A basal-bolus regimen that better matches physiological insulin secretion is offered as a basis of insulin regimen to achieve tight control of blood glucose in a daily life. An insulin regimen includes Multiple Daily Injections (MDI) using insulin pens and Continuous Subcutaneous Insulin Infusion (CSII) using insulin pumps. Administrating insulin subcutaneously with a dose accuracy requires high-precision and high-quality delivery devices, as well as usability, easier to understand, comfort, and reliability for patients. The development of insulin delivery devices has added an improvement in these items through the long periods of time and stages. In the future it is expected to develop delivery devices that are able to deal with an “individual” including an addition of assistive functions for ensuring more accuracy in patients’ procedures; a more improved portability than before; and having programming functions to support detailed parts of each patients’ life under diabetic care.

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Insulin degludec provided the basal insulin replacement therapy of a once daily treatment. The combination drug of insulin degludec/insulin aspart provided replacement therapy for both one prandial insulin and daily basal insulin by a single injection. Insulin detemir provided the basal insulin replacement therapy with lower intarasuject variation in fasting blood glucose and lower risk of nocturnal hypoglycaemia compared to NPH insulin. Liraglutide provided a new and favorable pharamacotherapy for type 2 diabetes based on the pharmacological action of GLP―1, glucose-dependent insulin secretion. Furthermore, the clinical development of semaglutide having pharmocokinetic profile suitable for once-weekly treatment was completed and it is expected to be approved for the effecive treatment of type 2 diabetes with reduced stress.

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Novel technology to deliver functional proteins as biopharmaceutical via pulmonary route has been developing because the methodology is applicable for relatively large molecules. In this review, inhalable insulin products will be introduced. Afrezza^® (owned by MannKind) is an insulin dry-powder-inhaler formulation approved by US FDA in 2014. A technique to prepare fine particles by using unique medical additive which was called as Technosphere, allowed the product to obtain not only narrow particles distribution which was useful to deliver the particles into alveolar region but also fast solubility and absorption after the accumulation in alveolar. As Afrezza^® is classified as ultra-rapid-acting insulin formulation, it is administered just before meal to prevent the increase of prandial blood sugar. Afrezza can induce cough which is a typical side effect of powder type of inhalation formulation and has limitation against the COPD and asthma patients. Dance-501 (owned by Dance Biopharm) is an insulin liquid aerosol formulation and is expecting for future trial (completed Phase 2). It is estimated that inhalation formulation of biopharmaceutical including insulin will be promising formulation as patient-friendly formulation.

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Diabetic patients require multiple daily injections of GLP-1 and/or insulin throughout their lifetime. Great effort for developing effective needle-free GLP-1 and insulin delivery technology, especially oral delivery, has been continued in worldwide, although these drugs are typical problematic peptide that is susceptible to degradation by enzymes and has low membrane permeability. Oral administration of biopharmaceuticals would offer not only the potential for improved medication adherence but also improved safety/efficacy in certain instances. Recently, large pharmaceutical companies have entered into partnerships with bioventure companies to develop noninvasive delivery systems for biopharmaceuticals and are energetically conducting clinical trials. This review provides an update on recent approaches that have shown promise in GLP-1 and insulin noninvasive delivery systems. In addition, the progress of basic research in needle-free delivery systems for biopharmaceuticals is discussed.

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SGLT2 inhibitors exert their anti-diabetic actions by inhibiting renal glucose reabsorption and increasing glucose excretion into urine. They selectively inhibit Na⁺/glucose cotransporter SGLT2 in proximal convoluted tubules in kidney. The drugs have been developed by modifying phlorizin, a natural O-glycoside, to obtain C-glycosides with high metabolic stability, and high affinity and selectivity to SGLT2. They are filtered by glomerulus in kidney to be excreted into glomerular filtrate and bind to SGLT2 on the apical membrane of renal tubules to inhibit it. SGLT2 inhibitors reduce glucotoxicity by lowering blood sugar of diabetic patients to improve the diabetic symptoms and disease state. The decrease of cardiovascular death and their renal protective effects have been reported and proved by large scale clinical studies, promising the significant contribution of SGLT2 inhibitors in the treatment of patients with diabetes mellitus.

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Type 1 diabetes (T1D) is an autoimmune disease in which blood glucose level is uncontrollable due to the destruction of pancreatic islet β-cells by auto-reactive immune cells. If immune suppression specific for β-cell-derived antigens, namely the immune tolerance could be induced, it would be possible to stop proceeding with destruction of β-cells at the early stage, and the dependence of patients’ insulin would be reduced. Moreover, if transplanted pancreatic islet grafts could be kept without continuous administration of immunosuppressants, patients would spend insulin-free lifetime. T1D arises from the breakdown of immune tolerance towards pancreatic β-cells that may result from defects in natural killer T (NKT) cells and regulatory T cells (Tregs) function. Given the similarities in the pathogenesis of disease between humans and NOD mice, we hypothesize that the activation of NKT cells may modulate the onset and severity of T1D. To date, the most powerful activator of NKT cells described is a synthetic α-galactosylcermide (α-GalCer). NKT cells activated by αGC rapidly produce large quantities of immunomodulatory cytokines, including IL-2, IL-4, IL-10 and IFN-γ. Of note, IL-2 and IL-10 are key cytokines for both the survival and expansion of Tregs and for promoting the generation of tolerogenic antigen-presenting cells (APCs). Thus, NKT cells have multiple functions by which they may induce the immune tolerance to self-reactive lymphoid cells. The contrasting effects of aqueous vs. liposomal delivery of α-GalCer have been attributed to differential cell targeting. Aqueous forms of α-GalCer are presented primarily by professional APCs, dendritic cells (DCs) whereas liposomal α-GalCer delivery results in presentation by B cells and subsequent IL-10 secretion by both B cells and NKT cells, production of tolerogenic DCs and generation of Foxp3⁺Tregs. We show the mode of action and the therapeutic potential of liposomal α-GalCer to protect exacerbation of T1D.

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Paliperidone palmitate long-acting injection (Xeplion^® aqueous suspension for IM injection, PP) is the long-acting injectable antipsychotic for schizophrenia, which approved in Japan on September 2013. PP is provided as prefilled syringe, which makes enable the injection without preparation just before injection. PP is injected as 150mg at Day 1 and 100mg at Day 8 to deltoid muscles, followed by the injection of 75 mg every 4 week to deltoid or gluteal muscle (appropriately increase or decrease within 25-150mg by depending on the state of patients), indicates the effect on schizophrenia without concomitant oral antipsychotics. In this paper, it is introduced as the characteristics of drug formulation and pharmacokinetics of PP.

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