Formulation of cell-based medicinal products: a question of life or death?

The formulation of cell-based medicinal products (CBMPs) poses major challenges because of their complexity, heterogeneity, interaction with their environment (e.g., the formulation buffer, interfaces), and susceptibility to degradation. These challenges can be quality, safety, and efficacy related. In this commentary we discuss the current status in formulation strategies of off-the-shelf and non-off-the-shelf (patient-specific) CBMPs and highlight advantages and disadvantages of each strategy. Analytical tools for the characterization and stability assessment of CBMP formulations are addressed as well. Finally, we discuss unmet needs and make some recommendations regarding the formulation of CBMPs. (C) 2020 American Pharmacists Association?. Published by Elsevier Inc. All rights reserved.Personalised Therapeutic

Ongoing challenges to develop high concentration monoclonal antibody-based formulations for subcutaneous administration: Quo Vadis?

Although many subcutaneously (s.c.) delivered, high-concentration antibody formulations (HCAF) have received regulatory approval and are widely used commercially, formulation scientists are still presented with many ongoing challenges during HCAF development with new mAb and mAb-based candidates. Depending on the specific physicochemical and biological properties of a particular mAb-based molecule, such challenges vary from pharmaceutical attributes e.g., stability, viscosity, manufacturability, to clinical performance e.g., bioavailability, immunogenicity, and finally to patient experience e.g., preference for s.c. vs. intravenous delivery and/or preferred interactions with health-care professionals. This commentary focuses on one key formulation obstacle encountered during HCAF development: how to maximize the dose of the drug? We examine methodologies for increasing the protein concentration, increasing the volume delivered, or combining both approaches together. We discuss commonly encountered hurdles, i.e., physical protein instability and solution volume limitations, and we provide recommendations to formulation scientists to facilitate their development of s.c. administered HCAF with new mAb-based product candidates.Drug Delivery Technolog

Labelled StealthR liposomes in experimental infection : an alternative to leukocyte scintigraphy?

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Sterically stabilized liposomes labeled with Indium-111 to image focal infection

Contains fulltext : 21192___.pdf (publisher's version ) (Open Access

Comparison of breast-conserving therapy with mastectomy for treatment of early breast cancer in community hospitals

Although the results of clinical trials support breast-conserving therapy as a replacement for mastectomy in early breast cancer, the question remains,whether these results apply in routine clinical practice. In the present analysis the breast cancer-specific survival and recurrence-free survival of 464 consecutive patients with breast tumours ≤ 3 cm across undergoing breast-conserving therapy were compared with a group of 459 patients with similar extent of disease and period of diagnosis undergoing mastectomy. All patients were treated in community hospitals in the south-eastern Netherlands. Median follow-up of both treatment groups was 6.2 years. After adjustment for the prognostic effects of age, tumour size, axillary nodal status and adjuvant systemic therapy, neither breast cancer-specific survival nor recurrence-free survival differed significantly between the breast-conserving therapy group and the mastectomy group. This finding indicates that in routine clinical practice breast-conserving therapy may be as effective as mastectomy

Detecting infection and inflammation with technetium-99m-labeled stealth liposomes

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Critical factors for liposome-incorporated tumour-associated antigens to induce protective tumour immunity to SL2 lymphoma cells in mice

Physical and immunogenic properties of re- constituted membranes designed for the presentation of tumour-associated antigens (TAA) to the immune system are described. Proteins and lipids of crude membranes of SL2 routine lymphosarcoma cells were partially solubi- lized with octylglucoside. Reconstituted membranes, con- sisting mainly of unilamellar vesicles with a diameter of 0.03-0.15 gm, were formed by detergent removal and were purified by floatation in a discontinuous sucrose gra- dient to remove non-lipid-bound protein. Subcutaneous immunization of syngeneic mice with reconstituted mem- branes or with purified reconstituted membranes induced protection against an intraperitoneal challenge with 103 viable SL2 cells. Reconstituted membranes were more im- munogenic than crude membranes in immunoprotection experiments when compared on the basis of protein dose. Detergent removal was required to obtain an immunogenic presentation form of SL2 membrane antigens and to avoid toxicity associated with the detergent. Reconstitution of SL2 membranes in the presence of exogenous phos- pholipid slightly increased the fraction of protein that as- sociated with the reconstituted membranes. However, the immunogenicity of the solubilized membrane TAA was not significantly affected by the presence of exogenous phospholipid. The reconstitution procedure described may be useful in identifying membrane factors required for the induction of immune responses against TAA. The versatil- ity of the system may be employed to develop safe alterna- tives for whole-cell vaccines

