Lipid-based nanomedicines

CHAPTER

Lipid-based nanomedicines: Current clinical status and future perspectives

13

Deep Pooja1, Amrita Kadari1, Hitesh Kulhari1,2 and Ramakrishna Sistla1 1

CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India 2Central University of Gujarat, Gandhinagar, Gujarat, India

CHAPTER OUTLINE 13.1 Lipid-Based Nanocarriers ...............................................................................510 13.2 Lipid-based clinical nanomedicines ................................................................510 13.2.1 Lipid-Based Formulations for the Treatment of Cancer ...................510 13.2.2 Lipid-Based Formulations for the Treatment Viral Infections ...........517 13.2.3 Lipid-Based Formulations for Pain Medication ..............................518 13.2.4 Lipid-Based Formulations for Antifungal Drugs .............................518 13.2.5 Lipid-Based Formulations for the Treatment of Age-Related Macular Degeneration .................................................................519 13.3 Ongoing Clinical Trials on Lipid-Based Formulations ........................................519 13.3.1 LEP-ETU (NCT00080418)........................................................522 13.3.2 LEM-ETU (NCT00024492).......................................................522 13.3.3 EndoTAG-1 (NCT00448305) ....................................................522 13.3.4 Marqibo (NCT00495079) .........................................................523 13.3.5 ThermoDox (NCT00826085).....................................................523 13.3.6 T4N5 Liposome Lotion (NCT00089180)....................................523 13.3.7 Liposomal SN-38 (NCT00311610) ...........................................524 13.3.8 Aroplatin (NCT00316511)........................................................524 13.3.9 Liprostin (NCT00053716) ........................................................525 13.3.10 OSI-211 (NCT00046800) ........................................................525 13.3.11 Arikace (NCT00777296) ..........................................................525 13.4 Conclusion and Future Perspective..................................................................525 Acknowledgments ...................................................................................................526 References .............................................................................................................526 Further Reading ......................................................................................................528

Lipid Nanocarriers for Drug Targeting. DOI: http://dx.doi.org/10.1016/B978-0-12-813687-4.00013-X © 2018 Elsevier Inc. All rights reserved.

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13.1 LIPID-BASED NANOCARRIERS Drug delivery systems of nanometric range are usually designated as “nanodrug delivery systems.” Among various nanodrug delivery systems, lipid-based nanosystems have emerged as an interesting system for the delivery of drug and genetic materials. A lipid-based nanosystem is generally composed of lipids and emulsifiers (Pooja et al., 2015a). Sometimes, it may also be a hydrophilic cosolvent. The lipids being used for the preparation of nanoformulations are triglycerides or mixed glycerides, composed of long- or medium- chain fatty acids. Emulsifiers are surface active agents and are responsible for the stability of dispersion formed during the preparation of lipid-based nanoformulations. In order to improve the stability of the formulations, a combination of emulsifier is used. The secondary emulsifier is also known as coemulsifier (Pooja et al., 2015b, 2016). Lipid-based nanosystems are mainly categorized into five major types: liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), lipid-drug conjugates, and lipid polymer hybrid nanoparticles. Table 13.1 summarizes the methods of preparation, advantages and disadvantages of different lipid-based nanosystems.

13.2 LIPID-BASED CLINICAL NANOMEDICINES Lipid-based nanomedicines are currently available in the market for the treatment of cancer, viral infections, pain management, fungal infections, and age-related macular generation (Table 13.2).

13.2.1 LIPID-BASED FORMULATIONS FOR THE TREATMENT OF CANCER Depocyt is an FDA approved liposome formulation of cytarabine for the treatment of patients with lymphomatous meningitis, a life-threatening complication of lymphoma. Cytarabine is metabolized intracellularly into its active triphosphate form, cytosine arabinoside triphosphate, which competes with deoxycytidine triphosphate and inhibits DNA polymerase. Depocyt is designed to produce sustained release of the cytarabine and is manufactured by a unique proprietary technology called DepoFoam. Following administration, the drug is released from DepoFoam by erosion and/or reorganization of the lipid membranes. Due to sustained release of drug, Depocyt has an extended half-life of up to 82.4 h, compared to 3.4 h for the native drug. Depocyt is composed of cholesterol, triolein, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dipalmitoyl-snglycero-3-phosphoglycerol (DPPG) (11:1:7:1 molar ratio) (Table 13.2). It is administered into the spinal fluid through intrathecal or intraventricular

Table 13.1 Methods of Preparation, Advantages and Disadvantages of Lipid-Based Nanocarriers Type of Lipidic Nanoparticles Liposomes

Solid lipid nanoparticles

Method of Preparation

Advantages

1. Thin film hydration method 2. French or high pressure extrusion method 3. Reverse phase evaporation method 4. Detergent removal method Novel technologies for liposome preparation 1. Supercritical fluid technology 2. Supercritical reverse phase evaporation method 3. Dual asymmetric centrifugation 4. Cross-flow filtration detergent depletion method 5. Freeze drying double emulsion method 1. High pressure homogenization 2. Solvent emulsification technique 3. Microemulsion technique 4. Solvent emulsification diffusion method 5. Solvent injection method

