USOO9622982B2

(12) United States Patent (10) Patent No.: US 9,622,982 B2 Bannister et al. (45) Date of Patent: Apr. 18, 2017

(54) CANCER DRUG AND USES 3 1/357 (2013.01); A61 K3I/366 (2013.01); A61K 31/40 (2013.01); A61K 31/4184 (71) Applicant: Health Clinics Limited, London (GB) (2013.01); A61 K3I/517 (2013.01); A61 K 31/7068 (2013.01); A61K 39/39558 (2013.01) (72) Inventors: Robin M. Bannister, Essex (GB); John (58) Field of Classification Search Brew, Hertfordshire (GB); Gregory A. None Stoloff, London (GB) See application file for complete search history. (73) Assignee: HEALTH CLINICS LIMITED, (56) References Cited London (GB (GB) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 2005/0209292 A1* 9/2005 Chuang ...... A61K 31,225 patent is extended or adjusted under 35 514,369 U.S.C. 154(b) by 99 days. (21) Appl. No.: 14/155,320 FOREIGN PATENT DOCUMENTS y x- - - 9 CN 1435167 A 8, 2003 (22) Filed: Jan. 14, 2014 WO OOO27359 A1 5, 2000 (65) Prior Publication Data OTHER PUBLICATIONS US 2014/O19929.6 A1 Jul. 17, 2014 Mrowska et al (International Journal of Oncology, 2008, vol. 32, pp. Related U.S. ApplicationO O Data Yao249-255).* et al (International Journal of Cancer, 2006, vol. 118, pp. 773-779). (60) Provisional application No. 61/752,360, filed on Jan. Babcook et al (Cancer Research, Apr. 15, 2013, vol. 73, No. 8, 14, 2013, provisional application No. 61/782,585, Suppl. 1, Abstract No. 3283).* filed on Mar. 14, 2013, provisional application No. Tousoulis et al (International Journal of Cardiology, 2011, vol. 149, 61/872,822, filed on Sep. 2, 2013. pp. 46–49).* Lee, et al., “Outcomes with first-line platinum-based combination

(51) Int. Cl. EEEaCC SS olumbia,insulship . , Lun ancer, A "E Sevier, 3. Fs 3:08: KNISA, NL, vol. 64, No. 3, pp. 308-311. 9. International Search Report PCT/EP2014/050635, mailed Jul. 17, A6 IK3I/55 (2006.01) 2014. A6 IK3I/I9 (2006.01) A6 IK 3L/225 (2006.01) * cited by examiner A6 IK3I/353 (2006.01) A 6LX 3L/357 (2006.01) Primary Examiner — Karen Canella A6 IK3I/366 (2006.01) (74) Attorney, Agent, or Firm — One3 IP Management, A6 IK 3/40 (2006.01) P.C.; Dean G. Stathakis; Peter D. Weinstein A6 IK 3/484 (2006.01) A 6LX 3/57 (2006.01) (57) ABSTRACT A6 IK3I/7068 (2006.01) A pharmaceutical composition comprising a cancer thera A 6LX 39/395 (2006.01) peutic that is capable of inhibiting and/or reducing the A6 IK3I/352 (2006.01) ability of a cancer cell to take up and utilize glucose or other A2.3L 33/10 (2016.01) energy source, a lipid or other building block of a cell (52) U.S. Cl. membrane or organelle, and/or . The pharmaceu CPC ...... A61K 9/4858 (2013.01); A23L 33/10 tical composition can comprise one or more cancer thera (2016.08); A61 K3I/05 (2013.01); A61 K peutics that can be administered individually or in combi 3 1/155 (2013.01); A61K 31/19 (2013.01); nation to an individual. A61K 31/225 (2013.01); A61K 31/352 (2013.01); A61 K3I/353 (2013.01); A61 K 23 Claims, 4 Drawing Sheets U.S. Patent Apr. 18, 2017 Sheet 1 of 4 US 9,622,982 B2

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3A 3. 8: : US 9,622,982 B2 1. 2 CANCER DRUG AND USES and has been found in many parts of the world. Artemisinin, and its derivatives are a group of drugs that are known to This application is a U.S. Non-Provisional application have a rapid action in patients for the treatment of Plasmo and claims priority pursuant to 35 U.S.C. 119(e) to U.S. dium falciparum malaria. Treatments containing an artemisi Provisional Patent Application 61/752,360, filed Jan. 14, nin derivative (artemisinin-combination therapies, ACTs) 2013, U.S. Provisional Patent Application 61/782,585, filed are now standard treatment worldwide for P falciparum Mar. 14, 2013, and U.S. Provisional Patent Application malaria. 61/872,822, filed Sep. 2, 2013, each of which is hereby Use of the drug by itself as a monotherapy is explicitly incorporated by reference in its entirety. discouraged by the World Health Organization, as there have 10 been signs that malarial parasites are developing resistance BACKGROUND to the drug. Therapies that combine artemisinin with some other antimalarial drug are the preferred treatment for The majority of cancer treatments are selected to inhibit malaria and are both effective and well tolerated in patients. or reduce a cancer cells ability to survive and/or their ability The drug is also increasingly being used in Plasmodium to divide to form more cancer cells. While currently there are 15 vivax malaria, as well as being a topic of research in cancer many cancer treatments that are prescribed to help an treatment (http://en.wikipedia.org). individual suffering from a cancer that have one or both of Because artemisinin itself has physical properties such as these abilities, it is worth noting that these same cancer poor bioavailability that limit its effectiveness, semisyn treatments have several shortcomings. Among these are that thetic derivatives of artemisinin have been developed. These an individual administered the treatment can suffer from a include: Artesunate, Artemether, Dihydroartemisinin, Arte serious side effect. In addition, many treatments are cancer linic acid, Artenimol and Artemotil. There are also simpli specific and only work on one type of cancer. Finally, their fied analogs in preclinical research, including, arterolane. use is generally very costly and beyond the reach of a large Artemisinin and its derivatives have been shown in some number of individuals suffering from a cancer. What is studies to have some anticancer and antitumor activity. For needed is a treatment that has the ability to inhibit or reduce 25 instance, Arthemether has shown a strong inhibitory effects a cancer cells ability to survive and/or divide while at the on brain glioma growth and angiogenesis in rats. It has also same time the treatment: (1) is tolerated by an individual; (2) shown a dose- and time-dependent cytotoxicity that induced works against many different cancers; and, (3) is affordable apoptosis and G2 cell cycle arrest in ovarian cancer cell so that all individuals suffering from a cancer can be lines, human leukemia HL60 cells, and human pancreatic administered the treatment. 30 cancer BXPC-3 and AsPC-1 cells. Dihydroartemisinin and Currently, there are whole classes of therapeutics that are other artemisinin-based endoperoxide compounds have been administered to individuals who suffer from a genetic, found to target human metastatic melanoma cells with metabolic or other disease or from a disease caused by a induction of NOXA-dependent mitochondrial apoptosis that bacteria, virus or parasite (a "disease treating therapeutic') occurs downstream of iron-dependent generation of cyto that treat the disease by inhibiting or reducing the ability of 35 toxic oxidative stress. a cell to survive and/or divide. In particular, these disease Other cancer therapeutics include drugs used as part of a therapeutics act by: (1) inhibiting or reducing the amount of chemotherapy regimen, including, alkylating agents, anti lipids, other fats and/or cholesterol taken up by cells; and/or metabolites, anthracyclines, plant alkaloids, topoisomerase (2) inhibiting or reducing the ability of a cell to take up or inhibitors, and other antitumour agents. Other cancer thera utilize glucose or another energy source. While these disease 40 peutics include monoclonal antibodies and the new tyrosine treating therapeutics act in a manner that can treat a cancer, kinase inhibitors, which directly target a molecular abnor currently they are not prescribed to patients Suffering from mality in certain types of cancer. Each of these other cancer CaCC. therapeutics could benefit from a formulation that results in Thus, it would be advantageous to use a disease treating a maintenance or reduction of the number of cancer cells a therapeutic to treat cancer (hereinafter a "cancer therapeu 45 patient has or the size of one or more tumors present in a tic'). Such a cancer therapeutic can be administered to an patient. individual either solely or in combination with one or more While these cancer therapeutics function for their of additional cancer therapeutics to treat a cancer. Moreover, intended purpose, their effectiveness can be improved as these cancer therapeutics affect a cancer cells metabolism through a formulation that enhances their ability to act on and ability to divide, they can be used against multiple 50 their target cells. One means of doing this is to formulate different cancer types, and in Some instances, all cancers. cancer therapeutics in a lipid formulation. Most cancer therapeutics are provided to a patient suffer ing from a cancer using a formulation that enables the SUMMARY therapeutic to dissolve in an aqueous solution that will mix with the patients plasma following transfusion. These for 55 In an aspect of the present invention, a pharmaceutical mulations are more concerned with solubility and are not composition comprising a therapeutic is used to treat a generally designed to enhance the effectiveness of the cancer cancer (a "cancer therapeutic'). In an embodiment, a cancer therapeutic. One means of increasing the effectiveness of therapeutic or derivative thereof, affects cellular metabo therapeutics that has been Successful in the past is the use of lism. In an embodiment, a cancer therapeutic reduces the lipid formulations. Lipid formulations have been shown to 60 amount of circulating glucose in an individual. In another increase the effectiveness of certain classes of drugs, such as embodiment, a cancer therapeutic reduces the amount of NSAIDs, while reducing some of their adverse side effects. circulating lipids, other fats and/or cholesterol. Among the classes of cancer therapeutics that would In an embodiment, a cancer therapeutic can enter a benefit from a lipid formulation are Artemisinin and its macrophage resulting in the macrophage increasing the level derivatives. Artemisinin is purified from the leaves of 65 of CD36 and LDL receptors, resulting in a reduction in Artemisia annua (annual wormwood). The drug is named circulating LDLS. In another embodiment, a cancer thera Qinghaosu in Chinese. Artemisia annua is a common herb peutic increases the Glut-4 receptor on muscle cells, which US 9,622,982 B2 3 4 results in a reduction in circulating glucose. In a further Zumab, Golimumab, Golimumab, Ibritumomab tiuxetan, embodiment, a cancer therapeutic is one that removes and Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, accepts electrons from molecules that results in the inter Ofatumumab, Omalizumab, Palivizumab, Panitumulab, ference of the glycolytic process in a cell. Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/ In an embodiment, a cancer therapeutic results in a cancer 5 or Trastuzumab. In an aspect of the present invention, the cell not being able to uptake Sufficient quantities of glucose artemesinin derivative is a butyrate ester of dihydroartem or another energy source resulting in the cell entering esinin. apoptosis and eventually dying. In a further embodiment, a In an aspect of the present invention, the cancer thera cancer therapeutic results in a cell not being able to uptake peutic is capable of reducing the number of cancer cells or sufficient quantities of a lipid, other fat and/or cholesterol, 10 tumor size in an individual Suffering from a cancer by, e.g., preventing the cancer cell from dividing and forming a at least 10%, at least 15%, at least 20%, at least 25%, at least progeny cancer cell. 30%, at least 35%, at least 40%, at least 45%, at least 50%, In an aspect, the present invention is a pharmaceutical at least 55%, at least 60%, at least 65%, at least 70%, at least composition comprising a cancer therapeutic and a pharma 75%, at least 80%, at least 85%, at least 90% or at least 95% ceutically acceptable lipid formulation. In a further aspect, 15 as compared to a patient not receiving the same treatment. the present invention is a cancer therapeutic is Artemisnin or In other aspects of this embodiment, a therapeutic com a derivative thereof, including, without limitation, Artesu pound capable of reducing the number of cancer cells or nate, Artemether, Dihydroartemisinin, Artelinic acid, Arteni tumor size in an individual Suffering from a cancer by, e.g., mol and/or Artemotil. In an aspect the present invention about 10% to about 100%, about 20% to about 100%, about includes a pharmaceutically acceptable solvent, a pharma 30% to about 100%, about 40% to about 100%, about 50% ceutically acceptable stabilizing agent, pharmaceutically to about 100%, about 60% to about 100%, about 70% to acceptable carrier and/or a pharmaceutically acceptable about 100%, about 80% to about 100%, about 10% to about component. 90%, about 20% to about 90%, about 30% to about 90%, In an aspect of the present invention, the cancer thera about 40% to about 90%, about 50% to about 90%, about peutic is an alkylating agent, including, without limitation 25 60% to about 90%, about 70% to about 90%, about 10% to Cisplatin, carboplatin, mechlorethamine, cyclophosph about 80%, about 20% to about 80%, about 30% to about amide, chlorambucil, ifosfamide and/or oxaliplatin. In a 80%, about 40% to about 80%, about 50% to about 80%, or further aspect of the present invention, the cancer therapeu about 60% to about 80%, about 10% to about 70%, about tic is an anti-metabolite, including, without limitation, aza 20% to about 70%, about 30% to about 70%, about 40% to thioprine and/or mercaptopurine and wherein, without limi 30 about 70%, or about 50% to about 70% as compared to a tation, the anti-metabolite is a synthetic, semisynthetic or patient not receiving the same treatment. derivative of an anti-metabolite. In an aspect of the present invention, the cancer therapeutic is a , including, BRIEF DESCRIPTION OF THE DRAWINGS without limitation, a Vinca alkaloid and/or a taxane, and further wherein, without limitation, the Vinca alkaloid is 35 FIG. 1 shows the results for samples assessed 72 hours Vincristine, Vinblastine, Vinorelbine and/or Vindesine and after wells containing MCF-7 cells (or no cells in a control) further, without limitation, the taxane is Taxol, Paclitaxel were administered a single dose of Artesunate and/or and/or Docetaxel and further wherein, without limitation, Sodium Butyrate. the taxane is a synthetic, semisynthetic or derivative of a FIG. 2 shows the results for samples assessed 72 hours taxane. In an aspect, the present invention the cancer thera 40 after wells containing MCF-7 cells (or no cells in a control) peutic is a topoisomerase, and further wherein, without were administered multiple doses (at 24 and 48 hours) of limitation, the topoisomerase is a type I topoisomerase Artesunate and/or Sodium Butyrate. and/or a type 2 topoisomerase. In an aspect, the present FIG. 3 shows the results for samples assessed 72 hours invention, the type 1 topoisomerase is camptothecins, and after wells containing MCF-7 cells (or no cells in a control) further wherein, the camptothecins is irinotecan and/or topo 45 were administered a single dose of Artesunate and/or Res tecan. In an aspect, the type II topoisomerase is amsacrine, Veratrol, Daidzein or Equol or no drug (far right panel). etoposide, etoposide phosphate and/or teniposide, and fur FIG. 4 shows the results for samples assessed 72 hours ther, wherein, without limitation, the topoisomerase is a after wells containing MCF-7 cells (or no cells in a control) synthetic, semisynthetic and/or derivative. In a further were administered multiple doses of Artesunate and/or Res aspect of the present invention, the derivative is epipodo 50 Veratrol, Daidzein or Equol or no drug (far right panel). phyllotoxins. In an aspect of the present invention, the cancer therapeutic is a cytotoxic antibiotic, and further DESCRIPTION wherein, without limitation, the cytotoxic antibiotic is actinomycin, anthracyclines, doxorubicin, daunorubicin, Aspects of the present specification disclose, in part, a valrubicin, idarubicin, epirubicin, bleomycin, plicamycin 55 therapeutic compound. A therapeutic compound, includes, and/or mitomycin. In an aspect of the present invention, the but is not limited to, a cancer therapeutic. A therapeutic cancer therapeutic is a hormone, and further wherein, with compound is a compound that provides pharmacological out limitation, the hormone is a lutenizing hormone releas activity or other direct effect in the diagnosis, cure, mitiga ing hormone agonist and further wherein, without limitation, tion, treatment, or prevention of cancer, or to affect the the hormone is leuprolidine, goserelin, triptorelin, histrelin, 60 structure or any function of the body of man or animals. A bicalutamide, flutamide and/or nilutamide. In an aspect of therapeutic compound disclosed herein may be used in the the present invention, the cancer therapeutic is an antibody, form of a pharmaceutically acceptable salt, Solvate, or and further wherein, without limitation, the antibody is solvate of a salt, e.g. the hydrochloride. Additionally, thera Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basil peutic compound disclosed herein may be provided as iximab, Belimumab, Bevacizumab, Bretuximab vedotin, 65 racemates, or as individual enantiomers, including the R- or Canakinumab, Cetuximab, Ceertolizumab pegol, Dacli S-enantiomer. Thus, the therapeutic compound disclosed Zumab, Denosumab, Eculizumab, Efalizumab, Gemtu herein may comprise a R-enantiomer only, a S-enantiomer US 9,622,982 B2 5 6 only, or a combination of both a R-enantiomer and a In an embodiment, a cancer therapeutic is a stilbenoid. In S-enantiomer of a therapeutic compound. A therapeutic a further embodiment, a stilbenoid includes, but is not compound disclosed herein may have anti-cancer activity. limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostil In an embodiment, a cancer therapeutic is an alkylating bene, Alpha-Viniferin, Ampelopsin A, Ampelopsin E. Dip agent. Alkylating agents are so named because of their 5 toindonesin C, Diptoindonesin F. Epsilon-Vinferin, Flexu ability to alkylate many nucleophilic functional groups osol A, Gnetin H, Hemsleyanol D. Hopeaphenol, Trans under conditions present in cells, including, but not limited Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. to cancer cells. In a further embodiment, an alkylating agent In a further embodiment a stilbenoid is a synthetic, semi includes, but is not limited to, Cisplatin, carboplatin, synthetic or derivative. 10 In an embodiment, a cancer therapeutic is an isoflavone. mechlorethamine, cyclophosphamide, chlorambucil, ifosf In a further embodiment, a isoflavone includes, but is not amide and/or oxaliplatin. In an embodiment, alkylating limited to, Daidzein and Genistein. In a further embodiment agents can function by impairing cell function by forming a isoflavone is a synthetic, semisynthetic or derivative. covalent bonds with the amino, carboxyl, sulfhydryl, and In an embodiment, a cancer therapeutic is an isoflavan phosphate groups in biologically important molecules or 15 diol. In a further embodiment, an isoflavandiol includes, but they can work by modifying a cell's DNA. In a further is not limited to, Equol. In an embodiment, Equol is one of embodiment an alkylating agent is a synthetic, semisynthetic two enantiomeric forms, either (S)-Equol and (R)-Equol. In or derivative. a further embodiment a isoflavandiol is a synthetic, semi In an embodiment, a cancer therapeutic is an anti-me synthetic or derivative. tabolite. Anti-metabolites masquerade as purines or pyrimi In an embodiment, a cancer therapeutic is a cytotoxic dines, the building-blocks of DNA and in general, prevent antibiotic. In an embodiment, a cytotoxic antibiotic is, these substances from becoming incorporated in to DNA without limitation, an actinomycin, an anthracenedione, an during the 'S' phase (of the cell cycle), stopping normal anthracycline, thalidomide, dichloroacetic acid, nicotinic development and division. Anti-metabolites can also affect acid, 2-deoxyglucose and/or chlofazimine. In an embodi RNA synthesis. In an embodiment, an antimetabolite 25 ment, an actinomycin is, without limitation, actinomycin D, includes, but is not limited to azathioprine and/or mercap bacitracin, colistin (polymyxin E) and/or polymyxin B. In topurine. In a further embodiment an anti-metabolite is a another embodiment, an antracenedione is, without limita synthetic, semisynthetic or derivative. tion, mitoxantrone and/or pixantrone. In a further embodi In an embodiment, a cancer therapeutic is a plant alkaloid ment, an anthracycline is, without limitation, bleomycin, and/or terpenoid. These alkaloids are derived from plants 30 doxorubicin (Adriamycin), daunorubicin (daunomycin), and block cell division by, in general, preventing microtu epirubicin, idarubicin, mitomycin, plicamycin and/or valru bule function. In an embodiment, a plant alkaloid and/or bicin. In a further embodiment a cytotoxic antibiotic is a terpenoid is a Vinca alkaloid, a podophyllotoxin and/or a synthetic, semisynthetic or derivative. taxane. Vinca alkaloids, in general, bind to specific sites on In an embodiment, a cancer therapeutic is a hormone. In tubulin, inhibiting the assembly of tubulin into microtu 35 an embodiment a hormone includes, but is not limited to, bules, generally during the M phase of the cell cycle. In an lutenizing hormone releasing hormone agonists. In an embodiment, a Vinca alkaloid is derived, without limitation, embodiment, a hormone includes, without limitation, leu from the Madagascar periwinkle, Catharanthus roseus (for prolidine, goserelin, triptorelin, histrelin, bicalutamide, flu merly known as Vinca rosea). In an embodiment, a Vinca tamide and nilutamide. alkaloid includes, without limitation, Vincristine, Vinblas 40 In an embodiment, a cancer therapeutic is an antibody. In tine, Vinorelbine and/or Vindesine. In an embodiment, a an embodiment, an anticancer antibody includes, but is not taxane includes, but is not limited, to Taxol, Paclitaxel limited to, Abciximab, Adalimumab, Alemtuzumab, Atli and/or Docetaxel. In a further embodiment a plant alkaloid Zumab, Basiliximab, Belimumab, Bevacizumab, Bretux or terpernoid is a synthetic, semisynthetic or derivative. In a imab vedotin, Canakinumab, Cetuximab, Ceertolizumab further embodiment, a podophyllotoxin is, without limita 45 pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, tion, an etoposide and/or teniposide. In an embodiment, a Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiux taxane is, without limitation, docetaxel and/or ortataxel. etan, Infliximab, Ipilimumab, Muromonab-CD3, Natali In an embodiment, a cancer therapeutic is a topoi Zumab, Ofatumumab, Omalizumab, PaliwiZumab, Panitu Somerase. Topoisomerases are essential enzymes that main muab. Ranibizumab, Rituximab, Tocilizumab, tain the topology of DNA. Inhibition of type I or type II 50 Tositumomab, Trastuzumab and/or any other known or topoisomerases interferes with both transcription and repli developed antibody that functions as a cancer therapeutic. cation of DNA by upsetting proper DNA supercoiling. In a In an embodiment, a cancer therapeutic is, without limi further embodiment, a topoisomerase is, without limitation, tation, a statin. In a further embodiment, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase a statin is, without limitation, atorvastatin, fluvastin, lovas inhibitor. In an embodiment a type I topoisomerase inhibitor 55 tatin, pitavastatin, pravastatin, rosuvastatin and/or simvas is, without limitation, a camptothecin. In another embodi tatin. ment, a camptothecin is, without limitation, exatecan, iri In an embodiment, a cancer therapeutic is, without limi notecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 tation, a therapeutic for the treatment of diabetes. In an (AR67) and/or ST 1481. In an embodiment, a type II embodiment, a therapeutic for the treatment of diabetes is, topoisomerase inhibitor is, without limitation, epipodophyl 60 without limitation, a biguanide, a thiazolidinedione, a secre lotoxin. In a further embodiment an epipodophyllotoxin is, tagogue, an alpha-glucosidase inhibitor and/or a peptide without limitation, an amsacrine, etoposid, etoposide phos analog. In an embodiment, a biguanide is, without limita phate and/or teniposide. In a further embodiment a topoi tion, metformin, phenformin and/or buformin. In another Somerase is a synthetic, semisynthetic or derivative, includ embodiment, a thiazolidinedione is, without limitation, ing those found in nature Such as, without limitation, 65 rosiglitaZone, pioglitaZone and/or troglitaZone. In an epipodophyllotoxins, Substances naturally occurring in the embodiment, a secretagogue is, without limitation, a Sulfo root of American Mayapple (Podophyllum peltatum). nylurea, a nonsulfonylurea and/or a meglitinide. In a further US 9,622,982 B2 7 8 embodiment, a Sulfonylurea is, without limitation, tolbuta isomerase inhibitor, a fructosebisphosphate inhibitor, a tri mide, acetohexamide, tolaZamide, chlorpropamide, glipzide, osephosphate isomerase inhibitor, a glyceraldehyde phos glyburide, glimepiride, gliclazide, glycopyramide and/or phate dehydrogenase inhibitor, a phosphoglycerate kinase gliquidone. In an embodiment, a meglitinide is, without inhibitor, a phosphoglycerate mutase inhibitor, an enolase limitation, repaglinide and/or nateglinide. In an embodi inhibitor and/or a pyruvate kinase inhibitor. ment, an alpha-glucosidase inhibitor is, without limitation, In an embodiment, a cancer therapeutic is, without limi miglitol, acarbose and/or Voglibose. In an embodiment, a tation, an anti-malarial therapeutic. In a further embodiment, peptide analog is, without limitation, an injectable incretin an anti-malarial therapeutic is, without limitation, amodia mimetic, an injectable glucagon-like peptide analog and/or quine, an artemisinin, atovaquone, chloroquine, clindamy agonist, a gastric inhibitory peptide analog, a dipeptidyl 10 peptidase-4 inhibitor and/or an injectable Amylin analogue. cin, doxycycline, halofantrine, mefloquine, primaquine, In a further embodiment, an injectable glucagon-like peptide proguanil, pyrimethamine, a quinine and related agent, analog and/or agonist is, without limitation, exenatide, lira rufigallol, and/or a Sulphonamide. In another embodiment, glutide and/or taspoglutide. In a further embodiment, a an artemisinin is, without limitation, arteether, artemether, dipeptidyl peptidase-4 inhibitor is, without limitation, Vilda 15 artemisinin, artesunate and/or dihydroartemisinin. In gliptin, Sitagliptin, saxagliptin, linagliptin, allogliptin and/or another embodiment, a quinine and related agent is, without septagliptin. In another embodiment, an injectable Amylin limitation, quinimax and/or quinidine. In another embodi analogue is, without limitation, pramlintide. In an embodi ment, a Sulfonamide is, without limitation, Sulfadoxine ment, a therapeutic for the treatment of diabetes is cinnamon and/or sulfamethoxypyridazine. and/or thiamine. In an embodiment, a cancer therapeutic is Artemisinin. In In an embodiment, a cancer therapeutic is, without limi a further embodiment, a cancer therapeutic is a derivative of tation, a Peroxisome proliferator-activated receptor gamma Artemesinin. Derivatives of Artemesinin include, but are not (PPAR-y or PPARG) agonist. In a further embodiment, a limited to, Artesunate, Artemether, Dihydroartemisinin, PPAR-y is, without limitation, rosiglitazone, troglitazone, Artelinic acid, arterolane, Artenimol and Artemotil. pioglitaZone, netoglitaZone, rivoglitaZone and/or ciglita 25 In An embodiment, Artesunate is prepared from dihy ZO. droartemisinin (DHA) by reacting it with succinic acid In an embodiment, a cancer therapeutic is a PPAR-13 anhydride in basic medium. Pyridine as base/solvent, agonist. In another embodiment, a PPAR-13 agonist is, sodium bicarbonate in and catalyst DMAP (N.N- without limitation, endurobol and/or GWO742. dimethylaminopyridine) and triethylamine in 1,2-dichlo In an embodiment, a cancer therapeutic is a PPAR-a 30 agonist. roethane have been used, with yields of up to 100%. A large In an embodiment, a cancer therapeutic is, without limi scale process involves treatment of DHA in tation an antibiotic. In another embodiment, an antibiotic is, with a mixture of pyridine, a catalytic amount of DMAP and without limitation, isoniazid, rifampicin, pyrazinamide and/ succinic anhydride. The dichloromethane mixture is stirred or ethambutol. 35 for 6-9 h to get artesunate in quantitative yield. The product In an embodiment, a cancer therapeutic is, without limi is further re-crystallized from dichloromethane. a-Artesu tation, an antihelminthic. In a further embodiment, an anti nate is exclusively formed (m.p. 135-137° C.). helminthic is, without limitation, abamectin, an aminoac In an embodiment, Artemether is a methyl ether deriva etonitriles, a benzimadazole, diethylcaramazine, , tive of artemisinin, which is a peroxide lactone isolated from levamisole, niclosamide, an octadepsipeptides, phosphoric 40 the Chinese antimalarial plant, Artemisia annua. It is also acid (metrifonate), praziquantel, a spiroindoles, Suramin known as dihydroartemisinin methyl ether, but its correct and/or pyrantel pamoate. In a further embodiment, an is (+)-(3-alpha.5a-beta,6-beta.8a aminoacetonitrile is, without limitation, monepantel. In beta, 9-alpha,12-beta, 12aR)-decahydro-10-methoxy-3,6,9- another embodiment, a benzimidazole is, without limitation, trimethyl-3, 12-epoxy-12H-pyrano(4.3-)-1,2-benzodiox albendazole, fenbendazole, a flubendazole, thiabendazole 45 epin. It is a relatively lipophilic and unstable drug. and triclabendazole. In an embodiment, a flubendazole is, In an embodiment, Dihydroartemisinin is the active without limitation, mebendazole. In another embodiment, an metabolite of all artemisinin compounds (artemisinin, arte octadepsipeptide is, without limitation, emodepside. In a Sunate, artemether, etc.) and is also available as a drug in further embodiment, a spiroindole is, without limitation, itself. It is a semi-synthetic derivative of artemisinin and is dequantel. 50 widely used as an intermediate in the preparation of other In an embodiment, a cancer therapeutic is, without limi artemisinin-derived antimalarial drugs. Dihydroartemisinin tation, a food additive and/or a vitamin. In a further embodi is the active metabolite of all artemisinin compounds (ar ment, a food additive and/or vitamin is, without limitation, temisinin, artesunate, artemether, etc.) and is also available tributerin, vitamin C, vitamin 812, vitamin D, resveratrol as a drug in itself. It is a semi-synthetic derivative of and/or coenzyme Q12. 55 artemisinin and is widely used as an intermediate in the In an embodiment, a cancer therapeutic is, without limi preparation of other artemisinin-derived antimalarial drugs. tation, a glucose intake inhibitor. In another embodiment, a In an embodiment, Artelinic acid (or its salt, artelinate) is glucose intake inhibitor is, without limitation, a GLUT-1 a semi-synthetic derivative of the natural compound receptor inhibitor. artemisinin. Artelinic acid has a lower rate of neurotoxicity In an embodiment a cancer therapeutic is, without limi 60 than the related artemisin derivatives arteether and tation, a lipid intake inhibitor. In a further embodiment, a artemether. lipid intake inhibitor is, without limitation, an LDL receptor In an embodiment, Artemotil (INN; also known as B-ar inhibitor, an SR-81 inhibitor, an SR-82 inhibitor and/or a teether), is a semi-synthetic derivative of artemisinin, a SR-83/CD36 (thrombospondin) receptor inhibitor. natural product of the Chinese plant Artemisia annua. In an embodiment, a cancer therapeutic is a glycolysis 65 In an embodiment, a cancer therapeutic is a butyrate ester inhibitor. In another embodiment, a glycolysis inhibitor is, of dihydroartemesinin with a structure that can include, but without limitation, a hexokinase inhibitor, a phosphoglucose is not limited to the following: US 9,622,982 B2 10

weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or 10 O. In an embodiment, a first therapeutic compound is admin istered to an individual and at a later date, a second thera In an embodiment, a cancer therapeutic is a dichloroac peutic compound is administered to the same individual. In etate ester. aspects of this embodiment, the first therapeutic compound In an embodiment, a patient is administered one or more 15 is artemesinin or a derivative thereof and the second thera of an alkylating agent, an anti-metabolite, a plant alkaloid, peutic compound is a different derivative of artemesinin. In a terpenoid, a topoisomerase inhibitor, a cytotoxic antibiot an embodiment, the first therapeutic compound is artemesi nin or a derivative thereof and the second therapeutic ics, a statin, an anti-diabetic drug, a PPAR-y, a PPAR-13, a compound is a cancer therapeutic that is not artemesinin or PPAR-a, an antibiotic, an antihelminthic, an anti-malaria a derivative thereof. drug, a vitamin and/or a food additive. In an embodiment, a In an embodiment, a first therapeutic compound is admin patient is administered one or more cancer therapeutics. In istered to an individual at the same time as a second an embodiment, a patient is administered one, two, three, therapeutic compound is administered to the individual. In four, five, six, seven eight, nine, ten, eleven, twelve, thirteen, aspects of this embodiment, the first therapeutic compound fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or 25 is a artemesinin or derivative thereof and the second thera twenty different cancer therapeutics. peutic compound is a different derivative of artemesinin. In In an embodiment, a cancer therapeutic and its derivatives an embodiment, the first therapeutic compound is artemesi have half-lives of the order of 1 hour, and therefore require nin or a derivative thereof and the second therapeutic at least daily dosing over several days. In a further embodi compound is a cancer therapeutic that is not artemesinin or ment, a cancer therapeutic, includes, but not limited to, 30 a derivative thereof. artemisinin and its derivatives have half-lives of 2 hours, 3 Aspects of the present specification disclose, in part, a hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, pharmaceutical composition. As used herein, the term “phar 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, maceutically acceptable” means any molecular entity or 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, composition that does not produce an adverse, allergic or 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 35 other untoward or unwanted reaction when administered to days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, an individual. As used herein, the term "pharmaceutically two months, three months, four months or more. acceptable composition' is synonymous with “pharmaceu In an embodiment, the period of administration of a tical composition' and means a therapeutically effective cancer therapeutic is for 1 day, 2 days, 3 days, 4 days, 5 days, concentration of an active ingredient, such as, e.g., any of 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 40 the therapeutic compounds disclosed herein. A pharmaceu days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, tical composition disclosed herein is useful for medical and 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, veterinary applications. A pharmaceutical composition may 5 months, 6 months, 7 months, 8 months, 9 months, 10 be administered to an individual alone, or in combination months, 11 months, 12 months, or more. In a further with other Supplementary active ingredients, agents, drugs embodiment, a period of during which administration is 45 or hormones. stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, A pharmaceutical composition disclosed herein may 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, optionally include a pharmaceutically-acceptable carrier that 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 facilitates processing of an active ingredient into pharma weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, ceutically-acceptable compositions. As used herein, the term 5 months, 6 months, 7 months, 8 months, 9 months, 10 50 “pharmacologically-acceptable carrier is synonymous with months, 11 months, 12 months, or more. “pharmacological carrier and means any carrier that has In an embodiment, a therapeutic compound is adminis Substantially no long term or permanent detrimental effect tered to an individual for a period of time followed by a when administered and encompasses terms such as “phar separate period of time. In another embodiment, a therapeu macologically acceptable vehicle, stabilizer, diluent, addi tic compound is administered for a first period and a second 55 tive, auxiliary or excipient.” Such a carrier generally is period following the first period, with administration mixed with an active compound or permitted to dilute or stopped during the second period, followed by a third period enclose the active compound and can be a solid, semi-solid, where administration of the therapeutic compound is started or liquid agent. It is understood that the active ingredients and then a fourth period following the third period where can be soluble or can be delivered as a suspension in the administration is stopped. In an aspect of this embodiment, 60 desired carrier or diluent. Any of a variety of pharmaceuti the period of administration of a therapeutic compound cally acceptable carriers can be used including, without followed by a period where administration is stopped is limitation, aqueous media Such as, e.g., water, Saline, gly repeated for a determined or undetermined period of time. In cine, hyaluronic acid and the like; Solid carriers such as, e.g., a further embodiment, a period of administration is for 1 day, mannitol, lactose, starch, magnesium Stearate, Sodium sac 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 65 charin, talcum, cellulose, glucose, Sucrose, magnesium car 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 bonate, and the like; Solvents; dispersion media; coatings; weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 antibacterial and antifungal agents; isotonic and absorption US 9,622,982 B2 11 12 delaying agents; or any other inactive ingredient. Selection carrier, a pharmaceutically-acceptable component, or both of a pharmacologically acceptable carrier can depend on the pharmaceutically-acceptable carrier and pharmaceutically mode of administration. Except insofar as any pharmaco acceptable component. logically acceptable carrier is incompatible with the active In a further embodiment, a pharmaceutical composition ingredient, its use in pharmaceutically acceptable composi comprises a cancer therapeutic that includes, without limi tions is contemplated. Non-limiting examples of specific tation, at least one of a statin, a treatment for diabetes, an uses of Such pharmaceutical carriers can be found in Phar antibiotic, a helminthic, a malarial treatment a vitamin or a maceutical Dosage Forms and Drug Delivery Systems food additive. In an embodiment, a pharmaceutical compo (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins sition includes, without limitation, a statin, a treatment for 10 diabetes, and a helminthic. In another embodiment, a phar Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE maceutical composition includes, without limitation, a treat AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ment for diabetes, a statin, an antibiotic and a food additive. ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Good Further embodiments can include other combinations of two man & Gilman's The Pharmacological Basis of Therapeu or more cancer therapeutics. tics (Joel G. Hardman et al., eds., McGraw-Hill Profes 15 In an embodiment, an individual that is administered a sional, 10th ed. 2001); and Handbook of Pharmaceutical cancer therapeutic Suffers mild or no side-effects as a result Excipients (Raymond C. Rowe et al., APhA Publications, of the administered therapeutics. 4th edition 2003). These protocols are routine procedures In an embodiment, a cancer therapeutic is administered in and any modifications are well within the scope of one conjunction with chemotherapy, radiation therapy, Surgery, skilled in the art and from the teaching herein. immunotherapy, including, without limitation, the deriva A pharmaceutical composition disclosed herein can tion of stem cells and/or dendritic cells blood transfusions, optionally include, without limitation, other pharmaceuti lavages, and/or other treatments, including, without limita cally acceptable components (or pharmaceutical compo tion, freezing a tumor. In a further embodiment, a cancer nents), including, without limitation, buffers, preservatives, therapeutic is administered prior to or after the initiation and tonicity adjusters, salts, antioxidants, osmolality adjusting 25 completion of chemotherapy, radiation therapy, immuno agents, physiological Substances, pharmacological Sub therapy, including, without limitation, the derivation of stem stances, bulking agents, emulsifying agents, wetting agents, cells and/or dendritic cells blood transfusions, lavages, and/ Sweetening or flavoring agents, and the like. Various buffers or other treatments, including, without limitation, freezing a and means for adjusting pH can be used to prepare a tumor. In a further embodiment, a cancer therapeutic is pharmaceutical composition disclosed herein, provided that 30 administered, prior to, during and/or after administration of the resulting preparation is pharmaceutically acceptable. chemotherapy, radiation therapy, Surgery, immunotherapy, Such buffers include, without limitation, acetate buffers, including, without limitation, the derivation of stem cells citrate buffers, phosphate buffers, neutral buffered saline, and/or dendritic cells blood transfusions, lavages, and/or phosphate buffered saline and borate buffers. It is understood other treatments, including, without limitation, freezing a that acids or bases can be used to adjust the pH of a 35 tumor. composition as needed. Pharmaceutically acceptable anti A therapeutic compound disclosed herein, or a pharma oxidants include, without limitation, Sodium metabisulfite, ceutical composition comprising Such a therapeutic com Sodium thiosulfate, acetylcysteine, butylated hydroxyani pound, may be formulated for either local or systemic sole and butylated hydroxytoluene. Useful preservatives delivery using topical, enteral or parenteral routes of admin include, without limitation, benzalkonium chloride, chlo 40 istration. Additionally, a therapeutic compound disclosed robutanol, thimerosal, phenylmercuric acetate, phenylmer herein may be formulated by itself in a pharmaceutical curic nitrate, a stabilized oxy chloro composition and chel composition, or may be formulated together with one or ants, such as, e.g., DTPA or DTPA-bisamide, calcium more other therapeutic compounds disclosed herein in a DTPA, and CaNaDTPA-bisamide. Tonicity adjustors useful single pharmaceutical composition. in a pharmaceutical composition include, without limitation, 45 A therapeutic compound disclosed herein, or a pharma salts such as, e.g., sodium chloride, potassium chloride, ceutical composition comprising Such a therapeutic com mannitol or glycerin and other pharmaceutically acceptable pound, may be made into an inhaled formulation. Inhaled tonicity adjustor. The pharmaceutical composition may be formulations suitable for enteral or parenteral administration provided as a salt and can be formed with many acids, include, without limitation, aerosols, dry powders. A thera including but not limited to, hydrochloric, Sulfuric, acetic, 50 peutic compound or composition disclosed herein intended lactic, tartaric, malic, Succinic, etc. Salts tend to be more for Such administration may be prepared according to any soluble in aqueous or other protonic solvents than are the method known to the art for the manufacture of pharma corresponding free base forms. It is understood that these ceutical compositions. and other Substances known in the art of pharmacology can In Such inhaled dosage forms, the therapeutic compound be included in a pharmaceutical composition. 55 or a pharmaceutical composition may be prepared for deliv In one embodiment, a pharmaceutical composition dis ery as an aerosol in a liquid propellant for use in a pres closed herein comprises a cancer therapeutic that has anti surised (PDI) or other metered dose inhaler (MDI). Propel cancer cell activity and a pharmaceutically-acceptable lipid lants suitable for use in a PDI or MDI include, without formulation. In another embodiment, a pharmaceutical com limitation, CFC-12, HFA-134a, HFA-227, HCFC-22 (dif position disclosed herein comprises a cancer therapeutic that 60 luorochloromethane), HFA-152 (difluoroethane and isobu has anti-cancer cell activity, a pharmaceutically-acceptable tane). A therapeutic compound may also be delivered using Solvent, and a pharmaceutically-acceptable lipid formula a nebulisers or other aerosol delivery system. A therapeutic tion. In aspects of this embodiment, a pharmaceutical com compound may be prepared for delivery as a dry powder for position disclosed herein may further comprise a pharma use in a dry powder inhaler (DPI). A dry powder for use in ceutically-acceptable stabilizing agent. In other aspects of 65 the inhalers will usually have a mass median aerodynamic this embodiment, a pharmaceutical composition disclosed diameter of less than 30 pm, preferably less than 20 pm and herein may further comprise a pharmaceutically-acceptable more preferably less than 10 pm. Microparticles having US 9,622,982 B2 13 14 aerodynamic diameters in the range of about 5 pm to about compound disclosed herein typically may be between about 0.5 pm will generally be deposited in the respiratory bron 0.0001% (w/v) to about 60% (w/v), about 0.001% (w/v) to chioles, whereas Smaller particles, having aerodynamic about 40.0% (w/v), or about 0.01% (w/v) to about 20.0% diameters in the range of about 2 pm to about 0.05 pm, are (w/v). In semi-solid formulations, a therapeutically effective likely to be deposited in the alveoli. A DPI may be a passive amount of a therapeutic compound disclosed herein typi delivery mechanism, which relies on the individuals inspi cally may also be between about 0.0001% (w/w) to about ration to introduce the particles into the lungs, or an active 60% (w/w), about 0.001% (w/w) to about 40.0% (w/w), or delivery mechanism, requiring a mechanism for delivering about 0.01% (w/w) to about 20.0% (w/w). the powder to the individual. In inhalatory formulations, a A therapeutic compound disclosed herein, or a pharma therapeutically effective amount of a therapeutic compound 10 ceutical composition comprising Such a therapeutic com disclosed herein for an inhaled formulation may be between pound, may be made into a liquid formulation. Liquid about 0.0001% (w/v) to about 60% (w/v), about 0.001% formulations suitable for enteral or parenteral administration (w/v) to about 40.0% (w/v), or about 0.01% (w/v) to about include, without limitation, Solutions, syrups, elixirs, disper 20.0% (w/v). In inhalatory formulations, a therapeutically sions, emulsions, and Suspensions, including, but not lim effective amount of a therapeutic compound disclosed herein 15 ited, to those used for intravenous administration. A thera for an inhaled formulation may also be between about peutic compound or composition disclosed herein intended 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to for Such administration may be prepared according to any about 40.0% (w/w), or about 0.01% (w/w) to about 20.0% method known to the art for the manufacture of pharma (w/w). ceutical compositions. In such liquid dosage forms, a thera A therapeutic compound disclosed herein, or a pharma peutic compound or composition disclosed herein may be ceutical composition comprising Such a therapeutic com admixed with (a) Suitable aqueous and nonaqueous carriers, pound, may be made into a solid formulation. Solid formu (b) diluents, (c) solvents, such as, e.g., water, ethanol, lations suitable for enteral or parenteral administration propylene glycol, polyethyleneglycol, glycerol, vegetable include, without limitation, capsules, tablets, pills, troches, oils. Such as, e.g., rapeseed oil and olive oil, and injectable lozenges, powders and granules Suitable for inhalation or for 25 organic esters such as ethyl oleate; and/or fluidity agents, reconstitution into sterile injectable Solutions or dispersions. Such as, e.g., Surfactants or coating agents like lecithin. In A therapeutic compound or composition disclosed herein the case of dispersions and Suspensions, fluidity can also be intended for Such administration may be prepared according controlled by maintaining a particular particle size. In liquid to any method known to the art for the manufacture of formulations, a therapeutically effective amount of a thera pharmaceutical compositions. In Such solid dosage forms, 30 peutic compound disclosed herein typically may be between the therapeutic compound may be admixed with (a) at least about 0.0001% (w/v) to about 60% (w/v), about 0.001% one inert customary excipient (or carrier). Such as, e.g., (w/v) to about 40.0% (w/v), or about 0.01% (w/v) to about sodium citrate or dicalcium phosphate or (b) fillers or 20.0% (w/v). extenders, as for example, starch, lactose, Sucrose, glucose, Syrups and elixirs may be formulated with Sweetening mannitol, isomalt, and silicic acid, (c) binders, such as, e.g., 35 agents, for example glycerol, propylene glycol, Sorbitol or carboxymethylcellulose, alignates, gelatin, polyvinylpyr Sucrose. Such formulations may also contain a demulcent, a rolidone, Sucrose and acacia, (d) humectants, such as, e.g., preservative, flavoring agents, and coloring agents. glycerol, (e) disintegrating agents, such as, e.g., agar-agar, Liquid Suspensions may be formulated by Suspending a calcium carbonate, corn starch, potato starch, tapioca starch, therapeutic compound disclosed herein in admixture with alginic acid, certain complex silicates and Sodium carbonate, 40 excipients Suitable for the manufacture of aqueous Suspen (f) solution retarders, such as, e.g., paraffin, (g) absorption sions. Such excipients are suspending agents, for example accelerators. Such as, e.g., quaternary ammonium com sodium carboxymethylcellulose, methylcellulose, hydroxy pounds, (h) wetting agents, such as, e.g., cetyl and propylmethylcellulose, sodium alginate, pectin, polyvinyl glycerol monostearate, (i) adsorbents, such as, e.g., kaolin pyrrolidone, polyvinyl alcohol, natural gum, agar, gum and bentonite, () lubricants, such as, e.g., talc, Stearic acid, 45 tragacanth and gum acacia; dispersing or wetting agents may calcium Stearate, magnesium Stearate, Solid polyethylene be a naturally occurring phosphatide, for example lecithin, glycols, sodium lauryl Sulfate or mixtures thereof, and (k) or condensation products of an alkylene oxide with fatty buffering agents. The tablets may be uncoated or they may acids, for example polyoxyethylene Stearate, or condensa be coated by known techniques to delay disintegration and tion products of oxide with long-chain aliphatic absorption in the gastrointestinal tract and thereby provide a 50 , for example heptadecaethyleneoxycetanol, or con Sustained action over a longer period. For example, a time densation products of ethylene oxide with partial esters delay material Such as glyceryl monostearate or glyceryl derived from fatty acids, for example polyoxyethylene sor distearate may be employed. In solid formulations, a thera bitan monooleate. peutically effective amount of a therapeutic compound dis Oily Suspensions may be formulated by Suspending a closed herein typically may be between about 0.0001% 55 therapeutic compound disclosed herein in admixture with (a) (w/w) to about 60% (w/w), about 0.001% (w/w) to about vegetable oils, such as, e.g., almond oil, arachis oil, avocado 40.0% (w/w), or about 0.01% (w/w) to about 20.0% (w/w). oil, canola oil, castor oil, coconut oil, corn oil, cottonseed A therapeutic compound disclosed herein, or a pharma oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive ceutical composition comprising Such a therapeutic com oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower pound, may be made into a semi-solid formulation. Semi 60 oil, Sesame oil, Soybean oil, Soya oil, Sunflower oil, walnut solid formulations suitable for topical administration oil, wheat germ oil, or a combination thereof, (b) a Saturated include, without limitation, ointments, creams, salves, and fatty acid, an unsaturated fatty acid, or a combination gels. A therapeutic compound or composition disclosed thereof. Such as, e.g., palmitic acid, Stearic acid, oleic acid, herein intended for Such administration may be prepared linoleic acid, linolenic acid, or a combination thereof (c) according to any method known to the art for the manufac 65 mineral oil such as, e.g., liquid paraffin, (d) Surfactants or ture of pharmaceutical compositions. In semi-solid formu detergents. The oily Suspensions may contain a thickening lations, a therapeutically effective amount of a therapeutic agent, for example beeswax, hard paraffin or cetyl alcohol. US 9,622,982 B2 15 16 Sweetening agents, such as those set forth above, and In aspects of this embodiment, a polymer composing the flavoring agents may be added to provide a palatable oral matrix is a polypeptide Such as, e.g., silk fibroin, keratin, or preparation. These compositions may be preserved by the collagen. In other aspects of this embodiment, a polymer addition of an antioxidant such as ascorbic acid. composing the matrix is a polysaccharide Such as, e.g., Dispersible powders and granules Suitable for preparation cellulose, agarose, elastin, chitosan, chitin, or a gly of an aqueous Suspension by the addition of water provide cosaminoglycan like chondroitin Sulfate, dermatan Sulfate, the combined therapeutic compounds in admixture with a keratan Sulfate, or hyaluronic acid. In yet other aspects of dispersing or Wetting agent, Suspending agent and one or this embodiment, a polymer composing the matrix is a more preservatives. polyester Such as, e.g., D-lactic acid, L-lactic acid, racemic 10 lactic acid, glycolic acid, caprolactone, and combinations A therapeutic compound disclosed herein may be in the thereof. form of oil-in-water emulsions. The oily phase may be a One of ordinary skill in the art appreciates that the vegetable oil as disclosed herein or a mineral oil as disclosed selection of a suitable polymer for forming a suitable herein or mixtures thereof. Suitable emulsifying agents may disclosed therapeutic compound delivery platform depends be naturally occurring gums, such as, e.g., gum acacia or 15 on several factors. The more relevant factors in the selection gum tragacanth, naturally occurring phosphatides, for of the appropriate polymer(s), include, without limitation, example Soya bean, lecithin, and esters or partial esters compatibility of polymer with a therapeutic compound, derived from fatty acids and hexitol anhydrides, for example desired release kinetics of a therapeutic compound, desired Sorbitan monooleate and condensation products of the said biodegradation kinetics of platform at implantation site, partial esters with ethylene oxide, for example polyoxyeth desired bioerodible kinetics of platform at implantation site, ylene Sorbitan monooleate. desired bioresorbable kinetics of platform at implantation A therapeutic compound disclosed herein, or a composi site, in vivo mechanical performance of platform, processing tion comprising Such a therapeutic compound, may also be temperatures, biocompatibility of platform, and patient tol incorporated into a therapeutic compound delivery platform erance. Other relevant factors that, to some extent, dictate in order to achieve a controlled release profile over time. 25 the in vitro and in vivo behavior of the polymer include the Such a therapeutic compound delivery platform comprises a chemical composition, spatial distribution of the constitu therapeutic compound disclosed herein dispersed within a ents, the molecular weight of the polymer and the degree of polymer matrix, typically a biodegradable, bioerodible, and/ crystallinity. or bioresorbable polymer matrix. As used herein, the term A therapeutic compound delivery platform includes both "polymer refers to synthetic homo- or copolymers, natu 30 a Sustained release therapeutic compound delivery platform rally occurring homo- or copolymers, as well as synthetic and an extended release therapeutic compound delivery modifications or derivatives thereof having a linear, platform. As used herein, the term “sustained release” refers branched or star structure. Copolymers can be arranged in to the release of a therapeutic compound disclosed herein any form, Such as, e.g., random, block, segmented, tapered over a period of about seven days or more. As used herein, blocks, graft, or triblock. Polymers are generally condensa 35 the term "extended release' refers to the release of a tion polymers. Polymers can be further modified to enhance therapeutic compound disclosed herein over a period of time their mechanical or degradation properties by introducing of less than about seven days. cross-linking agents or changing the hydrophobicity of the In aspects of this embodiment, a Sustained release thera side residues. If crosslinked, polymers are usually less than peutic compound delivery platform releases a therapeutic 5% crosslinked, usually less than 1% crosslinked. 40 compound disclosed herein with substantially Zero order Suitable polymers include, without limitation, alginates, release kinetics over a period of, e.g., about 7 days after aliphatic polyesters, polyalkylene oxalates, polyamides, administration, about 15 days after administration, about 30 polyamidoesters, polyanhydrides, polycarbonates, polyes days after administration, about 45 days after administration, ters, polyethylene glycol, polyhydroxyaliphatic carboxylic about 60 days after administration, about 75 days after acids, polyorthoesters, polyoxaesters, polypeptides, poly 45 administration, or about 90 days after administration. In phosphaZenes, polysaccharides, and polyurethanes. The other aspects of this embodiment, a Sustained release thera polymer usually comprises at least about 10% (w/w), at least peutic compound delivery platform releases a therapeutic about 20% (w/w), at least about 30% (w/w), at least about compound disclosed herein with substantially Zero order 40% (w/w), at least about 50% (w/w), at least about 60% release kinetics over a period of, e.g., at least 7 days after (w/w), at least about 70% (w/w), at least about 80% (w/w), 50 administration, at least 15 days after administration, at least or at least about 90% (w/w) of the therapeutic compound 30 days after administration, at least 45 days after admin delivery platform. Examples of biodegradable, bioerodible, istration, at least 60 days after administration, at least 75 and/or bioresorbable polymers and methods useful to make days after administration, or at least 90 days after adminis a therapeutic compound delivery platform are described in, tration. e.g., Drost, et. al., Controlled Release Formulation, U.S. Pat. 55 In aspects of this embodiment, a Sustained release thera No. 4,756,911; Smith, et. al., Sustained Release Drug Deliv peutic compound delivery platform releases a therapeutic ery Devices, U.S. Pat. No. 5,378.475; Wong and Kochinke, compound disclosed herein with substantially first order Formulation for Controlled Release of Drugs by Combining release kinetics over a period of, e.g., about 7 days after Hyrophilic and Hydrophobic Agents, U.S. Pat. No. 7,048, administration, about 15 days after administration, about 30 946; Hughes, et. al., Compositions and Methods for Local 60 days after administration, about 45 days after administration, ized Therapy of the Eye, U.S. Patent Publication 2005/ about 60 days after administration, about 75 days after 0181017; Hughes, Hypotensive Lipid-Containing administration, or about 90 days after administration. In Biodegradable Intraocular Implants and Related Methods, other aspects of this embodiment, a Sustained release thera U.S. Patent Publication 2005/0244464; Altman, et al., Silk peutic compound delivery platform releases a therapeutic Fibroin Hydrogels and Uses Thereof, U.S. Patent Publica 65 compound disclosed herein with substantially first order tion 2011/0008437; each of which is incorporated by refer release kinetics over a period of, e.g., at least 7 days after ence in its entirety. administration, at least 15 days after administration, at least US 9,622,982 B2 17 18 30 days after administration, at least 45 days after admin 1.1, more than 1.2, more than 1.4, more than 1.6, more than istration, at least 60 days after administration, at least 75 1.8, more than 2.0, more than 2.2, more than 2.4, more than days after administration, or at least 90 days after adminis 2.6, more than 2.8, more than 3.0, more than 3.2, more than tration. 3.4, or more than 3.6. In other aspects of this embodiment, In aspects of this embodiment, a therapeutic compound a therapeutic compound disclosed herein may have a log P delivery platform releases a therapeutic compound disclosed value in the range of, e.g., between 1.8 and 4.0, between 2.0 herein with substantially Zero order release kinetics over a and 4.0, between 2.1 and 4.0, between 2.2 and 4.0, or period of, e.g., about 1 day after administration, about 2 days between 2.3 and 4.0, between 2.4 and 4.0, between 2.5 and after administration, about 3 days after administration, about 4.0, between 2.6 and 4.0, or between 2.8 and 4.0. In other 4 days after administration, about 5 days after administra 10 tion, or about 6 days after administration. In other aspects of aspects of this embodiment, a therapeutic compound dis this embodiment, a therapeutic compound delivery platform closed herein may have a log P value in the range of e.g., releases a therapeutic compound disclosed herein with Sub between 3.0 and 4.0, or between 3.1 and 4.0, between 3.2 stantially Zero order release kinetics over a period of, e.g., at and 4.0, between 3.3 and 4.0, between 3.4 and 4.0, between most 1 day after administration, at most 2 days after admin 15 3.5 and 4.0, or between 3.6 and 4.0. In still other aspects of istration, at most 3 days after administration, at most 4 days this embodiment, a therapeutic compound disclosed herein after administration, at most 5 days after administration, or may have a log Pvalue in the range of, e.g., between 2.0 and at most 6 days after administration. 2.5, between 2.0 and 2.7, between 2.0 and 3.0, or between In aspects of this embodiment, a therapeutic compound 2.2 and 2.5. delivery platform releases a therapeutic compound disclosed A therapeutic compound disclosed herein may have a herein with substantially first order release kinetics over a polar Surface area that is hydrophobic. As used herein, the period of, e.g., about 1 day after administration, about 2 days term “polar surface area” refers to the surface sum over all after administration, about 3 days after administration, about of the polar atoms in the structure of a compound and is a 4 days after administration, about 5 days after administra measure of hydrophobicity. Typically, these polar atoms tion, or about 6 days after administration. In other aspects of 25 include, e.g., oxygen, , and their attached hydro this embodiment, a therapeutic compound delivery platform gens. In aspects of this embodiment, a therapeutic com releases a therapeutic compound disclosed herein with Sub pound disclosed herein may have a polar Surface area of stantially first order release kinetics over a period of, e.g., at e.g., less than 8.0 nm, less than 7.0 nm, less than 6.0 nm, most 1 day after administration, at most 2 days after admin less than 5.0 nm, less than 4.0 nm, or less than 3.0 nm. In istration, at most 3 days after administration, at most 4 days 30 other aspects of this embodiment, a therapeutic compound after administration, at most 5 days after administration, or disclosed herein may have a polar surface area in the range at most 6 days after administration. of, e.g., between 3.0 nm and 6.5 nm, between 3.0 nm and Atherapeutic compound disclosed herein may have a log 6.0 nm, between 3.0 nm and 5.5 nm, between 3.0 nm and Pvalue indicating that the compound is soluble in an organic 5.0 nm, between 3.0 nm and 4.5 nm, between 3.5 nm and solvent. As used herein, the term “log value' refers to the 35 6.5 nm, between 3.5 nm and 6.0 nm, between 3.5 nm and logarithm (base 10) of the partition coefficient (P) for a 5.5 nm, between 3.5 nm and 5.0 nm, between 3.5 nm and compound and is a measure of lipophilicity. Typically, P is 4.5 nm, between 4.0 nm and 6.5 nm, between 4.0 nm and defined as the ratio of concentrations of a unionized com 6.0 nm, between 4.0 nm and 5.5 nm, or between 4.0 nm. pound in the two phases of a mixture of two immiscible and 5.0 nm, between 4.0 nm and 4.5 nm, or between 4.5 solvents at equilibrium. Thus, log P=Log 10 (P), where 40 nm and 5.5 nm. In yet other aspects of this embodiment, P-solute in immiscible solvent 1/solute in immiscible a therapeutic compound disclosed herein may have a polar Solvent 2. With regard to organic and aqueous phases, the surface area in the range of e.g., between 2.0 nm and 6.5 log Pvalue of a compound is constant for any given pair of nm, between 2.0 nm and 6.0 nm, between 2.0 nm and 5.5 aqueous and organic Solvents, and its value can be deter nm, between 2.0 nm and 5.0 nm, between 2.0 nm and 4.5 mined empirically by one of several phase-partitioning 45 nm, between 2.5 nm and 6.5 nm, between 2.5 nm and 6.0 methods known to one skilled in the art including, e.g., a nm, between 2.5 nm and 5.5 nm, between 2.5 nm and 5.0 shake flask assay, a HPLC assay, and an interface between nm, or between 2.5 nm and 4.5 nm. two immiscible electrolyte solutions (ITIES) assay. Atherapeutic compound disclosed herein may be an ester In aspects of this embodiment, a therapeutic compound of a therapeutic compound. An ester of a therapeutic com disclosed herein may have a log P value indicating that the 50 pound increases the log P value relative to the same thera compound is substantially soluble in an organic solvent. In peutic compound, but without the ester modification. An aspects of this embodiment, a therapeutic compound dis ester group may be attached to a therapeutic compound by, closed herein may have a log P value indicating that the e.g., a carboxylic acid or hydroxyl functional group present compound is, e.g., at least 50% soluble in an organic Solvent, of the therapeutic compound. An ester of a therapeutic at least 60% soluble in an organic solvent, at least 70% 55 compound may have an increased hydrophobicity, and as soluble in an organic solvent, at least 80% soluble in an such, may be dissolved in a reduced volume of solvent organic Solvent, or at least 90% soluble in an organic disclosed herein. In some instances, an ester of a therapeutic Solvent. In aspects of this embodiment, a therapeutic com compound may be combined directly with an adjuvant pound disclosed herein may have a log P value indicating disclosed herein, thereby eliminating the need of a solvent. that the compound is between, e.g., about 50% to about 60 An ester of a therapeutic compound may enable the making 100% soluble in an organic solvent, about 60% to about of a pharmaceutical composition disclosed herein, in situa 100% soluble in an organic solvent, about 70% to about tions where a non-esterified form of the same therapeutic 100% soluble in an organic solvent, about 80% to about compound is otherwise immiscible in a solvent disclosed 100% soluble in an organic solvent, or about 90% to about herein. An ester of a therapeutic compound may still be 100% soluble in an organic solvent. 65 delivered in a manner that more effectively inhibits a pro In aspects of this embodiment, a therapeutic compound inflammatory response as long as the compound is combined disclosed herein may have a log P value of e.g., more than with an adjuvant disclosed herein. In one embodiment, a US 9,622,982 B2 19 20 therapeutic compound may be reacted with ethyl ester in Cs alcohol, or a Co alcohol. In other aspects of this order to form an ethyl ester of the therapeutic compound. embodiment, an alcohol may be, e.g., a primary alcohol, a In another embodiment, a pharmaceutical composition secondary alcohol, or a tertiary alcohol. In other aspects of disclosed herein does not comprise a pharmaceutically this embodiment, an alcohol may be, e.g., an acyclic alcohol, acceptable solvent disclosed herein. In an aspect of this a monohydric alcohol, a polyhydric alcohol (also known as embodiment, a pharmaceutical composition comprises a a polyol or Sugar alcohol), an unsaturated aliphatic alcohol, therapeutic compound and a pharmaceutically-acceptable an alicyclic alcohol, or a combination thereof. Examples of ity b's Rise a pharmaceutically-accept a monohydric alcohol include, without limitation, , able SOVent d1SCIOSed herein. ethanol, propanol, butanol, pentanol, and 1-hexadecanol. Aspects of the present specification disclose, in part, a 10 Examples of a polyhydric alcohol include, without limita pharmaceutically-acceptable solvent. A solvent is a liquid, tion, glycol, glycerol, arabitol, erythritol, Xylitol, maltitol, Solid, or gas that dissolves another Solid, liquid, or gaseous Sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (idi (the solute), resulting in a solution. Solvents useful in the tol), and isomalt. Examples of an unsaturated aliphatic pharmaceutical compositions disclosed herein include, with alcohol include, without limitation, prop-2-ene-1-ol. 3,7- out limitation, a pharmaceutically-acceptable polar aprotic 15 dimethylocta-2,6-dien-1-ol, and prop-2-in-1-ol. Examples Solvent, a pharmaceutically-acceptable polar protic solvent of an alicyclic alcohol include, without limitation, cyclo and a pharmaceutically-acceptable non-polar solvent. A hexane-1,2,3,4,5,6-hexyl and 2-(2-propyl)-5-methyl-cyclo pharmaceutically-acceptable polar aprotic solvent includes, hexane-1-ol. without limitation, dichloromethane (DCM), tetrahydro In another embodiment, a solvent may comprise an ester furan (THF), ethyl acetate, , dimethylformamide of pharmaceutically-acceptable alcohol and an acid. Suitable (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO). pharmaceutically-acceptable alcohols include the ones dis A pharmaceutically-acceptable polar protic solvent includes, closed herein. Suitable acids include, without limitation, without limitation, acetic acid, formic acid, ethanol, n-bu acetic acid, butaric acid, and formic acid. An ester of an tanol, 1-butanol, 2-butanol, , sec-butanol, tert alcohol and an acid include, without limitation, methyl butanol, n-propanol, isopropanol. 1.2 propan-diol, methanol, 25 acetate, methylbuterate, methyl formate, ethyl acetate, ethyl glycerol, and water. A pharmaceutically-acceptable non buterate, ethyl formate, propyl acetate, propyl buterate, polar solvent includes, without limitation, pentane, cyclo propyl formate, butyl acetate, butylbuterate, butyl formate, pentane, hexane, cyclohexane, , , 1,4-Diox isobutyl acetate, isobutylbuterate, isobutyl formate, pentyl ane, chloroform, n-methyl-pyrrilidone (NMP), and diethyl acetate, penty1 buterate, pentyl formate, and 1-hexadecyl ether. 30 acetate, 1-hexadecyl buterate, and 1-hexadecyl formate. A pharmaceutical composition disclosed herein may com In another embodiment, a solvent may comprise a phar prise a solvent in an amount sufficient to dissolve a thera maceutically-acceptable glycol ether. Glycol ethers are a peutic compound disclosed herein. In other aspects of this group of Solvents based on alkyl ethers of ethylene glycol. embodiment, a pharmaceutical composition disclosed herein Non-limiting examples include diethylene glycol monom may comprise a solvent in an amount of, e.g., less than about 35 ethyl ether (2-(2-methoxyethoxy)ethanol), diethylene glycol 90% (v/v), less than about 80% (v/v), less than about 70% monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene (v/v), less than about 65% (v/v), less than about 60% (v/v), glycol monopropyl ether (2-(2-propoxyethoxy)ethanol), less than about 55% (v/v), less than about 50% (v/v), less diethylene glycol monoisopropyl ether (2-(2-isopropoxy than about 45% (v/v), less than about 40% (v/v), less than ethoxy)ethanol), and diethylene glycol mono-n-butyl ether about 35% (v/v), less than about 30% (v/v), less than about 40 (2-(2-butoxyethoxy)ethanol). Diethylene glycol monoethyl 25% (v/v), less than about 20% (v/v), less than about 15% ether (2-(2-ethoxyethoxy)ethanol) is commercially available (v/v), less than about 10% (v/v), less than about 5% (v/v), or as TRANSCUTOLOR). less than about 1% (v/v). In other aspects of this embodi In another embodiment, a solvent may comprise a phar ment, a pharmaceutical composition disclosed herein may maceutically-acceptable diol. A diol or double alcohol is a comprise a solvent in an amount in a range of, e.g., about 1% 45 chemical compound containing two hydroxyl groups (-OH (v/v) to 90% (v/v), about 1% (v/v) to 70% (v/v), about 1% groups). (v/v) to 60% (v/v), about 1% (v/v) to 50% (v/v), about 1% In another embodiment, a solvent may comprise a phar (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v), about 1% maceutically-acceptable propylene glycol. Propylene gly (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% col, also called 1,2-propanediol or -1,2-diol, is an (v/v) to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% 50 organic compound with formula CHO or HO—CH2— (v/v) to 30% (v/v), about 2% (v/v) to 20% (v/v), about 2% CHOH CH. (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% In another embodiment, a solvent may comprise a phar (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v), about 4% maceutically-acceptable dipropylene glycol. Dipropylene (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% glycol is a mixture of three isomeric chemical compounds, (v/v) to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% 55 4-oxa-2,6-heptandiol. 2-(2-Hydroxy-propoxy)-propan-1-ol. (v/v) to 30% (v/v), about 6% (v/v) to 20% (v/v), about 6% and 2-(2-Hydroxy-1-methyl-ethoxy)-propan-1-ol. (v/v) to 10% (v/v), about 8% (v/v) to 50% (v/v), about 8% In another embodiment, a solvent may comprise a phar (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% maceutically-acceptable polypropylene glycol (PPG) poly (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% mer. PPG polymers polymers, also known as polypropylene (v/v) to 12% (v/v). 60 oxide (PPO) polymers or polyoxypropylene (POP) poly In one embodiment, a solvent may comprise a pharma mers, are prepared by polymerization of propylene oxide ceutically-acceptable alcohol. As used herein, the term and are commercially available over a wide range of "alcohol refers to an organic molecule comprising a molecular weights from 100 g/mol to 10,000,000 g/mol. hydroxyl functional group (-OH) bond to a carbon atom, PPG polymers with a low molecular mass are liquids or where the carbon atom is saturated. In aspects of this 65 low-melting solids, whereas PPG polymers of a higher embodiment, the alcohol may be, e.g., a C- alcohol, a Ca molecular mass are solids. A PPG polymer include, without alcohol, a C-s alcohol, a C-7 alcohol, a Co alcohol, a limitation, PPG 100, PPG 200, PPG 300, PPG 400, PPG US 9,622,982 B2 21 22 500, PPG 600, PPG 700, PPG 800, PPG 900, PPG 1000, emulsion disclosed herein. In other aspects of this embodi PPG 1100, PPG 1200, PPG 1300, PPG 1400, PPG 1500, ment, a pharmaceutical composition disclosed herein may PPG 1600, PPG 1700, PPG 1800, PPG 1900, PPG 2000, comprise an adjuvant in an amount of, e.g., at least 10% PPG 2100, PPG 2200, PPG 2300, PPG 2400, PPG 2500, (v/v), at least 20% (v/v), at least 30% (v/v), at least 35% PPG 2600, PPG 2700, PPG 2800, PPG 2900, PPG 3000, (v/v), at least 40% (v/v), at least 45% (v/v), at least 50% PPG 3250, PPG 3350, PPG 3500, PPG 3750, PPG 4000, (v/v), at least 55% (v/v), at least 60% (v/v), at least 65% PPG 4250, PPG 4500, PPG 4750, PPG 5000, PPG 5500, (v/v), at least 70% (v/v), at least 75% (v/v), at least 80% PPG 6000, PPG 6500, PPG 7000, PPG 7500, PPG 8000, (v/v), at least 85% (v/v), at least 90% (v/v), at least 95% PPG 8500, PPG 9000, PPG 9500, PPG 10,000, PPG 11,000, (v/v), or at least 99% (v/v). In other aspects of this embodi PPG 12,000, PPG 13,000, PPG 14,000, PPG 15,000, PPG 10 ment, a pharmaceutical composition disclosed herein may 16,000, PPG 17,000, PPG 18,000, PPG 19,000, or PPG comprise an adjuvant in an amount in a range of, e.g., about 20,000. 