Insoluble drug delivery strategies: review of recent advances and business prospects

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.KEY WORDS: Bioavailability, Cocrystals, Solubility, Inclusion complexation, Nanoparticles, Self-emulsifying formulations, Proliposomes     

Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE-/- mice

Heme-regulated eIF2alpha kinase (HRI) is essential for regulating globin translation in iron deficiency and in beta-thalassemia. We investigated the role of heme-regulated eIF2alpha kinase in hemoglobin and red blood cell production as well as in iron homeostasis in a mouse model of iron overload. We show that HRI deficiency does not significantly affect red cell parameters of hemochromatosis (HFE(-)(/)(-)) mice. Importantly, heme-regulated eIF2alpha kinase deficiency exacerbates decreases in hepcidin expression and splenic macrophage iron in HFE(-)(/)(-) mice. Furthermore, the serum level of bone morphogenic protein 2, which positively regulates hepcidin, is reduced in heme-regulated eIF2alpha kinase deficiency, but not in HFE deficiency.     

Usefulness of transesophageal three-dimensional echocardiography in the identification of individual segment/scallop prolapse of the mitral valve

We evaluated the potential usefulness of three-dimensional (3D) transesophageal echocardiography (TEE) in assessing individual scallop/segment prolapse in 36 adult patients with mitral valve prolapse (MVP) undergoing surgical correction. Intraoperative 3D TEE correctly identified the location of scallop/segment prolapse in 34 of 36 patients (94%). However, in 6 of these patients 3D TEE images revealed more scallops or segments with prolapse than the surgeon noted intraoperatively. Prolapse of these areas was less prominent and this could possibly explain the lack of correlation with the surgical findings in these patients. In another 2 patients areas of prolapse seen by the surgeon were missed by 3D TEE because some of those scallops/segments could not be well imaged due to image "drop out" and artifacts. Thus, perfect correlation between 3D TEE and surgery was noted in 28 of 36 (78%) patients. Noncoaptation of the MV was also identified in 2 patients. The prolapsed area of posterior (n = 28 observations) and anterior (n = 9 observations) MV leaflets ranged from 1 cm2 to 9 cm2 (mean 3.50 cm2+/- 2.14) and 1.20 cm2 to 5.99 cm2 (mean 3.21 cm2+/- 1.33), respectively. Interobserver and intraobserver agreement for location and area of MVP was excellent (r = 0.97 and r = 0.99, respectively; all P values are <0.0001). In conclusion, 3D TEE is useful in identifying the location of MVP. It may also be potentially useful in assessing the extent of individual scallop/segment prolapse and identifying sites of MV noncoaptation. This information could aid the surgeon in deciding the extent of MV resection.     

Malignant phyllodes tumor of the left atrium

Metastatic tumors to the heart usually involve right sided chambers. We report a rare case of malignant phyllodes tumor of breast with metastatic involvement of left atrium occurring through direct invasion from mediastinal micro-metastasis and presenting as a left atrial mass causing arrhythmia.     

Reservoir hosts of Leptospira inadai in India

Isolation of Leptospira from the kidneys of Rattus rattus wroughtoni hinton, Rattus rattus rufescens, Bandicota bengalensis and Bandicota indica was attempted in Bangalore in southern India. In total, 296 spirochaetes were isolated from 1,348 kidney cultures (an isolation rate of 22%). A batch of fifty-six isolates from India was identified, based on serological and polymerase chain reaction analysis, of which twenty-three isolates were identified as L. inadai by the World Health Organization/Food and Agriculture Organization Collaborating Centre for Reference and Research on Leptospirosis, in Brisbane. This is the first record of isolation of L. inadai from rodents. The preponderance of L. inadai in four different species of rodents suggests that these animals could be the natural reservoir hosts of L. inadai, and raises a critical question as to the likely impact of this species of Leptospira on the renal carrier status of other Leptospira pathogenic to humans and animals in this part of India. Virulence studies conducted at the University of Trieste in Italy, revealed that isolates of L. inadai from India were moderately or totally serum resistant when subjected to a serum killing test. To establish the possible seroprevalence of this species in the population, the inclusion of L. inadai in the battery of leptospiral antigens used for sero-epidemiological studies is recommended.     

Transesophageal echocardiographic identification of right vertebral artery

We describe a transesophageal technique for identifying the origin and precervical course of the right vertebral artery with the probe positioned in the upper esophagus. The technique was successful in 9 of 11 patients in whom it was attempted.