120 nm. In some embodiments, the nanoparticles in the pharmaceutical composition comprise the mTOR inhibitor coated with the albumin. In some embodiments, the albumin m the pharmaceutical composition is human albumin. In some embodiments, the mTOR inhibitor in the pharmaceutical composition is a limus drug. In some embodiments, the mTOR inhibitor is rapamycin.
• the present application also provides devices for subcutaneously administering to an individual a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, the device comprising a) a drug chamber containing a dried form of the pharmaceutical composition, and a solution chamber containing a reconstituting solution; and b) a removable divider separating the drug chamber and the solution chamber, wherein removal of the divider causes mixing of the dried pharmaceutical composition and reconstituting solution, thereby forming a reconstituted pharmaceutical composition.
• the device is a syringe, the syringe comprising an injection needle affixed to an end of the syringe and a pusher capable of expelling the reconstituted pharmaceutical composition from the syringe.
• the pharmaceutical composition of the device further comprises a saccharide.
• the mTOR inhibitor is a limus drug. In some embodiments of the de vice, the mTOR inhibitor is rapamycin.
• kits comprising any of the devices described herein for use in treating a disease.
• the kit further comprises instructions for using the kit to treat cancer.
• the kit further comprises instructions for using the kit to treat a mitochondrial disease.
• FIG. 1 shows rapamycin concentrations in whole blood samples taken from rats after subcutaneous (SC) or intravenous (IV) administration of a single dose of /rab-rapamycin (ABI-009) between 0 and 24 hours after administration
• FIG. 2 shows rapamycin concentrations in whole blood samples taken from rats after subcutaneous (SC) or intravenous (IV) administration of a single dose of «ad-rapamycin (ABI-009) between 0 and 168 hours after administration.
• FIG. 3 shows rapamycin concentrations in whole blood samples taken from rats after subcutaneous (SC) or intravenous (IV) administration of a single dose of n. «6-rapamycin (ABI-009) between 0 and 24 hours after administration.
• FIG. 4 shows the bioavailability of «a ⁇ -rapamycin (ABI-009) after subcutaneous (subQ) or intravenous (IV) administration of a single dose in rats as indicated by the calculated area under the curve (AUC)
• FIG. 5 shows the concentration of rapamycin in rat bone marrow (top) or brain (bottom) 24 or 168 hours after subcutaneous (subQ) or intravenous (IV) administration of a single dose of nab- rapamycin (ABI-009).
• FIG. 6 shows the concentration of rapamycin in rat heart (top) or liver (bottom) 24 or 168 hours after subcutaneous (subQ) or intravenous (IV) administration of a single dose of ha ⁇ -rapamycin (ABI-009).
• FIG. 7 shows the concentration of rapamycin in rat lung (top) or pancreas (bottom) 24 or 168 hours after subcutaneous (subQ) or intravenous (IV) administration of a single dose of nab- rapamycin (ABI-009).
• FIG. 8 shows a comparison of rapamycin concentrations over time in brain or whole blood from rats after 24, 72, and 120 post-administration of a single subcutaneous dose of «ad-rapamycin (ABI-009) at a dose of 1.7 mg/kg, 9.5 mg/kg or 17 mg/kg.
• FIG. 9 shows a comparison of histopathoiogy scores assessed on skins from rats among different treatment groups.
• FIG. 10 is a representative histogram image of skin from rat in Group 1 (0.9% saline). Histologic lesions are limited to an aggregate of mixed inflammatory cells (black arrow) within the subcutaneous tissues (SC). The dermis (D) and epidermis (E) are indicated.
• FIG. I I is a representative histogram image of skin from rat in Group 2 (HSA in 0.9% saline). Multifocal mixed inflammatory cell aggregates (black arrows) are visible within the subcutis (SC). The epidermis (E) and dermis (D) are unremarkable.
• FIG. 12 is a representati ve histogram image of skin from rat in Group 3 (ABI-QQ9, 1.7 rng/kg). Minimal mixed inflammatory cell infiltration (black arrow) is visible in the subcutaneous tissues (SC). The epidermis (E) and dermis (D) are indicated.
• FIG. 13 is a representative histogram image of skin from rat in Group 4 (AB1-009, 5 mg/kg). Scattered mixed inflammatory cell infiltration (right arrow') and a site of minimal necrosis (left arrow) are present in the subcutis (SC). The epidermis (E) and dermis (D) are unremarkable.
• FIG. 14 is a representative histogram image of skm from rat in Group 4 (ABI-009, 10 mg/kg).
• Subcutaneous (SC) mixed inflammatory ceil infiltration (right arrow) and a region of necrosis (left arrow) are captured.
• the epidermis (E) and dermis (D) are unremarkable.
• FIG. 15 shows the mean through rapamycin blood levels in rats administered with ABI-009 at 1.7 mg/kg, 5 nig/kg or 10 mg/kg.
• FIG. 16 show s the tumor growth results of a human hepatocellular carcinoma mouse xenograft model after 0-15 days of treatment with saline (Group 1), ABI-009 (intravenous route; Group 2), Rapamime (oral administration; Group 3), and ABI-009 (subcutaneous route; Group 4).
• FIG. 17 shows body weight changes m mice m a human hepatocellular carcinoma mouse xenograft model after 0-15 days of treatment with saline (Group 1), ABI-009
• compositions as described herein such as a composition comprising nanoparticles comprising an rnTOR inhibitor (such as rapamycin) and an albumin.
• methods of delivering an effective amount of an mTOR inhibitor (such as rapamycin) to a target tissue such as brain, bone marrow, heart, liver, lung, or pancreatic tissue, by subcutaneously administering a composition comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin.
• pro vided herein are methods of maintaining a blood level of an mTOR inhibitor (such as rapamycin) comprising subcutaneously administering a composition comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin.
• an mTOR inhibitor such as rapamycin
• Also provided herein are methods of treating a disease comprising subcutaneously administering a composition comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin.
• the disease is a cancer.
• an individual having a cancer is selected for treatment on the basis of having an mTOR- activating aberration.
• the disease is a mitochondrial disorder.
• compositions suitable for subcutaneous administration to an individual comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin and methods of administering such compositions.
• the compositions may comprise one or more agents for enhancing the dissolution of dried forms of the compositions and/or enhancing the stability' of the composition.
• the additional agent or agents may comprise a saccharide.
• the saccharide can be present in an amount that is effective to enhance the solubility', such as the rate of dissolution after addition of an aqueous solution to a dried form of the composition, and/or promote the stability of the compositions.
• the device comprises a drug chamber containing a dried form of the pharmaceutical composition and a solution chamber containing a reconstituting solution.
• the device further comprises a removable divider separating the drug chamber and the solution chamber, wherein removal or actuation of the divider causes or allows mixing of the dried pharmaceutical composition and reconstituting solution, thereby forming a reconstituted pharmaceutical composition.
• the device may be a syringe, which may further comprise a pusher. After reconstitution of the composition, the device is capable of, or can be adapted to be capable of, subcutaneously administering the composition to an individual.
• methods for subcutaneously administering a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, using a device as described herein.
• albumin may be“associated” with an mTOR inhibitor (such as rapamycin), e.g., the composition comprises albumin-associated mTOR inhibitor.
• an mTOR inhibitor such as rapamycin
• association or“associated” is used herein in a general sense and refers to the albumin affecting a behavior and/or properly of the TOR inhibitor (such as rapamy cin) in an aqueous composition.
• the albumin and the mTOR inhibitor (such as rapamycin) are considered as being“associated” if the albumin makes the mTOR inhibitor (such as rapamy cin) more readily suspendable in an aqueous medium as compared to a composition without the albumin.
• the albumin and mTOR inhibitor (such as rapamycin) are associated if the albumin stabilizes the mTOR inhibitor (such as rapamycin) m an aqueous suspension.
• the albumin and the mTOR inhibitor can be present in a particle or a nanoparticle, which are further described herein.
• composition may include any of the pharmaceutical compositions described herein.
• the ter “effective amount” used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
• an “effective amount” may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
• An effective amount may be considered in the context of administering one or more therapeutic agents, and a nanopanicle composition (e.g., a composition including rapamycin and an albumin) may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
• a nanopanicle composition e.g., a composition including rapamycin and an albumin
• “nab” ® stands for nanoparticle albumin-bound
• “nab- rapamycin” is an albumin stabilized nanoparticle formulation of rapamycin.
• TVa/ -rapamycin is also known as «a ⁇ -sirolimus, which has been previously described. See, for example, WO 2008/109163 Al, WO 2014/151853, WO 2008/137148 A2, and WO 2012/149451 Al, each of which is incorporated herein by reference in their entirety.
• by“pharmaceutically acceptable” or“pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g.
• the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
• Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U. S. Food and Drug administration.
• beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, reducing recurrence rate of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
• the treatment reduces the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the treatment.
• treatment is a reduction of pathological consequence of cancer.
• the methods of the invention contempl ate any one or more of these aspects of treatment.
• the terms“recurrence,”“relapse” or“relapsed” refers to the return of a cancer or disease after clinical assessment of the disappearance of disease. A diagnosis of distant metastasis or local recurrence can be considered a relapse.
• the term“refractory” or“resistant” refers to a cancer or disease that has not responded to treatment.
• reference to“not” a value or parameter generally means and describes “other than” a value or parameter.
• the method is not used to treat cancer of type X means the method is used to treat cancer of types other than X.
• compositions such as a pharmaceutical composition, comprising an inTQR inhibitor, such as rapamyein, and an albumin.
• a method for delivering an effective amount of an mTOR inhibitor (such as rapamyein) to a target tissue, such as brain, bone marrow, heart, liver, lung, or pancreatic tissue, of an individual, the method comprising subcutaneously administering a composition, such as a pharmaceutical composition, comprising
• nanoparticles comprising mTOR inhibitor (such as rapamyein) and an albumin.
• mTOR inhibitor such as rapamyein
• albumin an albumin.
• the individual has a tumor m the target tissue, such as the brain.
• a method for delivering an effective amount of an mTOR inhibitor (such as rapamyein) to the brain of an individual comprising subcutaneously administering a composition, such as a pharmaceutical composition, comprising nanoparticles comprising an mTOR inhibitor (such as rapamyein) and an albumin, wherein the dose of mTOR inhibitor (such as rapamyein) in the nanoparticles to deliver an effective amount of mTOR inhibitor (such as rapamyein) to the brain is any of about 0.1 mg/m 2 to about 10 mg/m 2 , and values and ranges therein.