• • • •

Excellent biodegradability Preventing drug leakage Increased drug stability via encapsulation Nontoxic, flexible, biocompatible, completely biodegradable, and nonimmunogenic

• Drug protection from chemical and enzymatic degradation • Ability to incorporate both hydrophilic and hydrophobic drugs • Production can be scaled up • Ease of manufacture • Avoidance of organic solvents • High drug entrapment efficiency • Possibility of sterilization • Small diameter and narrow size distribution • Biodegradability

Disadvantages • Low solubility • Sometimes phospholipid undergoes oxidation and hydrolysis-like reactions • Leakage and fusion of encapsulated drug/ molecules • Production cost is high

• Drug expulsion after polymorphic transition during storage • High operative temperature • Storage in refrigerated conditions

(Continued)

Table 13.1 Methods of Preparation, Advantages and Disadvantages of Lipid-Based Nanocarriers Continued Type of Lipidic Nanoparticles

Method of Preparation

Advantages

Disadvantages

• Efficient crossing of biological barriers Nanostructured lipid carriers

1. 2. 3. 4.

High pressure homogenization Solvent emulsification technique Microemulsion technique Solvent emulsification diffusion method 5. Solvent injection method

Lipid-drug conjugate nanoparticles

1. High pressure hot or cold homogenization method 2. Solvent emulsification technique 3. Microemulsion technique 4. Solvent emulsification Diffusion method 5. Solvent injection method

Lipid polymer hybrid nanoparticles

1. Two-step method: The polymeric core and lipid shell are prepared separately using two independent processes; then the two components are combined by direct hydration, sonication, or extrusion to obtain the desired lipid shell polymer core structure 2. Single-step method: Here a nanoprecipitation process is synchronized with a simultaneous self-assembly process Includes • Modified solvent extraction/ evaporation method • Modified nanoprecipitation method

• Improves drug loading • Firmly incorporates the drug during storage • Flexible modulation of release profile • Improved performance in producing final dosage forms such as creams, tablets, capsules and injectables • Suspensions of higher solid content can be produced (e.g., 30% 50% solid) • Higher loading capacity as compared to SLN and NLC • Hydrophilic drug is transformed to a more lipophilic, insoluble molecule by conjugation with a lipidic compound • Diffuse very fast into newly formed interfacial layers and stabilize the formed small droplets efficiently minimizing subsequent coalescence phenomena • Exhibit complementary characteristics of both polymeric nanoparticles and liposomes, particularly in terms of their physical stability and biocompatibility • Easier to perform, one-step method, relying on simultaneous self-assembly of the lipid and polymer, which has resulted in better products and higher production throughput

• Growth of particles • Unpredictable gelation tendency • Chances of polymeric transitions • Inherent low incorporation rate

• Technical complexity • Less efficient processes of preparing both polymeric core and liposome vesicles separately • Time-consuming preparation steps

Table 13.2 Summary of Liposome-Based, Marketed Formulation Product Name

Manufacturing Company

Active Ingredient

Lipid Composition (Molar Ratio)

Doxil

Doxorubicin

Lipodox

ALZA Corporation (Johnson & Johnson) Sun Pharma

Doxorubicin

Myocet

Teva Pharma B.V.

Doxorubicin

HSPC, CH and PEG2000-DSPE (56:39:5) DSPC, CH and PEG2000-DSPE (56:39:5) EPC and CH (55:45)

DaunoXome Depocyt

Gilead Sciences Enzon Pharmaceuticals, Inc. Gilead Sciences/ Fujisawa Healthcare

Daunorubicin Cytarabine

Ambisome Amphotec Abelcet Epaxal

Enzon Pharmaceuticals, Inc. Crucell UK Ltd.

Inflexal V

Berna Biotech Ltd, Berne Switzerland

DepoDur

SkyePharma PLC and Endo Pharmaceuticals Novartis

Visudyne

Amphotericin B Amphotericin B Amphotericin B Inactivated hepatitis A virus A mixture of three monovalent virosome pools {A (H1N1), A(H3N2), B} Morphine sulfate Verteporfin

DSPC and CH (2:1) CH, Triolein, DOPC and DPPG (11:1:7:1) HSPC, DSPG and CH (2:0.8:1) Cholesteryl sulfate DMPC and DMPG (7:3)

Approved Indication Kaposi’s sarcoma, ovarian and breast cancer Kaposi’s sarcoma, ovarian and breast cancer Combination therapy with cyclophosphamide in metastatic breast cancer Blood tumors Neoplastic meningitis and lymphomatous meningitis Fungal infections

Route of Administration Intravenous Intravenous Intravenous

Intravenous Spinal Intravenous

Fungal infections Fungal infections

Intravenous Intravenous

DOPC and DOPE

Hepatitis A

Intramuscular

DOPC and DOPE

Influenza

Intramuscular

CH, Triolein, DOPC and DPPG (11:1:7:1) DMPC and EPG (5:3)