Stability of doxorubicin-liposomes on storage : as an aqueous dispersion, frozen or freeze-dried

Shelf-life of doxorubicin (DXR) containing negatively charged liposomes was studied under various conditions. The following parameters were monitored: DXR-latency, stability against aggregation or fusion, and chemical stability of bilayer components and associated DXR. An ion exchange resin was used to remove free DXR from liposome-associated DXR. As an alternative for storing aqueous dispersions, the liposomes were frozen and freeze-dried. Variables under investigation were: type of cryoprotectant (saccharides, polyvinylpyrrolidone and mannitol), particle size (about 0.1, 0.25 and 0.65 μm), physical state of the bilayer (“gel”- or “fluid”-like, inclusion of α-tocopherolacetate). A comparison was made between the behaviour of a bilayer interacting compound (DXR) and a non-interacting compound (carboxyfluorescein, CF). When stored as aqueous dispersions extruded multilamellar structures (0.25 μm) showed lower DXR leakage rates than sonicated vesicles (0.1 μm). In the presence of various saccharides freezing and freeze-drying resulted in similar DXR latencies on thawing or rehydration; they provided adequate protection against aggregation or fusion. Other cryoprotectants failed. Latency of a bilayer-interacting drug like DXR, was hardly sensitive to variation of the bilayer structure; in contrast to this observation, latency of CF strongly depended on the bilayer composition. Under the experimental conditions no effects of ageing could be observed in terms of changing leakage profiles, aggregation behaviour or chemical decomposition of DXR

In vitro release studies on drugs suspended in non-polar media II. The release of paracetamol and chloramphenicol from suspensions in liquid paraffin

The release of paracetamol and chloramphenicol (water solubility 13 and 3.6 mg · g−1, respectively), suspended in liquid paraffin, to an underlying aqueous layer was investigated as a function of particle size (10–60 μm), concentration (0.5–6% m/m) and the presence of additives (DOSS-Na: di-(2-ethylhexyl) sodium sulphosuccinate and/or water) in the liquid paraffin. A hypothesis was formulated predicting the release to be independent of particle size, concentration and degree of coverage of the interface by particles, if the mass flow of the interface would exceed the dissolution rate of the particles at the interface. This limiting rate would approximate the intrinsic dissolution rate. The experimental results showed that for low concentrations the release was determined by the settling mass flow. With more concentrated suspensions the release was dissolution controlled and in general a good agreement with the proposed hypothesis was found. Addition of water (0.01 or 0.05% m/m) to the suspensions increased the degree of agglomeration and reduced the degree of interfacial coverage, but did not change the release rate. The presence of 0.2% m/m DOSS-Na in the paracetamol suspensions did not influence the rate either, but in combination with water (0.01 or 0.05% m/m) an increase was observed; the particles did not stay at the interface during dissolution, but they fell through it as such. With chloramphenicol this happened already in the presence of 0.2% m/m DOSS-Na. Water addition enhanced this effect dramatically

In vitro release studies on drugs suspended in non-polar media I. Release of sodium chloride from suspensions in liquid paraffin

The release of a readily water-soluble substance (sodium chloride) from a liquid paraffin phase to an underlying water phase was investigated as a function of particle size (10–50 μm) and concentration (up to 10% m/m). Transport of the suspended particles to the interface by sedimentation was the rate limiting step. The release rate increased with primary particle size and concentration. The small particles showed a more pronounced concentration dependence than the large ones. During settling, agglomerates were formed. But, mild shear rates kept the primary particles in the deglomerated state. Low concentrations of DOSS-Na (di(2-ethylhexyl) sodium sulphosuccinate) up to 0.2% m/m in liquid paraffin reduced the degree of agglomeration, while trace amounts of water (0.01 and 0.05% m/m) showed the opposite effect. The observed phenomena are discussed on basis of the DLVO-theory, supplemented with considerations about forces due to gravity, shear and liquid bridge formation, and the kinetics of agglomeration