30% (v/v) to about 99% (v/v), about 35% (v/v) to about 99% In another embodiment, a solvent may comprise a phar (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) maceutically-acceptable polyethylene glycol (PEG) poly to about 99% (v/v), about 50% (v/v) to about 99% (v/v), mer. PEG polymers, also known as polyethylene oxide 15 about 30% (v/v) to about 98% (v/v), about 35% (v/v) to (PEO) polymers or polyoxyethylene (POE) polymers, are about 98% (v/v), about 40% (v/v) to about 98% (v/v), about prepared by polymerization of ethylene oxide and are com 45% (v/v) to about 98% (v/v), about 50% (v/v) to about 98% mercially available over a wide range of molecular weights (v/v), about 30% (v/v) to about 95% (v/v), about 35% (v/v) from 100 g/mol to 10,000,000 g/mol. PEG polymers with a to about 95% (v/v), about 40% (v/v) to about 95% (v/v), low molecular mass are liquids or low-melting Solids, about 45% (v/v) to about 95% (v/v), or about 50% (v/v) to whereas PEG polymers of a higher molecular mass are about 95% (v/v). In yet other aspects of this embodiment, a solids. A PEG polymer include, without limitation, PEG pharmaceutical composition disclosed herein may comprise 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, an adjuvant in an amount in a range of, e.g., about 70% (v/v) PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG to about 97% (v/v), about 75% (v/v) to about 97% (v/v), 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 25 about 80% (v/v) to about 97% (v/v), about 85% (v/v) to 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG about 97% (v/v), about 88% (v/v) to about 97% (v/v), about 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97% 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG (v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG to about 96% (v/v), about 85% (v/v) to about 96% (v/v), 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 30 about 88% (v/v) to about 96% (v/v), about 89% (v/v) to 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG about 96% (v/v), about 90% (v/v) to about 96% (v/v), about 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93% PEG 13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG (v/v), about 85% (v/v) to about 93% (v/v), about 88% (v/v) 17,000, PEG 18,000, PEG 19,000, or PEG 20,000. to about 93% (v/v), about 89% (v/v) to about 93% (v/v), or In another embodiment, a solvent may comprise a phar 35 about 90% (v/v) to about 93% (v/v). maceutically-acceptable glyceride. Glycerides comprise a In one embodiment, an adjuvant may be a pharmaceuti substituted glycerol, where one, two, or all three hydroxyl cally-acceptable lipid. A lipid may be broadly defined as a groups of the glycerol are each esterified using a fatty acid hydrophobic or amphiphilic small molecule. The amphiphi to produce monoglycerides, diglycerides, and triglycerides, lic nature of some lipids allows them to form structures such respectively. In these compounds, each hydroxyl groups of 40 as vesicles, liposomes, or membranes in an aqueous envi glycerol may be esterified by different fatty acids. Addition ronment. Non-limiting examples, of lipids include fatty ally, glycerides may be acetylated to produce acetylated acids, glycerolipids (like monoglycerides, diglycerides, and monoglycerides, acetylated diglycerides, and acetylated tri triglycerides), phospholipids, sphingolipids, sterol lipids, glycerides. prenol lipids, saccharolipids, and polyketides. A pharmaceu In one embodiment, a solvent may comprise a pharma 45 tical composition disclosed herein may comprise a lipid Such ceutically-acceptable solid solvent. Solid solvents may be as, e.g. an oil, an oil-based liquid, a fat, a fatty acid, a useful in the manufacture of a solid dose formulation of a partially hydrolyzed fatty acid, a wax, a fatty acid ester, a pharmaceutical composition disclosed herein. Typically, a fatty acid salt, a fatty alcohol, a glyceride (mono-, di- or solid solvent is melted in order to dissolve a therapeutic tri-glyceride), a phospholipids, a glycol ester, a Sucrose compound. A pharmaceutically-acceptable Solid solvent 50 ester, a glycerol oleate derivative, a medium chain triglyc includes, without limitation, and PEG polymers eride, a partially hydrolyzed triglyceride, or a mixture above about 20,000 g/mol. thereof. Aspects of the present specification disclose, in part, a A lipid useful in the pharmaceutical compositions dis pharmaceutically-acceptable adjuvant. An adjuvant is a closed herein may be a pharmaceutically-acceptable fatty pharmacological agent that modifies the effect of other 55 acid. A fatty acid comprises a carboxylic acid with a long agents, such as, e.g., a therapeutic compound disclosed unbranched hydrocarbon chain which may be either satu herein. In addition, an adjuvant disclosed herein may be rated or unsaturated. Thus arrangement confers a fatty acid used as a solvent that dissolves a therapeutic compound with a polar, hydrophilic end, and a nonpolar, hydrophobic disclosed herein, forming a adjuvant Solution. An adjuvant end that is insoluble in water. Most naturally occurring fatty disclosed herein facilitates delivery of a therapeutic com 60 acids have a hydrocarbon chain of an even number of carbon pound in a manner that more effectively inhibits a pro atoms, typically between 4 and 24 carbons, and may be inflammatory response. In one embodiment, an adjuvant attached to functional groups containing oxygen, halogens, disclosed herein facilitates the delivery of a therapeutic nitrogen, and Sulfur. Synthetic or non-natural fatty acids may compound disclosed herein into macrophages. have a hydrocarbon chain of any number of carbon atoms A pharmaceutical composition disclosed herein may com 65 from between 3 and 40 carbons. Where a double bond exists, prise a pharmaceutically-acceptable adjuvant in an amount there is the possibility of either a cis or a trans geometric sufficient to mix with a solution disclosed herein or an isomerism, which significantly affects the molecule's US 9,622,982 B2 23 24 molecular configuration. Cis-double bonds cause the fatty In aspects of this embodiment, a pharmaceutically-accept acid chain to bend, an effect that is more pronounced the able Saturated or unsaturated fatty acid is liquid at room more double bonds there are in a chain. Most naturally temperature. The melting point of a fatty acid is largely occurring fatty acids are of the cis configuration, although determined by the degree of saturation/unsaturation of the the trans form does exist in Some natural and partially hydrocarbon chain. In aspects of this embodiment, a satu hydrogenated fats and oils. Examples of fatty acids include, rated or unsaturated fatty acid has a melting point tempera without limitation, Capryllic acid (8:0), pelargonic acid ture of, e.g., 20° C. or below, 15° C. or below, 10° C. or (9:0), Capric acid (10:0), Undecylic acid (11:0), Lauric acid below, 5° C. or below, 0°C. or below, -5°C. or below, -10° (12:0), Tridecylic acid (13:0), Myristic acid (14:0). Myris C. or below, -15° C. or below, or -20°C. or below. In other 10 aspects of this embodiment, a saturated or unsaturated fatty toleic acid (14:1), Pentadecyclic acid (15:0), Palmitic acid acid has a melting point temperature in the range of, e.g., (16:0), Palmitoleic acid (16:1), Sapienic acid (16:1), Mar about -20° C. to about 20° C., about -20° C. to about 18° garic acid (17:0), Stearic acid (18:0), Oleic acid (18:1), C., about -20°C. to about 16°C., about -20°C. to about 12° Elaidic acid (18:1), Vaccenic acid (18:1), Linoleic acid C., about -20° C. to about 8°C., about -20° C. to about 4° (18:2), Linoelaidic acid (18:2), C-Linolenic acid (18:3), 15 C., about -20°C. to about 0°C., about -15° C. to about 20° Y-Linolenic acid (18:3), Stearidonic acid (18:4). Nonade C., about -15°C. to about 18°C., about -15°C. to about 16° cylic acid (19:0), Arachidic acid (20:0), Eicosenoic acid C., about -15°C. to about 12°C., about -15° C. to about 8° (20:1), Dihomo-y-linolenic acid (20:3), Mead acid (20:3). C., about -15° C. to about 4°C., about -15° C. to about 0° Arachidonic acid (20:4), Eicosapentaenoic acid (20:5), C. Heneicosylic acid (21:0), Behenic acid (22:0), Erucic acid In another embodiment, an adjuvant may comprise one (22:1), Docosahexaenoic acid (22:6), Tricosylic acid (23:0), kind of pharmaceutically-acceptable fatty acid. In aspects of Lignoceric acid (24:0). Nervonic acid (24:1), Pentacosylic this embodiment, an adjuvant may comprise only palmitic acid (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0). acid, only Stearic acid, only oleic acid, only linoleic acid, or Montanic acid (28:0), Nonacosylic acid (29:0), Melissic acid only linolenic acid. (30:0), Henatriacontylic acid (31:0), Lacceroic acid (32:0). 25 In another embodiment, an adjuvant may comprise a Psyllic acid (33:0), Geddic acid (34:0). Ceroplastic acid plurality of different pharmaceutically-acceptable fatty (35:0), and Hexatriacontylic acid (36:0). acids. In aspects of this embodiment, an adjuvant may A lipid useful in the pharmaceutical compositions dis comprise, e.g., two or more different fatty acids, three or closed herein may be a pharmaceutically-acceptable par more different fatty acids, four or more different fatty acids, tially hydrogenated lipid. The process of hydrogenation adds 30 five or more different fatty acids, or six or more different hydrogen atoms to unsaturated lipid, eliminating double fatty acids. bonds and making them into partially or completely satu In other aspects of this embodiment, an adjuvant may rated lipid. Partial hydrogenation is a chemical rather than comprise two or more different pharmaceutically-acceptable enzymatic, that converts a part of cis-isomers into trans fatty acids including at least palmitic acid, Stearic acid, oleic unsaturated lipids instead of hydrogenating them com 35 acid, linoleic acid and/or linolenic acid, and any combina pletely. In the first reaction step, one hydrogen is added, with tion thereof. In other aspects of this embodiment, an adju the other, coordinatively unsaturated, carbon being attached vant may comprise a ratio of palmitic acid and/or Stearic acid to the catalyst. The second step is the addition of hydrogen and/or oleic acid:linolenic acid and/or linoleic acid of e.g., to the remaining carbon, producing a saturated fatty acid. at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, The first step is reversible, such that the hydrogen is read 40 at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least sorbed on the catalyst and the double bond is re-formed. The 15:1, or at least 20:1. In yet other aspects of this embodi intermediate with only one hydrogen added contains no ment, an adjuvant may comprise a ratio of palmitic acid double bond and can freely rotate. Thus, the double bond can and/or Stearic acid and/or oleic acid:linolenic acid and/or re-form as either cis or trans, of which trans is favored, linoleic acid in a range of, e.g., about 1:1 to about 20:1, regardless the starting material. 45 about 2:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 In an embodiment, an adjuvant may be a pharmaceuti to about 10:1. cally-acceptable Saturated or unsaturated fatty acid. In In other aspects of this embodiment, an adjuvant may aspects of this embodiment, a saturated or unsaturated fatty comprise four or more different pharmaceutically-accept acid comprises, e.g., at least 8, at least 10, at least 12, at least able fatty acids including at least palmitic acid, Stearic acid, 14, at least 16, at least 18, at least 20, at least 22, at least 24, 50 oleic acid, linoleic acid and/or linolenic acid, and any at least 26, at least 28, or at least 30 carbon atoms, In other combination thereof. In other aspects of this embodiment, an aspects of this embodiment, a saturated or unsaturated fatty adjuvant may comprise a ratio of palmitic acid; Stearic acid comprises, e.g., between 4 and 24 carbon atoms, acid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, between 6 and 24 carbon atoms, between 8 and 24 carbon 8:8:1:1, 7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or atoms, between 10 and 24 carbon atoms, between 12 and 24 55 1:1:1:1. In other aspects of this embodiment, an adjuvant carbon atoms, between 14 and 24 carbon atoms, or between may comprise a ratio of palmitic acid; Stearic acid:linolenic 16 and 24 carbon atoms, between 4 and 22 carbon atoms, acid:linoleic acid in a range of, e.g., about 10:10:1:1 to about between 6 and 22 carbon atoms, between 8 and 22 carbon 6:6:1:1, about 8:8:1:1 to about 4:4:1:1, or about 5:5:1:1 to atoms, between 10 and 22 carbon atoms, between 12 and 22 about 1:1:1:1. carbon atoms, between 14 and 22 carbon atoms, or between 60 A lipid useful in the pharmaceutical compositions dis 16 and 22 carbon atoms, between 4 and 20 carbon atoms, closed herein may be a pharmaceutically-acceptable omega between 6 and 20 carbon atoms, between 8 and 20 carbon fatty acid. Non-limiting examples of an omega fatty acid atoms, between 10 and 20 carbon atoms, between 12 and 20 include omega-3, omega-6, omega-7, and omega-9. carbon atoms, between 14 and 20 carbon atoms, or between Omega-3 fatty acids (also known as n-3 fatty acids or co-3 16 and 20 carbon atoms. If unsaturated, the fatty acid may 65 fatty acids) are a family of essential unsaturated fatty acids have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or that have in common a final carbon-carbon double bond in more, or 6 or more double bonds. the n-3 position, that is, the third bond, counting from the US 9,622,982 B2 25 26 methyl end of the fatty acid. The omega-3 fatty acids are oil (cocoa butter), walnut oil, wheat germ oil, or a mixture “essential fatty acids because they are vital for normal thereof. Each of these oils is commercially available from a metabolism and cannot be synthesized by the human body. number of sources well recognized by those skilled in the An omega-3 fatty acid includes, without limitation, Hexa art. decatrienoic acid (16:3), C-Linolenic acid (18:3), Steari An oil is typically a mixture of various fatty acids. For donic acid (18:4). Eicosatrienoic acid (20:3), Eicosatetra example, Rapeseed oil, obtained from the seeds of Brassica enoic acid (20:4), Eicosapentaenoic acid (20:5), napus, includes both omega-6 and omega-3 fatty acids in a Heneicosapentaenoic acid (21:5), Docosapentaenoic acid ratio of about 2:1. As another example, linseed oil, obtained (Clupanodonic acid) (22:5), Docosahexaenoic acid (22:6), from the seeds of Linum usitatissimum, includes abut 7% Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid 10 palmitic acid, about 3.4–4.6% stearic acid, about 18.5-22.6% (Nisinic acid) (24:6). oleic acid, about 14.2-17% linoleic acid, and about 51.9- Omega-6 fatty acids (also known as n-6 fatty acids or ()-6 55.2% C-linolenic acid. As another example, theobroma oil, fatty acids) are a family of unsaturated fatty acids that have obtained from the seeds of Theobroma cacao, includes in common a final carbon-carbon double bond in the n-6 glycerides derived from palmitic acid, Stearic acid, oleic position, that is, the sixth bond, counting from the methyl 15 acid, linoleic acid, and arichidic acid, with melting point of end of the fatty acid. An omega-6 fatty acid includes, 34-38°C. In aspects of this embodiment, a pharmaceutical without limitation, Linoleic acid (18:2), Y-linolenic acid composition comprises an oil including at least two different (18:3), Calendic acid (18:3), Eicosadienoic acid (20:2), fatty acids, at least three different fatty acids, at least four Dihomo-y-linolenic acid (20:3), Arachidonic acid (20:4). different fatty acids, at least five different fatty acids, or at Docosadienoic acid (22:2), Adrenic acid (22:4). Docosapen least six different fatty acids. taenoic acid (22:5), Tetracosatetraenoic acid (24:4), and A lipid useful in the pharmaceutical compositions dis Tetracosapentaenoic acid (24:5). closed herein may be a pharmaceutically-acceptable glyc Omega-7 fatty acids (also known as n-7 fatty acids or ()-7 erolipid. Glycerolipids are composed mainly of mono-, di-, fatty acids) are a family of unsaturated fatty acids that have and tri-substituted glycerols. One group of glycerolipids is in common a final carbon-carbon double bond in the n-7 25 the glycerides, where one, two, or all three hydroxyl groups position, that is, the seventh bond, counting from the methyl of glycerol are each esterified using a fatty acid to produce end of the fatty acid. An omega-7 fatty acid includes, monoglycerides, diglycerides, and triglycerides, respec without limitation, 5-Dodecenoic acid (12:1), 7-Tetrade tively. In these compounds, each hydroxyl groups of glyc cenoic acid (14:1), 9-Hexadecenoic acid (Palmitoleic acid) erol may be esterified by different fatty acids. Additionally, (16:1), 11-Decenoic acid (Vaccenic acid) (18:1), 9Z,11E 30 glycerides may be acetylated to produce acetylated mono conjugated Linoleic acid (Rumenic acid) (18:2), 13-Eicose glycerides, acetylated diglycerides, and acetylated triglyc noic acid (Paullinic acid) (20:1), 15-Docosenoic acid (22:1). erides. One group of glycerolipids is the glycerides, where and 17-Tetracosenoic acid (24:1). one, two, or all three hydroxyl groups of glycerol have Sugar Omega-9 fatty acids (also known as n-9 fatty acids or ()-9 residues attached via a glycosidic linkage. fatty acids) are a family of unsaturated fatty acids that have 35 A lipid useful in the pharmaceutical compositions dis in common a final carbon-carbon double bond in the n-9 closed herein may be a pharmaceutically-acceptable glycol position, that is, the ninth bond, counting from the methyl fatty acid ester. A pharmaceutically-acceptable glycol fatty end of the fatty acid. An omega-9 fatty acid includes, acid ester can be a monoester of a glycol, a diester of a without limitation, Oleic acid (18:1), Elaidic acid (18:1), glycol, or a triester of a glycol. A glycol fatty acid ester Eicosenoic acid (20:1). Mead acid (20:3), Erucic acid (22:1). 40 include, without limitation, a ethylene glycol fatty acid ester, Nervonic acid (24:1), and Ricinoleic acid. a diethylene glycol fatty acid ester, a propylene glycol fatty A lipid useful in the pharmaceutical compositions dis acid ester, and a dipropylene fatty acid ester. Non-limiting closed herein may be a pharmaceutically-acceptable fat. examples of glycol fatty acid esters include, e.g., ethelene Also known as a hard fat or Solid fat, a fat includes any fatty glycol caprylate, ethelene glycol pelargonate, ethelene gly acid that is solid at normal room temperature, such as, e.g. 45 col caprate, ethelene glycol undecylate, ethelene glycol about 20° C. Fats consist of a wide group of compounds that laurate, ethelene glycol tridecylate, ethelene glycol are generally soluble in organic solvents and generally myristate, ethelene glycol myristolate, ethelene glycol pen insoluble in water. A fat suitable as a lipid useful in the tadecyclate, ethelene glycol palmitate, ethelene glycol pharmaceutical compositions disclosed herein, may be a palmitoleate, ethelene glycol sapienate, ethelene glycol mar triglyceride, a triester of glycerol or any of several fatty 50 garate, ethelene glycol Stearate, ethelene glycol palmitoste acids. arate, ethelene glycol oleate, ethelene glycol elaidate, ethe A lipid useful in the pharmaceutical compositions dis lene glycol vaccinate, ethelene glycol linoleate, ethelene closed herein may be a pharmaceutically-acceptable oil. An glycol linoelaidate, ethelene glycol O-linolenate, ethelene oil, also known as a liquid fat, includes any fatty acid that is glycol Y-linolenate, ethelene glycol Stearidonate, ethelene liquid at normal room temperature, such as, e.g. about 20°C. 55 glycol capprylocaprate, ethelene glycol dicapprylocaprate, An oil Suitable as a lipid useful in the pharmaceutical diethelene glycol caprylate, diethelene glycol pelargonate, compositions disclosed herein, may be a natural oil, a diethelene glycol caprate, diethelene glycol undecylate, vegetable oil or any Substance that does not mix with water diethelene glycol laurate, diethelene glycol tridecylate, and has a greasy feel. Examples of Suitable natural oils diethelene glycol myristate, diethelene glycol myristolate, include, without limitation, mineral oil, triacetin, ethyl 60 diethelene glycol pentadecyclate, diethelene glycol palmi oleate, a hydrogenated natural oil, or a mixture thereof. tate, diethelene glycol palmitoleate, diethelene glycol sapi Examples of suitable vegetable oils include, without limi enate, diethelene glycol margarate, diethelene glycol Stear tation, almond oil, arachis oil, avocado oil, canola oil, castor ate, diethelene glycol palmitostearate, diethelene glycol oil, coconut oil, corn oil, cottonseed oil, grape seed oil, oleate, diethelene glycol elaidate, diethelene glycol vacci hazelnut oil, hemp oil, linseed oil (flax seed oil), olive oil, 65 nate, diethelene glycol linoleate, diethelene glycol linoelai palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, date, diethelene glycol O-linolenate, diethelene glycol Y-li sesame oil, Soybean oil, soya oil, Sunflower oil, theobroma nolenate, diethelene glycol stearidonate, diethelene glycol US 9,622,982 B2 27 28 capprylocaprate, diethelene glycol dicapprylocaprate, pro glyceride, a vaccinoyl PEG glyceride, a linoleoyl PEG pylene glycol caprylate, propylene glycol pelargonate, pro glyceride, a linoelaidoyl PEG glyceride, an O-linolenoyl pylene glycol caprate, propylene glycol undecylate, propyl PEG glyceride, a Y-linolenoyl PEG glyceride, a stearidonoyl ene glycol laurate, propylene glycol tridecylate, propylene PEG glyceride, a capprylocaproyl PEG glyceride, a dicap glycol myristate, propylene glycol myristolate, propylene 5 prylocaproyl PEG glyceride, a PPG caprylate, a PPG pelar glycol pentadecyclate, propylene glycol palmitate, propyl gonate, a PPG caprate, a PPG undecylate, a PPG laurate, a ene glycol palmitoleate, propylene glycol sapienate, propyl PPG tridecylate, a PPG myristate, a PPG myristolate, a PPG ene glycol margarate, propylene glycol Stearate, propylene pentadecyclate, a PPG palmitate, a PPG palmitoleate, a PPG glycol palmitostearate, propylene glycol oleate, propylene sapienate, a PPG margarate, a PPG stearate, a PPG palmi glycol elaidate, propylene glycol vaccinate, propylene gly- 10 to stearate, a PPG oleate, a PPG elaidate, a PPG vaccinate, a collinoleate, propylene glycol linoelaidate, propylene gly PPG linoleate, a PPG linoelaidate, a PPG O-linolenate, a col O-linolenate, propylene glycol Y-linolenate, propylene PPG Y-linolenate, a PPG stearidonate, a PPG capprylo glycol Stearidonate, propylene glycol capprylocaprate, pro caprate, a PPG dicapprylocaprate, a PPG glyceryl caprylate, pylene glycol dicapprylocaprate, dipropylene glycol capry a PPG glyceryl pelargonate, a PPG glyceryl caprate, a PPG late, dipropylene glycol pelargonate, dipropylene glycol 15 glyceryl undecylate, a PPG glyceryl laurate, a PPG glyceryl caprate, dipropylene glycol undecylate, dipropylene glycol tridecylate, a PPG glyceryl myristate, a PPG glyceryl myris laurate, dipropylene glycol tridecylate, dipropylene glycol tolate, a PPG glyceryl pentadecyclate, a PPG glyceryl palmi myristate, dipropylene glycol myristolate, dipropylene gly tate, a PPG glyceryl palmitoleate, a PPG glyceryl sapienate, col pentadecyclate, dipropylene glycol palmitate, dipropyl a PPG glyceryl margarate, a PPG glyceryl Stearate, a PPG ene glycol palmitoleate, dipropylene glycol sapienate, dipro- 20 glyceryl palmitostearate, a PPG glyceryl oleate, a PPG pylene glycol margarate, dipropylene glycol Stearate, glyceryl elaidate, a PPG glyceryl vaccinate, a PPG glyceryl dipropylene glycol palmitostearate, dipropylene glycol linoleate, a PPG glyceryl linoelaidate, a PPG glyceryl C-li oleate, dipropylene glycol elaidate, dipropylene glycol vac nolenate, a PPG glyceryl Y-linolenate, a PPG glyceryl Steari cinate, dipropylene glycollinoleate, dipropylene glycollino donate, a PPG glyceryl capprylocaprate, a PPG glyceryl elaidate, dipropylene glycol O-linolenate, dipropylene gly- 25 dicapprylocaprate, a capryloyl PPG glyceride, a pelargonoyl col Y-linolenate, dipropylene glycol Stearidonate, PPG glyceride, a caproyl PPG glyceride, an undecyloyl PPG dipropylene glycol capprylocaprate, dipropylene glycol glyceride, a lauroyl PPG glyceride, a tridecyloyl PPG glyc dicapprylocaprate, or any combination thereof. eride, a myristoyl PPG glyceride, a myristoloyl PPG glyc A lipid useful in the pharmaceutical compositions dis eride, a pentadecycloyl PPG glyceride, a palmitoyl PPG closed herein may be a pharmaceutically-acceptable 30 glyceride, a palmitoleoyl PPG glyceride, a sapienoyl PPG polyether fatty acid ester. A pharmaceutically-acceptable glyceride, a margaroyl PPG glyceride, a stearoyl PPG glyc polyether fatty acid ester can be a mono-fatty acid ester of eride, a palmitostearoyl PPG glyceride, an oleoyl PPG a polyether, a di-fatty acid ester of a polyether, or a tri-fatty glyceride, an elaidoyl PPG glyceride, a vaccinoyl PPG acid ester of a polyether. A polyether fatty acid ester glyceride, a linoleoyl PPG glyceride, a linoelaidoyl PPG includes, without limitation, a PEG fatty acid ester, a PEG 35 glyceride, an O-linolenoyl PPG glyceride, a Y-linolenoyl glyceryl fatty acid, a PEG fatty acid ester glyceride, a PPG PPG glyceride, a stearidonoyl PPG glyceride, a capprylo fatty acid ester, a PPG glyceryl fatty acid, and a PPG fatty caproyl PPG glyceride, a dicapprylocaproyl PPG glyceride, acid ester glyceride. A PEG or PPG may be a molecular mass or any combination thereof. of, e.g., 5-20,000. Non-limiting examples of polyether fatty Commercially available pharmaceutically-acceptable acid esters include, e.g., a PEG caprylate, a PEG pelargo- 40 polyether fatty acid esters include, without limitation, capry nate, a PEG caprate, a PEG undecylate, a PEG laurate, a locaproyl macrogol-8 glycerides (LABRASOL(R), propyl PEG tridecylate, a PEG myristate, a PEG myristolate, a PEG ene glycol monopalmitostearate (MONOSTEOL(R), glyc pentadecyclate, a PEG palmitate, a PEG palmitoleate, a PEG eryl dibelhenate (COMPRITOL.R. 888), glycerol behenate sapienate, a PEG margarate, a PEG stearate, a PEG palmi (COMPRITOL(R) EATO), behenoyl pollyoxyl-8 glycerides to stearate, PEG oleate, PEG elaidate, PEG vaccinate, PEG 45 (COMPRITOL(R) HD5 ATO), triglycerol disostearate linoleate, PEG linoelaidate, PEG C-linolenate, PEG Y-lino (PLUROL(R) Diisostearique), PEG-8 beeswax (APIFIL(R), lenate, PEG stearidonate, PEG capprylocaprate, PEG dicap lauroyl macrogol-32 glycerides (GELUCIRE 44/14), prylocaprate, a PEG glyceryl caprylate, a PEG glyceryl stearoyl macrogol-32 glycerides (GELUCIRE 50.13), pro pelargonate, a PEG glyceryl caprate, a PEG glyceryl pylene glycol dicaprylocaprate (LABRAFAC(R) PG), undecylate, a PEG glyceryl laurate, a PEG glyceryl tridecy- 50 polyglycerol-3 dioleate (PLUROL(R) Oleigue CC 497), pro late, a PEG glyceryl myristate, a PEG glyceryl myristolate, pylene glycol monolaurate (type I) (LAUROGLYCOLOR a PEG glyceryl pentadecyclate, a PEG glyceryl palmitate, a FCC), propylene glycol monolaurate (type II) (LAURO PEG glyceryl palmitoleate, a PEG glyceryl sapienate, a PEG GLYCOLR 90), propylene glycol monocaprylate (type I) glyceryl margarate, a PEG glyceryl Stearate, a PEG glyceryl (CAPRYOLR PGMC), propylene glycol monocaprylate palmitostearate, PEG glyceryl oleate, PEG glyceryl elaidate, 55 (type II) (CAPRYOLR 90), linoleoyl macrogol-6 glycerides PEG glyceryl vaccinate, PEG glyceryllinoleate, PEG glyc (LABRAFIL(R) M2125CS), oleoyl macrogol-6 glycerides eryl linoelaidate, PEG glyceryl C-linolenate, PEG glyceryl (LABRAFIL(R) M1944CS), lauroyl macrogol-6 glycerides Y-linolenate, PEG glyceryl Stearidonate, PEG glyceryl cap (LABRAFIL(R) M2130CS), glycerol dipalmitostearate prylocaprate, PEG glyceryl dicapprylocaprate, a capryloyl (Biogapress Vegetal BM297ATO), glycerol distearate (type PEG glyceride, a pelargonoyl PEG glyceride, a caproyl PEG 60 I) (PRECIROL(R) ATO 5), and glycerol monolinoleate glyceride, an undecyloyl PEG glyceride, a lauroyl PEG (MAISINETM 35-1). glyceride, a tridecyloyl PEG glyceride, a myristoyl PEG A lipid useful in the pharmaceutical compositions dis glyceride, a myristoloyl PEG glyceride, a pentadecycloyl closed herein may be a mixture of pharmaceutically-accept PEG glyceride, a palmitoyl PEG glyceride, a palmitoleoyl able lipids. Examples of mixtures of pharmaceutically PEG glyceride, a sapienoyl PEG glyceride, a margaroyl 65 acceptable lipids include, without limitation, a mixture of PEG glyceride, a stearoyl PEG glyceride, a palmitostearoyl one or more glycerolipids disclosed herein, one or more PEG glyceride, an oleoyl PEG glyceride, an elaidoyl PEG glycol fatty acid esters disclosed herein, more polyether fatty US 9,622,982 B2 29 30 acid esters disclosed herein. In aspects of this embodiment, sorbate 80 (TWEENR 80), and polysorbate 81 (TWEENR) a mixture of pharmaceutically-acceptable lipids includes a 81); poloxamers (polyethylene-polypropylene copolymers), mixture of mono-, di-, and triglycerides and PEG fatty acid like Poloxamer 124 (PLURONICR) L44), Poloxamer 181 esters having a melting point of about 33°C., a mixture of (PLURONICR) L61), Poloxamer 182 (PLURONICR) L62), mono-, di-, and triglycerides and PEG fatty acid esters 5 Poloxamer 184 (PLURONICR) L64), Poloxamer 188 having a melting point of about 35°C., a mixture of mono-, (PLURONICR F68), Poloxamer 237 (PLURONICR) F87), di-, and triglycerides and PEG fatty acid esters having a Poloxamer 338 (PLURONICR) L108), Poloxamer 407 melting point of about 37°C., a mixture of mono-, di-, and (PLURONICR) F127), polyoxyethyleneglycol dodecyl triglycerides and PEG fatty acid esters having a melting ethers, like BRIJR 30, and BRIJR 35; 2-dodecoxyethanol point of about 39° C., a mixture of pharmaceutically 10 (LUBROL(R)-PX); polyoxyethylene octyl phenyl ether (TRI acceptable lipids includes mono-, di-, and triglycerides and TONR X-100); sodium dodecyl sulfate (SDS): 3-(3- PEG fatty acid esters having a melting point of about 41° C. Cholamidopropyl)dimethylammonio-1-propanesulfonate a mixture of pharmaceutically-acceptable lipids includes (CHAPS): 3-(3-Cholamidopropyl)dimethylammonio-2- mono-, di-, and triglycerides and PEG fatty acid esters hydroxy-1-propanesulfonate (CHAPSO); sucrose monolau having a melting point of about 43° C., or a mixture of 15 rate; and Sodium cholate. Other non-limiting examples of pharmaceutically-acceptable lipids includes mono-, di-, and Surfactant excipients can be found in, e.g., Ansel, Supra, triglycerides and PEG fatty acid esters having a melting (1999); Gennaro, supra, (2000); Hardman, supra, (2001); point of about 45° C. Commercially available mixtures of and Rowe, Supra, (2003), each of which is hereby incorpo pharmaceutically-acceptable lipids include, without limita rated by reference in its entirety. tion, mixtures of PEG-6 stearate and ethylene glycol palmi In an aspect of this embodiment, an emulsifying agent tostearate and PEG-32 stearate (TEFOSE(R) 1500; may comprise a polysaccharide. Non-limiting examples of TEFOSE(R) 63), mixtures of triceteareth-4 phosphate and polysaccharides include guar gum, agar, alginate, calgene, a ethylene glycol palmitostearate and diethylene glycol palmi dextran (like dextran 1 K, dextran 4K, dextran 40K, dextran tostearate (SEDEFOSR 75), mixtures of glycerol monoste 60K, and dextran 70K), dextrin, glycogen, inulin, starch, a arate and PEG-75 stearate (GELOTR), mixtures of cetyl 25 starch derivative (like hydroxymethyl starch, hydroxyethyl alcohol and ethoxylated fatty alcohols (seteth-2-, steareth starch, hydroxypropyl Starch, hydroxybutyl starch, and 20) (EMULCIRE(R), mixtures of mono-, di-, and triglycer hydroxypentyl starch), hetastarch, cellulose, FICOLL, ides and PEG fatty acid esters having a melting point around methyl cellulose (MC), carboxymethyl cellulose (CMC), 33° C. (GELUCIRE(R) 33/01), mixtures of mono-, di-, and hydroxyethyl cellulose (HEC), hydroxypropyl cellulose triglycerides and PEG fatty acid esters having a melting 30 (HPC), hydroxyethyl methyl cellulose (HEMC), hydroxy point around 39° C. (GELUCIRE(R) 39/01), mixtures of propyl methyl cellulose (HPMC); polyvinyl acetates (PVA): mono-, di-, and triglycerides and PEG fatty acid esters polyvinyl pyrrollidones (PVP), also known as povidones, having a melting point around 43°C. (GELUCIRE(R) 43/01), having a K-value of less than or equal to 18, a K-value mixtures of glycerol monostearate 40-55 (type I) and diglyc greater than 18 or less than or equal to 95, or a K-value erides (GELEOL(R) Mono and Diglycerides), and mixtures 35 greater than 95, like PVP 12 (KOLLIDONR) 12), PVP 17 of medium-chain triglycerides (LABRAFAC(R) Lipophile (KOLLIDONR 17), PVP 25 (KOLLIDONR 25), PVP 30 WL 1349). (KOLLIDONR 30), PVP90 (KOLLIDONR 90); and poly Aspects of the present specification disclose, in part, a ethylene imines (PEI). pharmaceutically-acceptable stabilizing agent. A stabilizing In an aspect of this embodiment, an emulsifying agent agent reduces or eliminates formation of esters of a thera 40 may comprise a lectin. Lectins are Sugar-binding proteins peutic compound that may result as a unwanted reaction that are highly specific for their Sugar moieties. Lectins may with the particular solvent used. A stabilizing agent include, be classified according to the Sugar moiety that they bind to, without limitation, water, a sacrificial acid comprising a fatty and include, without limitation, mannose-binding lectins, acid component and acetic acid, ethyl acetate, a sodium galactose/N-acetylgalactosamine-binding lectins, N-acetyl acetate/acetic acid (E262), a monoglyceride, an acetylated 45 gluxosamine-binding lectins, N-acetylneuramine-binding monoglyceride, a diglyceride, an acetylated monoglyceride, lectins, N-acetylneuraminic acid-binding lectins, and an acetylated diglyceride, a fatty acid, and a fatty acid salt. fucose-binding lectins. Non-limiting examples of Surfac In one embodiment, a pharmaceutically-acceptable stabi tants include concanavain A, lentil lectin, Snowdrop lectin, lizing agent may comprise a pharmaceutically-acceptable Roin, peanut agglutinin, jacain, hairy vetch lectin, wheat emulsifying agent. An emulsifying agent (also known as an 50 germ agglutinin, elderberry lectin, Maackia anurensis leu emulgent) is a Substance that stabilizes an emulsion com koagglutinin, Maackia anurensis hemoagglutinin, Ulex prising a liquid dispersed phase and a liquid continuous europaeus agglutinin, and Aleuria aurantia lectin. phase by increasing its kinetic stability. Thus, in situations In an aspect of this embodiment, an emulsifying agent where the solvent and adjuvant used to make a pharmaceu may comprise a phospholipid. The structure of the phos tical composition disclosed herein are normally immiscible, 55 pholipid generally comprises a hydrophobic tail and a an emulsifying agent disclosed herein is used to create a hydrophilic head and is amphipathic in nature. Most phos homogenous and stable emulsion. An emulsifying agent pholipids contain a diglyceride, a phosphate group, and a includes, without limitation, a surfactant, a polysaccharide, simple organic molecule Such as choline; one exception to a lectin, and a phospholipid. this rule is sphingomyelin, which is derived from sphin In an aspect of this embodiment, an emulsifying agent 60 gosine instead of glycerol. Phospholipids include, without may comprise a Surfactant. As used hereon, the term "sur limitation, diacylglycerides and phosphosphingolipids. factant” refers to a natural or synthetic amphiphilic com Non-limiting examples of diacylglycerides include a phos pound. A surfactant can be non-ionic, Zwitterionic, or ionic. phatidic acid (phosphatidate) (PA), a phosphatidyletha Non-limiting examples of Surfactants include polysorbates nolamine (cephalin) (PE), a phosphatidylcholine (lecithin) like polysorbate 20 (TWEENR 20), polysorbate 40 65 (PC), a phosphatidylserine (PS), and a phosphoinositide (TWEENR 40), polysorbate 60 (TWEENR 60), polysorbate including phosphatidylinositol (PI), phosphatidylinositol 61 (TWEENR 61), polysorbate 65 (TWEENR 65), poly phosphate (PIP), phosphatidylinositol bisphosphate (PIP2), US 9,622,982 B2 31 32 and phosphatidylinositol triphosphate (PIP3). Non-limiting taken up by the liver, and ultimately loaded into macro examples of phosphosphingolipids include a ceramide phos phages which are present in inflamed tissues. phorylcholine (sphingomyelin) (SPH), ceramide phospho As another example, a pharmaceutical composition dis rylethanolamine (sphingomyelin) (Cer-PE), and ceramide closed herein may facilitate the delivery of a therapeutic phosphorylglycerol. compound disclosed herein into dentritic cells. One possible In one embodiment, a pharmaceutically-acceptable stabi mechanism to achieve selective biodistribution of the phar lizing agent does not comprise a pharmaceutically-accept maceutical compositions disclosed herein may be to take able emulsifying agent. advantage of the endocytotic/phagocytotic activity of den In another embodiment, a pharmaceutical composition tritic cells. Dendritic cells are immune cells forming part of does not comprise a pharmaceutically-acceptable emulsify 10 the mammalian immune system. The main function of ing agent. dendritic cells is to process antigen material and present it on The pharmaceutical compositions disclosed herein act as the surface to other cells of the immune system. Thus, a delivery system that enable a therapeutic compound dis dendritic cells function as antigen-presenting cells that act as closed herein to be more effectively delivered or targeted to messengers between innate and adaptive immunity. Den a cell type, tissue, organ, or region of the body in a manner 15 dritic cells are present in tissues in contact with the external that more effectively inhibits a pro-inflammatory response. environment, Such as, e.g., the skin (where there is a This inhibition results in an improved treatment of a chronic specialized dendritic cell type called Langerhans cells) and inflammation. For example, a pharmaceutical composition the inner lining of the nose, lungs, stomach and intestines. disclosed herein may facilitate the delivery of a therapeutic These cells can also be found in an immature state in the compound disclosed herein into macrophages. One possible blood. Once activated, they migrate to the lymph nodes mechanism that achieves this selective biodistribution is that where they interact with T cells and B cells to initiate and the pharmaceutical compositions disclosed herein may be shape the adaptive immune response. Dendritic cells are designed to take advantage of the activity of chylomicrons. known to endocytose and phagocytose lipid particles as part Chylomicrons are relatively large lipoprotein particles hav of their environmental monitoring and antigen presentation ing a diameter of 75 nm to 1,200 nm. Comprising triglyc 25 processes. Without wishing to be limited by any theory, upon erides (85-92%), phospholipids (6-12%), cholesterol (1-3%) topical or inhalatory administration, a pharmaceutical com and apolipoproteins (1-2%), chylomicrons transport dietary position disclosed herein can penetrate into the skin or inner lipids from the intestines to other locations in the body. lining of the nose, lungs, stomach and intestines, be endo Chylomicrons are one of the five major groups of lipopro cytosed/phagocytosed by dentritic cells, and ultimately teins, the others being VLDL, IDL, low-density lipoproteins 30 loaded into T cells and/or B cells which are present in (LDL), high-density lipoproteins (HDL), that enable fats and inflamed tissues. cholesterol to move within the water-based solution of the Aspects of the present specification disclose, in part, a bloodstream. method of preparing a pharmaceutical composition dis During digestion, fatty acids and cholesterol undergo closed herein. A method disclosed herein comprises the step processing in the gastrointestinal tract by the action of 35 of contacting a pharmaceutically-acceptable adjuvant dis pancreatic juices including lipases and emulsification with closed herein with a therapeutic compound disclosed herein bile salts to generate micelles. These micelles allow the under conditions which allow the therapeutic compound to absorption of lipid as free fatty acids by the absorptive cells dissolve in the pharmaceutically-acceptable adjuvant, of the Small intestine, known as enterocytes. Once in the thereby forming a pharmaceutical composition disclosed enterocytes, triglycerides and cholesterol are assembled into 40 herein. nascent chylomicrons. Nascent chylomicrons are primarily Aspects of the present specification disclose, in part, a composed of triglycerides (85%) and contain some choles method of preparing a pharmaceutical composition dis terol and cholesteryl esters. The main apolipoprotein com closed herein. A method disclosed herein comprises the ponent is apolipoprotein B-48 (APOB48). These nascent steps of a) contacting a pharmaceutically-acceptable solvent chylomicrons are released by exocytosis from enterocytes 45 disclosed herein with a therapeutic compound disclosed into lacteals, lymphatic vessels originating in the villi of the herein under conditions which allow the therapeutic com Small intestine, and are then secreted into the bloodstream at pound to dissolve in the pharmaceutically-acceptable sol the thoracic duct’s connection with the left subclavian vein. vent, thereby forming a solution; and b) contacting the While circulating in lymph and blood, chylomicrons Solution formed in step (a) with a pharmaceutically-accept exchange components with HDL. The HDL donates apoli 50 able adjuvant disclosed herein under conditions which allow poprotein C-II (APOC2) and apolipoprotein E (APOE) to the formation of a pharmaceutical composition. The meth the nascent chylomicron and thus converts it to a mature ods of preparing disclosed herein may further comprise a chylomicron (often referred to simply as “chylomicron'). step (c) of removing the pharmaceutically-acceptable sol APOC2 is the cofactor for lipoprotein lipase (LPL) activity. vent from the pharmaceutical composition. Once triglyceride stores are distributed, the chylomicron 55 The amount of a therapeutic compound that is contacted returns APOC2 to the HDL (but keeps APOE), and, thus, with the pharmaceutically-acceptable solvent in step (a) of becomes a chylomicron remnant, now only 30-50 nm. the method may be in any amount desired. Factors used to APOB48 and APOE are important to identify the chylomi determine the amount of a therapeutic compound used cron remnant in the liver for endocytosis and breakdown include, without limitation, the final amount the therapeutic into lipoproteins (VLDL, LDL and HDL). These lipopro 60 compound desired in the pharmaceutical composition, the teins are processed and stored by competent cells, including, desired concentration of a therapeutic compound in the e.g., hepatocytes, adipocytes and macrophages. Thus, with Solution, the hydrophobicity of the therapeutic compound, out wishing to be limited by any theory, upon oral admin the lipophobicity of the therapeutic compound, the tempera istration, a pharmaceutical composition disclosed herein can ture under which the contacting step (a) is performed, and be processed into micelles while in the gastrointestinal tract, 65 the time under which the contacting step (a) is performed absorbed by enterocytes and assembled into nascent chylo The volume of a pharmaceutically-acceptable solvent microns, remain associated with chylomicron remnants used in step (a) of the method may be any Volume desired. US 9,622,982 B2 33 34 Factors used to determine the volume of a pharmaceutically After contacting, the concentration of a therapeutic com acceptable solvent used include, without limitation, the final pound disclosed herein in the Solution may be in any amount of a pharmaceutical composition desired, the desired concentration desired. In aspects of this embodiment, the concentration of a therapeutic compound in the Solution, the concentration of a therapeutic compound disclosed herein in hydrophobicity of the therapeutic compound, and the lipo the solution may be, e.g., at least 0.00001 mg/mL, at least phobicity of the therapeutic compound. 