Pain management

Epidural

Age-related macular degeneration

Intravenous

Abbreviations: CH: Cholesterol, DMPC: 1,2-Dimyristoyl-sn-glycero-3-phosphocholine, DMPG: 1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol, DOPC: 1,2-Dioleoyl-sn-glycero-3-phosphocholine, DOPE: 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, DPPG: 1,2-Dipalmitoyl-sn-glycero-3phosphoglycerol, DSPC: 1,2-Distearoyl-sn-glycero-3-phosphocholine, EPC: Egg phosphatylcholine, EPG: Egg phosphatylglycerol, HSPC: Hydrogenated soybean L-α-phosphatidylcholine, PEG: Polyethylene glycol.

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CHAPTER 13 Lipid-based nanomedicines

administration. Chemical arachnoiditis is the major side effect of Depocyt and observed in all the studies. Therefore, patients receiving Depocyt are treated concurrently with dexamethasone (Pillai, 2014). Another lipid-based clinical nanomedicine of anticancer drug is Marqibo. It is a sphingomyelin and cholesterol (approximately 60:40 molar ratios)-based liposome formulation of vincristine sulfate, a microtubule inhibitor. Vincristine sulfate is a vinca alkaloid isolated from Catharanthus roseus. Vincristine sulfate is used to treat acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin’s disease, neuroblastoma, and small cell lung cancer. Marqibo has been approved for the treatment of Philadelphia chromosome-negative (Ph2) acute lymphoblastic leukemia (ALL) in second or greater relapse. Marqibo is recommended at a dose of 2.25 mg/m2 intravenously over 1 h once a week (Harrison and LysengWilliamson, 2013). The preclinical studies showed that liposome formulation of vincristine showed more improved pharmacokinetics and accumulation in tumor tissues than pure vincristine (Silverman and Deitcher, 2013). Doxorubicin HCl (DOX) is an anticancer drug isolated from cultures of Streptomyces peucetius var. caesius. Chemically, it is an anthracycline antibiotic which acts by inhibiting topoisomerase II, and intercalating with DNA and RNA polymerases. Native DOX causes cumulative dose-dependent cardiomyopathy, leading to potentially fatal congestive heart failure (Batist et al., 2002). Doxil is a poly(ethylene glycol)-coated, stealth liposome formulation of DOX, which is approved by FDA as the first nanodrug based formulation. It is composed of hydrogenated soybean L-α-phosphatidylcholine (HSPC), cholesterol, and PEG2000-DSPE in 56:39:5 molar ratios. Doxil is loaded via an ammonium sulfate gradient. The drug-loading is based on the exchange of amphipathic weak-base DOX with the ammonium ions (Fig. 13.1) (Barenholz, 2012). Free DOX base diffuses inside the aqueous phase of liposome, where it crystallizes as doxorubicin sulfate. The crystallized doxorubicin sulfate can’t diffuse back and results in accumulation inside the liposomes (Fritze et al., 2006). A graphic representation of Doxil is shown in Fig. 13.2. In clinical studies, the delivery of DOX was significantly better after intravenous administration as Doxil than free DOX (Fig. 13.3). PEGylated liposomes showed prolonged circulation time and avoidance of reticuloendothelial system. Doxil is indicated for the treatment of ovarian cancer at a dose of 50 mg/m3 intravenously every 4 weeks, for AIDS-related Kaposi’s sarcoma at a dose of 20 mg/m3 intravenously every 3 weeks (Hengge et al., 1993), and for multiple myeloma in combination with bortezomib at a dose of 30 mg/m3 intravenously on day 4, following bortezomib. Similarly, Lipo-Dox is also a PEGylated liposomal formulation of DOX, indicated for AIDS-related Kaposi’s sarcoma, which consisted of DPSC, cholesterol and PEG-2000-DSPE in 56:39:5 molar ratios. Myocet is another liposomal formulation of DOX, containing liposomeencapsulated doxorubicin-citrate complex. It consists of egg phosphatylcholine and cholesterol in 55:45 molar ratios. Myocet is remote-loaded by a citric acid

13.2 Lipid-Based Clinical Nanomedicines

FIGURE 13.1 Improved loading of doxorubicin in liposomes by weak-base exchange mechanism (Barenholz, 2012).

