Bojan Zorko

Optimisation of floating matrix tablets and evaluation of their gastric residence time

The present investigation concerns the development of the floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. The importance of the composition optimisation, the technological process development for the preparation of the floating tablets with a high dose of freely soluble drug and characterisation of those tablets (crushing force, floating properties in vitro and in vivo, drug release) was examined. Tablets containing hydroxypropyl methylcellulose (HPMC), drug and different additives were compressed. The investigation shows that tablet composition and mechanical strength have the greatest influence on the floating properties and drug release. With the incorporation of a gas-generating agent together with microcrystalline cellulose, besides optimum floating (floating lag time, 30 s; duration of floating, >8 h), the drug content was also increased. The drug release from those tablets was sufficiently sustained (more than 8 h) and non-Fickian transport of the drug from tablets was confirmed. Radiological evidence suggests that, that the formulated tablets did not adhere to the stomach mucus and that the mean gastric residence time was prolonged (>4 h).

Recording of electroneurograms from the nerves innervating the pancreas of a dog.

Electroneurograms (ENGs) from the vagus, splanchnic and pancreatic nerves innervating the pancreas of a dog, were recorded with chronically implanted silicone multi-electrode circular cuffs in an intact pancreas and in a pancreas partly disabled with alloxan. The cuffs contained 33 platinum electrodes (0.6x1.5 mm) arranged in three parallel circular groups integrated into the inner surface of the cuff. Each circular group contained 11 electrodes at a distance of 0.5 mm apart, with 6 mm between the circular groups. The cuffs had an inner diameter of 2.5 mm and the length of 18 mm. In a 2-year study, the cuffs were implanted into two adult Beagle dogs (one female and one male). In the vagus nerve, the cuff was installed on the nerve at the neck, whilst in the splanchnic nerve, the cuff was installed on the nerve before the celiac ganglion, and in the pancreatic nerve, the cuff was installed on the nerve just before it enters the pancreas. In each of the three implanted cuffs, the electrodes of the central circular group were connected to each other and this signal provided one input to a multi-channel ENG amplifying system. The electrodes of each of the two outer spiral groups were connected to each other and then both these groups were short-circuited. This signal then provided another input to the multi-channel ENG amplifying system. The ENG amplifying system was designed to amplify the ENGs 100000 times and to pass frequencies of between 500 and 10 kHz. In our study, three recordings in each animal were conducted. Recordings in the intact pancreas were conducted 2 and 6 months after the implantation, while the recording in the partly disabled pancreas, was conducted 10 months after the implantation and 10 days after the disablement. Due to the fact that the results obtained in both animals were actually quite similar, we present the results of the recordings obtained in one animal. In both animals the cuffs were left implanted for more than 1 year and were used for pancreatic stimulation, although this is not in this paper. The results show that cuffs implanted chronically on the nerves innervating the pancreas of a dog could reliably record the ENGs. This information could be used effectively in further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs.

Regeneration of the radial nerve in a dog influenced by electrical stimulation.

The effect of biphasic electric fields on nerve regeneration that follows injury to the left radial nerve of a dog was examined using electromyography (EMG). The left and right radial nerves were crushed with a serrated hemostat and the stimulating electrodes were positioned proximally and distally relative to the site of the injury. The left nerves received rectangular, biphasic current pulses (30µA, 0.5Hz) through the lesion for two months. The right radial nerves were treated as controls and regenerated without electrical stimulation. EMG activity was recorded intramuscularly from left and right musculus extensor digitorum (from Medical dictionary) communis (MEDC). Results obtained at the end of the two-month stimulation period showed a significant difference between the EMG activity of the stimulated and the unstimulated MEDC suggesting that the electrical treatment enhanced the nerve regeneration.

Modulation of hormone secretion by functional electrical stimulation of the intact and incompletely dysfunctional dog pancreas

The purpose of the present study was to modulate the secretion of insulin and glucagon in Beagle dogs by stimulation of nerves innervating the intact and partly dysfunctional pancreas. Three 33-electrode spiral cuffs were implanted on the vagus, splanchnic and pancreatic nerves in each of two animals. Partial dysfunction of the pancreas was induced with alloxan. The nerves were stimulated using rectangular, charge-balanced, biphasic, and constant current pulses (200 micros, 1 mA, 20 Hz, with a 100-micros delay between biphasic phases). Blood samples from the femoral artery were drawn before the experiment, at the beginning of stimulation, after 5 min of stimulation, and 5 min after the end of stimulation. Radioimmunoassay data showed that in the intact pancreas stimulation of the vagal nerve increased insulin (+99.2 microU/ml) and glucagon (+18.7 pg/ml) secretion and decreased C-peptide secretion (-0.15 ng/ml). Splanchnic nerve stimulation increased insulin (+1.7 microU/ml), C-peptide (+0.01 ng/ml), and glucagon (+50 pg/ml) secretion, whereas pancreatic nerve stimulation did not cause a marked change in any of the three hormones. In the partly dysfunctional pancreas, vagus nerve stimulation increased insulin (+15.5 microU/ml), glucagon (+11 pg/ml), and C-peptide (+0.03 ng/ml) secretion. Splanchnic nerve stimulation reduced insulin secretion (-2.5 microU/ml) and increased glucagon (+58.7 pg/ml) and C-peptide (+0.39 ng/ml) secretion, and pancreatic nerve stimulation increased insulin (+0.2 microU/ml), glucagon (+5.2 pg/ml), and C-peptide (+0.08 ng/ml) secretion. It was concluded that vagal nerve stimulation can significantly increase insulin secretion for a prolonged period of time in intact and in partly dysfunctional pancreas.

