Preference for a Novel Oral Alternative to Parenterally Administered Medications.

Background: Rani Therapeutics is developing a robotic pill (RP), an oral drug delivery platform called RaniPill™ that can deliver a number of biotherapeutics with high bioavailability; eliminating the need for injections. While patients in general prefer oral to injectable therapies, preference for a more frequent oral regimen compared to a less frequent injectable regimen is unknown. Two marketing surveys were conducted to gather data on preference for oral versus injectable therapies. A clinical study gathered data on participant preference for oral pills vs injections before and after swallowing a Mock-RP capsule. Methods: A total of 1689 adults taking injections (mean duration 3-7 years) to treat endocrine or inflammatory conditions were anonymously surveyed online for their preference to administer/prescribe medications orally via the RP. In the clinical study, 150 participants currently taking injections for chronic conditions evaluated the swallowability of a Mock-RP and completed a questionnaire regarding their preferences. Results: Majority of respondents surveyed stated they would be willing to convert to an oral alternative over their current parenteral therapy regardless of drug or disease. In the clinical study, all participants were able to swallow the Mock-RP and 91% indicated their preference for the oral route versus their current parenteral route of drug administration. Survey respondents and those in the clinical study using frequent injections were more willing to select a once-daily capsule compared to those injecting infrequently. Even study participants who inject infrequently (≥monthly: 80%) would prefer a once-daily pill over their injection regimen. Conclusion: Patients taking injections and prescribing physicians strongly prefer oral dosing to parenteral administration of biologics even if dosing frequency with the oral option, such as the RP, is increased.

Effect of seawater salinity, pH, and temperature on external corrosion behavior and microhardness of offshore oil and gas pipeline: RSM modelling and optimization.

This research aims to investigate the effects of seawater parameters like salinity, pH, and temperature on the external corrosion behaviour and microhardness of offshore oil and gas carbon steel pipes. The immersion tests were performed for 28 days following ASTM G-1 standards, simulating controlled artificial marine environments with varying pH levels, salinities, and temperatures. Besides, Field emission scanning electron microscopy (FESEM) analysis is performed to study the corrosion morphology. Additionally, a Vickers microhardness tester was used for microhardness analysis. The results revealed that an increase in salinity from 33.18 to 61.10 ppt can reduce the corrosion rate by 28%. In contrast, variations in seawater pH have a significant effect on corrosion rate, with a pH decrease from 8.50 to 7 causing a 42.54% increase in corrosion rate. However, the temperature of seawater was found to be the most prominent parameter, resulting in a 76.13% increase in corrosion rate and a 10.99% reduction in the microhardness of offshore pipelines. Moreover, the response surface methodology (RSM) modelling is used to determine the optimal seawater parameters for carbon steel pipes. Furthermore, the desirability factor for these parameters was 0.999, and the experimental validation displays a good agreement with predicted model values, with around 4.65% error for corrosion rate and 1.36% error for microhardness.

A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects.

Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli. The payload is delivered upon inflation of a balloon folded within the RP, which deflates immediately after drug delivery. Here we present results from two clinical studies demonstrating the safety, tolerability and performance of the RP in healthy humans. In the first study, three versions of the RP (A, B and C) were evaluated, which were identical in all respects except for the diameter of the balloon. The RP successfully delivered a biotherapeutic (octreotide) in 3 out of 12 subjects in group A, 10 out of 20 subjects in group B and 16 out of 20 subjects in group C, with a mean bioavailability of 65 ± 9% (based on successful drug deliveries in groups A and B). Thus,  reliability of drug delivery with the RP ranged from 25 to 80%, with success rate directly related to balloon size. In a separate study, the deployment of the RP was unaffected by fed or fasting conditions suggesting that the RP may be taken with or without food. These promising clinical data suggest that biotherapeutics currently administered parenterally may be safely and reliably delivered via this versatile, orally ingestible drug delivery platform.