Extraliposome medium Lipid bilayer hydrophobic part (rigid LO) Intraliposome precipitated drug Hydrated and charge hindered headgroups by PEG Head group attached Flexible highly hydrated polymer Intraliposome aqueous phase

FIGURE 13.2 Graphic representation of typical Doxil formulation (Barenholz, 2012).

gradient (Duong et al., 2016) that enhances drug encapsulation efficiency to more than 95%. Myocet significantly improves the pharmacokinetic profile of DOX. DOX administered as Myocet showed 20-fold higher area under the curve (AUC), 25-fold lower volume of distribution, and 9-fold decreased clearance

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CHAPTER 13 Lipid-based nanomedicines

DOXIL

1.80 µg DOX—equivalents per mL or gram

516

1.60 1.40 1.20

Cells Fluid

1.0

DOXIL

0.80 DOXIL

0.60 0.40 0.20 0.0

Free DOX Patient 6 (25 mg/m2)

Free DOX

Patient 8 (50 mg/m2)

Free DOX Patient 14 (50 mg/m2)

FIGURE 13.3 Improved delivery of doxorubicin after intravenous administration as Doxil in comparison to pure doxorubicin (Gabizon et al., 1995; Barenholz, 2012).

(Batist et al., 2002). In combination with cyclophosphamide, it is indicated for metastatic breast cancer at a dose of 60 75 mg/m3 every 3 weeks with 600 mg/m3 dose of cyclophosphamide. Both PEGylated and non-PEGylated liposome-based formulations of DOX cause less cardiotoxicity and are better tolerated than conventional DOX. However, due to longer circulation time, PEGylated formulations cause stomatitis (Chang and Yeh, 2012). DaunoXome is a non-PEGylated liposomal formulation of daunorubicin, which was the first anthracycline developed as anticancer agent. It is comprised of DSPC and cholesterol in 2:1 molar ratios and approved for AIDS-related Kaposi’s sarcoma by FDA. Other liposomal formulations of DOX are under clinical investigation, such as MM-302, which is targeted to HER2-positive metastatic breast cancer and ThermoDox, which is a thermo-sensitive formulation and releases DOX at elevated temperatures. CPX-351 is a liposomal formulation containing dual agents, both cytarabine and daunorubicin, in 5:1 fixed molar ratio. The formulation has shown promising efficacy in treatment of hematologic malignancies in Phase I and II studies. Several additional Phase II studies are still ongoing. Several liposomal formulations of other anticancer drugs are under clinical investigation, which includes cisplatin, docetaxel, paclitaxel, and irinotecan. Cisplatin is also one of the most commonly used anticancer drugs and its major limitation is neuro- and nephrotoxicity. Various liposomal formulations of cisplatin were developed (such as L-NDDP, SPI-77, Lipoplatin and LiPlaCis) and were tested clinically.

13.2 Lipid-Based Clinical Nanomedicines

Irinotecan is a semi-synthetic derivative of camptothecin, obtained from Camptotheca acuminata and elicits its anticancer activity by inhibiting topoisomerase I, specifically in S-phase. Irinotecan has shown its anticancer activity against many cancers, such as colorectal, gastric, nonsmall-cell and small-cell lung cancers, leukemia, and malignant gliomas (Rothenberg, 2001). MM-398, also known as PEP-02, is a novel PEGylated liposomal irinotecan that has shown improved pharmacokinetics and tumor biodistribution of the free irinotecan in clinical studies (Hann et al, 2007). In the Phase II study, improvement in survival end points was also noticed. On the basis of these studies, it was approved as second-line treatment for metastatic pancreatic cancer at dose of 120 mg/m3 every 3 week (Chen et al., 2008). Liposomal formulations of docetaxel (LE-DT) and paclitaxel (LEP-ETU) are also developed and under clinical investigation as these are wide spectrum anticancer agents and active against a variety of cancers.

13.2.2 LIPID-BASED FORMULATIONS FOR THE TREATMENT VIRAL INFECTIONS Lipid-based formulations have also been developed for the treatment of different viral infectious diseases, such as hepatitis A and influenza. Epaxal is liposome formulation of inactivated hepatitis A virus. Hepatitis A virus, strain RG-SB, is produced by propagating in MRC-5 human diploid cells, followed by purification and inactivation by exposure to formalin (Ott et al., 2012). Inactivated virus was encapsulated/bound to virosomes composed of phospholipids, lecithin (phosphatidylcholine) and cephalin (phosphatidylethanolamine) and of viral phospholipids. Epaxal, by Crucell (Bern, Switzerland), was the first virosome-based vaccine approved for commercial use. Virosomes are fusiogenic viral envelope proteins containing liposomes. These proteins allow the virosomes to fuse with target cells. In addition, virosomes protect molecules from degradation by endosomes and lysosomes (Kaneda, 2000). Virosomes are biocompatible, biodegradable, and nonimmunogenic itself and, therefore, have the desirable characteristics of an adjuvant system (Herzog et al., 2009). Epaxal is indicated for active immunization against hepatitis A of children from 1 year of age and adults. The safety and efficacy has been well documented in about 40 clinical studies involving over 6800 subjects, including more than 1500 children (Bovier, 2008). However, Epaxal is contraindicated in the patients who are hypersensitive to any of the vaccine components, eggs, chicken protein, or formaldehyde. Epaxal is supplied as 0.5 mL suspension in a prefilled syringe (Type I glass) with rubber plunger stopper (chlorobutyl) for intramuscular injection. The product needs to be stored in a refrigerator (2 8 C) and protected from light. In 2008, Crucell’s pediatric received approval as Epaxal Junior. This vaccine has superior tolerability, compared with alum-adjuvanted HAV vaccines and does not interfere with other pediatric vaccines (Moser et al., 2013).