• a composition such as a pharmaceutical composition
• nanoparticles comprising an mTOR inhibitor (such as rapamyein) and an albumin
• the dose of mTOR inhibitor (such as rapamyein) in the nanoparticles to deliver an effective amount of mTOR inhibitor (such as rapamyein) to the brain is any of about 0.1 mg/m 2 to about 10 mg/m 2 , and values and range
• the methods comprise maintaining a blood level of an mTOR inhibitor (such as rapamyein) m an individual, the method comprising subcutaneously administering a composition, such as a pharmaceutical composition, comprising
• nanoparticles comprising an mTOR inhibitor (such as rapamyein) and an albumin.
• the blood level of mTOR inhibitor (such as rapamyein) is at least any of 1 ng/ml, 5 ng/ml, 10 ng/ml, 25 ng/ml, 50 ng/ml, 75 ng/ml, 100 ng/ml, 150 ng/ml, or 200 ng/ml, and values and ranges therein.
• the individual has
• a method of treating a disease in an individual comprising subcutaneously administering to the individual a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
• the amount of the mTOR inhibitor in the pharmaceutical composition is at a dose of about 0.1 mg/m 2 to about 10 mg/m 2 , such as about 1 mg/m 2 to about 10 mg/m 2 for each administration.
• the amount of the mTOR inhibitor in the pharmaceutical composition is at a dose of about 5 mg/m 2 for each administration.
• the amount of mTOR inhibitor in the composition is below the level that induces a toxicological effect (e.g., an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can he controlled or tolerated when the mTOR inhibitor nanoparticle composition is subcutaneously administered to the individual.
• a toxicological effect e.g., an effect above a clinically acceptable level of toxicity
• a potential side effect can he controlled or tolerated when the mTOR inhibitor nanoparticle composition is subcutaneously administered to the individual.
• the toxicological effect is a rash associated with subcutaneous administration of the pharmaceutical composition.
• the concentration of the mTOR inhibitor (such as rapamycin) in the mTOR inhibitor nanoparticle composition is between about 0.1 mg/ml and about 100 mg/ml, including for example about any of 0.1 mg/ml to about 50 mg/ml, about 0.1 mg/mi to about 50 mg/ml, about 0.1 mg/ml to about 40 mg/tnl, about 0.1 mg/ml to about 10 mg/ml, or about 0.1 mg/ml to about 5 mg/ml, about 5 mg/ml to about 100 mg/ml, about 5 mg/ml to about 50 mg/ml, about 5 mg/ml to about 40 mg/ml, about 7.5 mg/ml to about 100 mg/ml, about 7.5 mg/ml to about 50 mg/ml, about 7.5 mg/ml to about 40 mg/ml, and values and ranges therein. In some embodiments, the concentration of the mTOR inhibitor (such as rapamycin) in the mTOR
• the effective amount of mTOR inhibitor (such as rapamycin) in the mTOR inhibitor nanoparticle composition is in any of the following ranges: about 0.1 mg/m 2 to about 5 mg/m 2 , about 5 mg/m 2 to about 10 mg/m 2 , about 10 mg/m 2 to about 20 mg/m 2 , about 10 to about 30 mg/m 2 , about 10 to about 45 mg/m 2 , about 10 to about 60 mg/m 2 , about 20 to about 30 mg/m 2 , about 20 to about 45 mg/m 2 , about 20 to about 60 mg/m 2 , about 30 to about 45 mg/m 2 , about 30 to about 60 mg/m 2 , or about 45 to about 60 mg/m 2 , each inclusive.
• the effective amount of TOR inhibitor (such as rapamycin) in the rnTOR inhibitor nanoparticle composition is between about 0.1 mg/m 2 and about 10 mg/m 2 in another exemplary non-limiting embodiment, the effective amount of mTOR inhibitor (such as rapamycin) in the mTOR inhibitor nanoparticle composition is between about 1 mg/m 2 and 10 mg/m 2 , such as 5 mg/m 2 .
• the dosing frequencies for the administration of the mTOR inhibitor nanoparticle composition include, but are not limited to, daily, ever) ' two days, every three days, every four days, every five days, every six days, weekly without break, three out of four weeks (such as on days 1,
• the mTOR inhibitor nanoparticle composition (such as rapamyein/albumin nanoparticle composition) is administered about once every 2 weeks, once every- 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some embodiments, the mTOR inhibitor nanoparticle composition (such as
• rapamyein/albumin nanoparticle composition is administered at least about any of lx, 2x,
• the intervals between each administration are less than about any of 6 months, 3 months, 1 month, 20 days, 15, days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the intervals between each administration are more than about any of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week.
• the administration of the mTOR inhibitor nanoparticle composition can be extended over an extended period of lime, such as from about a month up to about seven years.
• the rnTOR inhibitor nanoparticle composition (such as rapamyein/albumin nanoparticle composition) is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.
• Auxiliary- and adjuvant agents in any of the described compositions may include, for example, preserving, wetting, suspending, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms is generally provided by various antibacterial and antifungal agents, such as parabens, chlorohutanol, phenol, sorbic acid, and the like. Isotonic agents may also be included. Prolonged absorption of an injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
• the auxiliary agents also can include weting agents, emulsifying agents, pH buffering agents, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.
• Treatments according to any dosing regimen such as the exemplar dosing regimens discussed above can be repeated for multiple cycles (such as 1, 2, 3, 4, 5, 6, or more cycles, such as about 1-10 cycles, 1-7 cycles, 1-5 cycles, 1-4 cycles, 1-3 cycles).
• the treatment according to a specific dosing regimen is repeated for at least two, three or more cycles.
• the treatment according to a specific dosing regimen is continuously repeated (i.e. without an interval) for at least two, three or more cycles.
• the interval is at least about one, two, three or four weeks. In some embodiments, the interval is at least about one, two, three, four, five, six or more months. In some embodiments, the interval is about a lime period that allows the individual to gain weight (for example, the individual has a weight of about or at least about 90%, 92%, 95%, 97% of the weight prior to the initiation of the treatment(s) after the interval).
• the pharmaceutical composition is administered only once.
• the compositions comprising nanoparticles comprising an mTOR inhibitor and an albumin may store in a dried form, such a lyophilized form.
• a dried form such as a lyophilized form.
• To prepare the dried compositions for administration requires reconstitution with an aqueous solution, such as water.
• An aspect of the present application provides a device which contains a stable, fixed dose of a dried composition in close proximity to a reconstituting solution.
• the device comprises a divider winch, through limited handling, allows for predictable and reproducible reconstitution of the dried composition followed by subcutaneous administration of the composition using the device.
• This device improves the handling of dried compositions by, for example, reducing the handling time of the composition, reducing the opportunities for user error, and ensuring the reproducibility and consistency of the reconstitution process.
• composition into a syringe.
• compositions such as pharmaceutical compositions comprising nanoparticles comprising an mTOR inhibitor and an albumin.
• the devices described herein are particularly suitable for the subcutaneous administration of dried forms of compositions by sequential reconstitution of the dried form of the composition followed by administration of the reconstituted
• the device comprises a drug chamber containing a dried form of a pharmaceutical composition, such as those described herein, such as, for example, a lyophilized form of the pharmaceutical composition, and a solution chamber containing a reconstituting solution.
• the device comprises a divider separating the drug chamber and the solution chamber. Removal of the divider, or actuation of the divider, allows, and/or causes, mixing of the dried pharmaceutical composition and reconstituting solution, thereby forms a reconstituted pharmaceutical composition.
• the reconstituted pharmaceutical composition can be suitable for subcutaneous administration to an individual, such as a human.
• the device is a syringe comprising the solution chamber and the drug chamber.
• the syringe further comprises a pusher capable of expelling the reconstituted solution from the device.
• the syringe further comprises an injection needle, such as a hypodermic needle, suitable for subcutaneous administration affixed to an end of the syringe.
• compositions for subcutaneous administration contained within a device wherein the composition comprises a lyophilized form of the pharmaceutical composition, and wherein the device comprises a solution chamber containing a
• the divider of the device may in some embodiments comprise a guard which prevents unintended removal or actuation of the divider.
• the guard is removed from the device prior to removal or actuation of the divider.
• the guard is actuated to allow removal or actuation of the divider
• the device is a syringe comprising a suitable needle for injection.
• the device is a syringe adapted to couple with a suitable needle for injection. Depression of the pusher of the syringe causes expulsion of the reconstituted syringe through a needle.
• a device for subcutaneously administering a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin, the device comprising a drug chamber containing a dried form of the pharmaceutical composition, a solution chamber containing a reconstituting solution, a removable divider separating the drug chamber and the solution chamber, wherein removal of the divider causes mixing of the dried pharmaceutical composition and reconstituting solution, thereby forming a reconstituted pharmaceutical composition, wherein the dose of mTOR inhibitor (such as rapamycin) in the nanoparticles is any of about 0.2 mg to about 100 mg, about 0.2 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, each inclusive.
• an mTOR inhibitor such as rapamycin
• a device for subcutaneously administering a pharmaceutical composition comprising nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin, the pharmaceutical composition optionally comprising a saccharide, the device comprising a drug chamber containing a dried form of the mTOR inhibitor (such as rapamycin) and an albumin, the pharmaceutical composition optionally comprising a saccharide, the device comprising a drug chamber containing a dried form of the mTOR inhibitor (such as rapamycin) and an albumin, the pharmaceutical composition optionally comprising a saccharide, the device comprising a drug chamber containing a dried form of the mTOR inhibitor (such as rapamycin) and an albumin, the pharmaceutical composition optionally comprising a saccharide, the device comprising a drug chamber containing a dried form of the mTOR inhibitor (such as rapamycin) and an albumin, the pharmaceutical composition optionally comprising a saccharide, the device comprising a drug chamber containing a dried form of the m
• the dose of mTOR inhibitor (such as rapamycin) in the nanoparticles is any of about 0.2 mg to about 100 mg, about 0.2 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 rng to about 100 rng, each inclusive.
• the saccharide is selected from the group consisting of alginate, a starch, lactose, puliulan, hyaluronic acid, chitosan, glucose, galactose, mannose, N-acetylgiucos amine, sucrose, N-acetyl-D-gaJactosamine, maltose, or trehalose.
• the composition comprises a dried form of a pharmaceutical composition comprising nanoparticles comprising rapamycin and an albumin.