Plant growth promoting and antifungal asset of indigenous rhizobacteria secluded from saffron (Crocus sativus L.) rhizosphere.

Saffron (Crocus sativus L.) is an important plant in medicine. The Kashmir Valley (J&K, India) is one of the world's largest and finest saffron producing regions. However, over the past decade, there has been a strong declining trend in saffron production in this area. Plant Growth Promoting Rhizobacteria (PGPR) are free living soil bacteria that have ability to colonize the surfaces of the roots and ability to boost plant growth and development either directly or indirectly. Using the efficient PGPR as a bio-inoculant is another sustainable agricultural practice to improve soil health, grain yield quality, and biodiversity conservation. In the present study, a total of 13 bacterial strains were isolated from rhizospheric soil of saffron during the flowering stage of the tubers and were evaluated for various plant growth promoting characteristics under in vitro conditions such as the solubilization of phosphate, production of indole acetic acid, siderophore, hydrocyanic acid, and ammonia production and antagonism by dual culture test against Sclerotium rolfsii and Fusarium oxysporum. All the isolates were further tested for the production of hydrolytic enzymes such as protease, lipase, amylase, cellulase, and chitinase. The maximum proportions of bacterial isolates were gram-negative bacilli. About 77% of the bacterial isolates showed IAA production, 46% exhibited phosphate solubilization, 46% siderophore, 61% HCN, 100% ammonia production, 69% isolates showed protease activity, 62% lipase, 46% amylase, 85% cellulase, and 39% showed chitinase activity. Three isolates viz., AIS-3, AIS-8 and AIS-10 were found to have the most plant growth properties and effectively control the growth of Sclerotium rolfsii and Fusarium oxysporum. The bacterial isolates were identified as Brevibacterium frigoritolerans (AIS-3), Alcaligenes faecalis subsp. Phenolicus (AIS-8) and Bacillus aryabhattai (AIS-10) respectively by 16S rRNA sequence analysis. Therefore, these isolated rhizobacterial strains could be a promising source of plant growth stimulants to increase cormlets growth and increase saffron production.

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine-A pharmacokinetic and pharmacodynamic study.

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof-of-concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto-injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60-80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10-minute intervals between -20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule.

Biphasic transdermal iontophoretic drug delivery platform.

Transdermal iontophoresis is an active drug delivery method that has the potential to transform treatment of conditions such as acute pain that require a succession of on-demand metered-dose drug deliveries. However, current monophasic iontophoresis methods fail to meet these requirements due to their inability to halt the passive diffusion of active agents when therapy is not required. We have developed a biphasic iontophoretic system to overcome these limitations. The viability of this system was assessed in an in vitro porcine skin preparation using FeCl(2) (127 Daltons), a charged molecule which can undergo both active and passive transdermal diffusion. The transport properties of the system were modeled using a Fourier Transform-derived optimum estimate transfer function. Using this model, experimental results showed good correlation to predicted values for both cumulative dose (R(2)=0.912, n=10), and density dose (R(2)=0.802, n=10). Results also showed the ability to effectively deliver the compound during active periods while minimizing delivery during inactive periods. While preliminary, our results suggest biphasic iontophoresis is a viable means of delivering on-demand drug therapy while minimizing unwanted off-demand delivery.

In vitro and in vivo studies of ePTFE vascular grafts treated with P15 peptide.