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Another virosome-based marketed formulation is InflexalV. InflexalV was introduced in 1997 by Crucell company, Berna Biotech AG, for the immunization against influenza and has now been approved in 38 countries. It is the only virosomal-adjuvant influenza vaccine licensed for all age groups (from 6 months and up) (Herzog et al., 2009). It is composed of a mixture of three monovalent virosome pools (A(H1N1), A(H3N2), B), each formed with one influenza strain’s specific hemagglutinin and viral neuraminidase glycoproteins (Mischler and Metcalfe, 2002). The major advantages of InflexalV are high purity, demonstrated by low ova albumin content (,10 ng/dose) and no thiomersal or formaldehyde (Herzog et al., 2009). InflexalV is highly immunogenic and well tolerated in children, young adults, and the elderly (Mischler and Metcalfe, 2002).

13.2.3 LIPID-BASED FORMULATIONS FOR PAIN MEDICATION Morphine sulfate is a narcotic opioid analgesic and is a powerful pain reliever used for both acute (short term) and chronic pain. Although epidural infusions of morphine sulfate are well accepted and efficacious, several concerns remain to be solved, such as problems and complications related to catheter placement: the potential for epidural hematoma with anticoagulation, technical issues with the infusion pumps, and the time and labor necessary to place, adjust, and manage catheters and infusions (Nagle and Gerancher, 2007). A single bolus injection of DepoDur emerged as a solution for these concerns. DepoDur is an extended-release liposome injection of morphine sulfate. After epidural administration of DepoDur, morphine sulfate is released slowly from the liposomes and provides effective postoperative analgesia for 48 h (Hartrick and Hartrick, 2008). DepoDur is used to control the acute postoperative pain following lower abdominal and lower extremity surgery. DepoDur is a sterile suspension of morphine sulfate encapsulating multivesicular liposomes prepared using DepoFoam technology. The large size (7 40 μm) of DepoFoam particles results in longer retention in epidural space due to limited lymphatic and systemic uptake (Nagle and Gerancher, 2007). Each vial of DepoDur contains morphine sulfate (10 mg/mL), DOPC (4.2 mg/mL), cholesterol (3.3 mg/mL), DPPG (0.9 mg/mL), tricaprylin (0.3 mg/mL) and triolein (0.1 mg/mL).

13.2.4 LIPID-BASED FORMULATIONS FOR ANTIFUNGAL DRUGS Amphotericin B (AmB) is one of the most active antifungal agents. Amphotericin B, a polyene antibiotic is obtained from Streptomyces nodosus, which binds to ergosterol an essential component of the fungal cell membrane; it depolarizes the membrane and changes the cell membrane permeability, which leads to cell death. Its use is significantly limited by its severe and lethal toxicities, such as high fever, chills, hypotension, anorexia, nausea, vomiting, and significant

13.3 Ongoing Clinical Trials on Lipid-Based Formulations

nephrotoxicity. Therefore, different formulations have been developed for delivery of AmB. The three lipid-based formulations of AmB in clinical stages are Abelcet (Sigma-Tau Pharmaceuticals), AmBisome (Gilead Sciences, Inc.), and Amphotec (Sequus Pharmaceuticals). These formulations have different structures and pharmacokinetics. AmBisome is a true liposomal formulation consisting of HSPC, DSPG, cholesterol and AmB in 2:0.8:1:0.4 molar ratios. It improves the Cmax and AUC by 8- to 10-fold than that of AmB. Another formulation, Abelcet, which is also called AmB lipid complex (ABLC), is comprised of DMPC and DMPG (7:3 molar ratio) and has a ribbon-like structure. In clinical studies, ABLC (5 mg/kg) was found to have equivalent efficacy but significantly less toxicity than AmB (0.6 1 mg/kg). It was indicated for invasive fungal infections in patience having intolerance to conventional AmB therapy. Amphotec is also a lipid complex of AmB consisting of cholesteryl sulfate. It has shown higher AUC than AmB in clinical studies at a dose of 7.5 mg/kg. It has also shown less infusion-related toxicity and no nephrotoxicity. Smaller size of Amphotec leads to less RES uptake and clearance.

13.2.5 LIPID-BASED FORMULATIONS FOR THE TREATMENT OF AGERELATED MACULAR DEGENERATION The applications of lipid-based formulations have been extended to deliver photosensitizers for the treatment of age-related macular degeneration. Visudyne is an example of such a successful formulation. Visudyne is a lyophilized liposome formulation of verteporfin, a photosensitizer. Chemically, verteporfin is a benzoporphyrin derivative and is used for photodynamic therapy for the treatment of classic (“wet”) subfoveal choroidal neovascularization due to age-related macular generation (Christie and Kompella, 2008). Visudyne consists of verteporfin, egg phosphatidyl glycerol, and dimyristoyl phosphatidylcholine at the molar ratios of 1:5:3:5, respectively. The formulation also contains two antioxidants (ascorbyl palmitate, butylated hydroxytoluene) and a cryoprotectant (lactose) (Puri, 2014; Chang and Yeh, 2012). Visudyne is administered intravenously 15 min before exposure to nonthermal red light. After exposure to red light, verteporfin generates highly reactive, shortlived singlet oxygen and reactive oxygen radicals, which damage the abnormal endothelium and blockage of the vessels (Christie and Kompella, 2008).