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, In aspects of this embodiment, the amount of a therapeutic at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at compound that is contacted with the solvent in step (a) may least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at be, e.g., at least 10 mg, at least 20 mg, at least 30 mg, at least least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, 10 at least 1,000 mg/mL, or at least 1,200 mg/mL. In other 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least aspects of this embodiment, the concentration of a thera 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at peutic compound disclosed herein in the Solution may be, least 300 mg, at least 400 mg, at least 500 mg, at least 600 e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most mg, at least 700 mg, at least 800 mg, at least 900 mg.at least 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 15 at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg, at least 1,400 mg, or at least 1,500 mg. In other aspects mg/mL, or at most 3,000 mg/mL. In other aspects of this of this embodiment, the amount of a therapeutic compound embodiment, the concentration of a therapeutic compound that is contacted with the solvent in step (a) may be in the disclosed herein in the Solution may be in a range of, e.g., range of, e.g., about 10 mg to about 100 mg, about 50 mg about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 to about 150 mg, about 100 mg to about 250 mg, about 150 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about mg to about 350 mg, about 250 mg to about 500 mg, about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, 350 mg to about 600 mg, about 500 mg to about 750 mg. about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 600 mg to about 900 mg, about 750 mg to about 1,000 about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg, about 850 mg to about 1,200 mg. or about 1,000 mg to mg/mL, about 750 mg/mL to about 3,000 mg/mL, about about 1,500 mg. In other aspects of this embodiment, the 25 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to amount of a therapeutic compound that is dissolved in the about 2,000 mg/mL, about 250 mg/mL to about 2,000 Solvent in Step (a) may be in the range of, e.g., about 10 mg mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 to about 250 mg, about 10 mg to about 500 mg, about 10 mg mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about to about 750 mg, about 10 mg to about 1,000 mg, about 10 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, mg to about 1,500 mg, about 50 mg to about 250 mg, about 30 about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL 50 mg to about 500 mg, about 50 mg to about 750 mg, about to about 1,500 mg/mL, about 750 mg/mL to about 1,500 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about about 100 mg to about 250 mg, about 100 mg to about 500 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to mg, about 100 mg to about 750 mg, about 100 mg to about about 1,200 mg/mL, about 500 mg/mL to about 1,200 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg 35 mg/mL, about 750 mg/mL to about 1,200 mg/mL, about to about 500 mg, about 200 mg to about 750 mg, about 200 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to mg to about 1,000 mg, or about 200 mg to about 1,500 mg. about 1,000 mg/mL, about 250 mg/mL to about 1,000 Step (a) may be carried out at room temperature, in order mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 to allow a therapeutic compound to dissolve fully in the mg/mL to about 1,000 mg/mL, about 100 mg/mL to about pharmaceutically-acceptable solvent. However, in other 40 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about embodiments of the method, Step (a) may be carried out at 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about a temperature that is greater than room temperature. In 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about aspects of this embodiment, Step (a) may be carried out at 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 a temperature that is, e.g., greater than 21°C., greater than mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to 25°C., greater than 30° C., greater than 35° C. or greater 45 about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 than 37°C., greater than 40°C., greater than 42°C., greater mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about than 45° C., greater than 50° C., greater than 55° C., or 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to greater than 60° C. In aspects of this embodiment, Step (a) about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, may be carried out at a temperature that is between, e.g., about 0.001 mg/mL to about 10 mg/mL, or about 0.001 about 20° C. to about 30° C., about 25° C. to about 35° C., 50 mg/mL to about 100 mg/mL. about 30° C. to about 40° C., about 35° C. to about 45° C., The Volume of a pharmaceutically-acceptable adjuvant about 40° C. to about 50° C., about 45° C. to about 55° C., used in Step (b) of the method may be any volume desired. or about 50° C. to about 60°C. In certain cases, Step (a) may Factors used to determine the volume of a pharmaceutically be carried out at temperatures below room temperature, in acceptable adjuvant used include, without limitation, the order to allow a therapeutic compound to dissolve fully in 55 final amount of a pharmaceutical composition desired, the solvent. However, in other embodiments of the method, step desired concentration of a therapeutic compound in the (a) may be carried out at a temperature that is less than room pharmaceutical composition, the ratio of Solvent:adjuvant temperature, e.g., less than 10°C., greater than 5°C., greater used, and the miscibility of solvent and adjuvant. than 0°C., greater than -10°C. or greater than -20°C. The In aspects of this embodiment, the ratio of solution: contacting in Step (a) may comprise mixing the therapeutic 60 adjuvant may be, e.g., at least 5:1, at least 4:1, at least 3:1, compound and the pharmaceutically-acceptable solvent, at least 2:1, at least 0:1, at least 1:1, at least 1:2, at least 1:3, e.g., by stirring, inversion, Sonication, or Vortexing. The at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, mixing may be carried out for, e.g., at least 1 second, at least at least 1:9, at least 1:10, at least 1:15, at least 1:20, or at 5 seconds, at least 10 seconds, at least 20 seconds, at least least 1:25. In other aspects of this embodiment, the ratio of 30 seconds, at least 45 seconds, at least 60 seconds, or more, 65 Solution:adjuvant may be in a range of, e.g., about 5:1 to until the therapeutic compound is fully dissolved in the about 1:25, about 4:1 to about 1:25, about 3:1 to about 1:25, solvent. about 2:1 to about 1:25, about 0:1 to about 1:25, about 1:1 US 9,622,982 B2 35 36 to about 1:25, about 1:2 to about 1:25, about 1:3 to about formulated in six fats. In an embodiment, a cancer thera 1:25, about 1:4 to about 1:25, about 1:5 to about 1:25, about peutic, including, without limitation, artemesinin and/or its 5:1 to about 1:20, about 4:1 to about 1:20, about 3:1 to about derivatives is formulated in seven or more fats. 1:20, about 2:1 to about 1:20, about 0:1 to about 1:20, about In an embodiment, a cancer therapeutic, including, with 1:1 to about 1:20, about 1:2 to about 1:20, about 1:3 to about out limitation, artemesinin and/or its derivatives is formu 1:20, about 1:4 to about 1:20, about 1:5 to about 1:20, about lated in a fat that is a liquid. In an embodiment, a cancer 5:1 to about 1:15, about 4:1 to about 1:15, about 3:1 to about therapeutic, including, without limitation, artemesinin and/ 1:15, about 0:1 to about 1:15, about 2:1 to about 1:15, about or its derivatives is formulated in at fat that is a solid. In an 1:1 to about 1:15, about 1:2 to about 1:15, about 1:3 to about embodiment, a cancer therapeutic, including, without limi 1:15, about 1:4 to about 1:15, about 1:5 to about 1:15, about 10 tation, artemesinin and/or its derivatives is formulated in a 5:1 to about 1:12, about 4:1 to about 1:12, about 3:1 to about two or more fats that are liquids. In an embodiment, a cancer 1:12, about 2:1 to about 1:12, about 0:1 to about 1:12, about therapeutic, including, without limitation, artemesinin and/ 1:1 to about 1:12, about 1:2 to about 1:12, about 1:3 to about or its derivatives is formulated in two or more fats that are 1:12, about 1:4 to about 1:12, about 1:5 to about 1:12, about Solids. In an embodiment, a cancer therapeutic, including, 1:6 to about 1:12, about 1:7 to about 1:12, about 1:8 to about 15 without limitation, artemesinin and/or its derivatives is 1:12, about 5:1 to about 1:10, about 4:1 to about 1:10, about formulated in two or more fats, wherein at least one fat is a 3:1 to about 1:10, about 2:1 to about 1:10, about 0:1 to about Solid and at least one fat is a liquid. 1:10, about 1:1 to about 1:10, about 1:2 to about 1:10, about Step (b) may be carried out at room temperature, in order 1:3 to about 1:10, about 1:4 to about 1:10, about 1:5 to about to allow the Solution comprising the therapeutic compound 1:10, about 1:6 to about 1:10, about 1:7 to about 1:10, or to form the pharmaceutical composition. However, in other about 1:8 to about 1:10. embodiments of the method, Step (b) may be carried out at In an embodiment, the ratio of fat:fat, for instance, a temperature that is greater than room temperature. In without limitation, tributyrin, which is an ester composed of aspects of this embodiment, Step (b) may be carried out at butyric acid and glycerol and G43 (a sold fat) may be, e.g., a temperature that is, e.g., greater than 21°C., greater than at least 5:1, at least 4:1, at least 3:1, at least 2:1, at least 0:1, 25 25° C., greater than 30° C., greater than 35° C. or greater at least 1:1, at least 1.1:1, at least 1.2:1, at least 1.3:1, at least than 37°C., greater than 40°C., greater than 42°C., greater 1.4:1, at least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, than 45° C., greater than 50° C., greater than 55° C., or at least 1.9:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, greater than 60° C. In aspects of this embodiment, Step (a) at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, may be carried out at a temperature that is between, e.g., at least 1:15, at least 1:20, or at least 1:25. In other aspects 30 about 20° C. to about 30° C., about 25° C. to about 35° C., of this embodiment, the ratio of fat:fat may be in a range of about 30° C. to about 40° C., about 35° C. to about 45° C., e.g., about 5:1 to about 1:25, about 4:1 to about 1:25, about about 40° C. to about 50° C., about 45° C. to about 55° C., 3:1 to about 1:25, about 2:1 to about 1:25, about 0:1 to about or about 50° C. to about 60°C. In certain cases, Step (b) may 1:25, about 1:1 to about 1:25, about 1:2 to about 1:25, about be carried out at temperatures below room temperature, in 1:3 to about 1:25, about 1:4 to about 1:25, about 1:5 to about 35 order to allow a therapeutic compound to dissolve fully in a 1:25, about 5:1 to about 1:20, about 4:1 to about 1:20, about pharmaceutically-acceptable solvent. However, in other 3:1 to about 1:20, about 2:1 to about 1:20, about 0:1 to about embodiments of the method, step (b) may be carried out at 1:20, about 1:1 to about 1:20, about 1:2 to about 1:20, about a temperature that is less than room temperature, e.g., less 1:3 to about 1:20, about 1:4 to about 1:20, about 1:5 to about than 10° C., greater than 5° C., greater than 0° C., greater 1:20, about 5:1 to about 1:15, about 4:1 to about 1:15, about 40 than -10°C. or greater than -20°C. The contacting in Step 3:1 to about 1:15, about 0:1 to about 1:15, about 2:1 to about (b) may comprise mixing the solution and the pharmaceu 1:15, about 1:1 to about 1:15, about 1:2 to about 1:15, about tically-acceptable adjuvant, e.g., by stirring, inversion, Soni 1:3 to about 1:15, about 1:4 to about 1:15, about 1:5 to about cation, or Vortexing. The mixing may be carried out for, e.g., 1:15, about 5:1 to about 1:12, about 4:1 to about 1:12, about at least 1 second, at least 5 seconds, at least 10 seconds, at 3:1 to about 1:12, about 2:1 to about 1:12, about 0:1 to about 45 least 20 seconds, at least 30 seconds, at least 45 seconds, at 1:12, about 1:1 to about 1:12, about 1:2 to about 1:12, about least 60 seconds, or more, until the pharmaceutical compo 1:3 to about 1:12, about 1:4 to about 1:12, about 1:5 to about sition is formed. 1:12, about 1:6 to about 1:12, about 1:7 to about 1:12, about In certain embodiments, a rapid cooling step may be used 1:8 to about 1:12, about 5:1 to about 1:10, about 4:1 to about to reduce the temperature of a pharmaceutical composition 1:10, about 3:1 to about 1:10, about 2:1 to about 1:10, about 50 disclosed herein after its formation. For example, a rapid 0:1 to about 1:10, about 1:1 to about 1:10, about 1:2 to about cooling step may be used in procedures were temperatures 1:10, about 1:3 to about 1:10, about 1:4 to about 1:10, about greater than room temperature are used to allow a therapeu 1:5 to about 1:10, about 1:6 to about 1:10, about 1:7 to about tic compound to dissolve fully in the pharmaceutically 1:10, or about 1:8 to about 1:10. acceptable solvent and/or to allow the solution comprising In an embodiment, a cancer therapeutic, including, with 55 the therapeutic compound to form the pharmaceutical com out limitation, artemesinin and/or its derivatives is formu position. In aspects of this embodiment, a rapid cooling step lated in a one fat. In an embodiment, a cancer therapeutic, results in a temperature decrease of, e.g., about 30°C. in 20 including, without limitation, artemesinin and/or its deriva minutes, about 25° C. in 20 minutes, about 20° C. in 20 tives is formulated in two fats. In an embodiment, a cancer minutes, about 15° C. in 20 minutes, about 30° C. in 15 therapeutic, including, without limitation, artemesinin and/ 60 minutes, about 25° C. in 15 minutes, about 20° C. in 15 or its derivatives is formulated in three fats. In an embodi minutes, about 15° C. in 15 minutes, about 30° C. in 10 ment, a cancer therapeutic, including, without limitation, minutes, about 25° C. in 10 minutes, about 20° C. in 10 artemesinin and/or its derivatives is formulated in four fats. minutes, about 15° C. in 10 minutes, about 30° C. in 5 In an embodiment, a cancer therapeutic, including, without minutes, about 25° C. in 5 minutes, about 20° C. in 5 limitation, artemesinin and/or its derivatives is formulated in 65 minutes, about 15° C. in 5 minutes. In other aspects of this five fats. In an embodiment, a cancer therapeutic, including, embodiment, a rapid cooling step results in a temperature without limitation, artemesinin and/or its derivatives is decrease of, e.g., about 20° C. to about 30°C. in 20 minutes, US 9,622,982 B2 37 38 about 20° C. to about 30° C. in 15 minutes, about 20° C. to tion step is conducted at ambient pressure, e.g., 1 atm. about 30° C. in 10 minutes, about 20° C. to about 30° C. in However, under high vacuum conditions, the evaporation 5 minutes, about 15° C. to about 25°C. in 20 minutes, about step may be conducted at temperatures below ambient 15° C. to about 25°C. in 15 minutes, about 15° C. to about temperature, e.g., less than 22°C. 25° C. in 10 minutes, about 15° C. to about 25° C. in 5 In one embodiment, removal of solvent from the phar minutes, about 10° C. to about 20° C. in 20 minutes, about maceutical composition disclosed herein may be carried out 10° C. to about 20° C. in 15 minutes, about 10° C. to about at ambient atmospheric pressure and at a temperature above 20° C. in 10 minutes, or about 10° C. to about 20° C. in 5 ambient temperature. In aspects of this embodiment, minutes. removal of Solvent from the pharmaceutical composition In yet aspects of this embodiment, a rapid cooling step 10 disclosed herein may be carried out at ambient atmospheric results in a temperature decrease of e.g., about 2.0°C/min pressure and at a temperature of, e.g., more than 25 C. ute, about 1.9°C/minute, about 1.8° C./minute, about 1.7 more than 30°C., more than 35°C., more than 40°C., more C./minute, about 1.6° C./minute, about 1.5° C./minute, than 45° C., more than 50° C., more than 55° C., more than about 1.4° C./minute, about 1.3° C./minute, about 1.2 60° C., more than 65° C., more than 70° C., more than 80° C./minute, about 1.1° C./minute, about 1.0° C./minute, 15 C., or more than 25°C. In other aspects of this embodiment, about 0.9° C./minute, about 0.8° C./minute, about 0.7° removal of Solvent from the pharmaceutical composition C./minute, about 0.6° C./minute, about 0.5° C./minute, disclosed herein may be carried out at ambient atmospheric about 0.4° C./minute, about 0.3° C./minute, about 0.2° pressure and at a temperature in a range of, e.g., about 25° C./minute, or about 0.1° C./minute. In still aspects of this C. to about 100° C., about 25°C. to about 95°C., about 25° embodiment, a rapid cooling step results in a temperature C. to about 90° C., about 25°C. to about 85°C., about 25° decrease of, e.g., about 0.1° C. to about 0.4° C./minute, C. to about 80° C., about 25°C. to about 75° C., about 25° about 0.2°C. to about 0.6°C./minute, about 0.4°C. to about C. to about 70° C., about 25°C. to about 65°C., or about 25° 0.8°C/minute, about 0.6°C. to about 1.0°C/minute, about C. to about 60° C. 0.8°C. to about 1.2°C./minute, about 1.0° C. to about 1.4° In another embodiment, removal of solvent from the C./minute, about 1.2°C. to about 1.6°C./minute, about 1.4° 25 pharmaceutical composition disclosed herein may be carried C. to about 1.8° C./minute, about 1.6° C. to about 2.0° out under vacuum and at a temperature below ambient C./minute, about 0.1° C. to about 0.5°C/minute, about 0.5° temperature. In aspects of this embodiment, removal of C. to about 1.0° C./minute, about 1.0° C. to about 1.5° Solvent from the pharmaceutical composition disclosed C./minute, about 1.5° C. to about 2.0°C/minute, about 0.5° herein may be carried out under vacuum and at a tempera C. to about 1.5°C/minute, or about 1.0° C. to about 2.0° 30 ture of, e.g., less than 20°C., less than 18°C., less than 16° C./minute. C., less than 14° C., less than 12° C., less than 10° C., less In some embodiments, temperatures greater than room than 8°C., less than 6° C., less than 4°C., less than 2° C., temperature employed in either Step (a) or Step (b) or both or less than 0° C. In other aspects of this embodiment, may be used to remove the solvent from a pharmaceutical removal of Solvent from the pharmaceutical composition composition. In other embodiment, removal of solvent from 35 disclosed herein may be carried out under vacuum and at a a pharmaceutical composition requires a separate Step (c). In temperature in a range of, e.g., about -20° C. to about 20° Step (c), the solvent removal from a pharmaceutical com C., about -20°C. to about 18°C., about -20°C. to about 16° position may be accomplished using one of a variety of C., about -20°C. to about 14°C., about -20°C. to about 12° procedures known in the art, including, without limitation, C., about -20°C. to about 10°C., about -20° C. to about 8° evaporation, dialyzation, distillation, lypholization, and fil 40 C., about -20° C. to about 6°C., about -20° C. to about 4° tration. These removal procedures may be done under con C., about -20° C. to about 2°C., about -20° C. to about 0° ditions of ambient atmosphere, under low pressure, or under C., about -15°C. to about 20°C., about -10°C. to about 20° a vacuum and either at ambient temperature or at tempera C., about -5° C. to about 20° C., about 0° C. to about 20° tures requiring heating. C., about -10°C. to about 20°C., about -10°C. to about 18° In one embodiment, Step (c) may result in the complete 45 C., about -10°C. to about 16°C., about -10°C. to about 14° removal of a pharmaceutically-acceptable solvent from the C., about -10°C. to about 12°C., about -10°C. to about 10° pharmaceutical composition disclosed herein. In aspects of C., about -10° C. to about 8°C., about -10° C. to about 6° this embodiment, Step (c) may result in, e.g., at least 5%, at C., about -10° C. to about 4°C., about -10° C. to about 2 least 10%, at least 15%, at least 20%, at least 25%, at least C., or about -10° C. to about 0° C. 30%, at least 35%, at least 40%, at least 45%, at least 50%, 50 The final concentration of a therapeutic compound dis at least 55%, at least 60%, at least 65%, at least 70%, at least closed herein in a pharmaceutical composition disclosed 75%, at least 80%, at least 85%, at least 90%, at least 93%, herein may be of any concentration desired. In an aspect of at least 95%, at least 97%, or at least 99% removal of a this embodiment, the final concentration of a therapeutic pharmaceutically-acceptable solvent from the pharmaceuti compound in a pharmaceutical composition may be a thera cal composition disclosed herein. 55 peutically effective amount. In other aspects of this embodi Step (c) is conducted at a temperature that allows for the ment, the final concentration of a therapeutic compound in evaporation of a pharmaceutically-acceptable solvent dis a pharmaceutical composition may be, e.g., at least 0.00001 closed herein, and as such, an evaporation temperature is mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at Solvent dependant. Factors which influence an evaporation least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at temperature of a solvent disclosed herein include, without 60 least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at limitation, the particular solvent used, the amount of solvent least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, present, the particular therapeutic compound present, the at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200 particular adjuvant present, the Stability of the therapeutic mg/mL. In other aspects of this embodiment, the concen compound present, the reactivity of the therapeutic com tration of a therapeutic compound disclosed herein in the pound present, the particular atmospheric pressure used, the 65 Solution may be, e.g., at most 1,000 mg/mL, at most 1,100 time desired for complete evaporation. Generally, a phar mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at maceutical composition will require heating if the evapora most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 US 9,622,982 B2 39 40 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In In liquid and semi-solid formulations, a concentration of other aspects of this embodiment, the final concentration of a therapeutic compound disclosed herein typically may be a therapeutic compound in a pharmaceutical composition between about 50 mg/mL to about 1,000 mg/mL. In aspects may be in a range of, e.g., about 0.00001 mg/mL to about of this embodiment, a therapeutically effective amount of a 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, therapeutic compound disclosed herein may be from, e.g., about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to to about 3,000 mg/mL, about 1 mg/mL to about 3,000 about 200 mg/mL, about 50 mg/mL to about 300 mg/mL, mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 about 50 mg/mL to about 400 mg/mL, about 50 mg/mL to mg/mL to about 3,000 mg/mL, about 750 mg/mL to about about 500 mg/mL, about 50 mg/mL to about 600 mg/mL, 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, 10 about 50 mg/mL to about 700 mg/mL, about 50 mg/mL to about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL about 800 mg/mL, about 50 mg/mL to about 900 mg/mL, to about 2,000 mg/mL, about 500 mg/mL to about 2,000 about 50 mg/mL to about 1,000 mg/mL, about 100 mg/mL mg/mL, about 750 mg/mL to about 2,000 mg/mL, about to about 200 mg/mL, about 100 mg/mL to about 300 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 about 1,500 mg/mL, about 250 mg/mL to about 1,500 15 mg/mL to about 500 mg/mL, about 100 mg/mL to about 600 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 mg/mL, about 100 mg/mL to about 700 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about mg/mL to about 800 mg/mL, about 100 mg/mL to about 900 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 200 about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL mg/mL to about 300 mg/mL, about 200 mg/mL to about 400 to about 1,200 mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 200 mg/mL to about 500 mg/mL, about 200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about mg/mL to about 600 mg/mL, about 200 mg/mL to about 700 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to mg/mL, about 200 mg/mL to about 800 mg/mL, about 200 about 1,000 mg/mL, about 500 mg/mL to about 1,000 mg/mL to about 900 mg/mL, about 200 mg/mL to about mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 1,000 mg/mL, about 300 mg/mL to about 400 mg/mL, about mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 25 300 mg/mL to about 500 mg/mL, about 300 mg/mL to about mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 600 mg/mL, about 300 mg/mL to about 700 mg/mL, about mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 300 mg/mL to about 800 mg/mL, about 300 mg/mL to about mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, 900 mg/mL, about 300 mg/mL to about 1,000 mg/mL, about about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 400 mg/mL to about 500 mg/mL, about 400 mg/mL to about mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to 30 600 mg/mL, about 400 mg/mL to about 700 mg/mL, about about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, 400 mg/mL to about 800 mg/mL, about 400 mg/mL to about about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 900 mg/mL, about 400 mg/mL to about 1,000 mg/mL, about mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 500 mg/mL to about 600 mg/mL, about 500 mg/mL to about mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 700 mg/mL, about 500 mg/mL to about 800 mg/mL, about 0.001 mg/mL to about 100 mg/mL. 35 500 mg/mL to about 900 mg/mL, about 500 mg/mL to about A pharmaceutical composition produced using the meth 1,000 mg/mL, about 600 mg/mL to about 700 mg/mL, about ods disclosed herein may be formulated for either local or 600 mg/mL to about 800 mg/mL, about 600 mg/mL to about systemic delivery using topical, enteral or parenteral routes 900 mg/mL, or about 600 mg/mL to about 1,000 mg/mL. of administration. Additionally, a therapeutic compound In semi-solid and solid formulations, an amount of a disclosed herein may be formulated by itself in a pharma 40 therapeutic compound disclosed herein typically may be ceutical composition, or may be formulated together with between about 0.01% to about 45% by weight. In aspects of one or more other therapeutic compounds disclosed herein this embodiment, an amount of a therapeutic compound in a single pharmaceutical composition. disclosed herein may be from, e.g., about 0.1% to about 45% A pharmaceutical composition produced using the meth by weight, about 0.1% to about 40% by weight, about 0.1% ods disclosed herein may be a liquid formulation, semi-solid 45 to about 35% by weight, about 0.1% to about 30% by formulation, or a solid formulation. A formulation disclosed weight, about 0.1% to about 25% by weight, about 0.1% to herein can be produced in a manner to form one phase. Such about 20% by weight, about 0.1% to about 15% by weight, as, e.g., an oil or a solid. Alternatively, a formulation about 0.1% to about 10% by weight, about 0.1% to about 5% disclosed herein can be produced in a manner to form two by weight, about 1% to about 45% by weight, about 1% to phase, such as, e.g., an emulsion. A pharmaceutical compo 50 about 40% by weight, about 1% to about 35% by weight, sition disclosed herein intended for Such administration may about 1% to about 30% by weight, about 1% to about 25% be prepared according to any method known to the art for the by weight, about 1% to about 20% by weight, about 1% to manufacture of pharmaceutical compositions. Semi-solid about 15% by weight, about 1% to about 10% by weight, formulations suitable for topical administration include, about 1% to about 5% by weight, about 5% to about 45% by without limitation, ointments, creams, salves, and gels. 55 weight, about 5% to about 40% by weight, about 5% to A liquid formulation may be formed by using various about 35% by weight, about 5% to about 30% by weight, lipids like oils of other fatty acids that remain as liquids in about 5% to about 25% by weight, about 5% to about 20% the temperature range desired. In an embodiment, a phar by weight, about 5% to about 15% by weight, about 5% to maceutical composition disclosed herein is liquid at room about 10% by weight, about 10% to about 45% by weight, temperature. In aspects of this embodiment, a pharmaceu 60 about 10% to about 40% by weight, about 10% to about 35% tical composition disclosed herein may be formulated to be by weight, about 10% to about 30% by weight, about 10% a liquid at a temperature of, e.g., about 25° C. or higher, to about 25% by weight, about 10% to about 20% by weight, about 23°C. or higher, about 21°C. or higher, about 19°C. about 10% to about 15% by weight, about 15% to about 45% or higher, about 17° C. or higher, about 15° C. or higher, by weight, about 15% to about 40% by weight, about 15% about 12° C. or higher, about 10° C. or higher, about 8° C. 65 to about 35% by weight, about 15% to about 30% by weight, or higher, about 6° C. or higher, about 4°C. or higher, or about 15% to about 25% by weight, about 15% to about 20% about 0°C. or higher. by weight, about 20% to about 45% by weight, about 20% US 9,622,982 B2 41 42 to about 40% by weight, about 20% to about 35% by weight, ethylene glycol, and about 7% to about 13% of propylene about 20% to about 30% by weight, about 20% to about 25% glycol. In still another aspect of this embodiment, a solid by weight, about 25% to about 45% by weight, about 25% formulation comprises about 20% to about 30% by weight to about 40% by weight, about 25% to about 35% by weight, of therapeutic compound, about 35% to about 50% by or about 25% to about 30% by weight. weight of hard fat, about 15% to about 25% by weight of In another embodiment, a solid formulation comprises a partially-hydrogenated fat, about 7% to about 13% of poly cancer therapeutic, including, but not limited to, artemesinin ethylene glycol, and about 7% to about 13% of propylene or a derivative thereof, a mixture of mono-, di-, and triglyc glycol. In a further aspect of this embodiment, a solid erides and PEG fatty acid esters, a glyceryl monolinoleate, formulation comprises about 23% to about 27% by weight and a polyethylene glycol. In an aspect of this embodiment, 10 of therapeutic compound, about 41% to about 47% by a solid formulation comprises about 1% to about 30% by weight of hard fat, about 18% to about 22% by weight of weight of a cancer therapeutic, including, but not limited to, partially-hydrogenated fat, about 9% to about 11% of poly artemesinin or a derivative thereof, about 8% to about 70% ethylene glycol, and about 9% to about 11% of propylene by weight of a mixture of mono-, di-, and triglycerides and glycol. In other aspects of this embodiment, a polyethylene PEG fatty acid esters, about 2% to about 65% by weight of 15 glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG a glyceryl monolinoleate, and about 1% to about 15% of 400, a PEG 500, a PEG 600, or a PEG 700. polyethylene glycol. In another aspect of this embodiment, In another embodiment, a solid formulation comprises a a solid formulation comprises about 10% to about 30% by therapeutic compound, a mixture of mono-, di-, and triglyc weight of a cancer therapeutic, including, but not limited to, erides and PEG fatty acid esters, a glyceryl monolinoleate, artemesinin or a derivative thereof, about 20% to about 50% a polyethylene glycol, and a propylene glycol. In an aspect by weight of a mixture of mono-, di-, and triglycerides and of this embodiment, a solid formulation comprises about 1% PEG fatty acid esters, about 10% to about 30% by weight of to about 30% by weight of therapeutic compound, about 8% a glyceryl monolinoleate, and about 5% to about 15% of to about 70% by weight of a mixture of mono-, di-, and polyethylene glycol. In yet another aspect of this embodi triglycerides and PEG fatty acid esters, about 2% to about ment, a solid formulation comprises about 20% to about 25 65% by weight of a glyceryl monolinoleate, about 1% to 30% by weight of a cancer therapeutic, including, but not about 15% of polyethylene glycol, and about 1% to about limited to, artemesinin or a derivative thereof, about 30% to 15% of propylene glycol. In another aspect of this embodi about 50% by weight of a mixture of mono-, di-, and ment, a solid formulation comprises about 10% to about triglycerides and PEG fatty acid esters, about 10% to about 30% by weight of therapeutic compound, about 20% to 30% by weight of a glyceryl monolinoleate, and about 7% 30 about 50% by weight of a mixture of mono-, di-, and to about 13% of polyethylene glycol. In still another aspect triglycerides and PEG fatty acid esters, about 10% to about of this embodiment, a solid formulation comprises about 30% by weight of a glyceryl monolinoleate, about 5% to 20% to about 30% by weight of a cancer therapeutic, about 15% of polyethylene glycol, and about 5% to about including, but not limited to, artemesinin or a derivative 15% of propylene glycol. In yet another aspect of this thereof, about 35% to about 50% by weight of a mixture of 35 embodiment, a solid formulation comprises about 20% to mono-, di-, and triglycerides and PEG fatty acid esters, about 30% by weight of therapeutic compound, about 30% about 15% to about 25% by weight of a glyceryl monoli to about 50% by weight of a mixture of mono-, di-, and noleate, and about 7% to about 13% of polyethylene glycol. triglycerides and PEG fatty acid esters, about 10% to about In a further aspect of this embodiment, a solid formulation 30% by weight of a glyceryl monolinoleate, and about 7% comprises about 23% to about 27% by weight of a cancer 40 to about 13% of polyethylene glycol, and about 7% to about therapeutic, including, but not limited to, artemesinin or a 13% of propylene glycol. In still another aspect of this derivative thereof, about 41% to about 47% by weight of a embodiment, a solid formulation comprises about 20% to mixture of mono-, di-, and triglycerides and PEG fatty acid about 30% by weight of therapeutic compound, about 35% esters, about 18% to about 22% by weight of a glyceryl to about 50% by weight of a mixture of mono-, di-, and monolinoleate, and about 9% to about 11% of polyethylene 45 triglycerides and PEG fatty acid esters, about 15% to about glycol. In other aspects of this embodiment, a polyethylene 25% by weight of a glyceryl monolinoleate, about 7% to glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG about 13% of polyethylene glycol, and about 7% to about 400, a PEG 500, a PEG 600, or a PEG 700. 