Recording of ENGs from the nerves innervating the pancreas of a dog during the intravenous glucose tolerance test

Electroneurograms (ENGs) from the vagus nerve (VN), the splanchnic nerve (SN) and the pancreatic nerve (PN) innervating the pancreas of a dog, were recorded with chronically implanted 33-electrode spiral cuffs (cuff) before and after the pancreas were stimulated with intravenously (i.v.) administered glucose. In the cuffs platinum electrodes were arranged in three parallel spiral groups containing 11 electrodes on the inner surface. The cuffs had an inner diameter of 2 mm and a length of 18 mm. In a two-year study, the cuffs were implanted into two Beagle dogs and were also used for pancreatic stimulation, although this is not described in this paper. In the VN, the cuff was installed on the nerve at the neck, whilst in the SN, the cuff was installed on the nerve before the celiac ganglion, and in the PN, the cuff was installed on the nerve just before it enters the pancreas. Six months after implantation, when the model of interpretation of the results was developed, three recordings of ENG in each animal were conducted. The first one was conducted in the unstimulated pancreas while the second and the third were conducted 1 and 8 min after a known amount of glucose was i.v. administered. Since the results obtained in both animals were actually quite similar, we present the results obtained in one animal. To evaluate the changes in superficial activity of the nerves, elicited by the administration of glucose, the power spectra corresponding to ENGs, recorded from the nerves before and after the administration of glucose, were integrated within the band of frequencies ranging from 1 to 5 kHz. Accordingly, the magnitude of the integrated power spectrum (MIPS), corresponding to the ENG recorded from the SN before administration of glucose, was 2.863 au. One minute after glucose was administered the value fell to 2.795 au while 8 min after the administration the value returned to 2.8 au. The MIPS corresponding to the ENG recorded from the PN before the administration of glucose was 3.236 au. One minute after the administration the value fell to 2.901 au while 8 min after the administration the value rose to 3.009 au. The MIPS, corresponding to the ENG recorded from the VN before the administration of glucose, was 3.656 au. One minute after the administration the value fell to 3.565 au. Eight minutes after the administration the value rose to 3.689 au. The results show that 1 min after glucose was administered superficial activity in all three nerves was reduced while 8 min after administration the activity in the nerves returned to the same level of activity before the glucose was administered. This information could be effectively used in a further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs.

Selective recording of neuroelectric activity from the peripheral nerve

Abstract Electroneurograms (ENGs) from superficial regions of the sciatic nerve of a dog, innervating the tibialis anterior (TA) and gastrocnemius muscles (GM), arising mainly from muscle spindles and Golgi tendon organs were recorded selectively with an implanted 33-electrode spiral cuff (cuff). Relative positions of superficial regions within the cuff were defined by delivering stimulating pulses on groups of three electrodes (GTEs) within the cuff which were in contact with them. It was found that GTEs eliciting maximum contractions of muscles were GTE No. 3 for the TA muscle and GTE No. 8 for the GM muscle. In the first experiment the implanted leg was mounted into a special electronic brace. Extending forces were applied to the ankle rotating it by up to ±37° according to the neutral position, thus eliciting torques in the TA muscle of up to 1.2Nm. Channel 1 of the 4-channel preamplifier was connected to GTE No. 8, channel 2 to GTE No. 2, channel 3 to GTE No. 11 and channel 4 to GTE No. 5. Results show that only ENG recorded with GTE No. 8, being close to the region innervating the TA muscle, correspond to the mechanical load. In the second experiment the calcanean tendon (CT) of an implanted leg was dissected. The proximal end of the CT was connected to a force transducer and repetitive pull forces (about 12N) were applied to the CT. Channel 1 of the preamplifier was connected to GTE No. 5, channel 2 to GTE No. 1, channel 3 to the GTE No. 11 and channel 4 to GTE No. 8. Results show that only ENG recorded with GTE No. 5, being close to the region innervating the GM muscle, correspond to the mechanical load applied on CT.