13.3 ONGOING CLINICAL TRIALS ON LIPID-BASED FORMULATIONS Various lipid-based formulations are currently under clinical trials. These formulations are summarized in Table 13.3.

519

Table 13.3 Ongoing Clinical Trials on Lipid-Based Formulations Formulation

Drug

Sponsored by

NCT No.

Indicated for

Clinical Trial Phase

LEP-ETU LIPUSU

Paclitaxel Paclitaxel

NCT00080418 NCT01994031

Ovarian cancer Solid tumors

Phase I Phase IV

LEM-ETU EndoTAG-1

Mitoxantrone Paclitaxel

INSYS Therapeutics Inc. Nanjing Luye Sike Pharmaceutical Co., Ltd. INSYS Therapeutics Inc MediGene

NCT00024492 NCT00448305

Phase I Phase II

ARIKACE

Amikacin

Insmed Incorporated

NCT00777296

Marqibo

Vincristine sulfate

Spectrum Pharmaceuticals, Inc.

NCT00495079

ThermoDox

Doxorubicin

Celsion

NCT00826085 NCT00441376

T4N5 liposome lotion

Enzyme T4bacteriophage endonuclease V Irinotecan

National Cancer Institute (NCI)

NCT00089180

Solid tumors Pancreatic cancer and triple-negative breast cancer Cystic fibrosis with Pseudomonas lung infections Philadelphia chromosome-negative (Pha) acute lymphoblastic leukemia (ALL) Breast cancer Primary and metastatic tumors of the liver Nonmelanoma skin cancer

Alliance for Clinical Trials in Oncology PharmaEngine New York University School of Medicine

NCT00311610

Colorectal cancer

Phase II

NCT00813163 NCT00316511

Pancreatic neoplasm Malignancies, B-Cell lymphoma Malignant Pleural Mesotheliom

Phase II Phase I

Liposomal SN38 PEP-02 Aroplatin

Irinotecan Cisplatin

NCT00004033

Phase I and Phase 2 Phase II

Phase I Phase I Phase III

Phase II

SPI-077

Cisplatin

Liprostin

New York University School of Medicine Centre Hospitalier Universitaire Vaudois Endovasc

Lipoplatin

Cisplatin

Liprostin OSI-211

NCT00004083

Ovarian cancer

Phase II

NCT02702700

Pleural malignancies

Phase II

NCT00053716

Peripheral Arterial Occlusive Disease Ovarian Neoplasms Postoperative pain levels

Phase II

Lurtotecan Bupivacaine

Astellas Pharma Inc. Loma Linda University

NCT00046800 NCT02659501

Phase II Recruiting participants

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CHAPTER 13 Lipid-based nanomedicines

13.3.1 LEP-ETU (NCT00080418) LEP-ETU is a liposomal preparation of paclitaxel, an anticancer agent used for the treatment of breast cancer, lung cancer, ovarian cancer, Kaposi’s sarcoma, pancreatic cancer and cervical cancer. Paclitaxel is currently marketed as Taxol, which is formulated with polyoxyethylated castor oil often associated with hypersensitivity reactions. LEP-ETU is composed of synthetic phospholipids and cholesterol, and is indicated mainly for the treatment of breast cancer. Phase I study of the formulation showed better tolerability and enhanced antitumor activity with shorter infusion time and fewer side effects, even at higher doses than Taxol. As a consequence, it is under Phase II clinical trials. Slingerland et al. (2013) performed the preclinical studies in patients administered with LEP-ETU, which showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil with reduced toxicity. Liposomal paclitaxel, along with Nedaplatin is also tested in patients with advanced or recurrent esophageal carcinoma under Phase II clinical trial, which is completed. Another study, sponsored by Tianjin Medical University Cancer Institute and Hospital is currently recruiting patients for the study in which Nimotuzumab (hR3), an IgG1 humanized monoclonal antibody along with liposomal paclitaxel is used in the treatment of nonsmall-cell lung cancer. This new formulation for ovarian cancer treatment is also under clinical trials.

13.3.2 LEM-ETU (NCT00024492) Mitoxantrone, along with lyophilized lipids, has been formulated as liposome for the treatment of solid tumors. The Phase I study of this formulation is completed. The primary objective of the study is to improve the safety profile of drug and dose intensification with minimal side effects. This formulation is also being tested for the treatment of various other cancers, such as advanced recurrent or metastatic breast cancer, diffuse large B-cell lymphoma and lymphoma peripheral T cell, and non-Hodgkin’s lymphoma. It is currently recruiting participants in Phase I clinical trials.

