Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles.

PURPOSE: To investigate whether the widely accepted advantages as sociated with the use of chitosan as a nasal drug delivery system might be further improved by application of chitosan formulated a nanoparticles. METHODS: Insulin-chitosan nanoparticles were prepared by the ionotropic gelation of chitosan glutamate and tripolyphosphate pentasodium and by simple complexation of insulin and chitosan. The nasal absorption of insulin after administration in chitosan nanoparticle formulations and in chitosan solution and powder formulations wa evaluated in anaesthetised rats and/or in conscious sheep. RESULTS: Insulin-chitosan nanoparticle formulations produced a pharmacological response in the two animal models, although in both cases the response in terms of lowering the blood glucose levels was less (to 52.9 or 59.7% of basal level in the rat, 72.6% in the sheep than that of the nasal insulin chitosan solution formulation (40.1% in the rat, 53.0% in the sheep). The insulin-chitosan solution formulation was found to be significantly more effective than the complex and nanoparticle formulations. The hypoglycaemic response of the rat to the administration of post-loaded insulin-chitosan nanopar ticles and insulin-loaded chitosan nanoparticles was comparable. As shown in the sheep model, the most effective chitosan formulation for nasal insulin absorption was a chitosan powder delivery system with a bioavailability of 17.0% as compared to 1.3% and 3.6% for the chitosan nanoparticles and chitosan solution formulations, respectively. CONCLUSION: It was shown conclusively that chitosan nanoparticles did not improve the absorption enhancing effect of chitosan in solution or powder form and that chitosan powder was the most effective for mulation for nasal delivery of insulin in the sheep model.

The influence of incubation temperature and surfactant concentration on the interaction between dimyristoylphosphatidylcholine liposomes and poloxamer surfactants.

Differential scanning calorimetry and photon correlation spectroscopy have been used to study the interaction between poloxamers P338 and P407 and dimyristoylphosphatidylcholine (DMPC) liposomes. The extent of the interaction was found to be dependent on the incubation temperature in addition to the poloxamer concentration. At low poloxamer concentrations (0.1-1.0% w/v) an interaction with the phospholipid bilayer was detected by a reduction of the pre-transition enthalpy of DMPC. At higher concentrations (2.0-5.0% w/v), the main phase transition temperature of the liposomes decreased and the endotherm broadened with a shoulder on the high temperature side, indicative of phase separation. Maximum increases in the diameter of small freeze-thaw extruded liposomes were shown to occur at temperatures close to the poloxamer critical micelle temperatures. At higher temperatures and surfactant concentrations there was evidence of solubilization of phospholipid into mixed micelles.

Factors affecting the size distribution of liposomes produced by freeze-thaw extrusion.

This paper describes the development of a protocol for the production of liposomes using a freeze-thaw extrusion methodology. Laser diffraction particle size analysis showed that the median diameter of freeze-thawed egg phosphatidylcholine multilamellar vesicles (eggPC MLVs) was increased when cholesterol was included in the bilayers. Using a freeze-thaw cycle of 3 min freezing in liquid nitrogen at -196 degrees C followed by 3 min thawing at 50 degrees C resulted in an anomalously large particle size for eggPC/cholesterol formulations. When liposomes were repeatedly freeze-thawed a maximum size was achieved after five freeze-thaw cycles. Dispersion of liposomes in sodium chloride solutions promoted size increases following freeze-thawing, suggesting that vesicles had aggregated or fused. Poloxamers P338 and P407 inhibited the size increases observed during freeze-thawing for eggPC MLVs dispersed in 1.0 M NaCl, probably through steric prevention of aggregation and fusion.

A high sensitivity differential scanning calorimetry study of the interaction between poloxamers and dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine liposomes.

High sensitivity differential scanning calorimetry (HSDSC) has been used to measure the thermal behaviour of dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) liposomes to which poloxamer surfactants P338 or P407 had been added during or after preparation. The phospholipid pre-transition was more sensitive than the main transition to the association of poloxamers with liposomal bilayers. Poloxamers reduced the enthalpy of the pre-transition of liquid-crystalline state DMPC and DPPC MLVs but not that of gel state DPPC MLVs. Freezing and thawing DMPC and DPPC liposomes in the presence of poloxamers was shown to increase their interaction with the liposomal bilayers.