13% of propylene glycol. In a further aspect of this embodi In another embodiment, a solid formulation comprises a ment, a solid formulation comprises about 23% to about therapeutic compound, a hard fat, a partially-hydrogenated 50 27% by weight of therapeutic compound, about 41% to fat, a polyethylene glycol, and a propylene glycol. In an about 47% by weight of a mixture of mono-, di-, and aspect of this embodiment, a solid formulation comprises triglycerides and PEG fatty acid esters, about 18% to about about 1% to about 30% by weight of therapeutic compound, 22% by weight of a glyceryl monolinoleate, about 9% to about 8% to about 70% by weight of hard fat, about 2% to about 11% of polyethylene glycol, and about 9% to about about 65% by weight of partially-hydrogenated fat, about 55 11% of propylene glycol. In other aspects of this embodi 1% to about 15% of polyethylene glycol, and about 1% to ment, a polyethylene glycol is, e.g., a PEG 100, a PEG 200, about 15% of propylene glycol. In another aspect of this a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG embodiment, a solid formulation comprises about 10% to 700. about 30% by weight of therapeutic compound, about 20% In another embodiment, a solid formulation comprises a to about 50% by weight of hard fat, about 10% to about 30% 60 cancer therapeutic, including, but not limited to, artemesinin by weight of partially-hydrogenated fat, about 5% to about or a derivative thereof, a mixture of mono-, di-, and triglyc 15% of polyethylene glycol, and about 5% to about 15% of erides and PEG fatty acid esters, a glyceryl monolinoleate, propylene glycol. In yet another aspect of this embodiment, a polyethylene glycol, and a propylene glycol. In an aspect a solid formulation comprises about 20% to about 30% by of this embodiment, a solid formulation comprises about 1% weight of therapeutic compound, about 30% to about 50% 65 to about 30% by weight of a cancer therapeutic, including, by weight of hard fat, about 10% to about 30% by weight of but not limited to, artemesinin or a derivative thereof, about partially-hydrogenated fat, about 7% to about 13% of poly 8% to about 70% by weight of a mixture of mono-, di-, and US 9,622,982 B2 43 44 triglycerides and PEG fatty acid esters, about 2% to about comprises about 25% to about 44% by weight of therapeutic 65% by weight of a glyceryl monolinoleate, about 1% to compound, about 12% to about 14% by weight of hard fat, about 15% of polyethylene glycol, and about 1% to about about 32% to about 39% by weight of partially-hydroge 15% of propylene glycol. In another aspect of this embodi nated fat, about 12% to about 14% of polyethylene glycol, ment, a solid formulation comprises about 10% to about and about 4% of propylene glycol. In other aspects of this 30% by weight of a cancer therapeutic, including, but not embodiment, a polyethylene glycol is, e.g., a PEG 100, a limited to, artemesinin or a derivative thereof, about 20% to PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, about 50% by weight of a mixture of mono-, di-, and or a PEG 700. triglycerides and PEG fatty acid esters, about 10% to about In another embodiment, a semi-solid formulation com 30% by weight of a glyceryl monolinoleate, about 5% to 10 prises a therapeutic compound, a mixture of mono-, di-, and about 15% of polyethylene glycol, and about 5% to about triglycerides and PEG fatty acid esters, a glyceryl monoli 15% of propylene glycol. In yet another aspect of this noleate, a polyethylene glycol, and a propylene glycol. In an embodiment, a solid formulation comprises about 20% to aspect of this embodiment, a semi-solid formulation com about 30% by weight of a cancer therapeutic, including, but prises about 15% to about 55% by weight of therapeutic not limited to, artemesinin or a derivative thereof, about 15 compound, about 7% to about 20% by weight of a mixture 30% to about 50% by weight of a mixture of mono-, di-, and of mono-, di-, and triglycerides and PEG fatty acid esters, triglycerides and PEG fatty acid esters, about 10% to about about 20% to about 50% by weight of a glyceryl monoli 30% by weight of a glyceryl monolinoleate, and about 7% noleate, about 7% to about 20% of polyethylene glycol, and to about 13% of polyethylene glycol, and about 7% to about about 1% to about 8% of propylene glycol. In another aspect 13% of propylene glycol. In still another aspect of this of this embodiment, a semi-solid formulation comprises embodiment, a solid formulation comprises about 20% to about 20% to about 50% by weight of therapeutic com about 30% by weight of a cancer therapeutic, including, but pound, about 8% to about 18% by weight of a mixture of not limited to, artemesinin or a derivative thereof, about mono-, di-, and triglycerides and PEG fatty acid esters, 35% to about 50% by weight of a mixture of mono-, di-, and about 25% to about 45% by weight of a glyceryl monoli triglycerides and PEG fatty acid esters, about 15% to about 25 noleate, about 8% to about 18% of polyethylene glycol, and 25% by weight of a glyceryl monolinoleate, about 7% to about 2% to about 6% of propylene glycol. In another aspect about 13% of polyethylene glycol, and about 7% to about of this embodiment, a semi-solid formulation comprises 13% of propylene glycol. In a further aspect of this embodi about 20% to about 50% by weight of therapeutic com ment, a solid formulation comprises about 23% to about pound, about 10% to about 16% by weight of a mixture of 27% by weight of a cancer therapeutic, including, but not 30 mono-, di-, and triglycerides and PEG fatty acid esters, limited to, artemesinin or a derivative thereof, about 41% to about 25% to about 45% by weight of a glyceryl monoli about 47% by weight of a mixture of mono-, di-, and noleate, about 10% to about 16% of polyethylene glycol, triglycerides and PEG fatty acid esters, about 18% to about and about 2% to about 6% of propylene glycol. In yet 22% by weight of a glyceryl monolinoleate, about 9% to another aspect of this embodiment, a semi-solid formulation about 11% of polyethylene glycol, and about 9% to about 35 comprises about 20% to about 50% by weight of therapeutic 11% of propylene glycol. In other aspects of this embodi compound, about 11% to about 15% by weight of a mixture ment, a polyethylene glycol is, e.g., a PEG 100, a PEG 200, of mono-, di-, and triglycerides and PEG fatty acid esters, a PEG 300, a PEG 400, a PEG 500, a PEG 600, or a PEG about 30% to about 40% by weight of a glyceryl monoli 700. noleate, and about 11% to about 15% of polyethylene glycol, In another embodiment, a semi-solid formulation com 40 and about 3% to about 5% of propylene glycol. In still prises a therapeutic compound, a hard fat, a partially another aspect of this embodiment, a semi-solid formulation hydrogenated fat, a polyethylene glycol, and a propylene comprises about 25% to about 44% by weight of therapeutic glycol. In an aspect of this embodiment, a semi-solid for compound, about 12% to about 14% by weight of a mixture mulation comprises about 15% to about 55% by weight of of mono-, di-, and triglycerides and PEG fatty acid esters, therapeutic compound, about 7% to about 20% by weight of 45 about 32% to about 39% by weight of a glyceryl monoli hard fat, about 20% to about 50% by weight of partially noleate, about 12% to about 14% of polyethylene glycol, hydrogenated fat, about 7% to about 20% of polyethylene and about 4% of propylene glycol. In other aspects of this glycol, and about 1% to about 8% of propylene glycol. In embodiment, a polyethylene glycol is, e.g., a PEG 100, a another aspect of this embodiment, a semi-solid formulation PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, comprises about 20% to about 50% by weight of therapeutic 50 or a PEG 700. compound, about 8% to about 18% by weight of hard fat, In another embodiment, a semi-solid formulation com about 25% to about 45% by weight of partially-hydroge prises an ibuprofen, a mixture of mono-, di-, and triglycer nated fat, about 8% to about 18% of polyethylene glycol, ides and PEG fatty acid esters, a glyceryl monolinoleate, a and about 2% to about 6% of propylene glycol. In another polyethylene glycol, and a propylene glycol. In an aspect of aspect of this embodiment, a semi-solid formulation com 55 this embodiment, a semi-solid formulation comprises about prises about 20% to about 50% by weight of therapeutic 15% to about 55% by weight of an ibuprofen, about 7% to compound, about 10% to about 16% by weight of hard fat, about 20% by weight of a mixture of mono-, di-, and about 25% to about 45% by weight of partially-hydroge triglycerides and PEG fatty acid esters, about 20% to about nated fat, about 10% to about 16% of polyethylene glycol, 50% by weight of a glyceryl monolinoleate, about 7% to and about 2% to about 6% of propylene glycol. In yet 60 about 20% of polyethylene glycol, and about 1% to about another aspect of this embodiment, a semi-solid formulation 8% of propylene glycol. In another aspect of this embodi comprises about 20% to about 50% by weight of therapeutic ment, a semi-solid formulation comprises about 20% to compound, about 11% to about 15% by weight of hard fat, about 50% by weight of an ibuprofen, about 8% to about about 30% to about 40% by weight of partially-hydroge 18% by weight of a mixture of mono-, di-, and triglycerides nated fat, about 11% to about 15% of polyethylene glycol, 65 and PEG fatty acid esters, about 25% to about 45% by and about 3% to about 5% of propylene glycol. In still weight of a glyceryl monolinoleate, about 8% to about 18% another aspect of this embodiment, a semi-solid formulation of polyethylene glycol, and about 2% to about 6% of US 9,622,982 B2 45 46 propylene glycol. In another aspect of this embodiment, a of a salt of a therapeutic compound, about 7% to about 20% semi-solid formulation comprises about 20% to about 50% by weight of a mixture of mono-, di-, and triglycerides and by weight of an ibuprofen, about 10% to about 16% by PEG fatty acid esters, about 20% to about 50% by weight of weight of a mixture of mono-, di-, and triglycerides and PEG a glyceryl monolinoleate, about 7% to about 20% of poly fatty acid esters, about 25% to about 45% by weight of a ethylene glycol, and about 1% to about 8% of propylene glyceryl monolinoleate, about 10% to about 16% of poly glycol. In another aspect of this embodiment, a semi-solid ethylene glycol, and about 2% to about 6% of propylene formulation comprises about 15% to about 30% by weight glycol. In yet another aspect of this embodiment, a semi of a free acid of a therapeutic compound, about 1% to about solid formulation comprises about 20% to about 50% by 25% by weight of a salt of a therapeutic compound, about weight of an ibuprofen, about 11% to about 15% by weight 10 10% to about 16% by weight of a mixture of mono-, di-, and of a mixture of mono-, di-, and triglycerides and PEG fatty triglycerides and PEG fatty acid esters, about 25% to about acid esters, about 30% to about 40% by weight of a glyceryl 45% by weight of a glyceryl monolinoleate, about 10% to monolinoleate, and about 11% to about 15% of polyethylene about 16% of polyethylene glycol, and about 2% to about glycol, and about 3% to about 5% of propylene glycol. In 6% of propylene glycol. In yet another aspect of this still another aspect of this embodiment, a semi-solid formu 15 embodiment, a semi-solid formulation comprises about 15% lation comprises about 25% to about 44% by weight of an to about 30% by weight of a free acid of a therapeutic ibuprofen, about 12% to about 14% by weight of a mixture compound, about 1% to about 25% by weight of a salt of a of mono-, di-, and triglycerides and PEG fatty acid esters, therapeutic compound, about 11% to about 15% by weight about 32% to about 39% by weight of a glyceryl monoli of a mixture of mono-, di-, and triglycerides and PEG fatty noleate, about 12% to about 14% of polyethylene glycol, acid esters, about 30% to about 40% by weight of a glyceryl and about 4% of propylene glycol. In other aspects of this monolinoleate, and about 11% to about 15% of polyethylene embodiment, a polyethylene glycol is, e.g., a PEG 100, a glycol, and about 3% to about 5% of propylene glycol. In PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, still another aspect of this embodiment, a semi-solid formu or a PEG 700. lation comprises about 20% to about 24% by weight of a free In another embodiment, a semi-solid formulation com 25 acid of a therapeutic compound, about 5% to about 20% by prises a therapeutic compound, a hard fat, a partially weight of a salt of a therapeutic compound, about 12% to hydrogenated fat, a polyethylene glycol, and a propylene about 14% by weight of a mixture of mono-, di-, and glycol. In an aspect of this embodiment, a semi-solid for triglycerides and PEG fatty acid esters, about 32% to about mulation comprises about 10% to about 35% by weight of 39% by weight of a glyceryl monolinoleate, about 12% to a free acid of a therapeutic compound, about 1% to about 30 about 14% of polyethylene glycol, and about 4% of propyl 30% by weight of a salt of a therapeutic compound, about ene glycol. In other aspects of this embodiment, a polyeth 7% to about 20% by weight of hard fat, about 20% to about ylene glycol is, e.g., a PEG 100, a PEG 200, a PEG 300, a 50% by weight of partially-hydrogenated fat, about 7% to PEG 400, a PEG 500, a PEG 600, or a PEG 700. about 20% of polyethylene glycol, and about 1% to about In another embodiment, a semi-solid formulation com 8% of propylene glycol. In another aspect of this embodi 35 prises a cancer therapeutic, including, but not limited to, ment, a semi-solid formulation comprises about 15% to artemesinin or a derivative thereof, a mixture of mono-, di-, about 30% by weight of a free acid of a therapeutic com and triglycerides and PEG fatty acid esters, a glyceryl pound, about 1% to about 25% by weight of a salt of a monolinoleate, a polyethylene glycol, and a propylene gly therapeutic compound, about 10% to about 16% by weight col. In an aspect of this embodiment, a semi-solid formu of hard fat, about 25% to about 45% by weight of partially 40 lation comprises about 10% to about 35% by weight of a free hydrogenated fat, about 10% to about 16% of polyethylene acid of an ibuprofen, about 1% to about 30% by weight of glycol, and about 2% to about 6% of propylene glycol. In yet a salt of a cancer therapeutic, including, but not limited to, another aspect of this embodiment, a semi-solid formulation artemesinin or a derivative thereof, about 7% to about 20% comprises about 15% to about 30% by weight of a free acid by weight of a mixture of mono-, di-, and triglycerides and of a therapeutic compound, about 1% to about 25% by 45 PEG fatty acid esters, about 20% to about 50% by weight of weight of a salt of a therapeutic compound, about 11% to a glyceryl monolinoleate, about 7% to about 20% of poly about 15% by weight of hard fat, about 30% to about 40% ethylene glycol, and about 1% to about 8% of propylene by weight of partially-hydrogenated fat, about 11% to about glycol. In another aspect of this embodiment, a semi-solid 15% of polyethylene glycol, and about 3% to about 5% of formulation comprises about 15% to about 30% by weight propylene glycol. In still another aspect of this embodiment, 50 of a free acid of a cancer therapeutic, including, but not a semi-solid formulation comprises about 20% to about 24% limited to, artemesinin or a derivative thereof, about 1% to by weight of a free acid of a therapeutic compound, about about 25% by weight of a salt of a cancer therapeutic, 5% to about 20% by weight of a salt of a therapeutic including, but not limited to, artemesinin or a derivative compound, about 12% to about 14% by weight of hard fat, thereof, about 10% to about 16% by weight of a mixture of about 32% to about 39% by weight of partially-hydroge 55 mono-, di-, and triglycerides and PEG fatty acid esters, nated fat, about 12% to about 14% of polyethylene glycol, about 25% to about 45% by weight of a glyceryl monoli and about 4% of propylene glycol. In other aspects of this noleate, about 10% to about 16% of polyethylene glycol, embodiment, a polyethylene glycol is, e.g., a PEG 100, a and about 2% to about 6% of propylene glycol. In yet PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, another aspect of this embodiment, a semi-solid formulation or a PEG 700. 60 comprises about 15% to about 30% by weight of a free acid In another embodiment, a semi-solid formulation com of a cancer therapeutic, including, but not limited to, arte prises a therapeutic compound, a mixture of mono-, di-, and mesinin or a derivative thereof, about 1% to about 25% by triglycerides and PEG fatty acid esters, a glyceryl monoli weight of a salt of an ibuprofen, about 11% to about 15% by noleate, a polyethylene glycol, and a propylene glycol. In an weight of a mixture of mono-, di-, and triglycerides and PEG aspect of this embodiment, a semi-solid formulation com 65 fatty acid esters, about 30% to about 40% by weight of a prises about 10% to about 35% by weight of a free acid of glyceryl monolinoleate, and about 11% to about 15% of a therapeutic compound, about 1% to about 30% by weight polyethylene glycol, and about 3% to about 5% of propylene US 9,622,982 B2 47 48 glycol. In still another aspect of this embodiment, a semi temperature in the range of, e.g., about 22°C. to about 26° solid formulation comprises about 20% to about 24% by C., about 24°C. to about 28°C., about 26°C. to about 30° weight of a free acid of a cancer therapeutic, including, but C., about 28°C. to about 32°C., or about 30° C. to about 34° not limited to, artemesinin or a derivative thereof, about 5% C. to about 20% by weight of a salt of a cancer therapeutic, In one embodiment, a liquid formulation comprises a including, but not limited to, artemesinin or a derivative therapeutic compound, a glycol ether, a partially-hydroge thereof, about 12% to about 14% by weight of a mixture of nated fat, an oil, and an alcohol. In an aspect of this mono-, di-, and triglycerides and PEG fatty acid esters, embodiment, a liquid formulation comprises about 15% to about 32% to about 39% by weight of a glyceryl monoli about 35% by weight of therapeutic compound, about 5% to noleate, about 12% to about 14% of polyethylene glycol, 10 about 25% by weight of glycol ether, about 15% to about and about 4% of propylene glycol. In other aspects of this 40% by weight of partially-hydrogenated fat, about 15% to embodiment, a polyethylene glycol is, e.g., a PEG 100, a about 40% of an oil, and about 1% to about 15% of an PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, alcohol. In another aspect of this embodiment, a liquid or a PEG 700. formulation comprises about 20% to about 30% by weight A solid or semi-solid formulation disclosed herein takes 15 of therapeutic compound, about 10% to about 20% by advantage of the different melting point temperatures of the weight of glycol ether, about 20% to about 35% by weight various adjuvants like fatty acids. Formation of a solid or of partially-hydrogenated fat, about 20% to about 35% of an semi-solid dosage form can be by modifying the respective oil, and about 2% to about 10% of an alcohol. In yet another concentrations of the fatty acids comprising a pharmaceu aspect of this embodiment, a liquid formulation comprises tical composition disclosed herein. For example, linolenic about 23% to about 27% by weight of therapeutic com acid has a melting point temperature (T) of about -11° C. pound, about 13% to about 17% by weight of glycol ether, linoleic acid has a T of about -5°C., oleic acid has a T. about 25% to about 30% by weight of partially-hydroge of about 16°C., palmitic acid has a T of about 61-62°C., nated fat, about 25% to about 30% of an oil, and about 4% and Stearic acid has a T of about 67-72°C. Increasing the to about 8% of an alcohol. In still another aspect of this proportion(s) of palmitic, Stearic or oleic acid would 25 embodiment, a liquid formulation comprises about 24% to increase the overall melting temperature of a composition, about 26% by weight of therapeutic compound, about 14% while, conversely, increasing the proportion(s) of linoleic to about 16% by weight of glycol ether, about 26% to about and linolenic acid would decrease the melting temperature 28% by weight of partially-hydrogenated fat, about 26% to of a composition. Thus, by controlling the types and about 28% of an oil, and about 5% to about 7% of an amounts of the adjuvant components added, a pharmaceu 30 alcohol. In other aspects of this embodiment, an oil is tical composition disclosed herein can be made that is rapeseed oil or theobroma oil. substantially solid or semi-solid at room temperature, but In another embodiment, a liquid formulation comprises a melts when it is ingested, and reaches body temperature. The therapeutic compound, a glycol ether, a glyceryl monoli resulting melted composition readily forms micelles which noleate, an oil, and an alcohol. In an aspect of this embodi are absorbed by the intestine, assembled into chylomicrons, 35 ment, a liquid formulation comprises about 15% to about and ultimately absorbed by macrophages. The Solid dosage 35% by weight of therapeutic compound, about 5% to about form may be a powder, granule, tablet, capsule or Supposi 25% by weight of glycol ether, about 15% to about 40% by tory. weight of glyceryl monolinoleate, about 15% to about 40% In an embodiment, a pharmaceutical composition dis of an oil, and about 1% to about 15% of an alcohol. In closed herein is solid at room temperature. In aspects of this 40 another aspect of this embodiment, a liquid formulation embodiment, a pharmaceutical composition disclosed herein comprises about 20% to about 30% by weight of therapeutic may be formulated to be a solid at a temperature of, e.g., compound, about 10% to about 20% by weight of glycol about 35° C. or lower, about 33° C. or lower, about 31° C. ether, about 20% to about 35% by weight of glyceryl or lower, about 29° C. or lower, about 27°C. or lower, about monolinoleate, about 20% to about 35% of an oil, and about 25°C. or lower, about 23°C. or lower, about 21°C. or lower, 45 2% to about 10% of an alcohol. In yet another aspect of this about 19° C. or lower, about 17° C. or lower, about 15° C. embodiment, a liquid formulation comprises about 23% to or lower, about 12°C. or lower, about 10° C. or lower, about about 27% by weight of therapeutic compound, about 13% 8° C. or lower, about 6° C. or lower, about 4° C. or lower, to about 17% by weight of glycol ether, about 25% to about or about 0° C. or lower. 30% by weight of glyceryl monolinoleate, about 25% to In other aspects of this embodiment, a pharmaceutical 50 about 30% of an oil, and about 4% to about 8% of an composition disclosed has a melting point temperature of alcohol. In still another aspect of this embodiment, a liquid e.g., 5° C. or higher, 10°C. or higher, 15° C. or higher, 22 formulation comprises about 24% to about 26% by weight C. or higher, 23° C. or higher, 24°C. or higher, 25° C. or of therapeutic compound, about 14% to about 16% by higher, 26°C. or higher, 27°C. or higher, 28°C. or higher, weight of glycol ether, about 26% to about 28% by weight 29° C. or higher, 30° C. or higher, 31° C. or higher, 32° C. 55 of glyceryl monolinoleate, about 26% to about 28% of an or higher, 33° C. or higher, 34° C. or higher, or 35° C. or oil, and about 5% to about 7% of an alcohol. In other aspects higher. In other aspects of this embodiment, a pharmaceu of this embodiment, an oil is rapeseed oil or theobroma oil. tical composition disclosed has a melting point temperature In another embodiment, a liquid formulation comprises an in the range of, e.g., about 5° C. to about 24°C., about 10° ibuprofen, a diethylene glycol monoethyl ether, a glyceryl C. to about 24° C. about 22°C. to about 24°C., about 23° 60 monolinoleate, an oil, and an alcohol. In an aspect of this C. to about 25°C., about 24°C. to about 26°C., about 25° embodiment, a liquid formulation comprises about 15% to C. to about 27°C., about 26°C. to about 28°C., about 27° about 35% by weight of an ibuprofen, about 5% to about C. to about 29° C., about 28°C. to about 30° C., about 29° 25% by weight of diethylene glycol monoethyl ether, about C. to about 31° C., about 30° C. to about 32° C., about 31° 15% to about 40% by weight of glyceryl monolinoleate, C. to about 33°C., about 32° C. to about 34°C., or about 33° 65 about 15% to about 40% of an oil, and about 1% to about C. to about 35° C. In other aspects of this embodiment, a 15% of an alcohol. In another aspect of this embodiment, a pharmaceutical composition disclosed has a melting point liquid formulation comprises about 20% to about 30% by US 9,622,982 B2 49 50 weight of an ibuprofen, about 10% to about 20% by weight about 3% to about 7% by weight of an ibuprofen, about 2% of diethylene glycol monoethyl ether, about 20% to about to about 6% by weight of an ethyl acetate, and about 87% 35% by weight of glyceryl monolinoleate, about 20% to to about 95% of an oil. In still another aspect of this about 35% of an oil, and about 2% to about 10% of an embodiment, a liquid formulation comprises about 4% to alcohol. In yet another aspect of this embodiment, a liquid 5 about 6% by weight of an ibuprofen, about 3% to about 5% formulation comprises about 23% to about 27% by weight by weight of an ethyl acetate, and about 90% to about 92% of an ibuprofen, about 13% to about 17% by weight of of an oil. In other aspects of this embodiment, an ibuprofen diethylene glycol monoethyl ether, about 25% to about 30% may be a free acid of a salt of ibuprofen. In other aspects of by weight of glyceryl monolinoleate, about 25% to about this embodiment, an oil is rapeseed oil or theobroma oil. 30% of an oil, and about 4% to about 8% of an alcohol. In 10 In one embodiment, a Solid or semi-solid formulation still another aspect of this embodiment, a liquid formulation disclosed herein is formulated without a hydrophilic solvent comprises about 24% to about 26% by weight of an ibu like water. Such formulations result in the formation of profen, about 14% to about 16% by weight of diethylene co-crystals of the lipids and therapeutic compound. Stated glycol monoethyl ether, about 26% to about 28% by weight another way, Such formulations do not form liposomal of glyceryl monolinoleate, about 26% to about 28% of an 15 emulsions and/or micellular particles, which require hydro oil, and about 5% to about 7% of an alcohol. In other aspects philic solvent. of this embodiment, an ibuprofen may be a free acid of a salt In one embodiment, a solid formulation comprises a of ibuprofen. In other aspects of this embodiment, an oil is therapeutic compound, a hard fat, a partially-hydrogenated rapeseed oil or theobroma oil. fat, and a polyethylene glycol. In an aspect of this embodi In one embodiment, a liquid formulation comprises a ment, a solid formulation comprises about 1% to about 30% therapeutic compound, an ester of an alcohol, and an oil. In by weight of therapeutic compound, about 8% to about 70% an aspect of this embodiment, a liquid formulation com by weight of hard fat, about 2% to about 65% by weight of prises about 1% to about 10% by weight of therapeutic partially-hydrogenated fat, and about 1% to about 15% of compound, about 1% to about 10% by weight of an ester of polyethylene glycol. In another aspect of this embodiment, an alcohol, and about 80% to about 98% of an oil. In another 25 a solid formulation comprises about 10% to about 30% by aspect of this embodiment, a liquid formulation comprises weight of therapeutic compound, about 20% to about 50% about 2% to about 8% by weight of therapeutic compound, by weight of hard fat, about 10% to about 30% by weight of about 1% to about 7% by weight of an ester of an alcohol, partially-hydrogenated fat, and about 5% to about 15% of and about 85% to about 97% of an oil. In yet another aspect polyethylene glycol. In yet another aspect of this embodi of this embodiment, a liquid formulation comprises about 30 ment, a solid formulation comprises about 20% to about 3% to about 7% by weight of therapeutic compound, about 30% by weight of therapeutic compound, about 30% to 2% to about 6% by weight of an ester of an alcohol, and about 50% by weight of hard fat, about 10% to about 30% about 87% to about 95% of an oil. In still another aspect of by weight of partially-hydrogenated fat, and about 7% to this embodiment, a liquid formulation comprises about 4% about 13% of polyethylene glycol. In still another aspect of to about 6% by weight of therapeutic compound, about 3% 35 this embodiment, a solid formulation comprises about 20% to about 5% by weight of an ester of an alcohol, and about to about 30% by weight of therapeutic compound, about 90% to about 92% of an oil. In other aspects of this 35% to about 50% by weight of hard fat, about 15% to about embodiment, an oil is rapeseed oil or theobroma oil. 25% by weight of partially-hydrogenated fat, and about 7% In another embodiment, a liquid formulation comprises a to about 13% of polyethylene glycol. In a further aspect of therapeutic compound, an ethyl acetate, and an oil. In an 40 this embodiment, a solid formulation comprises about 23% aspect of this embodiment, a liquid formulation comprises to about 27% by weight of therapeutic compound, about about 1% to about 10% by weight of therapeutic compound, 41% to about 47% by weight of hard fat, about 18% to about about 1% to about 10% by weight of an ethyl acetate, and 22% by weight of partially-hydrogenated fat, and about 9% about 80% to about 98% of an oil. In another aspect of this to about 11% of polyethylene glycol. In other aspects of this embodiment, a liquid formulation comprises about 2% to 45 embodiment, a polyethylene glycol is, e.g., a PEG 100, a about 8% by weight of therapeutic compound, about 1% to PEG 200, a PEG 300, a PEG 400, a PEG 500, a PEG 600, about 7% by weight of an ethyl acetate, and about 85% to or a PEG 700. about 97% of an oil. In yet another aspect of this embodi In another embodiment, a solid formulation comprises a ment, a liquid formulation comprises about 3% to about 7% therapeutic compound, a mixture of mono-, di-, and triglyc by weight of therapeutic compound, about 2% to about 6% 50 erides and PEG fatty acid esters, a glyceryl monolinoleate, by weight of an ethyl acetate, and about 87% to about 95% and a polyethylene glycol. In an aspect of this embodiment, of an oil. In still another aspect of this embodiment, a liquid a solid formulation comprises about 1% to about 30% by formulation comprises about 4% to about 6% by weight of weight of therapeutic compound, about 8% to about 70% by therapeutic compound, about 3% to about 5% by weight of weight of a mixture of mono-, di-, and triglycerides and PEG an ethyl acetate, and about 90% to about 92% of an oil. In 55 fatty acid esters, about 2% to about 65% by weight of a other aspects of this embodiment, an oil is rapeseed oil or glyceryl monolinoleate, and about 1% to about 15% of theobroma oil. polyethylene glycol. In another aspect of this embodiment, In another embodiment, a liquid formulation comprises an a solid formulation comprises about 10% to about 30% by ibuprofen, an ethyl acetate, and an oil. In an aspect of this weight of therapeutic compound, about 20% to about 50% embodiment, a liquid formulation comprises about 1% to 60 by weight of a mixture of mono-, di-, and triglycerides and about 10% by weight of an ibuprofen, about 1% to about PEG fatty acid esters, about 10% to about 30% by weight of 10% by weight of an ethyl acetate, and about 80% to about a glyceryl monolinoleate, and about 5% to about 15% of 98% of an oil. In another aspect of this embodiment, a liquid polyethylene glycol. In yet another aspect of this embodi formulation comprises about 2% to about 8% by weight of ment, a solid formulation comprises about 20% to about an ibuprofen, about 1% to about 7% by weight of an ethyl 65 30% by weight of therapeutic compound, about 30% to acetate, and about 85% to about 97% of an oil. In yet another about 50% by weight of a mixture of mono-, di-, and aspect of this embodiment, a liquid formulation comprises triglycerides and PEG fatty acid esters, about 10% to about US 9,622,982 B2 51 52 30% by weight of a glyceryl monolinoleate, and about 7% A pharmaceutical composition disclosed herein may com to about 13% of polyethylene glycol. In still another aspect prise a therapeutic compound in a therapeutically effective of this embodiment, a solid formulation comprises about amount. As used herein, the term “effective amount” is 20% to about 30% by weight of therapeutic compound, synonymous with “therapeutically effective amount', about 35% to about 50% by weight of a mixture of mono-, “effective dose', or “therapeutically effective dose” and di-, and triglycerides and PEG fatty acid esters, about 15% when used in reference to reducing or maintaining a cancer to about 25% by weight of a glyceryl monolinoleate, and cell population and/or tumor cell size in an individual refers about 7% to about 13% of polyethylene glycol. In a further to the minimum dose of a therapeutic compound disclosed aspect of this embodiment, a solid formulation comprises herein necessary to achieve the desired therapeutic effect 10 and includes a dose sufficient to reduce or maintain of cancer about 23% to about 27% by weight of therapeutic com cell population and/or tumor cell size in an individual. The pound, about 41% to about 47% by weight of a mixture of effectiveness of a therapeutic compound disclosed herein mono-, di-, and triglycerides and PEG fatty acid esters, capable of reducing or maintaining a cancer cell population about 18% to about 22% by weight of a glyceryl monoli and/or tumor cell size in an individual can be determined by noleate, and about 9% to about 11% of polyethylene glycol. 15 observing an improvement in an individual based upon one In other aspects of this embodiment, a polyethylene glycol or more clinical symptoms, and/or physiological indicators is, e.g., a PEG 100, a PEG 200, a PEG 300, a PEG 400, a associated with reducing or maintaining a cancer cell popu PEG 500, a PEG 600, or a PEG 700. lation and/or tumor cell size in an individual. Maintenance In an embodiment, an artemesinin or a derivative thereof, or a reduction of cancer cell population and/or tumor cell is linked to an estrogen receptor modulator, including, size can be indicated by a reduced need for a concurrent without limitation, a selective estrogen receptor modulator. therapy. The effectiveness of a therapeutic compound dis In an embodiment the linkage is covalent bond. In a further closed herein capable of reducing or maintaining a cancer embodiment, the linkage is an ionic bond or a non-covalent cell population and/or tumor cell size in an individual can be bond. In an embodiment an artemesinin or a derivative determined by observing an improvement in an individual thereof, is linked to an estrogen receptor modulator, includ 25 based upon one or more clinical symptoms, and/or physi ing, without limitation, a selective estrogen receptor modu ological indicators associated with a reduction or mainte lator by a linker. In a further embodiment, the linker is a nance of cancer cell population and/or tumor cell size. chemical linker. In an embodiment the linker is synthetic, The appropriate effective amount of a therapeutic com semisynthetic or derived from a natural product. pound disclosed herein to be administered to reduce or Aspects of the present specification disclose, in part, 30 maintain of a cancer cell population and/or tumor cell size reduction or maintenance of cancer cell population and/or in an individual condition can be determined by a person of tumor cell size in an individual. As used herein, the term ordinary skill in the art by taking into account factors, “treating.” refers to reduction or maintenance of cancer cell including, without limitation, the measured number of can population and/or tumor cell size in an individual. For cer cells in blood samples or biopsies or CAT scans, PET example, the term “treating can mean reduction or main 35 scans, NMR and/or sonagrams taken from or of the indi tenance of cancer cell population and/or tumor cell size vidual, the particular characteristics, history and risk factors levels in an individual by, e.g., at least 20%, at least 25%, at of the patient, Such as, e.g., age, weight, general health and least 30%, at least 35%, at least 40%, at least 45%, at least the like, or any combination thereof. Additionally, where 50%, at least 55%, at least 60%, at least 65%, at least 70%, repeated administration of a therapeutic compound is used, at least 75%, at least 80%, at least 85%, at least 90% at least 40 an effective amount of a therapeutic compound will further 95%, or at least 100%. The actual symptoms associated with depend upon factors, including, without limitation, the fre cancer, including the detection of cancer cell population quency of administration, the half-life of the therapeutic and/or tumor cell size are well known and can be determined compound, or any combination thereof. In is known by a by a person of ordinary skill in the art by using commonly person of ordinary skill in the art that an effective amount of known testing means, including blood tests, CT scans son 45 atherapeutic compound disclosed herein can be extrapolated agrams and other tests known to those of ordinary skill. from in vitro assays and in vivo administration studies using Those of skill in the art will know the appropriate symptoms animal models prior to administration to humans or animals. or indicators associated with cancer and will know how to Wide variations in the necessary effective amount are to determine if an individual is a candidate for treatment as be expected in view of the differing efficiencies of the disclosed herein. 