[Usp 724 Drug Release Pdf Download
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Biopolymeric microparticles have been widely used for long-term release formulations of short half-life chemicals or synthetic peptides. Characterization of the drug release from microparticles is important to ensure product quality and desired pharmacological effect. However, there is no official method for long-term release parenteral dosage forms. Much work has been done to develop methods for in vitro drug release testing, generally grouped into three major categories: sample and separate, dialysis membrane, and continuous flow (flow-through cell) methods. In vitro drug release testing also plays an important role in providing insight into the in vivo performance of a product. In vitro release test with in vivo relevance can reduce the cost of conducting in vivo studies and accelerate drug product development. Therefore, investigation of the in vitro-in vivo correlation (IVIVC) is increasingly becoming an essential part of particulate formulation development. This review summarizes the principles of the in vitro release testing methods of biopolymeric particulate system with the recent research articles and discusses their characteristics including IVIVC, accelerated release testing methods, and stability of encapsulated drugs.
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Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.
Antibody-drug conjugates (ADCs) are a promising class of biopharmaceuticals that combine the target-specificity of monoclonal antibodies (mAbs) or mAb fragments with the potency of small molecule toxins1,2. They are designed to bind to an internalising cancer cell receptor leading to uptake of the ADC and subsequent intracellular release of the drug by enzymes, thiols or lysosomal pH. Routing the toxin to the tumour, while minimising the peripheral damage to healthy tissue, allows the use of highly potent drugs resulting in improved therapeutic outcomes. Presently, four ADCs are approved by the American Food and Drug Administration (FDA): brentuximab vedotin (Adcetris) for Hodgkin and anaplastic large cell lymphoma, ado-trastuzumab emtansine (Kadcyla) for HER2-positive metastatic breast cancer, gemtuzumab ozogamicin (Mylotarg) for acute myeloid leukaemia and inotuzumab ozogamicin (Besponsa) for the treatment of acute lymphoblastic leukaemia. For example, Adcetris afforded a 75% overall response rate in patients with relapsed or refractory Hodgkin lymphoma and a median duration of response of 21 months3. Encouraged by these first successes, over 60 ADCs are now in clinical trials for a variety of haematologic and solid tumour malignancies1,2,3.
Nevertheless, the current strategies do have some limitations, especially with respect to solid tumours. Haematologic tumours typically exhibit specific and homogenous expression of the target antigen and are well perfused and, therefore, accessible to the ADC3,4. On the other hand, therapy of solid tumours is hampered by the relatively limited number of suitable cancer-specific targets and the poor intratumoral distribution of ADCs2,4. The elevated interstitial pressure in solid tumours impedes penetration by large constructs such as ADCs5. This penetration can also be affected by the binding to cancer cells in the perivascular space and to antigens in the interstitial space, shed from dying cells5,6,7. The heterogeneous receptor expression observed in solid tumours further confounds homogeneous drug delivery1,5. Importantly, the number of solid tumour-specific receptors that ensure efficient internalisation and drug release is relatively limited. Low receptor copy numbers, slow internalisation kinetics, inefficient subcellular trafficking and receptor expression levels in normal tissues all complicate the selection of solid tumour targets for the current ADC approaches4,8,9. Furthermore, contrary to haematologic targets, solid tumour targets are typically only overexpressed in a subset of patient populations3,8. For example, only 20% of breast cancer patients have sufficient HER2 expression to be eligible for treatment with Kadcyla.
Herein, we report the first example of such click-to-release ADC therapy in tumour-bearing mice, enabled by the development of a diabody conjugate with a high tumour uptake combined with a fast blood clearance, and a new tetrazine activator that gives near-quantitative drug release (Fig. 1). Biodistribution and imaging experiments show that the ADC, comprising the TCO-linked drug monomethyl auristatin E (MMAE) and polyethylene glycol (PEG), matches the high tumour uptake of the parent mAb combined with very low levels in non-target tissues, and that the tetrazine activator can effectively reach this conjugate throughout the tumour. Efficacy studies in two mouse xenograft models demonstrate a potent therapeutic effect, whereas an analogous ADC containing the protease sensitive valine-citrulline linker, used in the marketed ADC Adcetris and designed for intracellular release, fails to control tumour growth in both models. These findings indicate that the click-to-release concept allows to expand the scope of ADC therapy to non-internalising receptors and stroma targets, forming the basis for a broader applicability across patient populations, thus potentially lowering the hurdle for success against solid tumours.
M.S.R., R.R., P.J.H. conceived the project; R.R., M.S.R., A.H.A.M.v.O., P.J.H., R.M.V., H.M.J. designed the studies; R.M.V., A.K., W.t.H. performed the organic synthesis; R.R. developed the radiochemistry; J.W. prepared the diabody conjugates; R.M.V., H.J.W. performed the ADC release studies with mass spectrometry; R.R., A.H.A.M.v.O. performed the in vitro and in vivo experiments; R.R., M.S.R., R.M.V., H.J.W., A.H.A.M.v.O., E.J.S, H.M.J., P.J.H. analysed results and/or edited the manuscript; M.S.R., R.R. wrote the manuscript.
R.R., A.H.A.M.v.O. and M.S.R. are employed by and shareholder of Tagworks. J.W. is employed by Avipep and P.J.H. is shareholder of Avipep. Both companies have a direct financial interest in the subject matter discussed in this manuscript. The remaining authors declare no competing interests.
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Dissolution is the process in which a substance forms a solution. Dissolution testing measures the extent and rate of solution formation from a dosage form, such as tablet, capsule, ointment, etc. The dissolution of a drug is important for its bioavailability and therapeutic effectiveness. Dissolution and drug release are terms used interchangeably.
To properly evaluate the dissolution of drug products, it is critical for procedures to be standardized. This standardization helps to show consistent quality in production and may serve as a predictive measure of efficacy.
A dissolution test uses an apparatus with specific test conditions in combination with acceptance criteria to evaluate the performance of the product. General chapter Dissolution includes 4 standardized apparatus: basket, paddle, reciprocating cylinder, and flow-through cell. Where specified in a monograph, USP dissolution tests are legal requirements. USP training and service are designed to help you meet regulatory compliance requirements while strengthening your quality standards.
The PVT assesses dissolution apparatus performance using the USP reference standard material and procedures. This page includes resources that may be used for the PVT. The PVT is an integral part of USP General Chapter Dissolution.
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