Many scientists have endeavoured to search for oral insulin formula by using polymer or lipid systems [1±6], protease inhibitors and permeation enhancers [7±10]. Other routes have also been explored as alternatives to insulin injections [11±13]. Although these formulations achieved varying degrees of success, there are many obstacles that must be overcome if clinically successful formulas are to be achieved.We developed a homogeneous liquid formula that has distinctly different physical properties from those of the pre-existing formulas. By simply mixing our liquid formula in excess water or phosphate buffered saline (PBS, pH 7.4), nano-sized particles ranging from 200 to 500 nm are formed. Encapsulation efficiency of insulin inside the particles was 70 to 100 %. The formula can be made without heat or physical force and can be sterilized easily by filtration.We name the submicron-sized lipid particles formed spontaneously in water`nanocubicles'. Nanocubicles can be similar to, but differ in some respects from, the so-called cubosomes [14,15]. For preparation of nano-sized cubosomes, the mixture of monoolein, emulsifier and water needs to be microfluidized at about 80 C and cooled slowly to room temperature. Since insulin cannot be stable under this harsh condition, cubosomes have been used in the form of large aggregates (10 mm~1 mm), prepared at room temperature by stirring, to test the possibility of their being used as a nasal insulin delivery system [16] but not as an oral formula [17]. AbstractAims/hypothesis. A patient with (insulin-dependent) diabetes mellitus receives at least one subcutaneous insulin injection a day to maintain low serum glucose concentrations. Since patients' compliance with such dosage regimens is too low, the development of an oral formula is clearly attractive. We present the development of a liquid formula that can be easily dispersed in water to produce particles named ªnanocu-biclesº which efficiently encapsulate insulin. Methods. Fasted streptozotocin±induced diabetic rats were administered orally with particles encapsulating insulin, and particles without insulin or soluble insulin in water. Groups of rats were also injected soluble insulin in PBS for control. Blood glucose concentration and insulin concentration were measured 1, 2, 3, 4 and 6 h after the administration of the insulin formulas.Results. In vitro experiments show that the particles can be taken up by the Caco-2 cells at a high ratio. The serum glucose concentration was controlled for more than 6 h after oral insulin administration but returned to the basal concentration in 3 h when 1 IU/kg of insulin was injected intravenously. Conclusion/interpretation. Our biocompatible and stable oral insulin formulation is easy to prepare and produces reproducible hypoglycaemic effects, therefore we anticipate clinical acceptance and utilization of this form of insulin therapy. [Diabetologia (2002) 45: 448±451]

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Although schizophrenia is a widespread disorder of unknown aetiology, we have previously shown that muscarinic M4 receptor (CHRM4) expression is decreased in the hippocampus and caudate-putamen from subjects with the disorder, implicating the receptor in its pathophysiology. These findings led us to determine whether variation in the CHRM4 gene sequence was associated with an altered risk of schizophrenia by sequencing the CHRM4 gene from the brains of 76 people with the disorder and 74 people with no history of psychiatric disorders. In addition, because the CHRM4 is a potential target for antipsychotic drug development, we investigated whether variations in CHRM4 sequence were associated with final recorded doses of, and life-time exposure to, antipsychotic drugs. Gene sequencing identified two single nucleotide polymorphisms (SNPs; rs2067482 and rs72910092) in the CHRM4 gene. For rs2067482, our data suggested that both genotype (1341C/C; p = 0.05) and allele (C; p = 0.03) were associated with an increased risk of schizophrenia. In addition, there was a strong trend (p = 0.08) towards an association between CHRM4 sequence and increased lifetime exposure to antipsychotic drugs. Furthermore, there was a trend for people with the C allele to be prescribed benzodiazepines more frequently (p = 0.06) than those with the T allele. These data, albeit on small cohorts, are consistent with genetic variance at rs2067482 contributing to an altered risk of developing schizophrenia which requires more forceful pharmacotherapy to achieve a clinical response.