Robert A. Baughman

Oral Delivery of Biologically Active Parathyroid Hormone

AbstractPurpose. Parathyroid hormone (PTH), the only drug known to stimulate bone formation, is a peptide therapeutic indicated in the treatment of osteoporosis. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH in rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy-4-methoxy)bensoyl]amino caprylic acid (4-MOAC). Methods. 4-MOAC was selected from a group of 100 delivery agents based on in vitro chromotography studies and in vivo screening studies in rats. The PTH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. Results. Monkeys were administered an aqueous solution containing 4-MOAC and PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtained. The relative bioavailability of oral PTH was 2.1% relative to subcutaneous administration. The biological activity of the orally-delivered PTH was further evaluated in a rat model of osteoporosis. These studies showed that the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4-MOAC and PTH. The preliminary evaluation of this interaction by NMR is described. Conclusions. 4-MOAC facilitates the absorption of PTH following oral administration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.

Acylated non-α-amino acids as novel agents for the oral delivery of heparin sodium, USP

Ten N-acylated, non-α-amino acids have been prepared as oral delivery agents and used to demonstrate the oral delivery of heparin in vivo in rats and primates. Following the oral administration of solutions containing a combination of heparin and a delivery agent to rats or primates, significant plasma heparin concentrations were evidenced by APTT and anti-Factor Xa assays. The estimated pharmacodynamic equivalence for an oral dosing solution containing heparin and a delivery agent is 39% in primates. In vitro experiments based on heparin affinity chromatography or heparin/methylene blue complexation were also performed to begin investigation of the mechanism by which these compounds facilitate heparin oral delivery. Results of in vitro studies suggest that absorption of the drug across the gastrointestinal membrane is the result of a non-covalent interaction between heparin and the delivery agent.

Orally administered heparin for preventing deep venous thrombosis

BACKGROUND Sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) is an acetylated amino acid molecule that facilitates the gastrointestinal absorption of heparin. This study was undertaken to evaluate the efficacy of orally administered combination SNAC:heparin in preventing deep venous thrombosis in a standard rat model. METHODS Forty-four adult male Sprague-Dawley rats were randomly divided into five groups: group I control, group II SNAC, group III oral heparin, group IV combination SNAC:heparin, and group V intravenous heparin. Thirty minutes after drug administration, the internal jugular vein was bathed in a sclerosant mixture for 2 minutes and reexplored at 120 minutes. Activated partial thromboplastin times (aPTT) were measured in 30 rats equally divided into three groups: group I SNAC, group II oral heparin, and group III combination SNAC:heparin. Forty-five minutes posttreatment, blood was obtained for aPTT levels. RESULTS The incidence of deep venous thrombosis in the control group was 89% (8 of 9) versus 25% (2 of 8) in the combination SNAC:heparin group (p < 0.01). There was also a significant reduction in clot weight among groups. Combination SNAC:heparin significantly increased aPTT levels compared with SNAC or oral heparin alone. CONCLUSION In a rat model of venous thrombosis, combination of orally administered heparin:SNAC elevated aPTT levels and significantly reduced the formation of deep venous thrombosis.

Pharmacokinetic Characterization of the Novel Pulmonary Delivery Excipient Fumaryl Diketopiperazine

Background: Technosphere® [Bis-3, 6(4-fumarylaminobutyl)-2, 5-diketopiperazine (FDKP)] microparticles, the integral component of the Technosphere inhalation system, deliver drugs to the deep lung and have been used to administer insulin and glucagon-like peptide-1 via inhalation in clinical studies. Three studies were conducted to characterize FDKP pharmacokinetics, including assessments in subjects with diabetic nephropathy (DNP), in subjects with chronic liver disease (CLD), and in healthy subjects. Methods: An open-label, nonrandomized, two-period, fixed-sequence crossover absorption, distribution, metabolism, and excretion (ADME) study was conducted in six healthy nonsmoking men who received single intravenous and oral doses of [14C]FDKP solution, with serial sampling of blood, urine, feces, and expired air. Additionally, two single-dose, open-label, parallel-design studies with 20 mg of inhaled FDKP were conducted in (1) 12 diabetic subjects with normal renal function and 24 DNP subjects and (2) 12 healthy subjects and 21 CLD subjects. Results: In the ADME study, >95% of the intravenous dose and <3% of the oral dose were recovered in urine, with no evidence of metabolism. No significant pharmacokinetic differences were observed between healthy subjects and CLD subjects [geometric mean (% coefficient of variation) area under the curve from time 0 to 480 minutes (AUC0-480): 26,710 (34.8) and 31,477 (28.8) ng/ml·min, respectively]. Maximum observed drug concentration (C max) and AUC0-480 were higher in DNP subjects than in subjects with normal renal function [C max: 159.9 (59.4) ng/ml versus 147.0 (44.3) ng/ml; AUC0-480: 36,869 (47.2) ng/ml·min versus 30,474 (31.8) ng/ml·min]. None of the differences observed were considered clinically significant. Conclusions: Fumaryl diketopiperazine is predominantly cleared unchanged by the kidney with essentially no oral bioavailability. Technosphere is a safe delivery vehicle for medications administered via inhalation.