50 various routes of administration. For instance, oral admin A composition or compound is administered to an indi istration of a therapeutic compound disclosed herein gener vidual. An individual is typically a human being, but can be ally would be expected to require higher dosage levels than an animal, including, but not limited to, dogs, cats, birds, administration by inhalation. Similarly, systemic adminis cattle, horses, sheep, goats, reptiles and other animals, tration of a therapeutic compound disclosed herein would be whether domesticated or not. Typically, any individual who 55 expected to require higher dosage levels than a local admin is a candidate for treatment is a candidate with some form of istration. Variations in these dosage levels can be adjusted cancer, whether the cancer is benign or malignant, a tumor, using standard empirical routines of optimization, which are Solid or otherwise, a cancer call not located in a tumor or well-known to a person of ordinary skill in the art. The Some other form of cancer. Among the most common types precise therapeutically effective dosage levels and patterns of cancer include, but are not limited to, bladder cancer, 60 are preferably determined by the attending physician in breast cancer, colon and rectal cancer, endometrial cancer, consideration of the above-identified factors. One skilled in kidney cancer, renal cancer, leukemia, lung cancer, mela the art will recognize that the condition of the individual can noma, non-Hodgkins lymphoma, pancreatic cancer, prostate be monitored throughout the course of therapy and that the cancer, stomach cancer and thyroid cancer. Pre-operative effective amount of a therapeutic compound disclosed herein evaluation typically includes routine history and physical 65 that is administered can be adjusted accordingly. examination in addition to thorough informed consent dis In an embodiment, in instances in which each of the closing all relevant risks and benefits of the procedure. therapeutic compounds themselves are administered, with US 9,622,982 B2 53 54 out limitation, as individual or separate dosage forms (e.g., In aspects of this embodiment, a therapeutically effective capsules or tablets), the kit comprises, without limitation, amount of a therapeutic compound disclosed herein reduces each of the therapeutic compounds making up the compo or maintains a cancer cell population and/or tumor cell size sition of the invention, along with instructions for use. In an in an individual by, e.g., at least 10%, at least 15%, at least additional embodiment, the therapeutic compound compo- 5 20%, at least 25%, at least 30%, at least 35%, at least 40%, nents, without limitation, may be packaged in any manner at least 45%, at least 50%, at least 55%, at least 60%, at least Suitable for administration, so long as the packaging, when 65%, at least 70%, at least 75%, at least 80%, at least 85%, considered along with the instructions for administration, at least 90%, at least 95% or at least 100%. In other aspects without limitation, clearly indicates the manner in which of this embodiment, a therapeutically effective amount of a each of the therapeutic compound components is to be 10 therapeutic compound disclosed herein reduces or maintains administered. In a further embodiment, each of the thera a cancer cell population and/or tumor cell size in an indi peutic compounds or a combination of Such therapeutic vidual by, e.g., at most 10%, at most 15%, at most 20%, at compounds may, without limitation, be combined into a most 25%, at most 30%, at most 35%, at most 40%, at most single administrable dosage form Such as a capsule, tablet, 45%, at most 50%, at most 55%, at most 60%, at most 65%, or other solid or liquid formulation. The therapeutic com- 15 at most 70%, at most 75%, at most 80%, at most 85%, at pound can be provided to an individual in a package. The most 90%, at most 95% or at most 100%. In yet other aspects package can be a container, for instance, without limitation, of this embodiment, a therapeutically effective amount of a a bottle, a canister, a tube or other enclosed vessel. The therapeutic compound disclosed herein reduces or maintains package can also be a packet. Such as a blister pack. a cancer cell population and/or tumor cell size in an indi In an embodiment, the individual or separate dosage is in 20 vidual by, e.g., about 10% to about 100%, about 10% to the form of a blister pack. In an aspect of this embodiment, about 90%, about 10% to about 80%, about 10% to about a blister pack is a term for several types of pre-formed 70%, about 10% to about 60%, about 10% to about 50%, plastic packaging used for Small consumer goods, foods, and about 10% to about 40%, about 20% to about 100%, about for pharmaceuticals. In a further embodiment, a blister pack 20% to about 90%, about 20% to about 80%, about 20% to is comprised of a cavity or pocket made from a formable 25 about 20%, about 20% to about 60%, about 20% to about web, usually a thermoformed plastic and typically includes 50%, about 20% to about 40%, about 30% to about 100%, a backing of paperboard or a lidding seal of aluminum foil about 30% to about 90%, about 30% to about 80%, about or plastic. In a further embodiment, a blister that folds onto 30% to about 70%, about 30% to about 60%, or about 30% itself is a clamshell. In an aspect of this embodiment, a to about 50%. blister pack is commonly used as unit-dose packaging for 30 In other aspects of this embodiment, a therapeutically pharmaceutical tablets, capsules or lozenges. In an embodi effective amount of a therapeutic compound disclosed herein ment, a blister pack can provide barrier protection for shelf generally is in the range of about 0.001 mg/kg/day to about life requirements, and a degree of tamper resistance and can 100 mg/kg/day. In aspects of this embodiment, an effective be used for packing physician samples of therapeutic com amount of a therapeutic compound disclosed herein may be, pound products or for Over The Counter (OTC) products in 35 e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at the pharmacy. least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 In an embodiment, an individual is provided a treatment mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at protocol wherein a pharmaceutical composition is adminis least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 tered on a periodic schedule, wherein the individual is mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at informed by electronic notification to administer the thera- 40 least 45 mg/kg/day, or at least 50 mg/kg/day. In other aspects peutic compound so that the individual is reminded to take of this embodiment, an effective amount of a therapeutic the therapeutic compound on a period schedule. In an aspect compound disclosed herein may be in the range of, e.g., of this embodiment, the electronic notification is by email, about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 text, instant messaging or by another electronic notification mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to method. In an embodiment, an individual is informed to 45 about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 administer the therapeutic compound on a period schedule mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, through receipt of a telephone call, postal mail, overnight about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 express (including, without limitation, FedEx and UPS) or mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to other method of notification. about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 In an embodiment, the effectiveness of a cancer thera- 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, peutic to kill cancer cells or reduce tumor size is enhanced or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet through the formulation of the cancer therapeutic with one other aspects of this embodiment, an effective amount of a or more fats as compared to the same cancer therapeutic not therapeutic compound disclosed herein may be in the range formulated in a fat. In a further embodiment, the effective of e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about ness of a cancer therapeutic to kill cancer cells or reduce 55 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/ tumor size is enhanced through the formulation of the cancer day to about 20 mg/kg/day, about 0.01 mg/kg/day to about therapeutic with one or more fats, wherein at least one fat is 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, a solid fat. In an embodiment, the effectiveness of a cancer about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 therapeutic to kill cancer cells or reduce tumor size is mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to enhanced through the formulation of the cancer therapeutic 60 about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 with one or more fats, wherein at least one fat is a liquid. In mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or an embodiment, the effectiveness of a cancer therapeutic, about 0.01 mg/kg/day to about 100 mg/kg/day. In still other including, without limitation, artemesinin and/or a deriva aspects of this embodiment, an effective amount of a thera tive thereof, to kill cancer cells or reduce tumor size is peutic compound disclosed herein may be in the range of enhanced through the formulation of the cancer therapeutic 65 e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 with one or more fats as compared to the same cancer mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to therapeutic not formulated in a fat. about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 US 9,622,982 B2 55 56 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, mg/day, about 150 mg/day to about 1,500 mg/day, about 200 about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/day to about 1,500 mg/day, about 250 mg/day to about mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to 1,500 mg/day, about 300 mg/day to about 1,500 mg/day, about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 about 350 mg/day to about 1,500 mg/day, about 400 mg/day mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or 5 to about 1,500 mg/day, about 450 mg/day to about 1,500 about 0.1 mg/kg/day to about 100 mg/kg/day. mg/day, about 500 mg/day to about 1,500 mg/day, about In other aspects of this embodiment, an effective amount 1,000 mg/day to about 3,000 mg/day, about 1,100 mg/day to of a therapeutic compound disclosed herein may be in the about 3,000 mg/day, about 1,200 mg/day to about 3,000 range of, e.g., about 1 mg/kg/day to about 10 mg/kg/day, mg/day, about 1,3000 mg/day to about 3,000 mg/day, about about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/ 10 1,400 mg/day to about 3,000 mg/day, about 1,500 mg/day to day to about 20 mg/kg/day, about 1 mg/kg/day to about 25 about 3,000 mg/day, about 1,600 mg/day to about 3,000 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about mg/day, about 1,700 mg/day to about 3,000 mg/day, about 1 mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to 1,800 mg/day to about 3,000 mg/day, about 1,900 mg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/ about 3,000 mg/day, or about 2,000 mg/day to about 3,000 day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 15 mg/day. mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to In other aspects of this embodiment, a therapeutically about 100 mg/kg/day. In yet other aspects of this embodi effective amount of a artemesinin and/or a derivative thereof ment, an effective amount of a therapeutic compound dis disclosed herein generally is in the range of about 0.001 closed herein may be in the range of, e.g., about 5 mg/kg/day mg/kg/day to about 100 mg/kg/day. In aspects of this to about 10 mg/kg/day, about 5 mg/kg/day to about 15 embodiment, an effective amount of a statin disclosed herein mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/ 5 mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/ 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to 25 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/ least 45 mg/kg/day, or at least 50 mg/kg/day. In other aspects day, or about 5 mg/kg/day to about 100 mg/kg/day. of this embodiment, an effective amount of a statin disclosed In other aspects of this embodiment, a therapeutically herein may be in the range of, e.g., about 0.001 mg/kg/day effective amount of a therapeutic compound disclosed herein to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 generally is in the range of about 1 mg/day to about 3,000 30 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, mg/day. In aspects of this embodiment, an effective amount about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 of a therapeutic compound disclosed herein may be, e.g., at mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to least 1 mg/day, at least 5 mg/day, at least 10 mg/day, at least about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 15 mg/day, at least 20 mg/day, at least 25 mg/day, at least 30 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, mg/day, at least 40 mg/day, at least 50 mg/day, at least 100 35 about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/day, at least 150 mg/day, at least 200 mg/day, at least 250 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day mg/day, at least 300 mg/day, at least 350 mg/day, at least 400 to about 100 mg/kg/day. In yet other aspects of this embodi mg/day, at least 450 mg/day, at least 500 mg/day, at least 550 ment, an effective amount of a statin disclosed herein may mg/day, at least 600 mg/day, at least 650 mg/day, at least 700 be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/day, at least 750 mg/day, at least 800 mg/day, at least 850 40 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, mg/day, at least 900 mg/day, at least 950 mg/day, at least about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 1,000 mg/day, at least 1,50 mg/day, at least 1,100 mg/day, at mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to least 1,150 mg/day, at least 1,200 mg/day, at least 1,250 about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/day, at least 1,300 mg/day, at least 1,350 mg/day, at least mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, 1,400 mg/day, at least 1,450 mg/day, at least 1,500 mg/day, 45 about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 at least 1,600 mg/day, at least 1,700 mg/day, at least 1,800 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to mg/day, at least 1,900 mg/day, at least 2,000 mg/day, at least about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 2,100 mg/day, at least 2,200 mg/day, at least 2,300 mg/day, mg/kg/day. In still other aspects of this embodiment, an at least 2,400 mg/day, at least 2,500 mg/day, at least 2,600 effective amount of a statin disclosed herein may be in the mg/day, at least 2,700 mg/day, at least 2,800 mg/day, at least 50 range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, 2.900 mg/day, or at least 3,000 mg/day. In yet other aspects about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 of this embodiment, an effective amount of a therapeutic mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to compound disclosed herein may be between, e.g., about 1 about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/day to about 1,000 mg/day, about 5 mg/day to about mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, 1,000 mg/day, about 10 mg/day to about 1,000 mg/day, 55 about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 about 15 mg/day to about 1,000 mg/day, about 20 mg/day to mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 1,000 mg/day, about 25 mg/day to about 1,000 about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/day, about 30 mg/day to about 1,000 mg/day, about 40 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day. mg/day to about 1,000 mg/day, about 50 mg/day to about In other aspects of this embodiment, an effective amount 1,000 mg/day, about 100 mg/day to about 1,000 mg/day, 60 of artemesinin and/or a derivative thereof disclosed herein about 150 mg/day to about 1,000 mg/day, about 200 mg/day may be in the range of, e.g., about 1 mg/kg/day to about 10 to about 1,000 mg/day, about 250 mg/day to about 1,000 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about mg/day, about 300 mg/day to about 1,000 mg/day, about 350 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to mg/day to about 1,000 mg/day, about 400 mg/day to about about 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/ 1,000 mg/day, about 450 mg/day to about 1,000 mg/day, 65 day, about 1 mg/kg/day to about 35 mg/kg/day, about 1 about 500 mg/day to about 1,000 mg/day, about 50 mg/day mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to to about 1,500 mg/day, about 100 mg/day to about 1,500 about 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/ US 9,622,982 B2 57 58 day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, mg/kg/day to about 100 mg/kg/day. In yet other aspects of at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 this embodiment, an effective amount of a statin disclosed mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at herein may be in the range of, e.g., about 5 mg/kg/day to least 45 mg/kg/day, or at least 50 mg/kg/day. In other aspects about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/ of this embodiment, in conjunction with aretemesinin and/or day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 a derivative thereof, a therapeutically effective amount of a mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to second, different cancer therapeutic may be in the range of about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/ e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/ mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to 10 day to about 20 mg/kg/day, about 0.001 mg/kg/day to about about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/ 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/ day, or about 5 mg/kg/day to about 100 mg/kg/day. day, about 0.001 mg/kg/day to about 35 mg/kg/day, about In other aspects of this embodiment, a therapeutically 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/ effective amount of artemesinin and/or a derivative thereof day to about 45 mg/kg/day, about 0.001 mg/kg/day to about disclosed herein generally is in the range of about 1 mg/day 15 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/ to about 3,000 mg/day. In aspects of this embodiment, an day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In effective amount of a statin disclosed herein may be, e.g., at yet other aspects of this embodiment, in conjunction with least 50 mg/day, at least 100 mg/day, at least 150 mg/day, at aretemesinin and/or a derivative thereof, a therapeutically least 200 mg/day, at least 250 mg/day, at least 300 mg/day, effective amount of a second, different cancer therapeutic at least 350 mg/day, at least 400 mg/day, at least 450 mg/day, may be in the range of, e.g., about 0.01 mg/kg/day to about at least 500 mg/day, at least 550 mg/day, at least 600 mg/day, 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, at least 650 mg/day, at least 700 mg/day, at least 750 mg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 at least 800 mg/day, at least 850 mg/day, at least 900 mg/day, mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to at least 950 mg/day, at least 1,000 mg/day, at least 1,50 about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/day, at least 1,100 mg/day, at least 1,150 mg/day, at least 25 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, 1,200 mg/day, at least 1,250 mg/day, at least 1,300 mg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 at least 1,350 mg/day, at least 1,400 mg/day, at least 1,450 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to mg/day, at least 1,500 mg/day, at least 1,600 mg/day, at least about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 1,700 mg/day, at least 1,800 mg/day, at least 1,900 mg/day, mg/kg/day. In still other aspects of this embodiment, in at least 2,000 mg/day, at least 2,100 mg/day, at least 2,200 30 conjunction with aretemesinin and/or a derivative thereof, a mg/day, at least 2,300 mg/day, at least 2,400 mg/day, at least therapeutically effective amount of a second, different can 2,500 mg/day, at least 2,600 mg/day, at least 2,700 mg/day, cer therapeutic herein may be in the range of, e.g., about 0.1 at least 2,800 mg/day, at least 2,900 mg/day, or at least 3,000 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to mg/day. In yet other aspects of this embodiment, an effective about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 amount of a statin disclosed herein may be between, e.g., 35 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 50 mg/day to about 1,000 mg/day, about 100 mg/day about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 to about 1,000 mg/day, about 150 mg/day to about 1,000 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to mg/day, about 200 mg/day to about 1,000 mg/day, about 250 about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/day to about 1,000 mg/day, about 300 mg/day to about mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, 1,000 mg/day, about 350 mg/day to about 1,000 mg/day, 40 about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 about 400 mg/day to about 1,000 mg/day, about 450 mg/day mg/kg/day to about 100 mg/kg/day. to about 1,000 mg/day, about 500 mg/day to about 1,000 Dosing can be single dosage or cumulative (serial dos mg/day, about 50 mg/day to about 1,500 mg/day, about 100 ing), and can be readily determined by one skilled in the art. mg/day to about 1,500 mg/day, about 150 mg/day to about For instance, reducing or maintaining a cancer cell popula 1,500 mg/day, about 200 mg/day to about 1,500 mg/day, 45 tion and/or tumor cell size in an individual may comprise a about 250 mg/day to about 1,500 mg/day, about 300 mg/day one-time administration of an effective dose of a pharma to about 1,500 mg/day, about 350 mg/day to about 1,500 ceutical composition disclosed herein. Alternatively, reduc mg/day, about 400 mg/day to about 1,500 mg/day, about 450 ing or maintaining a cancer cell population and/or tumor cell mg/day to about 1,500 mg/day, about 500 mg/day to about size in an individual may comprise multiple administrations 1,500 mg/day, about 1,000 mg/day to about 3,000 mg/day, 50 of an effective dose of a pharmaceutical composition carried about 1,100 mg/day to about 3,000 mg/day, about 1,200 out over a range of time periods, such as, e.g., once daily, mg/day to about 3,000 mg/day, about 1,3000 mg/day to twice daily, trice daily, once every few days, or once weekly. about 3,000 mg/day, about 1,400 mg/day to about 3,000 The timing of administration can vary from individual to mg/day, about 1,500 mg/day to about 3,000 mg/day, about individual, depending upon Such factors as the severity of an 1,600 mg/day to about 3,000 mg/day, about 1,700 mg/day to 55 individual’s symptoms. For example, an effective dose of a about 3,000 mg/day, about 1,800 mg/day to about 3,000 pharmaceutical composition disclosed herein can be admin mg/day, about 1,900 mg/day to about 3,000 mg/day, or about istered to an individual once daily for an indefinite period of 2,000 mg/day to about 3,000 mg/day. time, or until the individual no longer requires therapy. A In other aspects of this embodiment, in conjunction with person of ordinary skill in the art will recognize that the artemesinin and/or a derivative thereof, a therapeutically 60 condition of the individual can be monitored throughout the effective amount of a second, different cancer therapeutic is course of treatment and that the effective amount of a in the range of about 0.001 mg/kg/day to about 100 mg/kg/ pharmaceutical composition disclosed herein that is admin day. In aspects of this embodiment, in conjunction with istered can be adjusted accordingly. aretemesinin and/or a derivative thereof, a therapeutically Various routes of administration can be useful for admin effective amount of a second, different cancer therapeutic 65 istering a therapeutic compound disclosed herein, according may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/ to a method for reducing and/or maintaining a cancer cell day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least population and/or tumor cell size in an individual. A phar US 9,622,982 B2 59 60 maceutical composition may be administered to an indi about 40% to about 70%, or about 50% to about 70% as vidual by any of a variety of means depending, e.g., on the compared to a patient not receiving the same treatment. specific therapeutic compound or composition used, or other 8. The pharmaceutical composition of embodiment 1, compound to be included in the composition, and the wherein the cancer therapeutic is an alkylating agent. history, risk factors and symptoms of the individual. As 9. The pharmaceutical composition of embodiment 8, Such, topical, enteral, oral, intravenous, Subcutaneous, intra wherein the alkylating agent is Cisplatin, carboplatin, nasal, rectal, vaginal, intramuscular or parenteral routes of mechlorethamine, cyclophosphamide, chlorambucil, ifos administration may be suitable for reducing or maintaining famide and/or oxaliplatin. a cancer cell population and/or tumor cell size in an indi 10. The pharmaceutical composition of embodiment 1, 10 wherein the cancer therapeutic is an anti-metabolite. vidual as disclosed herein and such routes include both local 11. The pharmaceutical composition of embodiment 10, and systemic delivery of a therapeutic compound or com wherein the anti-metabolite is azathioprine and/or mer position disclosed herein. Compositions comprising either a captopurine. single therapeutic compound disclosed herein, or two or 12. The pharmaceutical composition of embodiment 10, more therapeutic compounds disclosed herein are intended 15 wherein the anti-metabolite is a synthetic, semisynthetic for inhaled, topical, intranasal, oral, Subcutaneous, Sublin or derivative of an anti-metabolite. gual, intravenous, rectal and/or vaginal use may be prepared 13. The pharmaceutical composition of embodiment 1, according to any method known to the art for the manufac wherein the cancer therapeutic is a terpenoid. ture of pharmaceutical compositions. A pharmaceutical 14. The pharmaceutical composition of embodiment 13, composition disclosed herein can be administered to an wherein the terpenoid is a Vinca alkaloid and/or a taxane. individual in a single formulation or in separate formula 15. The pharmaceutical composition of embodiment 14, tions, for combined, simultaneous or sequential administra wherein the Vinca alkaloid is Vincristine, Vinblastine, tion. Vinorelbine and/or Vindesine. Aspects of the present specification may also be described 16. The pharmaceutical composition of embodiment 14, as follows: 25 wherein the taxane is Taxol, Paclitaxel and/or Docetaxel. 1. A pharmaceutical composition comprising a cancer thera 17. The pharmaceutical composition of embodiment 14, peutic and a pharmaceutically acceptable lipid formula wherein the taxane is a synthetic, semisynthetic or deriva tion. tive of a taxane. 2. The pharmaceutical formulation of embodiment 1, 18. The pharmaceutical composition of embodiment 1, wherein the cancer therapeutic is Artemisnin. 30 wherein the cancer therapeutic is a topoisomerase. 3. The pharmaceutical formulation of embodiment 1, 19. The pharmaceutical composition of embodiment 18, wherein the cancer therapeutic is a derivative of Artem wherein the topoisomerase is a type I topoisomerase. esinin. 20. The pharmaceutical composition of embodiment 19, 4. The pharmaceutical formulation of embodiment 3, wherein the type 1 topoisomerase is camptothecins. wherein the derivative of Artemesinin is Artesunate, 35 21. The pharmaceutical composition of embodiment 20, Artemether, Dihydroartemisinin, Artelinic acid, Arteni wherein the campotothecins is irinotecan and/or topote mol and/or Artemotil. Ca 5. The pharmaceutical composition of embodiment 1, 22. The pharmaceutical composition of embodiment 18, wherein the composition includes a pharmaceutically wherein the topoisomerase is a type II topoisomerase. acceptable solvent, a pharmaceutically acceptable stabi 40 23. The pharmaceutical composition of embodiment 22, lizing agent, a pharmaceutically acceptable carrier and/or wherein the type II topoisomerase is amsacrine, etopo a pharmaceutically acceptable component. side, etoposide phosphate and/or teniposide. 6. The pharmaceutical composition of any proceeding 24. The pharmaceutical composition of any of embodiments embodiment, wherein the cancer therapeutic is capable of 18-23, wherein the topoisomerase is a synthetic, semi reducing the number of cancer cells or tumor size in an 45 synthetic and/or derivative. individual suffering from a cancer by, at least 10%, at least 25. The pharmaceutical composition of embodiment 24, 15%, at least 20%, at least 25%, at least 30%, at least wherein the derivative is epipodophyllotoxins. 35%, at least 40%, at least 45%, at least 50%, at least 26. The pharmaceutical composition of embodiment 1, 55%, at least 60%, at least 65%, at least 70%, at least wherein the cancer therapeutic is a cytotoxic antibiotic. 75%, at least 80%, at least 85%, at least 90% or at least 50 27. The pharmaceutical composition of embodiment 26, 95% as compared to a patient not receiving the same wherein the cytotoxic antibiotic is actinomycin, anthra treatment. cyclines, doxorubicin, daunorubicin, valrubicin, idarubi 7. The pharmaceutical composition of any proceeding cin, epirubicin, bleomycin, plicamycin and/or mitomycin. embodiment, wherein the cancer therapeutic is capable of 28. The pharmaceutical composition of embodiment 1, reducing the number of cancer cells or tumor size in an 55 wherein the cancer therapeutic is a hormone. individual suffering from a cancer by, about 10% to about 29. The pharmaceutical composition of embodiment 28, 100%, about 20% to about 100%, about 30% to about wherein the hormone is a lutenizing hormone releasing 100%, about 40% to about 100%, about 50% to about hormone agonist. 100%, about 60% to about 100%, about 70% to about 30. The pharmaceutical composition of embodiment 28, 100%, about 80% to about 100%, about 10% to about 60 wherein the hormone is leuprolidine, goserelin, triptore 90%, about 20% to about 90%, about 30% to about 90%, lin, histrelin, bicalutamide, flutamide and/or nilutamide. about 40% to about 90%, about 50% to about 90%, about 31. The pharmaceutical composition of embodiment 1, 60% to about 90%, about 70% to about 90%, about 10% wherein the cancer therapeutic is an antibody. to about 80%, about 20% to about 80%, about 30% to 32. The pharmaceutical composition of embodiment 31, about 80%, about 40% to about 80%, about 50% to about 65 wherein the antibody is Abciximab, Adalimumab, Alem 80%, or about 60% to about 80%, about 10% to about tuzumab, Atlizumab, Basiliximab, Belimumab, Bevaci 70%, about 20% to about 70%, about 30% to about 70%, Zumab, Bretuximab vedotin, Canakinumab, Cetuximab, US 9,622,982 B2 61 62 Ceertolizumab pegol, Daclizumab, Denosumab, Eculi administered to an individual at the same time as a second Zumab, Efalizumab, Gemtuzumab, Golimumab, Golim therapeutic compound is administered to the individual. umab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, 44. The pharmaceutical composition of any of the preceding Muromonab-CD3, Natalizumab, Ofatumumab, Omali embodiments, wherein the first therapeutic compound is a Zumab, Palivizumab, Panitumuab, Ranibizumab, Ritux artemesinin or derivative thereof and the second thera imab, Tocilizumab, Tositumomab and/or Trastuzumab. peutic compound is a different derivative of artemesinin. 33. The pharmaceutical composition of embodiment 3, 45. The pharmaceutical composition of any of the preceding wherein the derivative is a butyrate ester of dihydroarte embodiments, wherein the first therapeutic compound is mesinin. artemesinin or a derivative thereof and the second thera 10 peutic compound is a cancer therapeutic that is not 34. The pharmaceutical composition of any of the preceding artemesinin or a derivative thereof. embodiments, wherein the cancer therapeutic has a half 46. The pharmaceutical composition of any of the preceding life of one hour. embodiments, wherein the pharmaceutical composition is 35. The pharmaceutical composition of any of the preceding a liquid, a sold and/or a semi-solid. embodiments, wherein the dosing of the cancer therapeu 15 47. The pharmaceutical composition of embodiment 46, tic is daily. wherein, the pharmaceutical composition is provided to 36. The pharmaceutical composition of any of the preceding an individual in a capsule, tablet, pill, lozenge, powder embodiments, wherein the cancer therapeutic has a half and/or granule. life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 48. The pharmaceutical composition of embodiment 46, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, wherein the pharmaceutical composition is inhaled. 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 49. The pharmaceutical composition of embodiment 1, hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 wherein the pharmaceutical composition is formulated in days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 an oil-in-water emulsion. weeks, 3 weeks, 4 weeks, one month, two months, three 50. The pharmaceutical composition of embodiment 49, months and/or four months. 25 wherein the oil is a vegetable oil, an animal fat and/or a 37. The pharmaceutical composition of any of the preceding mineral oil. embodiments, wherein the cancer therapeutic is adminis 51. The pharmaceutical composition of embodiment 1, tered to an individual for a period of time followed by a wherein the pharmaceutical composition is released in a separate period of time. controlled release profile over time. 38. The pharmaceutical composition of any of the preceding 30 52. The pharmaceutical composition of embodiment 1, embodiments, wherein the cancer therapeutic is adminis wherein the pharmaceutical composition is provided in an tered for a first period and a second period following the extended release therapeutic compound delivery form. first period, with administration stopped during the sec 53. The pharmaceutical composition of embodiment 1, ond period, followed by a third period where administra wherein the pharmaceutical composition is provided in a tion of the therapeutic compound is started and then a 35 Sustained release therapeutic compound deliver form. fourth period following the third period where adminis 54. The pharmaceutical composition of embodiment 53, tration is stopped. wherein the Sustained release therapeutic compound 39. The pharmaceutical composition of any of the preceding delivery platform releases a therapeutic compound with embodiments, wherein the cancer therapeutic is adminis substantially Zero order release kinetics over a period of tered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 40 about 7 days after administration, about 15 days after days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, administration, about 30 days after administration, about 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 45 days after administration, about 60 days after admin weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, istration, about 75 days after administration and/or about 5 months, 6 months, 7 months, 8 months, 9 months, 10 90 days after administration. months, 11 months, 12 months, or more. In a further 45 55. The pharmaceutical composition of embodiment 53, embodiment, a period of during which administration is wherein the Sustained release therapeutic compound stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, delivery platform releases a therapeutic compound with 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, substantially Zero order release kinetics over a period of 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 at least 7 days after administration, at least 15 days after weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 50 administration, at least 30 days after administration, at 5 months, 6 months, 7 months, 8 months, 9 months, 10 least 45 days after administration, at least 60 days after months, 11 months and/or 12 months. administration, at least 75 days after administration, or at 40. The pharmaceutical composition of any of the preceding least 90 days after administration. embodiments, wherein a first cancer therapeutic S admin 56. The pharmaceutical composition of embodiment 53, istered to an individual and at a later date, a second cancer 55 wherein the Sustained release therapeutic compound therapeutic is administered to the same individual. delivery platform releases a therapeutic compound with 41. The pharmaceutical composition of any of the preceding substantially first order release kinetics over a period of embodiments, wherein the first therapeutic compound is about 7 days after administration, about 15 days after artemesinin or a derivative thereof and the second thera administration, about 30 days after administration, about peutic compound is a different derivative of artemesinin. 