• the method of subcutaneous administration comprises selecting an indivi dual for subcutaneous administration of the pharmaceutical composition, removing or actuating the divider, waiting for an indicated period of time for the dried composition and reconstituting solution to form a reconstituted pharmaceutical composition, inserting the needle at an appropriate angle into the individual, depressing the pusher with an appropriate force, and removing the needle from the individual.
• compositions, methods, and devices described herein may be useful for treating a disease or diseases in an individual, such as a human.
• the disease or diseases are one or more of pulmonary hypertension, a central nervous system disorder, a mitochondrial disorder, or a cancer.
• Pulmonary hypertension is a syndrome characterized by increased pulmonary artery pressure. PH is defined hemodynamicaily as a systolic pulmonary artery pressure greater than 30 mm Hg or evaluation of mean pulmonary artery pressure greater than 25 mm Hg. See Zaiman et a l, Am. J. Respir. Cell Mol Biol 33:425-31 (2005).
• the disease or diseases to be treated comprise pulmonary hypertension.
• the pulmonary hypertension is any of pulmonar' arterial hypertension (PAH), idiopathic pulmonary arterial hypertension (IP AH), heritable pul onary arterial hypertension (HP AH), drug and toxin induced PAH, PAH associated with connective tissue disease, and PAH associated with congenital heart defects.
• the pulmonary hypertension is severe pulmonary arterial hypertension.
• the pulmonar hypertension is World Health
• the pulmonary' hypertension is WHO Function Class II pulmonary arterial hypertension.
• the pulmonary hypertension is WHO Function Class III pulmonary arterial hypertension.
• the pulmonary hypertension is WHO Function Class IV pulmonary arterial hypertension.
• Central nervous system diseases also known as central nervous system disorders, are a spectrum of neurological disorders that affect the structure or function of the brain or spinal cord, which collectively form the central nervous system (CNS).
• CNS central nervous system
• the CNS disorder is a glioma.
• the C S disorder is a glioblastoma.
• the CNS disorder is epilepsy.
• the CNS disorder is cortical dysplasia (e.g., focal cortical dysplasia).
• the CNS disorder is selected from the group consisting of tuberous sclerosis complex, brain tumor, Fragile X syndrome, Down syndrome, Rett syndrome, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
• the CNS disorder is epilepsy.
• the individual has undergone an epilepsy surgery in some embodiments, the individual has at least 5 seizures in 30 days post epilepsy surgery or does not have a week of seizure freedom following epilepsy surgery.
• the method further comprises
• the CNS disorder is glioblastoma.
• the glioblastoma is recurrent glioblastoma.
• the glioblastoma is newly diagnosed glioblastoma.
• the individual has undergone surgical resection of newly diagnosed glioblastoma prior to the initiation of the nanoparticle administration.
• the mitochondrion is an organelle present in most eukaryotic cells. In addition to generating ATP, mitochondria are also involved in other cellular functions, such as cellular homeostasis, signaling pathways, and steroid synthesis.
• a mitochondrial-associated disorder i.e., a mitochondrial disorder
• a mitochondrial disorder can be treated with the methods described herein including, but not limited to, individuals having an ataxia, a kidney disorder, a liver disorder, a metabolic disorder, a myopathy, a neuropathy, a myelopathy, an encephalopathy, an oxidative phosphorylation disorder, an aging disorder, an autism spectrum disorder, a chrome inflammatory disorder, diabetes mellitus, and a fatty acid oxidation disorder.
• the individual having a mitochondrial-associated disorder has a mitochondrial DNA mutation-associated disorder in some embodiments, the individual having a mitochondrial-associated disorder has an X chromosome mutation-associated disorder.
• the individual having a mitochondrial-associated disorder has a nuclear DNA mutation-associated disorder.
• the individual having a mitochondrial-associated disorder has Leigh syndrome, such as maternally inherited Leigh syndrome.
• Leigh syndrome is infantile onset Leigh syndrome, juvenile onset Leigh syndrome, or adult onset Leigh syndrome.
• the individual having a mitochondrial-associated disorder has MELAS syndrome.
• the individual having a mitochondrial- associated disorder has NARP sy ndrome.
• Individuals having a metabolic disorder can be treated with the methods described herein including, but not limited to, disorders associated with cellular glucose consumption (e g., abnormally high cellular glucose consumption in one or more tissues), disorders associated with insulin resistance, hypoglycemia, hyperinsulinemic hypoglycemia, diabetes mellitus type 1, diabetes mellitus type 2, and metabolic syndrome.
• the methods described herein can be used for any one or more of the following purposes: alleviating one or more symptoms in an individual having a mitochondrial- associated disorder, reducing one or more symptoms in an individual having a mitochondrial - associated disorder, preventing one or more symptoms in an individual having a
• mitochondrial-associated disorder treating one or more symptoms m an individual having a mitochondrial-associated disorder, ameliorating one or more symptoms in an individual having a mitochondrial-associated disorder, and delaying onset of one or more symptoms in an individual having a mitochondrial -associated disorder.
• mitochondrial-associated disorder and“mitochondrial disorder” refer to any disease or disorder caused by dysfunction of a mitochondrion.
• Mitochondrial-associated disorders can cause a complex variety of symptoms. Symptoms of mitochondrial-associated disorders include, for example, muscle weakness, muscle cramps, seizures, food reflux, learning disabilities, deafness, short stature, paralysis of eye muscles, diabetes, cardiac problems, and stroke-like episodes. Symptoms of mitochondrial-associated disorders can range in severity from life-threatening to almost unnoticeab!e. [0085] An individual having a mitochondrial-associated disorder can be classified in one or more subsets of mitochondrial-associated disorders based on genotype, phenotypic presentation, and/or one or more symptoms.
• the individual having a mitochondrial-associated disorder has one or more of the following: an ataxia, a kidney disorder, a liver disorder, a metabolic disorder, a myopathy, a neuropathy, a myelopathy, an encephalopathy, an oxidative phosphorylation disorder, an aging disorder, an autism spectrum disorder, a chronic inflammatory disorder, or a fatty acid oxidation disorder.
• the individual having a mitochondrial-associated disorder has one or more of the following: an ataxia, a kidney disorder, a liver disorder, a metabolic disorder, a myopathy, a neuropathy, a myelopathy, an encephalopathy, or an oxidative phosphorylation disorder.
• the individual having a mitochondrial-associated disorder has one or more of the following: an aging disorder, an autism spectrum disorder, a chronic inflammatory disorder, diabetes mellitus, or a fatty acid oxidation disorder.
• the individual having a mitochondrial-associated disorder has at least an ataxia.
• the individual having a mitochondrial-associated disorder has at least a myelopathy and an encephalopathy.
• the individual having a mitochondrial-associated disorder has at least a neuropathy, a myelopathy, and an encephalopathy.
• the individual having a mitochondrial-associated disorder has at least a myopathy and a neuropathy.
• the methods described herein may be used to treat an individual having cancer with an mTQR-activating aberration at one or more genes (such as TSC1 , TSC2 , RPS6 , PTEN , TPS 3, RBl. ATRX , or FATl).
• an mTQR-activating aberration at one or more genes such as TSC1 , TSC2 , RPS6 , PTEN , TPS 3, RBl. ATRX , or FATl.
• An individual having cancer may be selected for treatment by the methods described herein on the basis of having an mTOR-activating aberration at one or more genes (such as TSC1, TSC2, RPS6, PTEN, TP53, RB1, ATRX , or FATl)
• the individual is selected for treatment on the basis of having an mTOR-activating aberration at TSC2.
• a cancer can be treated by the methods described herein (e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor) in an individual comprising subcutaneously administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual is selected for treatment on the basis of having an mTOR-activating aberration at TSC2.
• an advanced and/or malignant cancer e.g., PEComa
• an advanced and/or malignant cancer e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer can be treated by the methods described herein (e.g., an advanced and/or malignant cancer, e.g , PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor) in an individual comprising subcutaneously administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual has an mTOR-activating aberration at TSC2.
• the mTOR-activation aberration at TSC2 comprises a mutation in TSC2.
• the mutation is selected from the group consisting of splice site mutation, nonsense mutation, frameshift mutation, and missense mutation.
• the mTOR-activation aberration at TSC2 comprises a single-nucleotide variant (SNV).
• SNV single-nucleotide variant
• the SNV comprises a imitation selected from the group consisting of C1503T, C2743G, C5383T, C3755G, G760T, C3442T, G880A, T707C, A4949G, or a deletion of any one or more of the amino acids at the position of 1405-1409, 1960-1970, 4999, 5002, 3521, 5208, 5238-5255.
• the mTOR-activation aberration at TSC2 comprises a copy number variation of TSC2. In some embodiments, the mTOR-activation aberration at TSC2 is a loss of function mutation. In some embodiments, the mTOR-activation aberration m TSC2 comprises an aberrant expression level of TSC2. In some embodiments, the mTOR- activation aberration in TSC2 comprises an aberrant activity level of a protein encoded by TSC2. In some embodiments, the mTOR-activation aberration in TSC2 comprises a loss of heterozygosity of TSC2. In some embodiments, the mTOR inhibitor is a iimus drug. In some embodiments, the mTOR inhibitor is rapamycin or a derivative thereof. In some
• the mTOR inhibitor is rapamycin.
• the carrier protein is albumin (such as human serum albumin).
• the dose of the mTOR inhibitor in the composition for each administration is from about 0.1 mg/m 2 to about 100 mg/m 2 (e.g., about 0.1 mg/m 2 to about 10 mg/m 2 , about 10 mg/m 2 to about 50 mg/m 2 , about 50 mg/m 2 to about 100 mg/m 2 , about 75 mg/m to about 100 mg/m )
• the method comprises subcutaneously administering the nanoparticle composition to the individual weekly for about two weeks followed by a rest period of about one week.
• the cancer is selected from the group consisting of pancreatic neuroendocrine cancer, endometrial cancer, breast cancer, lymphangioleiomyomatosis (LAM), prostate cancer, hepatocellular carcinoma, melanoma, renal ceil carcinoma, bladder cancer, endometrial cancer, ovary cancer, gynecologic cancer, sarcoma, perivascular epithelioid cell neoplasms (PEComa), Hodgkin’s lymphoma and multiple myeloma.
• the cancer is a PEComa.
• the individual is selected for treatment based on having a TSC2 aberration (e.g, a TSC2 mutation), regardless of the nature of the cancer in some embodiments, the individual does not have a TSCl aberration (e.g., a TSCl mutation).