Orally Administered Unfractionated Heparin With Carrier Agent Is Therapeutic for Deep Venous Thrombosis

BACKGROUND Orally administered heparin (OHEP) is unreliable because of poor absorption. Sodium N-(8[2-hydroxybenzoyl]amino) caprylate (SNAC) is an amido acid that facilitates the gastrointestinal absorption of heparin. We evaluated the effectiveness of OHEP combined with SNAC (OHEP/SNAC) in the treatment of deep-vein thrombosis (DVT). METHODS AND RESULTS An internal jugular DVT was produced in 54 male Sprague-Dawley rats. Animals were assigned to 6 different groups for 7 days of treatment: untreated control, subcutaneous heparin (SC HEP) (300 U/kg SC TID), SNAC only (300 mg/kg PO TID), OHEP only (30 mg/kg PO TID), low-molecular-weight heparin (LMWH) (enoxaparin 5 mg/kg SC QD), and OHEP/SNAC (30 mg/kg:300 mg/kg PO TID). The activated partial thromboplastin time (aPTT) and anti-factor X (anti-Xa) levels were measured. The incidence of residual DVT after 1 week of treatment was 100% (9 of 9) in the control group versus 10% (1 of 10) in the OHEP/SNAC and 10% (1 of 10) in the LMWH groups (P<0.001). There was also a significant reduction in clot weights between these groups. Compared with controls, there were no significant differences in the residual DVT in the SNAC-only (6 of 6), OHEP-only (9 of 9), or SC HEP (8 of 10) groups. Combination OHEP/SNAC was as effective in the resolution of the clot and reducing clot weight as LMWH. The aPTT levels in the OHEP/SNAC group peaked at 30 minutes and were significantly higher than in all other groups (P<0.01). Anti-Xa levels were elevated at 15 minutes after dosing in the OHEP/SNAC group and remained significantly elevated at 4 hours (P<0.001). CONCLUSIONS OHEP combined with a novel carrier agent (SNAC) successfully treated DVT in this rat model.

Oral low–molecular weight heparin and delivery agent prevents jugular venous thrombosis in the rat

PURPOSE Sodium N-[10-(2-hydroxybenzoyl)amino]decanoate (SNAD) is a novel carrier that allows the gastrointestinal absorption of low-molecular weight heparin (LMWH). The purpose of this experiment was to evaluate oral LMWH with SNAD for the prevention of deep venous thrombosis. METHODS Sixty Sprague-Dawley rats were equally assigned to five experimental groups: group 1 (control), oral saline solution; group 2, oral LMWH (15 mg/kg); group 3, oral SNAD (300 mg/kg); group 4, subcutaneous LMWH (5 mg/kg); and group 5, oral LMWH (15 mg/kg) and SNAD (300 mg/kg). After treatment, the jugular vein was isolated, occluded, and bathed in an ethanol and formalin solution for 2 minutes. Two hours later, the vessel was examined for patency, presence of thrombus, and thrombus weight. Serum measurement of anti-factor Xa activity was performed in a separate set of 30 rats, which were placed into the following four groups: group A, LMWH (5 mg/kg); group B, oral LMWH (15 mg/kg) and SNAD (300 mg/kg); group C, oral LMWH (15 mg/kg); and group D, SNAD (300 mg/kg). RESULTS The animals that underwent oral LMWH/SNAD therapy had a statistically significant decrease in visible thrombi. The thrombus weight of the oral LMWH/SNAD group was significantly less than the weights of all other groups, except the subcutaneous LMWH group. Anti-factor Xa levels were significantly elevated in the LMWH/SNAD group. There was no statistically significant difference between the data for the oral LMWH/SNAD group and the subcutaneous LMWH group. CONCLUSION The combination of oral LMWH and SNAD prevented deep venous thrombosis. The oral LMWH and SNAD therapy effected an increase in levels of anti-factor Xa.

Oral Delivery of Sodium Cromolyn: Preliminary Studies In Vivo and In Vitro

AbstractPurpose. Herein we report the discovery of a group of derivatized α-amino acids that increase the oral bioavailability of sodium cromolyn. Methods. We prepared three N-acylated α-amino acids and used these compounds to demonstrate the oral delivery of cromolyn in an in vivo rat model. In vitro experiments, including permeation studies and near infrared spectroscopy, were also performed to initiate an understanding of the mechanism by which these compounds facilitate cromolyn oral delivery. Results. Following oral administration to rats of solutions containing a combination of cromolyn and the delivery agent, significant systemic plasma concentrations of the drug were detected. In vitro studies suggest that absorption of the drug across the gastrointestinal membrane is a passive process. Conclusions. The absolute oral bioavailability of sodium cromolyn in the rat model is estimated to be ~5%. Preliminary mechanistic studies suggest that a complex of the cromolyn/delivery agent facilitates permeation across/through the membrane.