13.3.3 ENDOTAG-1 (NCT00448305) EndoTAG-1 is composed of paclitaxel embedded in liposomal membranes for targeting tumor endothelial cells. It is indicated for the treatment of pancreatic cancer and triple-negative breast cancer. This novel composition is formulated using neutral and positive lipids. The positively charged lipids rapidly interact with the negatively charged endothelial cells, thereby preventing the growth of new blood vessels (Awada et al., 2014; Ignatiadis et al., 2016). Medigene has successfully completed Phase II clinical trials of EndoTAG-1.

13.3 Ongoing Clinical Trials on Lipid-Based Formulations

13.3.4 MARQIBO (NCT00495079) Marqibo is a proprietary sphingomyelin- and cholesterol-based liposomal formulation of vincristine (VCR) that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR (Silverman and Deitcher, 2013). A Phase II study, sponsored by Spectrum Pharmaceuticals, Inc., to evaluate the safety and efficacy of Marqibo (Vincristine sulfate liposomes injection) was conducted for the treatment of ALL and is completed. Phase I study of the formulation is also completed for malignant melanoma. Liposomal vincristine sulfate, along with dexamethasone, underwent Phase I and Phase II clinical trials in patients with relapsed or refractory ALL. The Phase II study indicated for aggressive non-Hodgkin’s lymphoma is also completed.

13.3.5 THERMODOX (NCT00826085) The US Food and Drug Administration (FDA) approved doxorubicin hydrochloride liposomal injection (Sun Pharma Global FZE), a generic version of Doxil Injection (doxorubicin hydrochloride liposome; Janssen Products, L.P.) on February 4, 2013, for the treatment of ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy, and for AIDSrelated Kaposi’s sarcoma after failure of prior systemic chemotherapy or intolerance to such therapy. ThermoDox is a thermo-sensitive liposomal formulation of doxorubicin for the treatment of regional breast cancer. Upon heating the tumor for 60 min, it is capable of selectively releasing its drug contents 25 times more onto the tumor site when exposed to temperatures .39.5 C. The Phase I and Phase II studies of the formulation are completed. In another clinical trial (NCT00441376), ThermoDox is used in combination with radiofrequency ablation in the treatment of primary and metastatic tumors of the liver and the Phase I study for this combination is completed.

13.3.6 T4N5 LIPOSOME LOTION (NCT00089180) Xeroderma pigmentosum (XP) is a rare genetic disease in which patients have defective DNA repair and are extremely sensitive to solar UV radiation exposure. A new treatment approach was tested in these patients. A prokaryotic DNA repair enzyme, specific (T4-bacteriophage endonuclease V) for UV-induced DNA damage, was delivered into the skin by means of topically applied liposomes (T4N5 liposome lotion) to supplement the deficient activity (Yarosh et al., 1996). The T4N5 liposome lotion is a topical preparation containing the enzyme T4bacteriophage endonuclease V, encapsulated within liposomes and indicated against actinic keratoses and other sun-induced skin damage in patients with XP. The Phase III study of T4N5 liposomal topical lotion was completed and is approved by FDA, which is used for the prevention of the recurrence of

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nonmelanoma skin cancer in patients who have undergone a kidney transplant also indicated for basal cell carcinoma of the skin, recurrent skin cancer squamous cell carcinoma of the skin. It is marketed in the United States with the brand name Dimericine.

13.3.7 LIPOSOMAL SN-38 (NCT00311610) This is a chemotherapeutic drug product consisting of the active metabolite of irinotecan (CPT-11), a known anticancer drug, encapsulated in liposomes and is under trials for various cancer, including colorectal cancer (NCT00311610), advanced neoplasm (NCT00046540), and colorectal neoplasms (NCT00361842) in combination with floxuridine. LE-SN-38 for advanced tumors is administered intravenously as infusion every 3 weeks to determine the safety and tolerability of study drug. The Phase II clinical trials of the liposomal formulation against colorectal cancer and colorectal neoplasm is completed and only Phase I study is completed for advanced neoplasm. PEP-02 is also a liposomal irinotecan-containing formulation investigated for Phase I and pharmacokinetic study in patients with metastatic colorectal cancer refractory to first-line oxaliplatin base therapy (NCT00940758). It is also investigated in patients with pancreatic neoplasms, in combination with 5-fluorouracil and leucovorin for solid tumors (NCT02884128). LE-SN-38 formulation showed a favorable pharmacokinetics profile and at therapeutically effective doses conducted in CD2F1 mice and beagle dogs (Pal et al., 2005).

