Process Development and Quality Control of Injectable Liposomal Therapeutics

Jensen, Greg; Bunch, T. H.; Hu, Ning; Eley, Crispin G. S.

doi:10.1201/9780849397264.ch15

Cited by 9 publications

(8 citation statements)

References 3 publications

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“…The reconstituted materials in each vial were examined for median particle size and for the upper limit of the range of diameters corresponding to 90% of the particles. The latter measure is referred to as the 90% passing diameter and is an indicator of the presence of particles larger than 100 nm in the small unilamellar vesicle dispersion (24). The results for four vials of each product are presented in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…The results of the comparison of these two liposomal amphotericin B products underscore the importance of controlling not only the chemical composition but also the process parameters and the quality control testing of the liposomes. Various stresses on liposomes, such as sterile filtration during production and filtration prior to use, requirements for refrigeration, lyophilization conditions, and dilution in infusion diluents, can lead to flocculation, aggregation, leakage of the drug, phase separation, and disintegration of the liposomes (24). To adequately monitor these variables, strict product quality control assays that include extensive chemical, physical, and biological testing should be done to ensure uniformity of the final product.…”

Section: Discussionmentioning

confidence: 99%

“…An example of this effect comes from the early development of AmBi, when it was reported that liposomes formed by sonication were more toxic in mice than those produced by homogenization even though the liposomes had the same drug-to-lipid molar ratios (1). Jensen et al (24) reported that other stresses on a liposomal product, such as sterile filtration during production, storage, and lyophilization procedures, also have to be controlled to produce batches that are reproducible from lot to lot and that sensitive assays have to be developed to monitor any changes. Another liposomal amphotericin B preparation, Anfogen (hereinafter referred to as Anfo; Genpharma, S.A., Argentina), was recently licensed in Argentina and is reported to have the same chemical composition as AmBi, but it is manufactured differently (Administración Nacional de Medicamentos, Alimentos y Tecnología Médica [Argentina] certificate of approval no.…”

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confidence: 99%

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Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Olson

Adler-Moore

Jensen

et al. 2008

Antimicrob Agents Chemother

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Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K 50 values were significantly lower for Anfogen (0.9 g/ml) than for AmBisome (20 g/ml), and the LD 50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.The use of the broad-spectrum fungicidal agent amphotericin B (37) has been limited to 1 mg/kg of body weight/day with a maximum cumulative dose of 2 to 4 g (19) because of its well-documented acute infusion-related toxicities and chronic renal toxicity. Three lipid-amphotericin B formulations approved in the United States and Europe have been developed to reduce these toxicities: Amphotec, Abelcet, and AmBisome (hereinafter referred to as AmBi). Each formulation demonstrates significant reduction in toxicities, the extent of which varies among the products. Amphotec (Three Rivers Pharmaceuticals, LLC, Cranberry Township, PA) consists of amphotericin B in a complex with cholesteryl sulfate at a 1:1 molar ratio to form stable colloidal discoidal structures with diameters of 100 Ϯ 22 nm (21), and the single-administration 50% lethal dose (LD 50 ) for mice is 36 mg/kg (21). Abelcet (Enzon Pharmaceuticals, Inc., Bridgewater, NJ), composed of amphotericin B, dimyristoyl phosphatidylcholine, and dimyristoyl phosphatidylglycerol in a 1:1 drug-to-lipid molar ratio, forms ribbon-like complexes (1.6 to 11 m), with 90% of the particles being smaller than 6 m in diameter, and the single-administration LD 50 for mice is Ͼ40 mg/kg (7). AmBi (Gilead Sciences, Inc., Foster City, CA.), a unilamellar liposomal formulation of amphotericin B in which particle diameters are approximately 80 nm, is composed of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, and amphotericin B in a 2:1:0.8:0.4 molar ratio, and the single-administration LD 50 for mice is Ͼ175 mg/kg (35).These different commercialized amphotericin B-lipid formulations vary in their pharmacokinetic profiles (4), although their efficacies in vivo at doses of 5 to 10 mg/kg are similar in preclinical models of candidiasis (17,20,34), cryptococcosis (10), aspergillosis (3,9,16,33), and coccidioidomycosis (13,18). The significantly lower toxicity of AmBi compared to the other formulations, however, has allowed t...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Olson

Adler-Moore

Jensen

et al. 2008

Antimicrob Agents Chemother

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“…Scalable production methods capable of replicating these sonicated batches came from high shear homogenization. This technology was well established in the Dairy industry but had to be substantially adapted for use in SUV production, including exceeding normal operating ranges, parameter optimization, and establishment of endpoints (Gamble 1988;Jensen et al, 2006). Figure 11 shows a comparative biodistribution of sonicated and homogenized 111 In liposomal preparations.…”

Section: Manufacturing and Quality Controlmentioning

confidence: 98%

Conventional Liposome Performance and Evaluation: Lessons from the Development of Vescan

Jensen

Bunch

2007

Journal of Liposome Research

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In the early 1980s, Vestar Inc., a company founded on the basis of science developed by the California Institute of Technology and the City of Hope, brought into development an imaging agent based on liposome encapsulated (111)In(3+). This agent, named Vescan, together with the gamma ray perturbed angular correlation spectroscopy technique to examine liposome integrity, was envisioned as a broadly applicable in vivo tumor diagnostic agent. While not ultimately commercialized, the agent was used to successfully image a variety of tumors, and was evaluated in late-stage clinical trials. Lessons learned from the formulation and process development of this product, and the wealth of non-clinical and clinical results, revealed valuable information about the properties of stable, RES avoiding conventional liposomes. This technology ultimately would lead (at NeXstar Pharmaceuticals and, later, at Gilead Sciences) to the technology that created commercialized liposomal products such as AmBisome and DaunoXome as well as other development stage product candidates.

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“…Liposomes are prepared using sterile production processes at laboratory or industrial scale. 3 , 28 , 29 , 30 , 31 , 32 Numerous R&D and clinical trials have been conducted in which cationic liposomes were used as non-viral gene delivery systems but none of these products have completed clinical phase studies. 33 , 34 Conventional, polymer-coated and targeted liposomes being used therapeutically were licensed through existing pharmaceutical legislation.…”

Section: Liposomesmentioning

confidence: 99%

Ocular Drug, Gene and Cellular Delivery Systems and Advanced Therapy Medicinal Products

Eldem¹,

Eldem²

2018

tjo

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Due to recent advances in science and technology, when the products used in therapy are examined, ophthalmology has a priority in terms of research and development, preclinical and clinical studies of innovative drugs, medical devices and drug-medical device combination products. Liposomes, micelles, nanoemulsions, nanoparticles with colloidal structures and intraocular implants as sustained-release drug delivery systems have been developed to overcome the barriers to ocular applications, increase absorption, decrease metabolism and elimination and increase the residence time in ocular tissues and compartments. Studies are also ongoing in the area of advanced therapies using gene or cell-based systems which are high-risk products due to their complex structures. In this review, ocular drug, gene and cellular delivery systems and related products and developments in advanced therapy medicinal products are presented in respect to the definition of drug (medicinal product) and current changes in legislation.

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Process Development and Quality Control of Injectable Liposomal Therapeutics

Cited by 9 publications

References 3 publications

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Conventional Liposome Performance and Evaluation: Lessons from the Development of Vescan

Ocular Drug, Gene and Cellular Delivery Systems and Advanced Therapy Medicinal Products

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