• a TSC2 aberration e.g, a TSC2 mutation
• the individual does not have a TSCl aberration (e.g., a TSCl mutation).
• a method of treating a cancer comprising subcutaneously administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual is selected for treatment on the basis of having a TSC2 aberration (e.g., a TSC2 mutation).
• a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual is selected for treatment on the basis of having a TSC2 aberration (e.g., a TSC2 mutation).
• a method of treating a cancer comprising subcutaneously administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual is selected for treatment on the basis of a) having a TSC2 aberration (e.g., a TSC2 mutation), and b) having a RPS6 aberration (e.g, aberrant phosphorylation level of the protein encoded by RPS6 (e.g., phosphorylation at residue S235, S236, S240, and/or S244).
• a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a method of treating a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• the individual is selected for treatment on the basis of a) having a TSC2 aberration (e.g.,
• a method of treating a cancer comprising subcutaneously administering to the individual an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and a carrier protein, wherein the individual is selected for treatment on the basis of a) having a TSC2 aberration (e.g., a TSC2 mutation), b) not having a TSCl mutation, and c) having a RPS6 aberration (e.g., aberrant phosphorylation level of the protein encoded by RPS6 (e.g., phosphorylation at residue S235, S236, S240, and or S244).
• a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• the mTOR- activation aberration at RPS6 comprises a positive status of phosphorylated S6 (pS6) (e.g., phosphorylation at residue S235, S236, S240, and/or S244).
• the mutation is selected from the group consisting of splice site mutation, nonsense mutation, frameshift mutation, and missense mutation in some embodiments, the mTOR inhibitor is a limus drag.
• the mTOR inhibitor is rapamycin or a derivative thereof.
• the mTOR inhibitor is rapamycin.
• the carrier protein is albumin (such as human serum albumin).
• the dose of the mTOR inhibitor m the composition for each administration is from about 0.1 mg/m 2 to about 100 mg/m 2 (e.g., about 0.1 mg/m 2 to about 10 mg/m 2 , about 10 mg/m 2 to about 50 mg/m 2 , about 50 mg/m 2 to about 100 mg/m 2 , about 75 mg/m 2 to about 100 mg/m 2 ).
• the method comprises subcutaneously administering the nanoparticle composition to the individual weekly for about two weeks followed by a rest period of about one week.
• the cancer is selected from the group consisting of pancreatic neuroendocrine cancer, endometrial cancer, breast cancer,
• the cancer is a PEComa.
• the individual is selected for treatment based on having a TSC2 aberration and aRPS6 aberration, regardless of the nature of the cancer.
• a method of treating a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer e.g., an advanced and/or malignant cancer, e.g., PEComa, e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a cancer e.g., an advanced and/or malignant cancer, e.g., locally advanced inoperable cancer, e.g., a solid tumor
• a composition comprising nanoparticles comprising rapamycin or a derivative thereof and an albumin
• the individual is selected for treatment on the basis of a) having a TSC2 aberration (e.g., a ISC 2 mutation), and b) having an aberrant phospho
• a method of treating a cancer comprising subcutaneously administering to the individual a composition comprising nanoparticles comprising rapamycin or a derivative thereof and an albumin, wherein the individual is selected for treatment on the basis of a) having a TSC2 aberration (e.g., a TSC2 mutation), b) does not have a TSCi mutation, and c) having an aberrant phosphorylation level of the protein encoded by RPS6 (e.g., phosphorylation at residue S235, S236, S240, and/or S244), wherein the dose of rapamycin or a derivative thereof m the composition for each
• administration is from about 10 mg/m 2 to about 100 mg/m 2 (e.g., about 25 mg/m 2 to about 100 mg/m 2 , about 50 mg/m 2 to about 100 mg/m 2 , about 75 mg/m 2 to about 100 mg/m 2 ), and wherein the composition is subcutaneously administered weekly for about two weeks followed by a rest period of about one week.
• the aberrant phosphorylation level of the protein encoded by RPS6 is a positive status of phosphory!ated S6 (pS6).
• the aberrant phosphorylation level of the protein encoded by RPS6 is an increased phosphorylation of S6 in the cancer as compared to a reference tissue.
• the reference tissue is derived from a non-cancerous tissue in the individual.
• the reference tissue is derived from a corresponding tissue in another individual that does not have the cancer.
• a method of treating a population of individuals having different cancers comprising subcutaneously administering to the population of individuals an effective amount of a composition comprising nanoparticles comprising an rnTOR inhibitor (e.g., rapamycin) and a earner protein (e.g., albumin), wherein each of the individuals has a TSC2 aberration (e.g., TSC2 mutation).
• the individuals do not have a TSC1 mutation.
• a method of selecting an individual for a treatment on the basis of having a cancer that harbors a TSC2 mutation comprises subcutaneously administering to the individual a composition comprising nanoparticles comprising rapamycin or a derivative thereof and an albumin, wherein optionally the dose of rapamycin or a derivative thereof in the composition for each administration is from about 10 mg/m 2 to about 100 mg/m 2 (e.g., about 25 mg/m 2 to about 100 mg/m 2 , about 50 mg/m 2 to about 100 mg/m 2 , about 75 mg/m 2 to about 100 mg/m 2 ), and wherein optionally the composition is subcutaneously administered weekly for about two weeks followed by a rest period of about one week.
• the indi vidual does not have a TSCI mutation.
• the cancer treated by the methods complemented m the application can be any cancer that harbors one or more mTOR-activation aberration at any of the genes selected from the group consisting of TSCI, TSC2, TP53, RBI, ATRX, TATI, PTEN, and RPS6.
• the cancer harbors one or more mTOR-activation aberration at any one of genes selected from the group consisting of TSCI, TSC2, TP 53, and RPS6.
• the cancer harbor at least one mTOR-activation aberration at RPS6 and at least one mTOR-activation aberration at TSCI, TSC2, or TP53.
• the cancer harbor at least one mTOR-activation aberration at RPS6 and at least one mTOR-activation aberration at TSCI, or TSC2.
• the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.
• the cancer is advanced. In some embodiments, the cancer is malignant. In some embodiments, the cancer is an inoperable locally advanced cancer.
• the cancer is selected from the group consisting of pancreatic neuroendocrine cancer, endometrial cancer, breast cancer, iymphangioleiomyomatosis (LAM), prostate cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, bladder cancer, endometrial cancer, ovary cancer, gynecologic cancer, sarcoma, perivascular epithelioid cell neoplasms (PECorna), Hodgkin’s lymphoma and multiple myeloma.
• pancreatic neuroendocrine cancer endometrial cancer
• breast cancer iymphangioleiomyomatosis
• LAM iymphangioleiomyomatosis
• prostate cancer hepatocellular carcinoma
• melanoma renal cell carcinoma
• bladder cancer endometrial cancer
• endometrial cancer ovary cancer
• gynecologic cancer sarcoma
• sarcoma perivascular epithelioid cell
• the cancer is a PEComa. In some embodiments, the cancer is advanced PEComa. In some embodiments, the cancer is advanced and malignant PEComa. In some embodiments, the PEComa is a uterine primary PEComa. In some embodiments, the PEComa is retroperitoneal primary PEComa. In some embodiments, the PEComa is kidney primary PEComa. In some embodiments, the PEComa is lung primary PEComa. In some embodiments, the PEComa is pelvis primary 7 PEComa.
• TSC2 is also known as Tuberin, Tuberous sclerosis 2 protein, protein phosphatase 1 regulatory subunit 160, TSC4, PPP1R160, and LAM.
• TSC2 protein functions as part of a complex with TSCI by negatively regulating mTORCl signaling.
• the nucleic acid sequence of a wildly pe TSC2 gene is identified by the Genbank accession number NC_000016.10, from nucleotide 2047936 to nucleotide 2088712 on the forward strand of chromosome 16 according to the GRCh38.p2 assembly of the human genome.
• the wildly pe TSC2 gene comprises 42 exons.
• a mutation of the TSC2 gene may occur in any one or any combination of the 42 exons, or in any intron or noncoding regions of the TSC2 gene.
• the amino acid sequence of a wiidtype TSC2 protein is identified by the Genhank accession number NP__ 000539.2.
• the amino acid sequence of a wiidtype TSC2 protein is identified by the Genbank accession number NP 001070651.1.
• the amino acid sequence of a wiidtype TSC2 protein is identified by the Genbank accession number NP 001107854.1.
• the nucleic acid sequence of a cDNA encoding a wiidtype TSC2 protein is identified by the Genbank accession number NM 000548.3. In some embodiments, the nucleic acid sequence of a cDNA encoding a wiidtype TSC2 protein is identified by the Genbank accession number NM_001077183.1. In some embodiments, the nucleic acid sequence of a cDNA encoding a wiidtype TSC2 protein is identified by the Genbank accession number NM 001114382.1.
• the individual is selected for treatment based on having an mTOR-activating aberration at TSC2.
• the mTOR-activation aberration at TSC2 comprises a mutation in TSC2.
• the mutation is selected from the group consisting of splice site mutation, nonsense mutation, frameshift mutation, and missense mutation.
• the mTOR-activation aberration at TSC2 comprises a single-nucleotide variant (SNV)
• SNV single-nucleotide variant
• the SNV comprises a mutation selected from the group consisting of C15G3T, C2743G, C5383T, C3755G, G760T, C3442T, G880A, T707C, A4949G, or a deletion of any one or more of the amino acids at the position of 1405-1409, 1960-1970, 4999, 5002, 3521 , 5208, 5238-5255.
• the mutation is a two-point mutation.
• the mTOR-activation aberration at TSC2 is a loss of function mutation.
• the mTOR-activation aberration at TSC2 comprises a homozygous deletion. In some embodiments, the mTOR-activation aberration at TSC2 comprises a copy number variation of TSC2. In some embodiments, the mTOR-activation aberration at TSC2 comprises an aberrant expression level of TSC2. In some embodiments, the mTOR-activation aberration at TSC2 comprises an aberrant activity level of a protein encoded by TSC2.
• Ribosomal protein S6 ( RPS6 ) is also known as S6. Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a cytoplasmic ribosomal protein that is a component of the 40S subunit. The protein belongs to the S6E family of ribosomal proteins. It is the major substrate of protein kinases in the ribosome, with subsets of five C -terminal serine residues phosphorylated by different protein kinases.