60 45 days after administration, about 60 days after admin 42. The pharmaceutical composition of any of the preceding istration, about 75 days after administration, or about 90 embodiments, wherein the first therapeutic compound is days after administration. artemesinin or a derivative thereof and the second thera 57. The pharmaceutical composition of embodiment 53, peutic compound is a cancer therapeutic that is not wherein the Sustained release therapeutic compound artemesinin or a derivative thereof. 65 delivery platform releases a therapeutic compound with 43. The pharmaceutical composition of any of the preceding substantially first order release kinetics over a period of at embodiments, wherein a first therapeutic compound is least 7 days after administration, at least 15 days after US 9,622,982 B2 63 64 administration, at least 30 days after administration, at between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 least 45 days after administration, at least 60 days after and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or administration, at least 75 days after administration, or at between 3.6 and 4.0. least 90 days after administration. 67. The pharmaceutical composition of any preceeding 58. The pharmaceutical composition of embodiment 53, 5 embodiment, wherein, a therapeutic compound has a log wherein a therapeutic compound delivery platform P value in the range of, e.g., between 2.0 and 2.5, between releases a therapeutic compound with Substantially Zero 2.0 and 2.7, between 2.0 and 3.0, or between 2.2 and 2.5. order release kinetics over a period of about 1 day after 68. The pharmaceutical composition of any preceeding administration, about 2 days after administration, about 3 embodiment, wherein a therapeutic compound has a polar days after administration, about 4 days after administra 10 surface area of, e.g., less than 8.0 nm, less than 7.0 nm, tion, about 5 days after administration, or about 6 days less than 6.0 nm, less than 5.0 nm, less than 4.0 nm, or after administration. less than 3.0 nm. 59. The pharmaceutical composition of embodiment 53, 69. The pharmaceutical composition of any preceeding wherein a therapeutic compound delivery platform embodiment, wherein a therapeutic compound has a polar releases a therapeutic compound with Substantially Zero 15 surface area in the range of, e.g., between 3.0 nm and 6.5 order release kinetics over a period of, e.g., at most 1 day nm, between 3.0 nm and 6.0 nm, between 3.0 nm and after administration, at most 2 days after administration, 5.5 nm, between 3.0 nm and 5.0 nm, between 3.0 nm. at most 3 days after administration, at most 4 days after and 4.5 nm, between 3.5 nm and 6.5 nm, between 3.5 administration, at most 5 days after administration, or at nm and 6.0 nm, between 3.5 nm and 5.5 nm, between most 6 days after administration. 3.5 nm and 5.0 nm, between 3.5 nm and 4.5 nm, 60. The pharmaceutical composition of embodiment 53, between 4.0 nm and 6.5 nm, between 4.0 nm and 6.0 wherein a therapeutic compound delivery platform nm, between 4.0 nm and 5.5 nm, or between 4.0 nm. releases a therapeutic compound disclosed herein with and 5.0 nm, between 4.0 nm and 4.5 nm, or between substantially first order release kinetics over a period of 25 4.5 nm and 5.5 nm. about 1 day after administration, about 2 days after 70. The pharmaceutical composition of any preceeding administration, about 3 days after administration, about 4 embodiment, wherein a therapeutic compound has a polar days after administration, about 5 days after administra surface area in the range of e.g., between 2.0 nm and 6.5 tion, or about 6 days after administration. nm, between 2.0 nm and 6.0 nm, between 2.0 nm and 61. The pharmaceutical composition of embodiment 53, 30 5.5 nm, between 2.0 nm and 5.0 nm, between 2.0 nm. wherein a therapeutic compound delivery platform and 4.5 nm, between 2.5 nm and 6.5 nm, between 2.5 releases a therapeutic compound disclosed herein with nm and 6.0 nm, between 2.5 nm and 5.5 nm, between substantially first order release kinetics over a period of at 2.5 nm and 5.0 nm, or between 2.5 nm and 4.5 nm. most 1 day after administration, at most 2 days after 71. The pharmaceutical composition of embodiment 1, administration, at most 3 days after administration, at 35 wherein the cancer therapeutic is an ester. most 4 days after administration, at most 5 days after 72. The pharmaceutical composition of embodiment 5, administration, or at most 6 days after administration. wherein the solvent is in an amount sufficient to dissolve 62. The pharmaceutical composition of any preceeding a cancer therapeutic. embodiment, wherein a therapeutic compound has a log P 73. The pharmaceutical composition of embodiment 72, value indicating that the compound is at least 50% soluble 40 wherein the pharmaceutical comprises a solvent in an in an organic solvent, at least 60% soluble in an organic amount of less than about 90% (v/v), less than about 80% solvent, at least 70% soluble in an organic solvent, at least (v/v), less than about 70% (v/v), less than about 65% 80% soluble in an organic solvent, or at least 90% soluble (v/v), less than about 60% (v/v), less than about 55% in an organic solvent. (v/v), less than about 50% (v/v), less than about 45% 63. The pharmaceutical composition of any preceeding 45 (v/v), less than about 40% (v/v), less than about 35% embodiment, wherein a therapeutic compound has a log P (v/v), less than about 30% (v/v), less than about 25% value indicating that the compound is between, e.g., about (v/v), less than about 20% (v/v), less than about 15% 50% to about 100% soluble in an organic solvent, about (v/v), less than about 10% (v/v), less than about 5% (v/v), 60% to about 100% soluble in an organic solvent, about or less than about 1% (v/v). 70% to about 100% soluble in an organic solvent, about 50 74. The pharmaceutical composition of embodiment 72, 80% to about 100% soluble in an organic solvent, or about wherein the pharmaceutical composition comprises a sol 90% to about 100% soluble in an organic solvent. vent in an amount in a range of, e.g., about 1% (v/v) to 64. The pharmaceutical composition of any preceeding 90% (v/v), about 1% (v/v) to 70% (v/v), about 1% (v/v) embodiment, wherein a therapeutic compound has a log P to 60% (v/v), about 1% (v/v) to 50% (v/v), about 1% (v/v) value of, e.g., more than 1.1, more than 1.2, more than 1.4. 55 to 40% (v/v), about 1% (v/v) to 30% (v/v), about 1% (v/v) more than 1.6, more than 1.8, more than 2.0, more than to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v) 2.2, more than 2.4, more than 2.6, more than 2.8, more to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) than 3.0, more than 3.2, more than 3.4, or more than 3.6. to 30% (v/v), about 2% (v/v) to 20% (v/v), about 2% (v/v) 65. The pharmaceutical composition of any preceeding to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v) embodiment, wherein a therapeutic compound has a log P 60 to 40% (v/v), about 4% (v/v) to 30% (v/v), about 4% (v/v) value in the range of, e.g., between 1.8 and 4.0, between to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v) 2.0 and 4.0, between 2.1 and 4.0, between 2.2 and 4.0, or to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) between 2.3 and 4.0, between 2.4 and 4.0, between 2.5 to 30% (v/v), about 6% (v/v) to 20% (v/v), about 6% (v/v) and 4.0, between 2.6 and 4.0, or between 2.8 and 4.0. to 10% (v/v), about 8% (v/v) to 50% (v/v), about 8% (v/v) 66. The pharmaceutical composition of any preceeding 65 to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v) embodiment, wherein a therapeutic compound has a log P to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% value in the range of, e.g., between 3.0 and 4.0, or (v/v) to 12% (v/v). US 9,622,982 B2 65 66 75. The pharmaceutical composition of embodiment 5, (9:0), Capric acid (10:0), Undecylic acid (11:0), Lauric wherein the solvent comprises a pharmaceutically accept acid (12:0), Tridecylic acid (13:0), Myristic acid (14:0). able alcohol. Myristoleic acid (14:1), Pentadecyclic acid (15:0), Palm 76. The pharmaceutical composition of embodiment 75, itic acid (16:0), Palmitoleic acid (16:1), Sapienic acid wherein the alcohol is a Calcohol, a Calcohol, a Cs (16:1), Margaric acid (17:0), Stearic acid (18:0), Oleic alcohol, a C-7 alcohol, a Co alcohol, a C-1s alcohol, or acid (18:1), Elaidic acid (18:1), Vaccenic acid (18:1), a Co alcohol. Linoleic acid (18:2), Linoelaidic acid (18:2), C-Linolenic 77. The pharmaceutical composition of embodiment 75, acid (18:3), Y-Linolenic acid (18:3), Stearidonic acid wherein the alcohol is a primary alcohol, a secondary (18:4). Nonadecylic acid (19:0), Arachidic acid (20:0), alcohol, or a tertiary alcohol. 10 Eicosenoic acid (20:1), Dihomo-y-linolenic acid (20:3), 78. The pharmaceutical composition of embodiment 75, Mead acid (20:3), Arachidonic acid (20:4), Eicosapentae wherein the alcohol is an acyclic alcohol, a monohydric noic acid (20:5), Heneicosylic acid (21:0), Behenic acid alcohol, a polyhydric alcohol (also known as a polyol or (22:0), Erucic acid (22:1), Docosahexaenoic acid (22:6), Sugar alcohol), an unsaturated aliphatic alcohol, an alicy Tricosylic acid (23:0), Lignoceric acid (24:0), Nervonic clic alcohol, or a combination thereof. 15 acid (24:1), Pentacosylic acid (25:0), Cerotic acid (26:0), 79. The pharmaceutical composition of embodiment 75, Heptacosylic acid (27:0), Montanic acid (28:0), Nonaco wherein the alcohol is an unsaturated aliphatic alcohol. sylic acid (29:0), Melissic acid (30:0), Henatriacontylic 80. The pharmaceutical composition of embodiment 75, acid (31:0), Lacceroic acid (32:0), Psyllic acid (33:0), wherein the unsaturated aliphatic alcohol is prop-2-ene Geddic acid (34:0). Ceroplastic acid (35:0), and/or 1-ol. 3,7-dimethylocta-2,6-dien-1-ol, and prop-2-in-1-ol. Hexatriacontylic acid (36:0). 81. The pharmaceutical composition of embodiment 75, 92. The pharmaceutical composition of embodiment 88, wherein an alcohol is an alicyclic alcohol. wherein the lipid is a pharmaceutically-acceptable Satu 82. The pharmaceutical composition of embodiment 75, rated or unsaturated fatty acid. wherein the alicyclic alcohol is cyclohexane-1,2,3,4,5,6- 93. The pharmaceutical composition of embodiment 92. hexyl and 2-(2-propyl)-5-methyl-cyclohexane-1-ol. 25 wherein the Saturated or unsaturated fatty acid comprises 83. The pharmaceutical composition of embodiment 5, at least 8, at least 10, at least 12, at least 14, at least 16, wherein a solvent is an ester of pharmaceutically-accept at least 18, at least 20, at least 22, at least 24, at least 26, able alcohol and an acid. at least 28, or at least 30 carbon atoms, 84. The pharmaceutical composition of embodiment 83 94. The pharmaceutical composition of embodiment 92. wherein an ester of a pharmaceutically-acceptable acid is 30 wherein the Saturated or unsaturated fatty acid comprises acetic acid, butaric acid, and formic acid. between 4 and 24 carbonatoms, between 6 and 24 carbon 85. The pharmaceutical composition of embodiment 83, atoms, between 8 and 24 carbon atoms, between 10 and wherein the ester of an alcohol and an acid are methyl 24 carbon atoms, between 12 and 24 carbon atoms, acetate, methyl buterate, methyl formate, ethyl acetate, between 14 and 24 carbon atoms, or between 16 and 24 ethylbuterate, ethyl formate, propyl acetate, propylbuter 35 carbon atoms, between 4 and 22 carbon atoms, between 6 ate, propyl formate, butyl acetate, butyl buterate, butyl and 22 carbon atoms, between 8 and 22 carbon atoms, formate, isobutyl acetate, isobutylbuterate, isobutyl for between 10 and 22 carbon atoms, between 12 and 22 mate, pentyl acetate, pentylbuterate, pentyl formate, and carbon atoms, between 14 and 22 carbon atoms, or 1-hexadecyl acetate, 1-hexadecyl buterate or 1-hexadecyl between 16 and 22 carbon atoms, between 4 and 20 formate. 40 carbon atoms, between 6 and 20 carbon atoms, between 8 86. The pharmaceutical composition of embodiment 5, and 20 carbon atoms, between 10 and 20 carbon atoms, wherein the solvent is a pharmaceutically-acceptable gly between 12 and 20 carbon atoms, between 14 and 20 col either. carbon atoms, or between 16 and 20 carbon atoms. 87. The pharmaceutical composition of embodiment 86, 95. The pharmaceutical composition of embodiment 92. wherein the glycol ether is diethylene glycol monomethyl 45 wherein the unsaturated fatty acid has 1 or more, 2 or ether (2-(2-methoxyethoxy)ethanol), diethylene glycol more, 3 or more, 4 or more, 5 or more, or 6 or more double monoethyl ether (2-(2-ethoxyethoxy)ethanol), diethylene bonds. glycol monopropyl ether (2-(2-propoxyethoxy)ethanol), 96. The pharmaceutical composition of any proceeding diethylene glycol monoisopropyl ether (2-(2-isopropoxy embodiment, wherein the concentration of a therapeutic ethoxy)ethanol), and diethylene glycol mono-n-butyl 50 compound is at least 0.00001 mg/mL, at least 0.0001 ether (2-(2-butoxyethoxy)ethanol). mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at 88. The pharmaceutical composition of embodiment 5, least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at wherein the composition comprises one or more lipids. least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, 89. The pharmaceutical composition of embodiment 88, at least 200 mg/mL, at least 500 mg/mL, at least 700 wherein the lipid is a fatty acids, glycerolipids, diglycer 55 mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. ides, and triglycerides), phospholipids, sphingolipids, Ste 97. The pharmaceutical composition of any proceeding rol lipids, prenol lipids, saccharolipids, and/or embodiment, wherein the concentration of a therapeutic polyketides. compound is at most 1,000 mg/mL, at most 1,100 mg/mL, 90. The pharmaceutical composition of embodiment 88, at most 1,200 mg/mL, at most 1,300 mg/mL, at most wherein the lipid is an oil, an oil-based liquid, a fat, a fatty 60 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 acid, a partially hydrolyzed fatty acid, a wax, a fatty acid mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. ester, a fatty acid salt, a fatty alcohol, a glyceride (mono-, 98. The pharmaceutical composition of any proceeding di- or tri-glyceride), a phospholipids, a glycol ester, a embodiment, wherein the concentration of a therapeutic Sucrose ester, a glycerol oleate derivative, a medium chain compound is about 0.00001 mg/mL to about 3,000 triglyceride and.or a partially hydrolyzed triglyceride. 65 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, 91. The pharmaceutical composition of embodiment 88, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 wherein the lipid is Capryllic acid (8:0), pelargonic acid mg/mL to about 3,000 mg/mL, about 1 mg/mL to about US 9,622,982 B2 67 68 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, least 1.9:1, at least 1:2, at least 1:3, at least 1:4, at least about 500 mg/mL to about 3,000 mg/mL, about 750 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to least 1:10, at least 1:15, at least 1:20, or at least 1:25. about 3,000 mg/mL, about 100 mg/mL to about 2,000 102. The pharmaceutical composition of any proceeding mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 5 embodiment, wherein the ratio offat:fat may be in a range 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to of about 5:1 to about 1:25, about 4:1 to about 1:25, about about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 3:1 to about 1:25, about 2:1 to about 1:25, about 0:1 to mg/mL, about 100 mg/mL to about 1,500 mg/mL, about about 1:25, about 1:1 to about 1:25, about 1:2 to about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to 1:25, about 1:3 to about 1:25, about 1:4 to about 1:25, about 1,500 mg/mL, about 750 mg/mL to about 1,500 10 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about about 1:5 to about 1:25, about 5:1 to about 1:20, about 4:1 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to to about 1:20, about 3:1 to about 1:20, about 2:1 to about about 1,200 mg/mL, about 500 mg/mL to about 1,200 1:20, about 0:1 to about 1:20, about 1:1 to about 1:20, mg/mL, about 750 mg/mL to about 1,200 mg/mL, about about 1:2 to about 1:20, about 1:3 to about 1:20, about 1:4 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to 15 to about 1:20, about 1:5 to about 1:20, about 5:1 to about about 1,000 mg/mL, about 250 mg/mL to about 1,000 1:15, about 4:1 to about 1:15, about 3:1 to about 1:15, mg/mL, about 500 mg/mL to about 1,000 mg/mL, about about 0:1 to about 1:15, about 2:1 to about 1:15, about 1:1 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to to about 1:15, about 1:2 to about 1:15, about 1:3 to about about 750 mg/mL, about 250 mg/mL to about 750 1:15, about 1:4 to about 1:15, about 1:5 to about 1:15, mg/mL, about 500 mg/mL to about 750 mg/mL, about about 5:1 to about 1:12, about 4:1 to about 1:12, about 3:1 100 mg/mL to about 500 mg/mL, about 250 mg/mL to to about 1:12, about 2:1 to about 1:12, about 0:1 to about about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 1:12, about 1:1 to about 1:12, about 1:2 to about 1:12, mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 1:3 to about 1:12, about 1:4 to about 1:12, about 1:5 about 0.00001 mg/mL to about 0.01 mg/mL, about to about 1:12, about 1:6 to about 1:12, about 1:7 to about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 25 1:12, about 1:8 to about 1:12, about 5:1 to about 1:10, mg/mL to about 1 mg/mL, about 0.001 mg/mL to about about 4:1 to about 1:10, about 3:1 to about 1:10, about 2:1 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, to about 1:10, about 0:1 to about 1:10, about 1:1 to about about 0.001 mg/mL to about 1 mg/mL, about 0.001 1:10, about 1:2 to about 1:10, about 1:3 to about 1:10, mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 1:4 to about 1:10, about 1:5 to about 1:10, about 1:6 about 100 mg/mL. 30 to about 1:10, about 1:7 to about 1:10, or about 1:8 to 99. The pharmaceutical composition of any proceeding about 1:10. embodiment, wherein the ratio of solution:adjuvant is at 103. The pharmaceutical composition of any proceeding least 5:1, at least 4:1, at least 3:1, at least 2:1, at least 0:1, at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least embodiment, wherein the ratio of fat:fat, in a pharmaceu 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at 35 tical composition containing artemesinin or a derivate least 1:10, at least 1:15, at least 1:20, or at least 1:25. thereof, is at least 5:1, at least 4:1, at least 3:1, at least 2:1, 100. The pharmaceutical composition of any proceeding at least 0:1, at least 1:1, at least 1.1:1, at least 1.2:1, at least embodiment, wherein the ratio of solution:adjuvant is 1.3:1, at least 1.4:1, at least 1.5:1, at least 1.6:1, at least about 5:1 to about 1:25, about 4:1 to about 1:25, about 3:1 1.7:1, at least 1.8:1, at least 1.9:1, at least 1:2, at least 1:3, to about 1:25, about 2:1 to about 1:25, about 0:1 to about 40 at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:25, about 1:1 to about 1:25, about 1:2 to about 1:25, 1:8, at least 1:9, at least 1:10, at least 1:15, at least 1:20, about 1:3 to about 1:25, about 1:4 to about 1:25, about 1:5 or at least 1:25. to about 1:25, about 5:1 to about 1:20, about 4:1 to about 104. The pharmaceutical composition of any proceeding 1:20, about 3:1 to about 1:20, about 2:1 to about 1:20, embodiment, wherein the ratio of fat:fat, in a pharmaceu about 0:1 to about 1:20, about 1:1 to about 1:20, about 1:2 45 tical composition containing artemesinin or a derivate to about 1:20, about 1:3 to about 1:20, about 1:4 to about thereof, is in a range of about 5:1 to about 1:25, about 4:1 1:20, about 1:5 to about 1:20, about 5:1 to about 1:15, to about 1:25, about 3:1 to about 1:25, about 2:1 to about about 4:1 to about 1:15, about 3:1 to about 1:15, about 0:1 1:25, about 0:1 to about 1:25, about 1:1 to about 1:25, to about 1:15, about 2:1 to about 1:15, about 1:1 to about about 1:2 to about 1:25, about 1:3 to about 1:25, about 1:4 1:15, about 1:2 to about 1:15, about 1:3 to about 1:15, 50 to about 1:25, about 1:5 to about 1:25, about 5:1 to about about 1:4 to about 1:15, about 1:5 to about 1:15, about 5:1 1:20, about 4:1 to about 1:20, about 3:1 to about 1:20, to about 1:12, about 4:1 to about 1:12, about 3:1 to about about 2:1 to about 1:20, about 0:1 to about 1:20, about 1:1 1:12, about 2:1 to about 1:12, about 0:1 to about 1:12, to about 1:20, about 1:2 to about 1:20, about 1:3 to about about 1:1 to about 1:12, about 1:2 to about 1:12, about 1:3 1:20, about 1:4 to about 1:20, about 1:5 to about 1:20, to about 1:12, about 1:4 to about 1:12, about 1:5 to about 55 about 5:1 to about 1:15, about 4:1 to about 1:15, about 3:1 1:12, about 1:6 to about 1:12, about 1:7 to about 1:12, to about 1:15, about 0:1 to about 1:15, about 2:1 to about about 1:8 to about 1:12, about 5:1 to about 1:10, about 4:1 1:15, about 1:1 to about 1:15, about 1:2 to about 1:15, to about 1:10, about 3:1 to about 1:10, about 2:1 to about about 1:3 to about 1:15, about 1:4 to about 1:15, about 1:5 1:10, about 0:1 to about 1:10, about 1:1 to about 1:10, to about 1:15, about 5:1 to about 1:12, about 4:1 to about about 1:2 to about 1:10, about 1:3 to about 1:10, about 1:4 60 1:12, about 3:1 to about 1:12, about 2:1 to about 1:12, to about 1:10, about 1:5 to about 1:10, about 1:6 to about about 0:1 to about 1:12, about 1:1 to about 1:12, about 1:2 1:10, about 1:7 to about 1:10, or about 1:8 to about 1:10. to about 1:12, about 1:3 to about 1:12, about 1:4 to about 101. The pharmaceutical composition of any proceeding 1:12, about 1:5 to about 1:12, about 1:6 to about 1:12, embodiment, wherein the ratio of fat:fat, is at least 5:1, at about 1:7 to about 1:12, about 1:8 to about 1:12, about 5:1 least 4:1, at least 3:1, at least 2:1, at least 0:1, at least 1:1, 65 to about 1:10, about 4:1 to about 1:10, about 3:1 to about at least 1.1:1, at least 1.2:1, at least 1.3:1, at least 1.4:1, at 1:10, about 2:1 to about 1:10, about 0:1 to about 1:10, least 1.5:1, at least 1.6:1, at least 1.7:1, at least 1.8:1, at about 1:1 to about 1:10, about 1:2 to about 1:10, about 1:3 US 9,622,982 B2 69 70 to about 1:10, about 1:4 to about 1:10, about 1:5 to about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, 1:10, about 1:6 to about 1:10, about 1:7 to about 1:10, or about 750 mg/mL to about 1,500 mg/mL, about 1,000 about 1:8 to about 1:10. mg/mL to about 1,500 mg/mL, about 100 mg/mL to about 105. The pharmaceutical composition of embodiment 88, 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, wherein a cancer therapeutic is formulated in a one fat. about 500 mg/mL to about 1,200 mg/mL, about 750 106. The pharmaceutical composition of embodiment 88, mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to wherein artemesinin or a derivative thereof is formulated about 1,200 mg/mL, about 100 mg/mL to about 1,000 in one fat. mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 107. The pharmaceutical composition of embodiment 88, 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to wherein a cancer therapeutic is formulated in two fats. 10 about 1,000 mg/mL, about 100 mg/mL to about 750 108. The pharmaceutical composition of embodiment 88, mg/mL, about 250 mg/mL to about 750 mg/mL, about wherein artemesinin or a derivative thereof is formulated 500 mg/mL to about 750 mg/mL, about 100 mg/mL to in two fats. about 500 mg/mL, about 250 mg/mL to about 500 109. The pharmaceutical composition of embodiment 88, mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, wherein a cancer therapeutic is formulated in three fats, 15 about 0.00001 mg/mL to about 0.001 mg/mL, about four fats, five fats, six fats or seven or more fats. 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 110. The pharmaceutical composition of embodiment 88, mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to wherein artemesinin or a derivative thereof is formulated about 1 mg/mL, about 0.001 mg/mL to about 0.01 in three fats, four fats, five fats, six fats or seven or more mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about fats. 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to 111. The pharmaceutical composition of embodiment 88, about 10 mg/mL, or about 0.001 mg/mL to about 100 wherein a cancer therapeutic is formulated in a fat that is mg/mL. a liquid. 120. The pharmaceutical composition of any of embodi 112. The pharmaceutical composition of embodiment 88, ments 1-4, wherein the composition is a liquid, semi-solid wherein a cancer therapeutic is formulated in at fat that is 25 or a solid formulation. a Solid. 121. The pharmaceutical composition of any of embodi 113. The pharmaceutical composition of embodiment 88, ments 1-4 and 88, wherein the pharmaceutical composi wherein a cancer therapeutic is formulated in a two or tion comprises tributyrin and G43 more fats that are liquids. 122. The pharmaceutical composition of any of embodi 114. The pharmaceutical composition of embodiment 88, 30 ments 1-4, wherein an artemesinin or a derivative thereof wherein a cancer therapeutic is formulated in two or more is linked to a estrogen receptor modulator. fats that are solids. 123. The pharmaceutical composition of embodiment 122, 115. The pharmaceutical composition of embodiment 88, wherein the estrogen receptor modulator is a selective wherein a cancer therapeutic is formulated in two or more estrogen receptor modulator. fats, wherein at least one fat is a solid and at least one fat 35 124. The pharmaceutical composition of embodiment 1, is a liquid. wherein the cancer therapeutic is a stilbenoid. 116. The pharmaceutical composition of any of embodi 125. The pharmaceutical composition of embodiment 124, ments 111-115, wherein the cancer therapeutic is artem wherein the stilbenoid is Resveratrol, Piceatannol, Pino esinin and/or a derivative thereof. Sylvin, Pterostilbene, Alpha-Viniferin, Ampelopsin A, 117. The pharmaceutical composition of any proceeding 40 Ampelopsin E, Diptoindonesin C, Diptoindonesin F, embodiment, wherein the concentration of a cancer thera Epsilon-Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, peutic is at least 0.00001 mg/mL, at least 0.0001 mg/mL, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 and Diptoindonesin A. mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 126. The pharmaceutical composition of embodiment 1, mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 45 wherein the cancer therapeutic is an isoflavone. 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at 127. The pharmaceutical composition of embodiment 124, least 1,000 mg/mL, or at least 1,200 mg/mL. wherein the isoflavone is Daidzein or Genistein. 118. The pharmaceutical composition of any proceeding 128. The pharmaceutical composition of embodiment 1, embodiment, wherein the concentration of a cancer thera wherein the cancer therapeutic is an isoflavondiol. peutic is at most 1,000 mg/mL, at most 1,100 mg/mL, at 50 129. The pharmaceutical composition of embodiment 124, most 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 wherein the isoflavondiol is Daidzein or Genistein. mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at 130. The pharmaceutical composition of any of embodi most 2,000 mg/mL, or at most 3,000 mg/mL. ments 124-129, wherein the cancer therapeutic is admin 119. The pharmaceutical composition of any proceeding istered with an Artemesinin. embodiment, wherein the concentration of a cancer thera 55 131. The pharmaceutical composition of embodiment 130, peutic is about 0.00001 mg/mL to about 3,000 mg/mL, wherein the Artemesinin is a derivative of Artemesinin. about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 132. The pharmaceutical composition of embodiment 131, mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about wherein the derivative is Artesunate, Artemether, Dihy 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, droartemisinin, Artelinic acid, Artenimol and/or Artemo about 250 mg/mL to about 3,000 mg/mL, about 500 60 til. mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 133. The pharmaceutical composition of any of embodi 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, ments 124-129, wherein the stilbenoid, isoflavone and/or about 100 mg/mL to about 2,000 mg/mL, about 250 isoflavondiol is a synthetic, semisynthetic or derivative. mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 134. A pharmaceutical composition comprising one or more 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, 65 cancer therapeutics. about 1,000 mg/mL to about 2,000 mg/mL, about 100 135. The pharmaceutical formulation of embodiment 134, mg/mL to about 1,500 mg/mL, about 250 mg/mL to about wherein a cancer therapeutic is selected from an alkylat US 9,622,982 B2 71 72 ing agent, an anti-metabolite, a plant alkaloid, a terpenoid, 154. The pharmaceutical formulation of embodiment 135, a topoisomerase inhibitor, a cytotoxic antibiotics, a statin, wherein the thiazolidinedione is rosiglitaZone, pioglita an anti-diabetic drug, a PPAR-y, a PPAR-J3, a PPAR-a, an Zone and/or troglitaZone. antibiotic, an antihelminthic, an anti-malaria drug, a vita 155. The pharmaceutical formulation of embodiment 135, min and/or a food additive. wherein the Secretagogue is a Sulfonylurea, a nonsulfo 136. The pharmaceutical formulation of embodiment 135, nylurea and/or a meglitinide. wherein the alkylating agent is carboplatin, chlorambucil, 156. The pharmaceutical formulation of embodiment 135, cisplatin, cyclophosphamide, ifosfamide, Oxaliplatin and/ wherein the sulfonylurea is tolbutamide, acetohexamide, or mechlorethamine. tolaZamide, chlorpropamide, glipzide, glyburide, 137. The pharmaceutical formulation of embodiment 135, 10 glimepiride, gliclazide, glycopyramide and/or gliquidone. wherein the antimetabolite is azathioprine and/or mercap 157. The pharmaceutical formulation of embodiment 135, topurine. wherein the meglitinide is repaglinide and/or nateglinide. 138. The pharmaceutical formulation of embodiment 135, 158. The pharmaceutical formulation of embodiment 135, wherein the plant alkaloid is a Vinca alkaloid, a podo 15 wherein the alpha-glucosidase inhibitor is miglitol, acar phyllotoxin and/or a taxane. bose and/or Voglibose. 139. The pharmaceutical formulation of embodiment 135, 159. The pharmaceutical formulation of embodiment 135, wherein the Vinca alkaloid is Vincristine, vinblastine, wherein the peptide analog is an injectable incretin vinorelbine and/or vindesine. mimetic, an injectable glucagon-like peptide analog and/ 140. The pharmaceutical formulation of embodiment 135, or agonist, a gastric inhibitory peptide analog, a dipeptidyl wherein the podophyllotoxin is etoposide and/or tenipo peptidase-4 inhibitor and/or an injectable Amylin ana side. logue. 141. The pharmaceutical formulation of embodiment 135, 160. The pharmaceutical formulation of embodiment 135, wherein the taxane is docetaxel and/or ortataxel. wherein the glucagon-like peptide analog and/or agonist 142. The pharmaceutical formulation of embodiment 135, 25 is exenatide, liraglutide and/or taspoglutide. wherein the topoisomerase is a type (topoisomerase 161. The pharmaceutical formulation of embodiment 135, inhibitor or a type II topoisomerase inhibitor. wherein the dipeptidyl peptidase-4 inhibitor is vildaglip 143. The pharmaceutical formulation of embodiment 135, tin, Sitagliptin, saxagliptin, linagliptin, allogliptin and/or wherein the type I topoisomerase inhibitor is a camptoth Septagliptin. 30 162. The pharmaceutical formulation of embodiment 135, ecin. wherein the injectable Amylin analogue is pramlintide. 144. The pharmaceutical formulation of embodiment 135, 163. The pharmaceutical formulation of embodiment 135, wherein the camptothecin is exatecan, irinotecan, lurto wherein the cancer therapeutic is cinnamon and/or thia tecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) mine. and/or ST 1481. 35 164. The pharmaceutical formulation of embodiment 135, 145. The pharmaceutical formulation of embodiment 135, wherein the Peroxisome proliferator-activated receptor wherein the type II topoisomerase inhibitor is epipodo gamma is rosiglitaZone, troglitaZone, pioglitaZone, neto phyllotoxin. glitaZone, rivoglitaZone and/or ciglitaZone. 146. The pharmaceutical formulation of embodiment 135, 165. The pharmaceutical formulation of embodiment 135, wherein the epipodophyllotoxin is, without limitation, 40 wherein the PPAR-r3 agonist is endurobol and/or amsacrine, etoposid, etoposide phosphate and/or tenipo GWOT42. side. 166. The pharmaceutical formulation of embodiment 135, 147. The pharmaceutical formulation of embodiment 135, wherein the antibiotic is isoniazid, rifampicin, pyraZina wherein the cytotoxic antibiotic is an actinomycin, an mide and/or ethambutol. anthracenedione, an anthracycline, thalidomide, dichloro 45 167. The pharmaceutical formulation of embodiment 135, acetic acid, nicotinic acid, 2-deoxyglucose and/or chlo wherein the antihelminthic is abamectin, an aminoac fazimine. etonitriles, a benzimadazole, diethylcaramazine, ivermec 148. The pharmaceutical formulation of embodiment 135, tin, levamisole, niclosamide, an octadepsipeptides, phos wherein the actinomycin is actinomycin D. bacitracin, phoric acid (metrifonate), praziquantel, a spiroindoles, colistin (polymyxin E) and/or polymyxin B. 50 Suramin and/or pyrantel pamoate. 149. The pharmaceutical formulation of embodiment 135, 168. The pharmaceutical formulation of embodiment 135, wherein the antracenedione is mitoxantrone and/or pix wherein the aminoacetonitrile is monepantel. antrOne. 169. The pharmaceutical formulation of embodiment 135, 150. The pharmaceutical formulation of embodiment 135, wherein the benzimidazole is albendazole, fenbendazole, wherein the anthracycline is bleomycin, doxorubicin 55 aflubendazole, thiabendazole and triclabendazole. (Adriamycin), daunorubicin (daunomycin), epirubicin, 170. The pharmaceutical formulation of embodiment 135, idarubicin, mitomycin, plicamycin and/or valrubicin. wherein the flubendazole is mebendazole. 151. The pharmaceutical formulation of embodiment 135, 171. The pharmaceutical formulation of embodiment 135, wherein the statin is atorvastatin, fluvastin, lovastatin, wherein the octadepsipeptide is emodepside. pitavastatin, pravastatin, rosuvastatin and/or simvastatin. 60 172. The pharmaceutical formulation of embodiment 135, 152. The pharmaceutical formulation of embodiment 135, wherein the spiroindole is dequantel. wherein the treatment of diabetes is a biguanide, a thi 173. The pharmaceutical formulation of embodiment 135, aZolidinedione, a secretagogue, an alpha-glucosidase wherein the anti-malarial therapeutic is amodiaquine, an inhibitor and/or a peptide analog. artemisinin, atovaquone, chloroquine, clindamycin, doxy 153. The pharmaceutical formulation of embodiment 135, 65 cycline, halofantrine, mefloquine, primaquine, proguanil, wherein the biguanide is metformin, phenformin and/or pyrimethamine, a quinine and related agent, rufigallol, buformin. and/or a Sulphonamide. US 9,622,982 B2 73 74 174. The pharmaceutical formulation of embodiment 135, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, wherein the artemisinin is artemether, artesunate and/or 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 dihydroartemisinin. weeks, 3 weeks, 4 weeks, one month, two months, three 175. The pharmaceutical formulation of embodiment 135, months and/or four months. wherein the quinine and related agent is quinimax and/or 5 187. The pharmaceutical composition of any of the preced quinidine. ing embodiments, wherein a cancer therapeutic is admin 176. The pharmaceutical formulation of embodiment 135, istered to an individual for a period of time followed by wherein the sulfonamide is sulfadoxine and/or sulfame a separate period of time. thoxypyridazine. 188. The pharmaceutical composition of any of the preced 177. The pharmaceutical formulation of embodiment 135, 10 ing embodiments, wherein a cancer therapeutic is admin wherein the food additive and/or vitamin is tributerin, istered for a first period and a second period following the vitamin C, vitamin 812, vitamin D, resveratrol and/or first period, with administration stopped during the sec coenzyme Q12. ond period, followed by a third period where administra 178. The pharmaceutical formulation of embodiment 135, tion of the cancer therapeutic is started and then a fourth wherein the glucose intake inhibitor is a GLUT-1 receptor 15 period following the third period where administration is inhibitor. stopped. 179. The pharmaceutical formulation of embodiment 135, 189. The pharmaceutical composition of any of the preced wherein the lipid intake inhibitor is an LDL receptor ing embodiments, wherein a cancer therapeutic is admin inhibitor, an SR-81 inhibitor, an SR-82 inhibitor and/or a istered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, SR-83/CD36 (thrombospondin) receptor inhibitor. 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 180. The pharmaceutical formulation of any of embodi 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 ments 136-179, wherein an individual is administered one weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, or more of the cancer therapeutics. 5 months, 6 months, 7 months, 8 months, 9 months, 10 181. The pharmaceutical composition of any of the proceed months, 11 months, 12 months, or more. ing embodiments, wherein a pharmaceutical composition 25 190. The pharmaceutical composition of any of the preced includes a pharmaceutically acceptable solvent, a phar ing embodiments, wherein a first cancer therapeutic s maceutically acceptable stabilizing agent, a pharmaceu administered to an individual and at a later date, a second tically acceptable carrier and/or a pharmaceutically cancer therapeutic is administered to the same individual acceptable component. 191. The pharmaceutical composition of any of the preced 182. The pharmaceutical composition of any proceeding 30 ing embodiments, wherein a first cancer therapeutic is embodiment, wherein a cancer therapeutic is capable of administered to an individual at the same time as a second reducing the number of cancer cells or tumor size in an cancer therapeutic is administered to the individual. individual suffering from a cancer by, at least 10%, at least 192. The pharmaceutical composition of any of the preced 15%, at least 20%, at least 25%, at least 30%, at least ing embodiments, wherein the pharmaceutical composi 35%, at least 40%, at least 45%, at least 50%, at least 35 tion is a liquid, a sold and/or a semi-solid. 