Pharmacokinetics and Pharmacodynamics of Inhaled GLP‐1 (MKC253): Proof‐of‐Concept Studies in Healthy Normal Volunteers and in Patients With Type 2 Diabetes

MKC253 is glucagon‐like peptide 1 (GLP‐1, 7–36 amide) adsorbed onto Technosphere microparticles for oral inhalation. The pharmacokinetics of inhaled GLP‐1 and the pharmacokinetic–pharmacodynamic (PK–PD) relationship between inhaled GLP‐1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with type 2 diabetes. Inhaled GLP‐1 was absorbed quickly, with peak concentrations occurring within 5 min, and levels returned to baseline within 30 min. Inhaled GLP‐1 appeared to produce plasma levels of GLP‐1 comparable to those of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose excursions in subjects with type 2 diabetes. An Emax (maximum effect) model described the relationship between GLP‐1 concentration and insulin release. The variability in the Emax may be due to differences in baseline glucose levels, differences resulting from genetic polymorphisms in GLP‐1 receptors (GLP‐1Rs), or the stage of diabetes of the patient.

Treatment of Experimentally Induced Caval Thrombosis With Oral Low Molecular Weight Heparin and Delivery Agent in a Porcine Model of Deep Venous Thrombosis

OBJECTIVE This experiment evaluated enterally administered low molecular weight heparin (LMWH) combined with sodium N-[10-(2-hydroxybenzoyl)amino] decanoate (SNAD) for the treatment of induced venous thrombosis. SUMMARY BACKGROUND DATA SNAD is a delivery agent that potentiates the gastrointestinal absorption of LMWH. METHODS Forty female pigs were equally assigned to four groups: control (saline); enteral LMWH, 2,000 IU/kg; enteral SNAD, 50 mg/kg; and enteral LMWH, 2,000 IU/kg and SNAD, 50 mg/kg. Under fluoroscopic guidance, the infrarenal vena cava was occluded with a balloon catheter. Two milliliters of ethanol was injected into the distal vena cava. The inflated balloon catheter remained in situ for 5 days, at which time animals angiographically exhibiting thrombus were randomly assigned to the four groups. Study medications were dosed at 12-hour intervals by means of a gastrostomy tube placed previously. After 7 days of treatment, thrombus was extracted. A separate group of 10 animals was used to measure plasma antifactor Xa levels for 6 hours after enteral dosing of LMWH/SNAD. RESULTS The amount of residual thrombus after treatment with enteral LMWH/SNAD was significantly decreased. Antifactor Xa levels were significantly elevated in the LMWH/SNAD group versus baseline. CONCLUSION The combination of enterally administered LMWH and SNAD given for 7 days appeared to decrease caval thrombosis in this model of deep vein thrombosis. Enteral LMWH/SNAD effected an increase in plasma levels of antifactor Xa.

Inhaled Technosphere Insulin Versus Inhaled Technosphere Placebo in Insulin-Naïve Subjects With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetes Agents.

OBJECTIVE To investigate the efficacy and safety of prandial Technosphere inhaled insulin (TI), an inhaled insulin with a distinct time action profile, in insulin-naïve type 2 diabetes (T2D) inadequately controlled on oral antidiabetes agents (OADs). RESEARCH DESIGN AND METHODS Subjects with T2D with HbA1c levels ≥7.5% (58.5 mmol/mol) and ≤10.0% (86.0 mmol/mol) on metformin alone or two or more OADs were randomized to add-on prandial TI (n = 177) or prandial Technosphere inhaled placebo (TP) (n = 176) to their OAD regimen in this double-blind, placebo-controlled trial. Primary end point was change in HbA1c at 24 weeks. RESULTS TI significantly reduced HbA1c by −0.8% (−9.0 mmol/mol) from a baseline of 8.3% (66.8 mmol/mol) compared with TP −0.4% (−4.6 mmol/mol) (treatment difference −0.4% [95% CI −0.57, −0.23]; P < 0.0001). More TI-treated subjects achieved an HbA1c ≤7.0% (53.0 mmol/mol) (38% vs. 19%; P = 0.0005). Mean fasting plasma glucose was similarly reduced in both groups. Postprandial hyperglycemia, based on 7-point glucose profiles, was effectively controlled by TI. Mean weight change was 0.5 kg for TI and −1.1 kg for the TP group (P < 0.0001). Mild, transient dry cough was the most common adverse event, occurring similarly in both groups (TI, 23.7%; TP, 19.9%) and led to discontinuation in only 1.1% of TI-treated and 3.4% of TP-treated subjects. There was a small decline in forced expiratory volume in 1 s in both groups, with a slightly larger decline in the group receiving TI (TI, −0.13 L; TP, −0.04 L). The difference resolved after treatment discontinuation. CONCLUSIONS Prandial TI added to one or more OADs in inadequately controlled T2D is an effective treatment option. Mild, transient dry cough was the most common adverse event.