• Phosphorylation is induced by a wide range of stimuli, including growth factors, tumor-promoting agents, and mitogens. Dephosphorylation occurs at growth arrest.
• the protein may contribute to the control of cell growth and proliferation through the selective translation of particular classes of mRNA. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.
• the nucleic acid sequence of a wildtype RPS6 gene is identified by the Genbank accession number NC 000009.12, from nucleotide 19375715 to nucleotide 19380236 on the forward strand of chromosome 9 according to the GRCh38.pl3 assembly of the human genome.
• the wildtype RPS6 gene comprises 6 exons.
• a mutation of the RPS6 gene may occur in any one or any combination of the 6 exons, or in any intron or noncoding regions of the RPS6 gene.
• the amino acid sequence of a wildtype RPS6 protein is identified by the Genbank accession number NM__0010i0.3.
• the individual is selected for treatment on the basis of having an mTOR-activating aberration &XRPS6.
• the mTOR-activation aberration a X RPS6 comprises an aberrant phosphorylation level of the protein encoded by RPS6 (e.g ., phosphorylation at residue S235, S236, S240, and/or S244).
• the aberrant phosphorylation level of the protein encoded by RPS6 is a positive status of phosphorylated S6 (pS6).
• the aberrant phosphorylation level of the protein encoded by RPS6 is an increased phosphorylation of S6 in the cancer as compared to a reference tissue.
• the reference tissue is derived from a non-cancerous tissue m the individual in some embodiments, the reference tissue is derived from a corresponding tissue in another individual that does not have the cancer. The status of.
• phosphorylated S6 can be assessed via IHC staining with an antibody that binds to phosphorylated residue(s) in S6 (e.g , an antibody that detects endogenous levels of ribosomal protein S6 only wiien phosphorylated at Ser235 and 236).
• the expression level of RPS'6 is assessed by immunohistochemistry.
• the mTOR-activation aberration at RPS6 comprises an aberrant expression level of RPS6.
• the methods described herein in some embodiments comprise subcutaneous administration of nanoparticle compositions of mTOR inhibitors.
• mTOR is a
• PI3K phosphatidylinositoi 3-kinase
• Akt protein kinase B pathway
• rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP!)
• mTORCl mTOR Complex 1
• mTORC2 mTOR Complex 2
• mTORCl is composed of mTOR, regulatory -associated protein of mTOR (Raptor), mammalian lethal with SEC 13 protein 8 (MLST8), PRAS40 and DEPTOR (Kim et al. (2002). Cell 110: 163-75; Fang et al. (2001) Science 294 (5548): 1942-5).
• mTORCl integrates four major signal inputs: nutrients (such as amino acids and phosphatidic acid), growth factors (insulin), energy and stress (such as hypoxia and DNA damage). Amino acid availability is signaled to mTORCl via a pathway involving the Rag and Regulator (LAMTOR1-3) Growth factors and hormones (e.g, insulin) signal to mTORCl via Akt, which inactivates TSC2 to prevent inhibition of mTORCl.
• nutrients such as amino acids and phosphatidic acid
• growth factors insulin
• energy and stress such as hypoxia and DNA damage
• Active mTORCl has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy (Atgl3, ULK1), ribosome biogenesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. Accordingly, mTORCl activity promotes either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable.
• mTORC2 is composed of mTOR, rapamycin-insensitive companion of mTOR (RICTQR), ObE, and mammalian stress-activated protein kinase interacting protein 1 (mSINl). In contrast to mTORCl, for winch many upstream signals and cellular functions have been defined (see above), relatively little is known about mTORC2 biology. mTORC2 regulates cytoskeletal organization through its stimulation of F-actin stress fibers, paxillin, RhoA, Racl, Cdc42, and protein kinase C a (PKCa).
• PKCa protein kinase C a
• the mTQR inhibitor is an inhibitor of mTQRCl. In some embodiments, the mTOR inhibitor is an inhibitor of mTORC2. In some embodiments, the mTOR inhibitor is an inhibitor of both mTORCl and mT()RC2.
• the mTOR inhibitor is a limus drug.
• lirnus drags include, but are not limited to, rapamycin, temsirohmus (CCI-779), everolimus (RAD001), ridaforolimus (AP -23573), deforolimus ( MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506).
• the hmus drug is selected from the group consisting of temsirohmus (CCI-779), everolimus (RADOOI ), ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506).
• the mTOR inhibitor is an mTOR kinase inhibitor, such as CC-115 or CC-223.
• the mTOR inhibitor is rapamycin.
• Rapamycin is a macrolide antibiotic that complexes with FKBP-12 and inhibits the mTOR pathway by binding mTORCl .
• the mTOR inhibitor is selected from the group consisting of rapamycin (sirolimus), BEZ235 (NVP-BEZ235), everolimus (also known as RADOOI, Zortress, Certican, and Afmitor), AZD8055, temsirohmus (also known as CCI-779 and Torisel), CC-115, CC-223, PI-103, Ku-0063794, INK 128, AZD2014, NVP-BGT226, PF- 04691502, CHS 132799, GDC-0980 (RG7422), Torin 1, WAY-600, WYE-125132, WYE- 687, GSK2126458, PF-05212384 (PKI-587), PP-121, OSI-027, Palomid 529, PP242, XI .765. GSK1059615, WYE-354, and ridaforolimus (also known as deforolimus).
• rapamycin sirolimus
• BEZ235 is an imidazoquiionine derivative that is an mTORCl catalytic inhibitor (Roper J, et al. PLoS One, 201 1 , 6(9), e25 ! 32).
• Everolimus is the 40-O ⁇ (2- hydroxy ethyl) deri vative of rapamycin and binds the cyclophilin FKBP-12, and this complex also mTORCl.
• AZD8055 is a small molecule that inhibits the phosphorylation of mTORCl (p70S6K and 4E-BP1).
• Temsirohmus is a small molecule that forms a complex with the FK506-binding protein and prohibits the activation of mTOR when it resides in the mTORC l complex.
• PI-103 is a small molecule that inhibits the activation of the rapamycin- sensitive (mTORCl) complex (Knight et al. (2006) Cell. 125: 733-47).
• KU-0063794 is a small molecule that inhibits the phosphorylation of mTORC l at Ser2448 in a dose-dependent and time-dependeni manner.
• GDC-0980 is an orally bioavailable small molecule that inhibits Class I PI3 Kinase and TORC1.
• Torin 1 is a potent small molecule inhibitor of mTQR.
• WAY-600 is a potent, ATP- competitive and selective inhibitor of mTOR.
• WYE-125132 is an ATP -competitive small molecule inhibitor of mTORCl.
• GSK2126458 is an inhibitor of mTORCl .
• PKI-587 is a highly potent dual inhibitor of RI3Ka, R13Kg and mTOR.
• PP-121 is a multi -target inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl.
• OSI-027 is a selective and potent dual inhibitor of mTORCl and mTORC2 with IC50 of 22 nM and 65 nM, respectively
• Palomid 529 is a small molecule inhibitor of mTORCl that lacks affinity for ABCB1/ABCG2 and has good brain penetration (Lin et al. (2013) hit J Cancer DOI: 10.1002/ijc. 28126 (e-published ahead of print).
• PP242 is a selecti ve mTOR inhibitor.
• XL765 is a dual inhibitor of mTOR/PI3k for mTOR, pi 10a, pi 10b, pi 10g and pi 105.
• GSK1059615 is a novel and dual inhibitor of RBKa, R13Kb, PI3K5, RI3Kg and mTOR.
• WYE-354 inhibits mTORCl in HEK293 ceils (0.2 pM-5 mM) and in HUVEC ceils (10 nM-1 mM).
• WYE-354 is a potent, specific and ATP -competitive inhibitor of mTOR.
• Deforolimus (Ridaforolimus, AP23573, MK-8669) is a selective mTOR inhibitor.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising (in various embodiments consisting essentially of or consisting of) an mTOR inhibitor (such as rapamycin) and an albumin (such as human serum albumin).
• an mTOR inhibitor such as rapamycin
• an albumin such as human serum albumin.
• Nanoparticles of poorly water soluble drugs have been disclosed m, for example, US 5916596 A; US 6506405 Bl; US 6749868 Bl, US 6537579 Bl, US 7820788 B2, and US 8911786 B2, and also in U S 2006/0263434 Al, US 2007/0082838 Al, and WO 2008/137148 A2, each of which is incorporated herein by reference in their entirety.
• compositions such as pharmaceutical compositions, comprising nanoparticles comprising an mTOR inhibitor and an albumin.
• the mTOR inhibitors are agents selected from the compounds that inhibit the mammalian target of rapamycin
• the mTOR inhibitor is rapamycin (also known as sirohmus) or an analog thereof.
• the mTOR inhibitor is a limus drug, which includes rapamycin and its analogs. Examples of limus drugs include, but are not limited to, temsirolimus (CCI-779), everolimus (RADOOl), ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrohmus, and tacrolimus (FK-506).
• the limus drug is selected from the group consisting of temsiroimms (CCI- 779), everolirnus (RADOOl), ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506).
• the mTOR inhibitor is an mTOR kinase inhibitor, such as CC-115 or CC-223.
• the mTOR inhibitor is selected from the group consisting of rapamycin (sirolimus), BEZ235 (NVP-BEZ235), everolirnus (also known as RADOOl, Zortress, Certican, and Afimtor), AZD8055,temsirolimus (also known as CO-779 and Torisel), CC- 115, CC-223, PI-103, Ku-0063794, INK 128, AZD2014, NVP-BGT226, PF-04691502,
• the pharmaceutical compositions further comprise an agent or agents for enhancing dissolution of dried forms of the compositions and/or enhancing the stability of the composition.
• the additional agent or agents comprise a saccharide.
• the saccharide may be, but is not limited to, monosaccharides, disaccharides, polysaccharides, and derivatives or modifications thereof.
• the saccharide may be, for example, any of mannitol, sucrose, fructose, lactose, maltose, dextrose, or trehalose.
• the additional agent or agents comprise glycine.
• the present application therefore in one aspect provides a pharmaceutical composition suitable for subcutaneous administration to an individual comprising a) nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin, and h) a saccharide.
• an mTOR inhibitor such as rapamycin
• the saccharide is present in an amount that is effective to increase the stability of the nanoparticles m the composition as compared to a nanoparticle composition without the saccharide. In some embodiments, the saccharide is in an amount that is effective to improve filterability of the nanoparticle composition as compared to a composition without the saccharide.