Guidelines for the prevention and detection of controlled substance diversion.

Controlled substance diversion is a problem all hospitals face with far ranging legal and medical implications. Drug diversion or tampering can take many forms, such as simple theft, theft by substitution, theft by charting, and under-medicating the patient. The diversion of controlled substances by professional staff from patient care areas can frequently be prevented and detected at the nursing staff level. Often, diversion can be detected in daily hospital practice by performing careful narcotic counts, witnessing the "wasting" of partial doses, and routinely examining product packaging. Such procedures should be hospital policy and strictly enforced. Use of the guidelines presented in this report in conjunction with an effective inservice program can educate health care professionals in the problem of drug diversion. Drug diversion must be reported to maintain patient care standards, employee morale, and ultimely provide the necessary help and guidance to an impaired staff member.

Nifedipine serum concentrations following sublingual and oral doses.

Although nifedipine is commonly administered sublingually in the clinical setting, a comparison of the serum concentrations obtained by this route vs oral administration has not been previously made. Nifedipine serum concentrations were measured in 6 healthy subjects following sublingual or oral administration of one nifedipine 10 mg capsule. Serum nifedipine concentrations were measured at regular intervals and demonstrated that sublingual administration produced measurable nifedipine concentrations sooner than oral administration. Peak nifedipine serum concentrations were less following sublingual administration (41.9 +/- 24.9 ng/ml) than following oral administration (99.6 +/- 49.8 ng/ml, p less than 0.05). The time to peak nifedipine serum concentration was also longer following sublingual administration than with the oral dose (74 +/- 24 minutes vs 40 +/- 14 minutes, p less than 0.05). Despite these differences, the areas under the serum concentration-time curve of the two routes of administration were similar. These differences in nifedipine concentrations may be an important consideration when choosing the route of administration of nifedipine.

Drugman--a computerized supplement to a hospital's drug information newsletter.

A computerized supplement to a hospital's drug information newsletter, called Drugman, is described. The pharmacy department of a 452-bed teaching hospital developed Drugman. The program uses the "Converse" software, which was developed by the hospital's computer medicine department. The program provides information on new drugs recently added to the formulary and updated information on current formulary drugs. It also provides information on investigational drugs. A staff pharmacist is responsible for coordinating the writing and review of each new-drug monograph in the system, as well as the computer entry and up-dating of existing monographs. The program is available to all medical, nursing, and pharmacy personnel via computer terminals located on each nursing unit and in the pharmacy department. Survey questions at the end of the program elicit user response to the program and suggestions for additions or changes. In the initial 14-month period, the general response to Drugman has been favorable. Drugman represents a new method of disseminating drug information via computer in an individual hospital. The program complements traditional drug information sources and has been received positively in our hospital.

Implementation and operation of a hospital pediatric satellite pharmacy.

The planning, implementation, operation, and evaluation of a hospital pediatric satellite pharmacy are described. An initial three-month project involving establishment of a pediatric satellite pharmacy that provided unit dose drug distribution, intravenous admixtures, and a few clinical services was completed and evaluated. Positive evaluations by the medical and nursing staffs resulted in continuation of the satellite as a permanent program. Clinical services initially provided by the pediatric pharmacist were expanded to include acquisition of admission drug histories, instruction on discharge medication, participation on pediatric medical rounds and on the pediatric cardiopulmonary arrest team, operation of the poison control center, distribution of pediatric drug information, preparation of chemotherapy and monitoring of investigational protocols, and provision of pediatric nursing inservice education and community education. A five-year evaluation of the services provided by the pediatric satellite pharmacy was completed by 71 pediatric nurses and 27 Mayo Clinic physicians, all of whom had worked with the system regularly. The tabulated results are presented. Responses to overall services of the pediatric pharmacy were designated good to excellent by 100% of the physicians and by 98.6% of the nurses, indicating that the pediatric satellite pharmacy is a successful and beneficial program at this institution.