Oral cyclosporine A - the current picture of its liposomal and other delivery systems

Czogalla, Aleksander

doi:10.2478/s11658-008-0041-6

Cited by 74 publications

(47 citation statements)

References 73 publications

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“…The molecular imaging agents had binding affinities that ranged from subnanomolar to double digit nanomolar and moderate to high plasma protein binding as well as a range in log D (lipophilicity) (Figures 2 and S4). However, the BODIPY-650 agent, with lipophilicity most similar to higher-molecular-weight oral therapeutics such as cyclosporine A (log P = 2.92, 28 oral bioavailability = 30% 29 ), resulted in high nonspecific sticking to antigen-negative and blocked cells (Figure 2C). The fluorophore on the lowest-molecular-weight compound, DDAO, has a p K a of 5, resulting in intracellular fluorescence quenching following internalization, which is an important mechanism for long-term retention.…”

Section: Resultsmentioning

confidence: 99%

Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening

Bhatnagar

Verma

et al. 2018

Mol. Pharmaceutics

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Molecular imaging is advantageous for screening diseases such as breast cancer by providing precise spatial information on disease-associated biomarkers, something neither blood tests nor anatomical imaging can achieve. However, the high cost and risks of ionizing radiation for several molecular imaging modalities have prevented a feasible and scalable approach for screening. Clinical studies have demonstrated the ability to detect breast tumors using nonspecific probes such as indocyanine green, but the lack of molecular information and required intravenous contrast agent does not provide a significant benefit over current noninvasive imaging techniques. Here we demonstrate that negatively charged sulfate groups, commonly used to improve solubility of near-infrared fluorophores, enable sufficient oral absorption and targeting of fluorescent molecular imaging agents for completely noninvasive detection of diseased tissue such as breast cancer. These functional groups improve the pharmacokinetic properties of affinity ligands to achieve targeting efficiencies compatible with clinical imaging devices using safe, nonionizing radiation (near-infrared light). Together, this enables development of a “disease screening pill” capable of oral absorption and systemic availability, target binding, background clearance, and imaging at clinically relevant depths for breast cancer screening. This approach should be adaptable to other molecular targets and diseases for use as a new class of screening agents.

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Section: Resultsmentioning

confidence: 99%

Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening

Bhatnagar

Verma

et al. 2018

Mol. Pharmaceutics

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“…A prime example for the use of phospholipids to enhance its solubility is Cyclosporin A (CyA) (marketed under a number of trade names, such as Cicloral® (Hexal AG), Ciclosol® (Sandoz Pharmaceutical AG), Immunosporin®, Sandimmun® (Novartis Pharma), Neoimmun (Kwizda Pharma), Sandimmun®, (Novartis Pharma), Gengraf® (Abbott Laboratories)), an immunosuppressant with a very low aqueous solubility of only 9.29 µg/ml (86). Several lipid-based formulation principles have been described (14). CyA could be incorporated into a vesicular lecithin system, and the pharmacokinetic behavior of that formulation was compared with that of Sandimmun Neoral® (Novartis Pharma), a combination of cremophor, long-chain mono-, di-and triglycerides from corn oil, DL-α-tocopherol and propylene glycol, which forms a microemulsion in water (44).…”

Section: Liquid and Semiliquid Systemsmentioning

confidence: 99%

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Kromp²,

et al. 2010

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Phospholipids become increasingly important as formulation excipients and as active ingredients per se. The present article summarizes particular features of commonly used phospholipids and their application spectrum within oral drug formulation and elucidates current strategies to improve bioavailability and disposition of orally administered drugs. Advantages of phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low membrane penetration potential, but also improvement or alteration of uptake and release of drugs, protection of sensitive active agents from degradation in the gastrointestinal tract, reduction of gastrointestinal side effects of non-steroidal anti-inflammatory drugs and even masking of bitter taste of orally applied drugs. Technological strategies to achieve these effects are highly diverse and offer various possibilities of liquid, semi-liquid and solid lipid-based formulations for drug delivery optimization.

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“…Neoral® (launched in 1994) was able to reduce this variability by more effectively solubilizing cyclosporine A in the small intestine. Formulation optimization subsequent to the launch of Neoral® has aimed at further reducing PK variability (64). Therefore, the cyclosporine A case study highlights, in line with the authors' own experiences, the important interplay between structural features and delivery considerations when designing and developing a peptide for oral delivery.…”

Section: Oral Delivery Of Peptides Drug Substance and Drug Product Chmentioning

confidence: 80%

“…The potential for oral peptide therapeutics is exemplified by cyclosporine A, a natural product. Its physicochemical, formulation, ADME and PK (pharmacokinetic) properties have been extensively described in the literature and are summarized in Table IV ( [63][64][65]. Characteristics of this molecule include a cyclic structure, modified peptide bonds, and unnatural amino acids that help stabilize cyclosporine A against classical peptide degradation routes (i.e., exo-and endo-peptidases).…”

Section: Oral Delivery Of Peptides Drug Substance and Drug Product Chmentioning

confidence: 99%

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

Bak

Leung

Barrett

et al. 2014

AAPS J

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Abstract. Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.

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Oral cyclosporine A - the current picture of its liposomal and other delivery systems

Cited by 74 publications

References 73 publications

Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening

Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

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