• the saccharide is present in an amount effective to enhance the solubility' of the pharmaceutical composition.
• the enhanced solubility comprises improved rate of dissolution of a dried form of the nanoparticle composition after addition of a reconstituting solution.
• the saccharide is present in an amount that reduces the incidence or severity of post-administration side effects when the nanoparticle composition is administered subcutaneously.
• the side effect is rash and the composition comprises nanoparticles comprising an mTOR inhibitor and an albumin and the saccharide is present in an amount that reduces the incidence of rash after subcutaneous administration of the nanoparticle composition.
• the pharmaceutical composition comprises nanoparticles comprising an mTOR inhibitor and an albumin, wherein the weight ratio of the albumin to the mTOR inhibitor in the composition is about 0.01 : 1 to about 100: 1.
• the composition comprises nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin, wherein the weight ratio of the albumin to the mTOR inhibitor (such as rapamycin) in the composition is about 18: 1 or less (including for example any of about 1 : 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12: 1, about 4: 1 to about 10: 1, about 5: 1 to about 9: 1, and about 9: 1).
• the composition comprises nanoparticles comprising rapamycin, or a derivative thereof, and an albumin, wherein the weight ratio of the albumin to the rapamycin or derivative thereof in the composition is about 18: 1 or less (including for example any of about 1 : 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 12:1, about 4: 1 to about 10: 1 , about 5: 1 to about 9: 1, and about 9: 1).
• the mTOR inhibitor (such as rapamycin) is coated with albumin.
• the particles (such as nanoparticles) described herein have an average or mean diameter of no greater than about any of 1000, 900, 800, 700, 600, 500, 400, 300, 200, 150, 120, and 100 nm. In some embodiments, the average or mean diameter of the particles is no greater than about 200 nm. In some embodiments, the average or mean diameter of the particles is between about 20 nm to about 400 nm. In some embodiments, the average or mean diameter of the particles is between about 40 nm to about 200 nm. In some embodiments, the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the average mea diameter of the particles is less than or equal to 120 nm. In some embodiments, the average mean diameter of the particles is about 100-120 nm, for example about 100 nm. In some embodiments, the particles are sterile-filterable. Methods of determining average particle sizes are known in the art, for example, dynamic light scattering (DLS) has been routinely used in determining the size of submicrometre-sized particles. International Standard ISG22412 Particle Size Analysis - Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008 and Dynamic Light Scatering Common Terms Defined, Malvern Instruments Limited, 2011. In some embodiments, the particle size is measured as the volume-weighted mean particle size (Dv50) of the nanoparticles in the composition
• compositions described herein may be a stable aqueous suspension of the mTQR inhibitor, such as a stable aqueous suspension of the mTOR inhibitor at a concentration of any of about 0.1 to about 200 mg/ml, about 0.1 to about 150 mg/ml, about 0.1 to about 100 mg/ml, about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, and about 5 mg/ml.
• the concentration of the mTOR inhibitor is at least about any of 0.2 mg/ml, 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 100 mg/ml, 150 mg/ml, or 200 mg/ml.
• the composition is a dry (such as iyophiiized) composition that can be reconstituted, resuspended, or rehydrated to form generally a stable aqueous suspension of th e nanoparticles comprising an mTOR inhibitor and an albumin.
• the composition is a liquid (such as aqueous) composition obtained by reconstituting or resuspending a dry composition.
• the composition is an intermediate liquid (such as aqueous) composition that can be dried (such as Iyophiiized).
• the nanoparticles comprising the mTOR inhibitor are associated (e g., coated) with an albumin (such as human albumin or human serum albumin).
• the composition comprises an mTOR inhibitor (such as rapamycin) in both nanoparticle and non-nanoparticle forms (e.g., in the form of solutions or in the form of soluble albumin/nanoparticle complexes), wherein at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the mTOR inhibitor in the composition are in nanoparticle form.
• the mTOR inhibitor (such as rapamycin) in the nanoparticles constitutes more than about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticles by weight.
• the nanoparticles have a non polymeric matrix.
• the nanoparticles comprise a core of an mTOR inhibitor (such as rapamycin) that is substantially free of polymeric materials (such as polymeric matrix).
• the composition comprises an albumin m both nanoparticle and non-nanoparticle portions of the composition, wherein at least about any one of 5G%, 60%, 70% , 80%», 90%, 95% ) , or 99% of the albumin in the composition are in non
• the weight ratio of an albumin (such as human albumin or human serum albumin) and a mTOR inhibitor (such as rapamycin) in the mTOR inhibitor nanoparticle composition is about 18: 1 or less, such as about 15: 1 or less, for example about 10: 1 or less.
• the weight ratio of an albumin (such as human albumin or human serum albumin) and an mTOR inhibitor (such as rapamycin) in the composition falls within the range of any one of about 1: 1 to about 18: 1, about 2: 1 to about 15: 1, about 3: 1 to about 13: 1 , about 4: 1 to about 12: 1, about 5: 1 to about 10: 1.
• the weight ratio of an albumin and an mTOR inhibitor (such as rapamycin) in the nanoparticle portion of the composition is about any one of 1 :2, 1:3, 1:4, 1 :5, 1:9, 1 : 10, 1: 15, or less.
• the weight ratio of the albumin (such as human albumin or human serum albumin) and the mTOR inhibitor (such as rapamycin) in the composition is any one of the following: about 1: 1 to about 18: 1, about 1 : 1 to about 15: 1, about 1 : 1 to about 12: 1, about 1: 1 to about 10: 1, about 1 : 1 to about 9: 1, about 1 : 1 to about 8: 1, about 1 : 1 to about 7: 1, about 1: 1 to about 6: 1 , about 1: 1 to about 5: 1, about 1 : 1 to about 4: 1 , about 1: 1 to about 3: 1, about 1 : 1 to about 2: 1, about 1 : 1 to about 1 : 1.
• the nanoparticles described herein may be present in a dry formulation (such as lyophilized composition) or suspended in a biocompatible medium, such as a reconstituting solution.
• Suitable biocompatible media include, but are not limited to, water, buffered aqueous media, saline, buffered saline, optionally buffered solutions of amino acids, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, lipid- containing emulsions, and the like.
• the pharmaceutically acceptable carrier comprises an albumin (such as human albumin or human serum albumin).
• the albumin may either be natural in origin or synthetically prepared.
• the albumin is human albumin or human serum albumin.
• the albumin is a recombinant albumin.
• HSA Human serum albumin
• the ammo acid sequence of HSA contains a total of 17 disulfide bridges, one free thiol (Cys34), and a single tryptophan (Trp214).
• Intravenous use of HSA solution has been indicated for the prevention and treatment of hypovolemic shock (see, e.g., Tullis, JAMA, 237: 355-360, 460-463, (1977)) and Houser et al..
• HSA Human serum albumin
• hydrophobic binding sites a total of eight for fatty acids, an endogenous ligand of HSA
• binds a diverse set of drugs, especially neutral and negatively charged hydrophobic compounds Goodman et al., The Pharmacological Basis of Therapeutics, 9 th ed, McGraw-Hill New Y ork (1996)).
• Two high affinity binding sites have been proposed m subdomains PA and HI A of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface which function as attachment points for polar ligand features (see, e.g., Fehske et al., Biochem.
• the composition described herein is substantially free (such as free) of surfactants, such as Cremophor (or polyoxy ethylated castor oil, including Cremophor EL® (BASF)).
• the mTOR inhibitor nanoparticle composition (such as rapamycm/albumm nanoparticle composition) is substantially free (such as free) of surfactants.
• a composition is“substantially free of Cremophor” or“substantially free of surfactant” if the amount of Cremophor or surfactant in the composition is not sufficient to cause one or more side effect(s) in an individual when the mTOR inhibitor nanoparticle composition (such as rapamycin/albumin nanoparticle composition) is administered to the individual.
• the mTOR inhibitor nanoparticle composition (such as rapamycin/albumin nanoparticle composition) contains less than about any one of 20%, 15%, 10%, 7.5%, 5%, 2.5%, or 1% organic solvent or surfactant.
• the albumin is human albumin or human serum albumin. In some embodiments, the albumin is recombinant albumin.
• an albumin in the composition described herein will vary depending on other components in the composition.
• the composition comprises an albumin in an amount that is sufficient to stabilize the mTGR inhibitor (such as rapamycin) in an aqueous suspension, for example, in the form of a stable colloidal suspension (such as a stable suspension of nanoparticles).
• the albumin is in an amount that reduces the sedimentation rate of the mTOR inhibitor (such as rapamycin) in an aqueous medium.
• the amount of the albumin also depends on the size and densi ty of nanoparticles of the mTOR inhibitor.
• An mTOR inhibitor (such as rapamycin) is‘"stabilized” in an aqueous suspension if it remains suspended in an aqueous medium (such as without visible precipitation or sedimentation) for an extended period of time, such as for at least about any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours.
• the suspension is generally, but not necessarily, suitable for administration to an individual (such as a human). Stability of the suspension is generally (but not necessarily) evaluated at a storage temperature (such as room temperature (such as 20-25 °C) or refrigerated conditions (such as 4 °C)).
• a suspension is stable at a storage temperature if it exhibits no flocculation or particle agglomeration visible to the naked eye or when viewed using an optical microscope at 1000 times, at about fifteen minutes after preparation of the suspension. Stability can also be evaluated under accelerated testing conditions, such as at a temperature that is about 40 °C or higher.
• the albumin is present m an amount that is sufficient to stabilize the mTOR inhibitor (such as rapamycin) in an aqueous suspension at a certain concentration.
• the concentration of the mTOR inhibitor (such as rapamycin) in the composition is about 0.1 to about 100 mg/ml, including for example about any of 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, or about 5 mg/ml.
• the concentration of the mTOR inhibitor is at least about any of 1.3 mg/'ml, 1.5 mg/'ml, 2 mg/ml, 3 mg/ml, 4 mg/'ml, 5 mg/ml, 6 mg/ml, 7 mg/ ' ml, 8 mg/'ml, 9 mg/ml, 10 rng/rnl, 15 mg/'ml, 20 mg/ml, 25 mg/rnl, 30 mg/'ml, 40 mg/ml, and 50 mg/'ml.
• the albumin is present in an amount that avoids use of surfactants (such as Cremophor), so that the composition is free or substantially free of surfactant (such as Cremophor).