55%, at least 60%, at least 65%, at least 70%, at least 193. The pharmaceutical composition of embodiment 192, 75%, at least 80%, at least 85%, at least 90% or at least wherein, the pharmaceutical composition is provided to 95% as compared to a patient not receiving the same an individual in a capsule, tablet, pill, lozenge, powder treatment. and/or granule. 183. The pharmaceutical composition of any proceeding 40 194. The pharmaceutical composition of embodiment 192, embodiment, wherein a cancer therapeutic is capable of wherein the pharmaceutical composition is inhaled. reducing the number of cancer cells or tumor size in an 195. The pharmaceutical composition of embodiment 134, individual suffering from a cancer by, about 10% to about wherein the pharmaceutical composition is formulated in 100%, about 20% to about 100%, about 30% to about an oil-in-water emulsion. 100%, about 40% to about 100%, about 50% to about 45 196. The pharmaceutical composition of embodiment 195, 100%, about 60% to about 100%, about 70% to about wherein the oil is a vegetable oil, an animal fat and/or a 100%, about 80% to about 100%, about 10% to about mineral oil. 90%, about 20% to about 90%, about 30% to about 90%, 197. The pharmaceutical composition of any of embodi about 40% to about 90%, about 50% to about 90%, about ments 134-180, wherein the pharmaceutical composition 60% to about 90%, about 70% to about 90%, about 10% 50 is released in a controlled release profile over time. to about 80%, about 20% to about 80%, about 30% to 198. The pharmaceutical composition of any of embodi about 80%, about 40% to about 80%, about 50% to about ments 134-180, wherein the pharmaceutical composition 80%, or about 60% to about 80%, about 10% to about is provided in an extended release cancer therapeutic 70%, about 20% to about 70%, about 30% to about 70%, delivery form. about 40% to 70%, about 50% to 70% as compared to a 55 199. The pharmaceutical composition of any of embodi patient not receiving the same treatment. ments 134-180, wherein the pharmaceutical composition 184. The pharmaceutical composition of any of the preced is provided in a Sustained release cancer therapeutic ing embodiments, wherein a cancer therapeutic has a deliver form. half-life of one hour. 200. The pharmaceutical composition of embodiment 199, 185. The pharmaceutical composition of any of the preced 60 wherein the sustained release cancer therapeutic delivery ing embodiments, wherein the dosing of a cancer thera platform releases a cancer therapeutic with Substantially peutic is daily. Zero order release kinetics over a period of about 7 days 186. The pharmaceutical composition of any of the preced after administration, about 15 days after administration, ing embodiments, wherein a cancer therapeutic has a about 30 days after administration, about 45 days after half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 65 administration, about 60 days after administration, about hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 75 days after administration and/or about 90 days after hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, administration. US 9,622,982 B2 75 76 201. The pharmaceutical composition of embodiment 199, 209. The pharmaceutical composition of any proceeding wherein the sustained release cancer therapeutic delivery embodiment, wherein the concentration of a cancer thera platform releases a cancer therapeutic with Substantially peutic is at most 1,000 mg/ml, at most 1,100 mg/ml, at Zero order release kinetics over a period of at least 7 days most 1,200 mg/ml, at most 1,300 mg/ml, at most 1,400 after administration, at least 15 days after administration, mg/ml, at most 1,500 mg/ml, at most 2,000 mg/ml, at at least 30 days after administration, at least 45 days after most 2,000 mg/ml, or at most 3,000 mg/ml. administration, at least 60 days after administration, at 210. The pharmaceutical composition of any proceeding least 75 days after administration, or at least 90 days after embodiment, wherein the concentration of a cancer thera administration. peutic is about 0.00001 mg/ml to about 3,000 mg/ml, 202. The pharmaceutical composition of embodiment 199, 10 wherein the sustained release cancer therapeutic delivery about 0.0001 mg/ml to about 3,000 mg/ml, about 0.01 platform releases a cancer therapeutic with Substantially mg/ml to about 3,000 mg/ml, about 0.1 mg/ml to about first order release kinetics over a period of about 7 days 3,000 mg/ml, about 1 mg/ml to about 3,000 mg/ml, about after administration, about 15 days after administration, 250 mg/ml to about 3,000 mg/ml, about 500 mg/ml to about 30 days after administration, about 45 days after 15 about 3,000 mg/ml, about 750 mg/ml to about 3,000 administration, about 60 days after administration, about mg/ml, about 1,000 mg/ml to about 3,000 mg/ml, about 75 days after administration, or about 90 days after 100 mg/ml to about 2,000 mg/ml, about 250 mg/ml to administration. about 2,000 mg/ml, about 500 mg/ml to about 2,000 203. The pharmaceutical composition of embodiment 199, mg/ml, about 750 mg/ml to about 2,000 mg/ml, about wherein the sustained release cancer therapeutic delivery 1,000 mg/ml to about 2,000 mg/ml, about 100 mg/ml to platform releases a cancer therapeutic with Substantially about 1,500 mg/ml, about 250 mg/ml to about 1,500 first order release kinetics over a period of at least 7 days mg/ml, about 500 mg/ml to about 1,500 mg/ml, about 750 after administration, at least 15 days after administration, mg/ml to about 1,500 mg/ml, about 1,000 mg/ml to about at least 30 days after administration, at least 45 days after 1,500 mg/ml, about 100 mg/ml to about 1,200 mg/ml, administration, at least 60 days after administration, at 25 about 250 mg/ml to about 1,200 mg/ml, about 500 mg/ml least 75 days after administration, or at least 90 days after to about 1,200 mg/ml, about 750 mg/ml to about 1,200 administration. mg/ml, about 1,000 mg/ml to about 1,200 mg/ml, about 204. The pharmaceutical composition of embodiment 199, 100 mg/ml to about 1,000 mg/ml, about 250 mg/ml to wherein a cancer therapeutic delivery platform releases a about 1,000 mg/ml, about 500 mg/ml to about 1,000 cancer therapeutic with substantially Zero order release 30 mg/ml, about 750 mg/ml to about 1,000 mg/ml, about 100 kinetics over a period of about 1 day after administration, mg/ml to about 750 mg/ml, about 250 mg/ml to about 750 about 2 days after administration, about 3 days after mg/ml, about 500 mg/ml to about 750 mg/ml, about 100 administration, about 4 days after administration, about 5 mg/ml to about 500 mg/ml, about 250 mg/ml to about 500 days after administration, or about 6 days after adminis mg/ml, about 0.00001 mg/ml to about 0.0001 mg/ml, tration. 35 about 0.00001 mg/ml to about 0.001 mg/ml, about 205. The pharmaceutical composition of embodiment 199, 0.00001 mg/ml to about 0.01 mg/ml, about 0.00001 wherein a cancer therapeutic delivery platform releases a mg/ml to about 0.1 mg/ml, about 0.00001 mg/ml to about cancer therapeutic with substantially Zero order release 1 mg/ml, about 0.001 mg/ml to about 0.01 mg/ml, about kinetics over a period of, e.g., at most 1 day after 0.001 mg/ml to about 0.1 mg/ml, about 0.001 mg/ml to administration, at most 2 days after administration, at 40 about 1 mg/ml, about 0.001 mg/ml to about 10 mg/ml, or most 3 days after administration, at most 4 days after about 0.001 mg/ml to about 100 mg/ml. administration, at most 5 days after administration, or at 211. The pharmaceutical composition of any of embodi most 6 days after administration. ments 134-180, wherein a cancer therapeutic is formu 206. The pharmaceutical composition of embodiment 199, lated in one fat. wherein a cancer therapeutic delivery platform releases a 45 212. The pharmaceutical composition of any of embodi cancer therapeutic disclosed herein with substantially first ments 134-180, wherein a cancer therapeutic is formu order release kinetics over a period of about 1 day after lated in two fats. administration, about 2 days after administration, about 3 213. The pharmaceutical composition of any of embodi days after administration, about 4 days after administra ments 134-180, wherein a cancer therapeutic is formu tion, about 5 days after administration, or about 6 days 50 lated in three fats, four fats, five fats, six fats or seven or after administration. more fats. 207. The pharmaceutical composition of embodiment 199, 214. The pharmaceutical composition of any of embodi wherein a cancer therapeutic delivery platform releases a ments 134-180, wherein a cancer therapeutic is formu cancer therapeutic disclosed herein with substantially first lated in a fat that is a liquid. order release kinetics over a period of at most 1 day after 55 215. The pharmaceutical composition of any of embodi administration, at most 2 days after administration, at ments 134-180, wherein a cancer therapeutic is formu most 3 days after administration, at most 4 days after lated in at fat that is a solid. administration, at most 5 days after administration, or at 216. The pharmaceutical composition of any of embodi most 6 days after administration. ments 134-180, wherein a cancer therapeutic is formu 208. The pharmaceutical composition of any proceeding 60 lated in two or more fats that are liquids. embodiment, wherein the concentration of a cancer thera 217. The pharmaceutical composition of any of embodi peutic is at least 0.00001 mg/ml, at least 0.0001 mg/ml, at ments 134-180, wherein a cancer therapeutic is formu least 0.001 mg/ml, at least 0.01 mg/ml, at least 0.1 mg/ml, lated in two or more fats that are solids. at least 1 mg/ml, at least 10 mg/ml, at least 25 mg/ml, at 218. The pharmaceutical composition of any of embodi least 50 mg/ml, at least 100 mg/ml, at least 200 mg/ml, at 65 ments 134-180, wherein a cancer therapeutic is formu least 500 mg/ml, at least 700 mg/ml, at least 1,000 mg/ml, lated in two or more fats, wherein at least one fat is a solid or at least 1,200 mg/ml. and at least one fat is a liquid. US 9,622,982 B2 77 78 219. The pharmaceutical composition of any proceeding The metastatic breast cancer consisted of tumors, including embodiment, wherein the concentration of a cancer thera several found in both lungs. The physician prescribed a peutic is at least 0.00001 mg/ml, at least 0.0001 mg/ml, at standard set of cancer therapeutics in an attempt to reduce or least 0.001 mg/ml, at least 0.01 mg/ml, at least 0.1 mg/ml, at least 1 mg/ml, at least 10 mg/ml, at least 25 mg/ml, at maintain the tumors. The patient did not tolerate the cancer least 50 mg/ml, at least 100 mg/ml, at least 200 mg/ml, at therapeutics that were administered that consisted of Taxol least 500 mg/ml, at least 700 mg/ml, at least 1,000 mg/ml, and capecitabine. The physician placed the patient on a or at least 1,200 mg/ml. paliative care regime and provided the patient with several 220. The pharmaceutical composition of any proceeding doses of the aromatase inhibitor, letrazole. Following this embodiment, wherein the concentration of a cancer thera treatment, the patient was administered a CAT scan, which peutic is at most 1,000 mg/ml, at most 1,100 mg/ml, at 10 revealed that her tumors were progressing, including one most 1,200 mg/ml, at most 1,300 mg/ml, at most 1,400 tumor in a lung that had grown by 50% in three months. The mg/ml, at most 1,500 mg/ml, at most 2,000 mg/ml, at patient was next administered a treatment consisting of most 2,000 mg/ml, or at most 3,000 mg/ml. artemether at a dose of 40 mg OD, presented in a lipid filled 221. The pharmaceutical composition of any proceeding capsule comprising tributyrin and G43. A CAT scan given to embodiment, wherein the concentration of a cancer thera 15 the patient several months after administration of artemether peutic is about 0.00001 mg/ml to about 3,000 mg/ml, found that all tumor growth had stopped and the breast about 0.0001 mg/ml to about 3,000 mg/ml, about 0.01 cancer did not progress in the patient during the period of mg/ml to about 3,000 mg/ml, about 0.1 mg/ml to about artemether administration. 3,000 mg/ml, about 1 mg/ml to about 3,000 mg/ml, about 250 mg/ml to about 3,000 mg/ml, about 500 mg/ml to Example 2 about 3,000 mg/ml, about 750 mg/ml to about 3,000 mg/ml, about 1,000 mg/ml to about 3,000 mg/ml, about A patient comprising a 50 year old woman was diagnosed 100 mg/ml to about 2,000 mg/ml, about 250 mg/ml to by her physician with extensive metastaic breast cancer. The about 2,000 mg/ml, about 500 mg/ml to about 2,000 patient presented with tumors in brain liver and lungs. The mg/ml, about 750 mg/ml to about 2,000 mg/ml, about 25 patient also presented with symptoms that included short 1,000 mg/ml to about 2,000 mg/ml, about 100 mg/ml to ness of breath and a persistent cough. The patient informed about 1,500 mg/ml, about 250 mg/ml to about 1,500 the physician that she would not take part in a standard mg/ml, about 500 mg/ml to about 1,500 mg/ml, about 750 chemotherapy treatment protocol. The physician informed mg/ml to about 1,500 mg/ml, about 1,000 mg/ml to about the patient that she would only live for about three months 1,500 mg/ml, about 100 mg/ml to about 1,200 mg/ml, 30 survival. The patient was instead administered artemether at about 250 mg/ml to about 1,200 mg/ml, about 500 mg/ml a dose of 40 mg OD, presented as a lipid filled capsule to about 1,200 mg/ml, about 750 mg/ml to about 1,200 comprising tributyrin and G43. As a result of the treatment, mg/ml, about 1,000 mg/ml to about 1,200 mg/ml, about the symptoms the patient Suffered from, including, shortness 100 mg/ml to about 1,000 mg/ml, about 250 mg/ml to of breath and a persistent cough diminished over the weeks about 1,000 mg/ml, about 500 mg/ml to about 1,000 35 following treatment with arthemether. The patient continues mg/ml, about 750 mg/ml to about 1,000 mg/ml, about 100 to Survive, six months following the initial diagnosis. mg/ml to about 750 mg/ml, about 250 mg/ml to about 750 mg/ml, about 500 mg/ml to about 750 mg/ml, about 100 Example 3 mg/ml to about 500 mg/ml, about 250 mg/ml to about 500 mg/ml, about 0.00001 mg/ml to about 0.0001 mg/ml, 40 A patient comprising a 53 year old male was diagnosed about 0.00001 mg/ml to about 0.001 mg/ml, about with prostate cancer by his physician with several tumors in 0.00001 mg/ml to about 0.01 mg/ml, about 0.00001 the prostate. The physician prescribed a hormone therapeu mg/ml to about 0.1 mg/ml, about 0.00001 mg/ml to about tic formulated in a lipid formulation comprising tributyrin 1 mg/ml, about 0.001 mg/ml to about 0.01 mg/ml, about and G43. The patent was administered the therapeutic over 0.001 mg/ml to about 0.1 mg/ml, about 0.001 mg/ml to 45 a six month period, with a reduction in the size of the tumors. about 1 mg/ml, about 0.001 mg/ml to about 10 mg/ml, or After several more months of treatment, the cancer was about 0.001 mg/ml to about 100 mg/ml. determined to be in remission 222. The pharmaceutical composition of any of embodi ments 134-180, wherein the composition is a liquid, Example 4 semi-solid or a solid formulation 50 223. The pharmaceutical composition of any of embodi A patient comprising a 41 year old male was diagnosed ments 134-180, wherein the therapeutic results in a cancer with pancreatic cancer by his physician which had metas cell not being able to uptake Sufficient quantities of tasized into the brain and liver. The physician prescribed glucose or other energy source resulting in the cell enter chemotherapy, comprising a mixture of cancer therapeutics, ing apoptosis and eventually dying. 55 including Gemzar, Tarceva and Avastin formulated in a lipid 224. The pharmaceutical composition of any of embodi formulation given as a liquid intravenously. The progression ments 134-180, wherein the cancer therapeutic results in of the cancer slowed over time and several of the tumors a cell not being able to uptake Sufficient quantities of a were reduced in size. The patient who was given a three lipid, other fat and/or cholesterol, preventing the cancer month life span lived for an additional four years following cell from dividing and forming a progeny cancer cell. 60 initiation of treatment. EXAMPLES Example 5 Example 1 A patient comprising a 37 year old female was diagnosed 65 with acute myeloid leukemia by her physician which had A patient comprising a 49 year old woman was diagnosed metastasized. The physician prescribed chemotherapy, com by her physician with advanced metastatic breast cancer. prising a 40 mg OD of arthemether formulated in a lipid US 9,622,982 B2 79 80 formulation comprising tributyrin and G43. The progression sicker. The chemotherapy was Supplemented with of the cancer slowed over time. The patient continues to live Arthemether, Simvastin, Metformin, Mebendazole and and their health is improving. Tributyrin. Following initiation of the treatment with these four drugs, the patient, began to become physically stronger. Example 6 5 A patient comprising a 71 year old woman was diagnosed Example 9 by her physician with advanced metastatic breast cancer. The metastatic breast cancer consisted of tumors, including To assess the effect of Artesunate in combination with several found in both lungs. The physician prescribed a 10 standard set of cancer therapeutics in an attempt to reduce or several other therapeutics, MCF-7 cells were treated with maintain the tumors. The patient did not tolerate the cancer different concentrations of these therapeutic compounds therapeutics that were administered that consisted of Taxol either once or through repeated dosing. The percentage of and capecitabine. The physician placed the patient on a survival was calculated based on the LDH contents of cells. paliative care regime and provided the patient with several 15 doses of the aromatase inhibitor, letrazole. Following this Protocol followed: treatment, the patient was administered a CAT scan, which Day -1: Seeding Cells in Wells of Plate revealed that her tumors were progressing, including one tumor in a lung that had grown by 50% in three months. The 1. 100 ul of cells suspension (3x10" cells/ml) were added to patient was next administered a treatment consisting of 20 each well (3000 cells/well), with a total of 5 plates were artemether at a dose of 40 mg OD, presented in a lipid filled seeded. capsule comprising tributyrin and G43. A CAT scan given to 2. Plates were left at room temperature in the hood for 1 hour the patient several months after administration of artemether before being placed in the incubator. found that all tumor growth had stopped and the breast 3. Some wells were left with no cells as background control. cancer did not progress in the patient during the period of 25 artemether administration. Day 0: Treatment 50 ul of each therapeutic treatment was added to wells Example 7 already containing 100 ul of the cell Suspension at the doses indicated in the template below for Sodium Butyrate, A patient comprising a 70 year old female was diagnosed through similar concentrations were used for Resveratrol, with primary peritoneal cancer by her physician with several Daidzein and Equol:

Artesunate

1OOO SOO 2SO 12S 62.5 1OOO SOO 2SO 12S 62.5 ng ml ng/ml ng/ml ng/ml ng/ml () ng ml ng/ml ng/ml ng/ml ng/ml () Sodium 4 mM Butyrate 2 mM 1 mM O.5 mM O.25 mM O.125 nM () Cells in Vehic. Cells in Vehic. Cells in CM Cells in Vehicle Cells in MMC Vehicle

45 tumors in her peritoneum that included Small tumors Preparation of Artesunate for Therapeutic Treatment attached to her large intestine. The female was on chemo Using an analytical balance, Artesunate was weighed therapy and did not see either a reduction in her Cancer straight into a 1.5 ml screw cap tube. Antigen 125 (“CA) test or in the size or number of tumors. The appropriate volume of 100% Ethanol was added to The female began taking a combination of Metformin, 50 Artesunate to obtain a concentration of 10 mg/ml. Lipitor and Mebendazole purchased from a pharmacy. The This was further diluted in 100% Ethanol to 1 mg/ml patient was administered the therapeutic combination over a (1:10). six month period, and during that time period, experienced 4 ug/ml was obtained by diluting 1 mg/ml (1:250) in a reduction in the size of the tumors. After several more complete medium. Further double decreasing dilutions months of treatment, the cancer was determined to be in 55 were carried out in complete medium containing 0.4% remission. Ethanol. Example 8 Preparation of Sodium Butyrate Dilutions for Therapeutic Treatment A patient comprising a 45 year old male was diagnosed 60 Using an analytical balance, Sodium Butyrate was with pancreatic cancer by his physician, which had metas weighed straight into a 15 ml falcon tube. tasized into his brain and liver. The physician prescribed The appropriate Volume of complete medium was added chemotherapy, comprising a mixture of cancer therapeutics, to Sodium Butyrate to obtain a concentration of 100 including Gemzar, Tarceva and Avastin formulated in a lipid mM. formulation given as a liquid intravenously. The progression 65 This was further diluted in complete medium to 16 mM of the cancer slowed over time and several of the tumors (1:6.25). Further double decreasing dilutions were car were reduced in size but the patient became progressively ried out in complete medium. US 9,622,982 B2 81 82 Preparation of Resveratrol Dilutions for Therapeutic Treat and the plates were then incubating at room tempera ment ture in the dark for 30 min. Using an analytical balance, Sodium Butyrate was 50 ul of Stop solution was added to each well and then the weighed straight into a 15 ml falcon tube. plate was read at 492 nm. The appropriate Volume of complete medium was added 5 Day 2: Re-Dosing, LDH-48 h and LDH-Re-Dosing at 24h to Sodium Butyrate to obtain a concentration of 100 8. After 48 h of cells treatment, one of the 2 plates that had mM. been re-dosed after 24 h was re-dosed again (treatments This was further diluted in complete medium to 16 mM were prepared as described above for re-dosing). One of (1:6.25). Further double decreasing dilutions were car the 2 plates that had been treated just once will remain as 10 it was in the incubator. The remaining 2 plates were used ried out in complete medium. to measure the '% of survival by LDH after 48 h of single Preparation of Daidzein Dilutions for Therapeutic Treatment treatment and after re-dosing at 24 h (LDH assay was Using an analytical balance, Sodium Butyrate was performed as described above). weighed straight into a 15 ml falcon tube. Day 3: LDH-72 hand LDH-Re-Dosing at 24 h and at 48 h. The appropriate Volume of complete medium was added 15 After 72 h of cells treatment, there were just 2 plates left in to Sodium Butyrate to obtain a concentration of 100 the incubator. They were used to measure the '% of survival mM. by LDH after 72 h of single treatment and after re-dosing at This was further diluted in complete medium to 16 mM 24 h and 48 h (LDH assay was performed as described (1:6.25). Further double decreasing dilutions were car above). ried out in complete medium. In FIGS. 1 and 2, the results are provided for samples Preparation of Equol Dilutions for Therapeutic Treatment assessed 72 hours after wells containing MCF-7 cells (or no Using an analytical balance, Sodium Butyrate was cells in a control) were administered either a single or a weighed straight into a 15 ml falcon tube. multiple dose of Artesunate and/or Sodium Butyrate. As The appropriate Volume of complete medium was added seen in both figures, Artesunate and Sodium Butyrate indi to Sodium Butyrate to obtain a concentration of 100 25 vidually decreased the survival of MCF-7 cells dosed once mM. or multiple times with one or the other therapeutic treatment. This was further diluted in complete medium to 16 mM When Artesunate and Sodium Butyrate were administered in (1:6.25). Further double decreasing dilutions were car combination to the MCF-7 cells, the percent of cells that ried out in complete medium. survived was less than when Artesunate and Sodium Preparation of Controls 30 Butyrate were administered individually. (see FIGS. 1 and 2 mg of MMC were resuspended in 4 ml of sterile water 2). Further, the percent of cells decreased even more as the to obtain a stock at 0.5 mg/ml. A second dilution of dose of Sodium Butyrate administered with Artesunate was MMC was carried out by diluting 0.5 mg/ml in com increased. (see FIGS. 1 and 2). plete medium to 0.1 mg/ml (1:5). In FIGS. 3 and 4, the results are provided for samples Complete medium was prepared at 0.4% Ethanol 35 assessed 72 hours after wells containing MCF-7 cells (or no 4. Once the treatments were ready, 50 ul/well of Artesunate cells in a control) were administered either a single or a was added to the plates. Next, 50 ul of Sodium Butyrate, multiple dose of Artesunate and/or Resveratrol, Daidzein or Resveratrol, Daidzein or Equol were added to the wells Equol. As seen in both figures, Artesunate decreased the already containing 100 ul of cells suspension plus 50 ul of survival of MCF-7 cells dosed once or multiple times with Artesunate. 40 the therapeutic treatment, while Resveratrol, Daidzein and 5. 50 ul of complete medium at 0.4% Ethanol and 50 ul of Equol when dosed singly had only minimal effect on the just complete medium were added to the corresponding percent of survival of MCF-7 cells, with the percent of control wells already containing either 100 ul of cells Survival decreasing marginally when these therapeutic treat (positive control) or just 100 ul of complete medium ments were administered more than once to the cultured (background control) 45 cells. When Artesunate and Resveratrol, Daidzein or Equol 6. 100 ul of MMC at 100 ug/ml was added to the corre were administered in combination to the MCF-7 cells, the sponding wells already containing 100 ul of cells in percent of cells that survived was less than when Artesunate complete medium as a negative control and finally, plates Resveratrol, Daidzein or Equol were administered individu were placed in the incubator. ally. (see FIGS. 1 and 2). Further, the percent of cells Day 1: Re-Dosing and LDH-24 h 50 decreased even more as the dose of Resveratrol, Daidzein or 7. 24 h after treatment of cells with a the aforementioned Equol administered with Artesunate was increased and as therapeutics, two of the plates were re-dosed with the the dose of Resveratrol, Daidzein or Equol administered same treatments described above, while another two with Artesunate was increased. (see FIGS. 1 and 2). plates were left incubating as they were and the remaining In closing, it is to be understood that although aspects of plate was used to measure the percent of survival by LDH 55 the present specification are highlighted by referring to through the following method: specific embodiments, one skilled in the art will readily Media was removed from the wells by using a multichan appreciate that these disclosed embodiments are only illus nel pipette. trative of the principles of the subject matter disclosed Wells were washed with 200 ul/well of PBS previously herein. Therefore, it should be understood that the disclosed warmed at 37° C. 60 Subject matter is in no way limited to a particular method 100 ul of Titron 1 x in PBS previously warmed at 37° C. ology, protocol, and/or reagent, etc., described herein. As were added to the wells. Subsequently, the plate was Such, various modifications or changes to or alternative placed at 37° C. in the dark for 45 min. configurations of the disclosed subject matter can be made 50 ul from each well was transferred to a non sterile in accordance with the teachings herein without departing 96-well plate. 65 from the spirit of the present specification. Lastly, the 50 ul of LDH substrate were added to each well of the non terminology used herein is for the purpose of describing sterile plate already containing 50 ul/well of lysed cells particular embodiments only, and is not intended to limit the US 9,622,982 B2 83 84 scope of the present invention, which is defined solely by the intended merely to better illuminate the present invention claims. Accordingly, the present invention is not limited to and does not pose a limitation on the scope of the invention that precisely as shown and described. otherwise claimed. No language in the present specification Certain embodiments of the present invention are should be construed as indicating any non-claimed element described herein, including the best mode known to the 5 essential to the practice of the invention. inventors for carrying out the invention. Of course, varia Specific embodiments disclosed herein may be further tions on these described embodiments will become apparent limited in the claims using consisting of or consisting to those of ordinary skill in the art upon reading the essentially of language. When used in the claims, whether as foregoing description. The inventor expects skilled artisans filed or added per amendment, the transition term “consist to employ such variations as appropriate, and the inventors 10 ing of excludes any element, step, or ingredient not speci intend for the present invention to be practiced otherwise fied in the claims. The transition term "consisting essentially than specifically described herein. Accordingly, this inven of limits the scope of a claim to the specified materials or tion includes all modifications and equivalents of the Subject steps and those that do not materially affect the basic and matter recited in the claims appended hereto as permitted by novel characteristic(s). Embodiments of the present inven applicable law. Moreover, any combination of the above- 15 tion so claimed are inherently or expressly described and described embodiments in all possible variations thereof is enabled herein. encompassed by the invention unless otherwise indicated All patents, patent publications, and other publications herein or otherwise clearly contradicted by context. referenced and identified in the present specification are Groupings of alternative embodiments, elements, or steps individually and expressly incorporated herein by reference of the present invention are not to be construed as limita- 20 in their entirety for the purpose of describing and disclosing, tions. Each group member may be referred to and claimed for example, the compositions and methodologies described individually or in any combination with other group mem in Such publications that might be used in connection with bers disclosed herein. It is anticipated that one or more the present invention. These publications are provided solely members of a group may be included in, or deleted from, a for their disclosure prior to the filing date of the present group for reasons of convenience and/or patentability. When 25 application. Nothing in this regard should be construed as an any such inclusion or deletion occurs, the specification is admission that the inventors are not entitled to antedate Such deemed to contain the group as modified thus fulfilling the disclosure by virtue of prior invention or for any other written description of all Markush groups used in the reason. All statements as to the date or representation as to appended claims. the contents of these documents is based on the information Unless otherwise indicated, all numbers expressing a 30 available to the applicants and does not constitute any characteristic, item, quantity, parameter, property, term, and admission as to the correctness of the dates or contents of so forth used in the present specification and claims are to be these documents. understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the The invention claimed is: characteristic, item, quantity, parameter, property, or term so 35 1. A method of treating a cancer, the method comprising qualified encompasses a range of plus or minus ten percent administering one or more cancer therapeutics to an indi above and below the value of the stated characteristic, item, vidual with the cancer, wherein the one or more cancer quantity, parameter, property, or term. Accordingly, unless therapeutics include indicated to the contrary, the numerical parameters set forth a) a first cancer therapeutic that is a therapeutically in the specification and attached claims are approximations 40 effective does of an anti-diabetic drug; that may vary. At the very least, and not as an attempt to limit b) a second cancer therapeutic that is a therapeutically the application of the doctrine of equivalents to the scope of effective dose of a statin; and the claims, each numerical indication should at least be c) a third cancer therapeutic that is a therapeutically construed in light of the number of reported significant digits effective dose of a glycolysis inhibitor. and by applying ordinary rounding techniques. Notwith- 45 2. The method according to claim 1, wherein the anti standing that the numerical ranges and values setting forth diabetic drug is a biguanide, a thiazolidinedione, a secret the broad scope of the invention are approximations, the agogue, an alpha-glucosidase inhibitor and/or a peptide numerical ranges and values set forth in the specific analog, a cinnamon, a thiamine or any combination thereof. examples are reported as precisely as possible. Any numeri 3. The method according to claim 2, wherein the bigu cal range or value, however, inherently contains certain 50 anide is a metformin, a phenformin and/or a buformin. errors necessarily resulting from the standard deviation 4. The method according to claim 1, wherein the statin is found in their respective testing measurements. Recitation of an atorvastatin, a fluvastin, a lovastatin, a pitavastatin, a numerical ranges of values herein is merely intended to pravastatin, a rosuvastatin, a simvastatin or any combination serve as a shorthand method of referring individually to each thereof. separate numerical value falling within the range. Unless 55 5. The method according to claim 1, wherein the glyco otherwise indicated herein, each individual value of a lysis inhibitor includes a hexokinase inhibitor, a phosphog numerical range is incorporated into the present specifica lucose isomerase inhibitor, a fructosebisphosphate inhibitor, tion as if it were individually recited herein. a triosephosphate isomerase inhibitor, a glyceraldehyde The terms “a,” “an,” “the' and similar referents used in phosphate dehydrogenase inhibitor, a phosphoglycerate the context of describing the present invention (especially in 60 kinase inhibitor, a phosphoglycerate mutase inhibitor, an the context of the following claims) are to be construed to enolase inhibitor and/or a pyruvate kinase inhibitor, an cover both the singular and the plural, unless otherwise anti-helminthic agent, an anti-malarial agent, an antibiotic or indicated herein or clearly contradicted by context. All any combination thereof. methods described herein can be performed in any suitable 6. The method according to claim 5, wherein the anti order unless otherwise indicated herein or otherwise clearly 65 helminthic agent includes an abamectin, an aminoacetoni contradicted by context. The use of any and all examples, or triles, a benzimidazole, a diethylcarbamazine, an ivermectin, exemplary language (e.g., “such as') provided herein is a levamisole, niclosamide, an octadepsipeptides, a phos US 9,622,982 B2 85 86 phoric acid, a praziquantel, a spiroindoles, a Suramin, a 14. The method according to claim 13, wherein the pyrantel pamoate or any combination thereof. glucose intake inhibitor includes a GLUT-1 receptor inhibi 7. The method according to claim 6, wherein the benz tOr. is an albendazole, a fenbendazole, a flubendazole, 15. The method according to claim 14, wherein the a thiabendazole or a triclabendazole. GLUT-1 receptor inhibitor is Vitamin C. 8. The method according to claim 7, wherein the fluben 16. The method according to claim 1, further comprising dazole is a mebendazole. administering a fourth cancer therapeutic that is a therapeu 9. The method according to claim 5, wherein the anti tically effective dose of a therapeutic that is a lipid intake malarial agent includes an amodiaquine, an artemisinin, an inhibitor. atovaquone, a chloroquine, a clindamycin, a doxycycline, a 10 17. The method according to claim 16, wherein the lipid halofantrine, a mefloquine, a primaquine, a proguanil, a intake inhibitor includes an LDL receptor inhibitor, an pyrimethamine, a quinine, a rufigallol, a Sulphonamide or SR-81 inhibitor, an SR-82 inhibitor, a SR-83/CD36receptor any combination thereof. inhibitor or any combination thereof. 10. The method according to claim 9, wherein the 18. The method according to claim 17, wherein the LDL artemisinin is an arteether, an artelinate, an artelinic acid, an 15 receptor inhibitor is Vitamin D. artemether, an artemotil, an artemisinin, an artenimol, an 19. The method according to claim 1, wherein the one or arterolane, an artesunate, a dihydroartemisinin and/or a more cancer therapeutics comprise metformin, atorvastatin, dihydroartemisinin methyl ether. mebendazole and doxycycline. 11. The method according to claim 5, wherein the thera 20. The method according to claim 1, done in conjunction peutically effective dose of the anti-diabetic drug is in an with a chemotherapy, a radiation therapy, a Surgery, an amount of 1 mg/kg/day to about 40 mg/kg/day, the thera immunotherapy, or a freezing a tumor. peutically effective dose of the statin is in an amount of 0.01 21. The method according to claim 1, wherein the cancer mg/kg/day to about 10 mg/kg/day, the therapeutically effec is a brain cancer, a bladder cancer, a breast cancer, a colon tive dose of the anti-helminthic agent is in an amount of 0.01 cancer, a rectal cancer, an endometrial cancer, a kidney mg/kg/day to about 10 mg/kg/day and the therapeutically 25 cancer, a renal cancer, a leukemia, a lung cancer, a mela effective dose of the anti-malarial agent is in an amount of noma, a non-Hodgkins lymphoma, a pancreatic cancer, a 0.01 mg/kg/day to about 10 mg/kg/day. prostate cancer, a stomach cancer or a thyroid cancer. 12. The method according to claim 5, wherein the one or 22. The method according to claim 1, wherein the one or more cancer therapeutics comprise an anti-diabetic drug, a more cancer therapeutics comprise an anti-diabetic drug, a statin, an anti-helminthic agent and an anti-malaria agent. 30 statin, an anti-helminthic agent and an anti-malaria agent. 13. The method according to claim 1, further comprising 23. The method according to claim 1, wherein the one or administering a fourth cancer therapeutic that is a therapeu more cancer therapeutics comprise a biguanide, a statin, a tically effective dose of a therapeutic that is a glucose intake benzimidazole and a doxycycline. inhibitor. k k k k k