13.3.8 AROPLATIN (NCT00316511) Cisplatin is an anticancer drug from the class of platinum-containing chemotherapeutic agents and forms platinum complexes upon binding to DNA, causing the DNA strands to crosslink, ultimately triggers cells to die in a programmed way. This drug is indicated for the treatment of testicular, ovarian, bladder, head and neck, esophageal, small and nonsmall-cell lung, breast, cervical, stomach, and prostate cancers. It is also indicated for Hodgkin’s and non-Hodgkin’s lymphomas, neuroblastoma, sarcomas, multiple myeloma, melanoma, and mesothelioma. These platinum-based chemotherapeutic drugs, although utilized for variety of cancers, are limited due to its higher toxicity issues and suboptimal pharmacokinetic properties (Liu et al., 2013). New York University School of Medicine, in collaboration with National Cancer Institute, have performed the Phase II clinical trials of liposome-entrapped cisplatin analog (L-NDDP), Aroplatin, which was administered intrapleurally to patients with malignant pleural mesotheliom. This formulation also underwent Phase I clinical trial for lymphoma and neoplasms, sponsored by Agenus Inc. Combination therapy of Aroplatin, along with gemcitabine and capecitabine is also under clinical trials for pancreatic and colorectal cancers respectively. SPI-077 (NCT00004083), a stealth liposomal formulation of

13.4 Conclusion and Future Perspective

chemotherapeutic drug cisplatin under Phase II clinical trial, has been performed with an objective to determine the response rate in patients with recurrent platinum-sensitive ovarian epithelial cancer.

13.3.9 LIPROSTIN (NCT00053716) Peripheral arterial occlusive disease is a condition, caused by atherosclerosis, with intense pain due to a decrease in arterial blood flow to lower limb and feet. Prostaglandin E1 is a vasoactive hormone used for treatment of peripheral arterial occlusive disease. It is the first clinical research trial (Phase II) in which liposomal prostaglandin E1 (Lipoprostin) is given twice to each artery to be treated, just before and after angioplasty. When the angioplasty procedure is completed, a 12-h intravenous infusion of Liprostin is given to complete the treatment procedure.

13.3.10 OSI-211 (NCT00046800) Lurtotecan encapsulated liposome is being investigated for the treatment of various tumors, such as ovarian neoplasms (NCT00046800), carcinoma, small cell (NCT00046787), fallopian tube and peritoneal cavity cancer (NCT00010179), and head and neck cancer (NCT00022594). The Phase II clinical trials are completed for the above indicated cancers. This formulation has shown reasonable hematologic toxicity in an open-label Phase II study (Seiden et al., 2004).

13.3.11 ARIKACE (NCT00777296) This is a liposomal formulation incorporating amikacin in nanoscale liposomes and is indicated for the treatment of cystic fibrosis with pseudomonas lung infections (Clancy et al., 2013). The Phase I and Phase II studies have been completed by Insmed Inc., a biopharmaceutical company. Arikace as inhalation therapy was studied to determine the safety and tolerability of 28 days of daily dosing of 560 mg of Arikace, versus placebo, in patients with cystic fibrosis. This delivery system is under Phase III clinical trials in subjects with nontuberculous mycobacterial lung infection caused by Mycobacterium avium complex.

13.4 CONCLUSION AND FUTURE PERSPECTIVE Lipid-based nanomedicines are the true leaders in the clinical success of nanomedicines. These nanomedicines have great potential in clinical practice for the treatment of various diseases. However, the most successful lipid-based formulation is the oldest liposome. Although other lipid-based formulations, such as

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SLNs, lipid-drug conjugates, and lipid nanostructures have been extensively explored in preclinical studies, the clinical future still need to be tested. Apart from synthetic drug molecules, lipid-based nanomedicines have also shown promise in the delivery of biological drugs and imaging agents. The interdisciplinary research of nanotechnology, material science, and pharmaceutical science will bring advancement in the development of clinically successful nanomedicines. Stimuli-responsive or targeted lipid nanomedicines may be another future of current lipid nanomedicines.

ACKNOWLEDGMENTS Authors acknowledge Director, CSIR-Indian Institute of Chemical Technology, Hyderabad for encouragement. A.K. would like to thank ICMR (Indian Council of Medical Research), New Delhi for awarding Senior Research Fellowship. H.K. acknowledges Department of Science and Technology, New Delhi for DST INSPIRE Faculty award. Figures presented in this chapter have been reprinted after permission from Elsevier under licence number 4019380324146.

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FURTHER READING Allen, T.M., Cullis, P.R., 2013. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev. 65, 36 48. Ghate, V.M., Lewis, S.A., Prabhu, P., 2016. Nanostructured lipid carriers for the topical delivery of tretinoin. Eur. J. Pharm. Biopharm. 108, 253 261. Pattni, B.S., Chupin, V.V., 2015. New developments in liposomal drug delivery. Chem. Rev. 115, 10938 10966. Trevaskis, N.L., Kaminskas, L.M., Porter, C.J.H., 2015. From sewer to saviour—targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14, 781 803. Zhang, L., Zhu, D., Dong, X., Sun, H., Song, C., Wang, C., et al., 2015. Folatemodified lipid polymer hybrid nanoparticles for targeted paclitaxel delivery. Int. J. Nanomedicine 10, 2101 2114.