• the composition, in liquid form comprises from about 0.1% to about 50% (w/v) (e.g., about 0.5% (w/v), about 5% (w/v), about 10% (w/v), about 15%
• the composition in liquid form, comprises about 0.5% to about 5% (w/v) of albumin.
• the weight ratio of the albumin to the mTOR inhibitor (such as rapamycin) in the mTOR inhibitor nanoparticle composition is such that a sufficient amount of mTOR inhibitor binds to, or is transported by, the cell.
• the weight ratio of an albumin to an mTOR inhibitor (such as rapamycin) will have to be optimized for different albumin and mTOR inhibitor combinations
• the weight ratio of an albumin to an mTOR inhibitor (such as rapamycin) (w/w) is about 0.01:1 to about 100:1, about 0.02:1 to about 50:1, about 005:1 to about 20:1, about 0.1:1 to about 20:1, about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or about 9:1.
• the albumin to mTOR inhibitor (such as rapamycin) weight ratio is about any of 18:1 or less, 15:1 or less, 14:1 or less, 13:1 or less, 12:1 or less, 11:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6:1 or less, 5:1 or less, 4:1 or less, and 3:1 or less.
• the weight ratio of the albumin (such as human albumin or human serum albumin) to the mTOR inhibitor (such as rapamycin) in the composition is any one of the following: about 1:1 to about 18:1, about 1:1 to about 15:1, about 1:1 to about 12:1, about 1:1 to about 10:1, about 1:1 to about 9:1, about 1:1 to about 8:1, about 1:1 to about 7:1, about 1:1 to about 6:1, about 1:1 to about 5:1, about 1:1 to about 4: 1, about 1 : 1 to about 3:1, about 1 : 1 to about 2: 1, about 1 : 1 to about 1 : 1.
• the albumin allows the composition to be administered to an individual (such as a human) without significant side effects.
• the albumin (such as human serum albumin or human albumin) is in an amount that is effective to reduce one or more side effects of subcutaneous administration of the mTOR inhibitor (such rapamycin) to a human.
• the mTOR inhibitor such rapamycin
• administration such as subcutaneous administration, of the mTOR inhibitor (such as rapamycin) refers to reduction, alleviation, elimination, or avoidance of one or more undesirable effects caused by the mTOR inhibitor, as well as side effects caused by delivery vehicles (such as solvents that render the Iimus drugs suitable for injection) used to deliver the mTOR inhibitor.
• mTOR inhibitor such as rapamycin
• side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, venous thrombosis, extravasation, and combinations thereof.
• side effects are merely exemplary and other side effects, or combination of side effects, associated with limus drugs (such as rapamycin) can be reduced.
• the mTOR inhibitor nanoparticle compositions described herein comprise naiioparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nrn.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nrn.
• the mTOR inhibitor nanoparticle compositions described herein comprise naiioparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm).
• the average or mean diameter of the naiioparticles is about 100-120 nm, for example about 100 nm.
• compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm). In some embodiments, the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm. In some embodiments, the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the average or mean diameter of the nanoparticles is about 10 to about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the average or mean diameter of the nanoparticles is about 40 to about 120 n .
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater tha about 150 nm (for example about 100 nm).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the nanoparticles have an average diameter of no greater tha about 150 nm (for example about 100 nm).
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle is about 100-120 nm, for example about 100 nm.
• compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm). In some embodiments, the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm. In some embodiments, the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the average or mean diameter of the nanoparticles is about 10 to about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the average or mean diameter of the nanoparticles is about 40 to about 120 nm. In some embodiments, the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm), wherein the weight ratio of albumin and mTOR inhibitor m the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticles is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticles is about 40 run to about 120 n .
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• the mTOR inhibitor nanoparticle comprising an mTOR inhibitor (such as rapamycin) and an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• the mTOR inhibitor nanoparticle such as rapamycin
• albumin such as human albumin or
• compositions described herein comprise nanoparticles comprising rapamycin and human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 n ), wherein the weight ratio of albumin and mTOR inhibitor in the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticles is about 10 nrn to about 150 nm.
• the average or mean diameter of the na oparticles is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e g., coated) with an albumin (such as human albumin or human serum albumin).
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of about 10 nm to about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of about 40 nm to about 120 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm).
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of about 10 nm to about 150 nm. In some embodiments, the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of about 40 nm to about 120 nm. In some embodiments, the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor naiioparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g, coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm.
• the mTOR inhibitor nanopartide compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as huma albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm.
• an mTOR inhibitor such as rapamycin
• an albumin such as huma albumin or human serum albumin
• the mTOR inhibitor nanopartide compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 10 nm to about 150 nm.
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanopartide compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 40 nm to about 120 nm.
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 40 nm to about 120 nm.
• the mTOR inhibitor nanopartide such as rapamycin
• compositions described herein comprise nanopanicles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the composition furth er comprises a saccharide, wherein the nanoparticles have an average di ameter of no greater than about 150 nm (for example about 100 nm).
• the mTOR inhibitor nanopartide compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 10 nm to about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 40 nm to about 120 nm. In some embodiments, the average or mean diameter of the nanoparticies is about 100-120 nm, for example abo ut 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticies comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticies comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticies have an average diameter of no greater than about 200 nm, wlierein the w eight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticies comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticies have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticies comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the nanoparticies have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticies comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the nanoparticies have an average diameter of no greater than about 150 nm (for example about 100 nm), wherein the weight ratio of albumin and the rapamycin in the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticies is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticies is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g., coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g, coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1 )
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) associated (e.g, coated) with an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin associated (e.g., coated) with human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm), wherein the weight ratio of albumin and the rapamycin in the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticles is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticles is about 40 nm to about 120 nrn.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin) in some embodiments, the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nm.
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 run).
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin stabilized by human albumin (such as human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nrn).
• the average or mean diameter of the nanoparticles is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticles is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanopartic!es have an average diameter of no greater than about 150 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 n ).
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin stabilized by human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm).
• the average or mean diameter of the nanoparticles is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticles is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nrn.
• the mTOR inhibitor nanoparticle compositions described here comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 200 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanoparticles have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• an albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the nanopanicles have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9:1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin stabilized by human albumin (such as human serum albumin), wherein the nanoparti cles have an average diameter of no greater than about 150 nm (for example about 100 nm), wherein the weight ratio of albumin and the rapamycin m the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticles is about 10 rirn to about 150 nrn.
• the average or mean diameter of the nanoparticles is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the composition further comprises a saccharide, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• the mTOR inhibitor nanopartide compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 200 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor in the composition is no greater than about 9:1 (such as about 9: 1 or about 8: 1).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising an mTOR inhibitor (such as rapamycin) stabilized by an albumin (such as human albumin or human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of about 150 nm, wherein the weight ratio of the albumin and the mTOR inhibitor m the composition is no greater than about 9: 1 (such as about 9: 1 or about 8: 1 ).
• an mTOR inhibitor such as rapamycin
• albumin such as human albumin or human serum albumin
• the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising rapamycin stabilized by human albumin (such as human serum albumin), wherein the composition further comprises a saccharide, wherein the nanoparticles have an average diameter of no greater than about 150 nm (for example about 100 nm), wherein the weight ratio of albumin and the rapamycin in the composition is about 9: 1 or about 8: 1.
• the average or mean diameter of the nanoparticles is about 10 nm to about 150 nm.
• the average or mean diameter of the nanoparticles is about 40 nm to about 120 nm.
• the average or mean diameter of the nanoparticles is about 100-120 nm, for example about 100 nm.
• the mTOR inhibitor nanoparticle composition comprises nab- rapamycin.
• the mTOR inhibitor nanoparticle composition is nab- rapamycin.
• Nab -rapamycin is a formulation of rapamycin stabilized by human albumin USP, which can be dispersed in directly injectable physiological solution. The weight ratio of human albumin and rapamycin is about 8: 1 to about 9:1.
• a suitable aqueous medium such as 0.9% sodium chloride injection or 5% dextrose injection
• nab- rapamycm forms a stable colloidal suspension of rapamycin.
• the mean particle size of the nanoparticles in the colloidal suspension is about 100 nanometers.
• nab- rapamycin can be reconstituted in a wide range of concentrations ranging from dilute (0.1 mg/m! rapamycin or a derivative thereof) to concentrated (20 mg/ml rapamycin or a derivative thereof), including for example about 2 mg/ml to about 8 mg/ml, or about 5 mg/ml.
• nanoparticles containing an mTOR inhibitor such as rapamycin
• an albumin such as human serum albumin or human albumin
• these methods are disclosed in, for example, U. S. Pat. Nos.5,916,596; 6,506,405; 6,749,868, 6,537,579, 7,820,788, and 8,911,786, and also in U. S. Pat. Pub. Nos. 2007/0082838, 2006/0263434 and PCT Application WO08/137148.
• the mTOR inhibitor (such as rapamycin) is dissolved in an organic solvent, and the solution can be added to an albumin solution. The mixture is subjected to high pressure homogenization. The organic solvent can then be removed by evaporation. The dispersion obtained can be further lyophilized.
• Suitable organic solvents include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art.
• the organic solvent can be methylene chloride or chloroform/ethanol (for example with a ratio of 1:9, 1 :8, 1:7, 1 :6, 1 :5, 1 :4, 1:3, 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1).
• nanoparticles described herein can be present in a composition that includes other agents, earners, excipients, diluents, or stabilizers.
• agents earners, excipients, diluents, or stabilizers.
• certain negatively charged particles for example, to increase stability by increasing the negative zeta potential of nanoparfieles, certain negatively charged particles.
• Such negatively charged components include, but are not limited to bile salts of bile acids consisting of g!ycocho!ic acid, cholic acid, chenodeoxy cholic acid, taurocliolic acid, giycochenodeoxy cholic acid, taurochenodeoxy cholic acid, litochoiic acid, ursodeoxycholic acid, dehydrocholic acid and others; phospholipids including lecithin (egg yolk) based phospholipids which include the following phosphatidylcholines:
• palmitoyloleoylphosphatidylcholine palmitoyllinoleoylphosphatidylcholine
• stearoylarachidoylphosphaiidylcholine and dipalmiioylphosphatidylcholine.
• Other phospholipids including L-a-dimynstoylphosphatidylcholine (DMPC),
• DQPC dioleoylphosphatidyicholine
• DSPC distearyolphosphatidylchoiine
• HSPC hydrogenated soy phosphatidylcholine
• Negatively charged surfactants or emulsifiers are also suitable as additives, e.g., sodium cholesteryl sulfate and the like.