The purpose of this study is to evaluate the effectiveness of P15 cell-binding peptide treated ePTFE vascular grafts in vitro and in vivo. The P15 peptide was covalently immobilized onto ePTFE vascular grafts by an atmospheric plasma coating method. In vitro cell growth properties were studied using primary human umbilical vein endothelial cells (HUVECs) and primary human umbilical artery smooth muscle cells (HUASMCs). X-ray photoelectron spectroscopy and amino-acid analysis were used to analyze the surface characteristics of the peptide treated and untreated grafts. The cell growth study showed that the P15 peptide effectively promoted the adhesion and proliferation of endothelial cells. 700% more endothelial cells were proliferated on the P15-treated ePTFE grafts compared to the untreated ePTFE controls. In contrast, the P15 peptide was significantly less effective for promoting the adhesion and proliferation of smooth muscle cells than endothelial cells; only about 100% more smooth muscle cells proliferated on the P15-treated samples compared to the untreated control samples. The sheep model was used in the in vivo study. The amount of neointimal hyperplasia present at the arterial and venous sides of the anastomosis and the degree of endothelialization on the luminal surface of the grafts were assessed. Four P15-treated grafts and two control grafts were implanted as arteriovenous grafts between the femoral artery and vein or the carotid artery and jugular vein in two sheep (n = 6). The in vivo study showed that the thickness of the neointimal hyperplasia of untreated grafts was 3-times thicker than that of P15-treated grafts (P < 0.05) at the venous side of the anastomosis. P15-treated grafts also had a higher degree of endothelialization on the graft lumen.

In vitro study of cell-promoting multiple-armed peptides.

The purpose of this study was to compare the effectiveness of several linear and branch cell-binding peptides to promote cell growth in prosthetic vascular grafts. In this in vitro study, the peptides were covalently immobilized onto expanded polytetrafluoroethylene (ePTFE) vascular grafts. Cell-growth properties were studied using primary human umbilical vein endothelial cells (HUVECs) and primary human umbilical artery smooth muscle cells (HUASMCs). Linear peptides (P15 and P15') and multiple-armed peptides (MAP4-I and MAP4-II) were covalently bonded onto ePTFE grafts by an atmospheric plasma coating method. X-ray photoelectron spectroscopy and amino acid analysis were used to analyze the surface characteristics of the peptide-coated samples. Cell adhesion, proliferation, and morphology were evaluated by culturing HUVECs and HUASMCs onto the surfaces of different samples: ePTFE control, chemically activated ePTFE, P15-coated ePTFE, and MAP4-coated ePTFE. The cell culture experiments were repeated several times to obtain statistically reliable cell-growth data. Cell-growth data were statistically analyzed by the two-way statistical analysis of variance. The study showed that multiple-armed MAP4 peptides were significantly more effective in promoting endothelial cells than the structurally similar linear P15 peptides. There were 800% more HUVECs proliferated on the MAP4-coated ePTFE samples compared with the ePTFE control. MAP4 peptides were 80% more effective for promoting HUVECs than P15 peptides. In contrast, MAP4 peptides were significantly less effective for promoting HUASMCs than HUVECs. There were only about 100% more HUASMCs proliferated on the MAP4-coated ePTFE samples compared with the ePTFE control. MAP4 and P15 peptides had similar cell-promoting characteristics for SMCs.

Peptide-coated vascular grafts: an in vivo study in sheep.

The data on function and patency of prosthetic vascular grafts in various clinical settings are limited. The purpose of this in vivo study was to compare the function and patency of P15-coated expanded polytetrafluoroethylene (ePTFE) vascular grafts to uncoated ePTFE grafts in sheep. The P15 cell-binding peptide was covalently immobilized onto the surface of ePTFE grafts by a novel atmospheric plasma coating method. We evaluated the amount of neointimal tissue ingrowth present at the arterial and venous sides of the anastomoses and the degree of endothelial cell resurfacing of the luminal surface of the graft. Four P15-coated grafts and two control grafts were implanted as arteriovenous grafts between the femoral artery and vein and the carotid artery and jugular vein in two sheep (n = 6). One animal was euthanized after 14 days and the other after 28 days. The study showed the intimal ingrowth was significantly less. The average intimal thickness of P15-coated grafts (658 microm) was approximately two and a half times less than that of uncoated samples (1657 microm). The newly formed endothelial cell lining was thicker and its coverage was more uniform for P15-coated grafts compared to the uncoated controls.