• the composition is suitable for administration to a human. In some embodiments, the composition is suitable for administration to a mammal such as, in the veterinary context, domestic pets and agricultural animals. In some embodiments, the composition is suitable for administration after reconstitution.
• Suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose,
• the formulations can additionally include lubricating agents, welting agents, emulsifying and suspending agents, and/or preserving agents.
• Formulations suitable for subcutaneous administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
• the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, immediately prior to use.
• Extemporaneous solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
• the composition is formulated to have a pH range of about 4.5 to about 9.0, including for example pH ranges of about any of 5.0 to about 8.0, about 6.5 to about 7.5, and about 6 5 to about 7.0.
• the pH of the composition is formulated to no less than about 6, including for example no less than about any of 6.5, 7, or 8 (such as about 8).
• the composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol.
• kits of the invention include one or more containers comprising an mTOR inhibitor nanoparticle composition (such as rapamyc /aJbumin nanoparticle composition) (or unit dosage form and/or article of manufacture) suitable for sub-cutaneous administration, and in some embodiments, further comprise a device for subcutaneously administering the mTOR inhibitor nanoparticle composition.
• the kit further comprises instructions for use in accordance with any of the methods described herein.
• the kit may further comprise a description of selection of individuals suitable for treatment. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
• kits of the invention are in suitable packaging.
• suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar® or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
• the present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
• the instructions relating to the use of the mTOR inhibitor nanoparticle composition generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
• the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
• kits may be provided that contain sufficient dosages of an mTOR inhibi tor nanoparticl e composition (such as rapamycin/albumin nanoparticle composition) to provide effective treatment of an individual for an extended period, such as any of a week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 w eeks. 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the mTOR inhibitor nanoparticle composition (such as rapamycin/albumin nanoparticle composition) and instructions for use, packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
• kits may further comprise a device which contains the mTOR inhibitor nanoparticle composition.
• the instructions may further comprise instructions for use of the device.
• Example 1 Pharmacokinetics study following subcutaneous and intravenous dosing of ABI-009 in Sprague Dawley (SD) rats
• subcutaneous administration enhanced bioavailability as indicated by total area under the curve (AUC) compared with intravenous administration.
• AUC total area under the curve
• Subcutaneous administration of only 0.56 mg/kg ABi-009 produced similar drug exposure at l/3rd the dose of IV ABI-009 (1.7 mg/kg).
• subcutaneous administration reduced the maximum concentration achieved ⁇ ( ' max) and delayed the time to reach the maximum concentration (Cmax time). Rapamycin peak levels and AUC in blood increased with higher subcutaneous ABI-009 doses.
• Tissues were harvested from the rats described above in Example 1 at either 24 hours or 168 hours (see Table 1 for study design) post-administration by subcutaneous (subQ) or intravenous (IV) route of ABI-009
• the concentration of rapamycin in particular rat tissues 24 or 168 hours post-administration is indicated in Figure 5 (bone marrow and brain).
• Figure 6 heart and lung
• Figure 7 lung and pancreas.
• the subcutaneous route of administration resulted in significant distribution to all organs tested, including bone marrow, brain, heart, liver, lung, and pancreas.
• the pattern of organ distribution was similar between subcutaneous and intravenous but subcutaneous administration at 0.56 mg/kg dose was able to produce similar tissue concentrations as intravenous administration at 1.7 mg/kg dose.
• the brain concentration was relatively stable between 24 and 168 hours.
• Rats were subcutaneously administered a single dose of « «h-rapamycin (ABI-009) at a dose of 1.7 mg/kg, 9.5 mg/kg, or 17 mg/kg. Rats were sacrificed at 24, 72, and 120 hours and whole blood and bram tissue were collected.
• « «h-rapamycin ABSI-009
• Rapamycin concentrations were measured at each time points for each sample. As indicated in Fig. 5, a dose-dependent increase in brain rapamycin levels was observed. Surprisingly, while blood levels of rapamycin rapidly approached baseline, even at the high 17 mg/kg dose, brain rapamycin levels were well-maintained over the entire 120 hours, even at the lowest dose. See also Fig. 8.
• Example 3 neA-rapamydn nauopartide formulations containing a sugar
• Formulations of r?aZ>-rapamycin (ABI-009) will be prepared with and without saccharides, including formulations of sucrose and formulations of trehalose.
• formulations will be lyophilized and then reconstituted with water at various concentrations from 1 mg/ml to 40 mg/ml rapamycin. The formulations will then be lyophilized again and incubated at 40 °C for 15 days.
• the formulations will be reconstituted with water and concurrently or subsequently assayed for albumin oligomers and polymers and reconstitution time.
• Formulations that exhibit reduced albumin oligomers and polymers, and/or rapid reconstitution, will be selected as enhanced formulations for subcutaneous administration.
• the objectives of the study were to assess the overall safety and local toxicity at injection sites following repeated ABI-009 SC injections in SD rats. The signs of clinical distress were observed to determine toxicity . Skin samples from the injection sites were analyzed for signs of inflammation and necrosis by histopathology.
• Rats w3 ⁇ 4re divided into 5 groups of 3 animals each. Rats w3 ⁇ 4re weighed and dosed subcutaneously, as specified in Table 5, ever' 4 days for 4 weeks (7 injections).
• Vehicle controls consist of 0.9% saline solution and HSA m 0.9% saline solution.
• Final concentration of HSA solution is 90 mg/ml, based on the albumin:rapamycin ratio of 9: 1 of the test article ABI-009 (manufacture lot # C345-001, Fisher lot #51394.2).
• Each vial of ABI-009 (C345-001) contains 97.4 mg rapamycin and 874 mg human albumin.
• HSA saline solution is diluted from 20% Grifols albumin stock solution (200 mg/ml).
• ABI-009 dosing solutions first make a stock ABI-009 solution of 10 mg/ml, then dilute to desired concentrations for dosing solution using HSA-saline solution. A vial of 100 mg of ABI-009 was dissolved in 10 ml of 0.9% saline to prepare a solution of 10 mg/ml.
• ABI-009 solution of 5 mg/ml was prepared by diluting 0.6 ml of stock solution (10 mg/ml) with 0.6 ml of HSA-0.9% saline to prepare a solution of 5.0 mg/ml for group 4.
• ABI- 009 solution of 1.7 g/ml was prepared by diluting 0.3 ml of ABI-009 solution from group 4 (5 0 mg/ml) with 0.6 ml of HSA-0.9% saline to prepare a solution of 1 7 mg/ml for group 3.
• the rats were anesthetized, weighed, and administered with ABI-009 solutions, HSA solution and saline according to Table 6 by subcutaneous (SC) injection every 4 days for 4 weeks (7 injections).
• SC subcutaneous
• Rats were examined once daily for clinical signs of overall toxicity and the local injection sites for reactions to subcutaneous injection. The signs of clinical distress were observed to determine toxicity. Piloerection, weight loss, lethargy, discharges, neurological symptoms, morbidity, redness and inflammation of injection site, and any other signs considered abnormal for animal behavior. Pictures of the injection site for all rats were taken before and after the SC injection.
• rats treated with ABI-009 (Groups 3, 4, and 5) were anesthetized and bled for samples into pre-chilled K2EDTA tubes before each administration (except 1st dose). Whole blood was collected, stored in labeled Eppendorf tubes at -80 ° C, and analyzed for trough rapamycin levels.
• rats were normal post dosing of ABI-009 at current dose regimen (1.7-10 mg/kg, 7 doses), with no body weight loss observed during the study.
• the histopathology results demonstrated dose-associated local signs of toxicity, with mild to marked necrosis at the highest ABI-009 dose (10 mg/kg).
• Mixed inflammation cells infiltration may possibly be caused by the heteroprotein HSA.
• ABI-009 at 1.7 mg/kg solution concentration 1.7 mg/mi
• Trough blood rapamycin levels increased with higher ABI-009 dose.
• Athymic nude mice were housed in filter-topped cages. Cancer cells were injected subcutaneously into both flanks (lxl 0 7 per flank) in 0.1 ml phosphate-buffered saline with 20% Matrigel®.
• Treatment Day 1 began with the presence of tumors (tumor average -100-150 mm 3 ). Animals were sorted into 4 groups.
• [Q2Q3] Group 1 comprising 5 mice, received saline by intravenous route 2x weekly for 6 weeks.
• Group 2 comprising 5 mice, received ABI-009 at 7.5 mg/kg by intravenous route 2x weekly for 6 weeks.
• Total rapamycin dose was 15 mg/kg/wk.
• Group 3 comprising 5 mice, received rapamune at 3 mg/kg 5x weekly for 6 weeks by oral administration.
• Total rapamycin dose was 15 mg/kg/wk.
• Group 4 comprising 3 mice, received ABI-009 at 7.5 mg/kg by subcutaneous route 2x weekly for 6 weeks.
• Total rapamycin dose was 15 mg/kg/wk.
• Measurements are made three-times weekly (Monday, Wednesday, and Friday) until predefined sacrifice time points and termination 6 weeks later or when tumors reach maximum volume of 2,000 mm 3 . Signs of distress will be recorded daily. Tumors will be harvested and stored. Blood samples will be collected at the same time with tumor harvest.
• Results The study is ongoing. Preliminary tumor volume results (mean and standard error of mean, SEM) of each group are summarized in Table 10, below. The tumor growth inhibition (TGI) compared to saline (group 1) and P-va!ue of the TGI vs. saline are reported in Table 10, as well. The results are also summarized in FIG. 16.
• Equal weekly doses of ABI-009 intravenously (group 2) resulted in significantly greater TGI than oral Rapamune (TGI 66.7% vs saline control, P ::: 0.0016 vs oral Rapamune).
• ABI-009 by subcutaneous route (group 4) produced the most profound tumor growth inhibition (TGI 89.8%, P 0.0001 vs. saline control, P ⁇ 0.0001 vs oral Rapamune).
• ABI-009 administered by intravenous or subcutaneous route resulted in significantly greater antitumor activity compared with equal weekly dose of oral Rapamune in a TSC2-deficient SNU-398 human hepatocellular carcinoma xenograft mouse model.
• ABI- 009 by subcutaneous route was surprisingly effective even compared to ABI-009 by intravenous route. No major toxicity or weight loss were observed in any treatment group.

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