Osmotic Delivery Research Articles

Effects of temporary calf removal and osmotic pump delivery of gonadotropin-releasing hormone on synchronized estrus, conception to a timed artificial insemination and gonadotropin secretion in norgestomet-estradiol valerate-treated cattle

The objective of this study was to determine whether a constant, lowdose infusion of gonadotropin-releasing hormone (GnRH) following norgestomet-estradiol valerate estrus synchronization (SMB) and temporary calf removal (CR) would enhance fertility to a timed, 48-h artificial insemination (AI) in cattle. A subcutaneous osmotic pump was employed to deliver approximately 2.5 μg GnRH per hour for 6 to 7 d following norgestomet implant removal. In Experiment 1, suckled Brahman crossbred cows (n = 221) were assigned randomly to one of four treatments: 1) SMB (n = 58); 2) SMB+48−h CR (SMB+CR, n = 55); 3) SMB+GnRH (n = 56); and 4) SMB+CR+GnRH (n = 52). Virgin heifers (n = 69), 12 to 14 months of age, were allotted to Treatments 1 and 3. The CR (cows) and GnRH (cows and heifers) treatments began at SMB implant removal and all females were inseminated 48 h later. Experiment 2 assessed luteinizing hormone (LH) secretion following SMB implant removal and(or) osmotic pump insertion in 44 cyclic cows (n = 11/treatment group) treated as in Experiment 1. Cows received SMB treatment either early (Days 3 to 5) or late (Days 11 to 15) in the estrous cycle (n = 22/period). Conception rate at timed AI for SMB+CR was superior (50.9%; P<0.025) to all other treatments (SMB, 27.5%; SMB+GnRH, 26.9%; SMB+CR+GnRH, 26.9%). Gonadotropin-releasing hormone attenuated the positive effects of CR by reducing (P<0.02) cumulative pregnancy rates on Day 24 in SMB+CR+GnRH cows. Conception at timed AI in virgin SMB heifers (52.9%) was higher (P<0.025) than SMB+GnRH heifers (25.7%), and it remained higher (P<0.05) on Day 24 (85.3% vs 60.0%). Gonadotropin-releasing hormone stimulated a premature, preovulatory-like surge of LH which peaked 6.8±0.6 h following pump insertion. As employed here, GnRH reduced fertility by disrupting the normal sequence of endogenous endocrine events in progestogen-primed females.

Evaluation of two oxprenolol oral osmotic (OROS) delivery systems in patients with essential hypertension

The effects of two oxprenolol oral osmotic (OROS) delivery systems on heart rate and blood pressure before and during recovery from exercise at a predetermined load were examined in twelve patients with hypertension previously responding to beta-blocker monotherapy. Haemodynamic responses were attenuated during the 24 h after single and repeated (15 days') once daily administrations of 10/170 and 16/260 oxprenolol OROS. At 24 h after repeated doses, compared to placebo there were significant reductions in resting blood pressure and in heart rate immediately following exercise. Attenuation of heart rate after exercise was dose related but differences between the systems with respect to resting heart rate and blood pressure were inconsistent. Antihypertensive responses after repeated doses were greater than those after single doses. However, reductions in resting and exercise heart rates were consistently less on chronic therapy. This may reflect enhanced expression of the partial agonist activity of oxprenolol due to altered receptor sensitivity after prolonged beta-blockade. The plasma oxprenolol profiles after both systems indicated slow absorption and substantial concentrations were apparent 24 h after drug administration. These observations suggest that both oxprenolol OROS systems display sustained drug release and on once daily dosing provide 24 h beta-blockade and control of blood pressure at rest and following exercise.

In vivo biosynthesis and transport of oxytocin, vasopressin and neurophysin from the hypothalamus to the spinal cord

The biosynthesis of oxytocin, vasopressin and their associated neurophysins were studied in the projection from the paraventricular nucleus of the hypothalamus to the spinal cord in individual freely-moving adult male rats. Neuropeptide biosynthesis was studied in vivo by the delivery of [ 35S]cysteine through stereotaxically implanted indwelling cannulae using an osmotic minipump delivery system. Following the appropriate chase times, the neural lobe and spinal cord segments T 1-T 4., and T 12-L 2 were removed from fresh tissue; in addition, the nucleus of the solitary tract was punched from frozen coronal sections. The radiolabeled peptides were purified from the tissue homogenates by sequential linear and exponential gradient elution from reverse-phase high performance liquid chromatography columns. This approach has allowed us to purify radiolabeled oxytocin and vasopressin from both the upper and lower spinal cord. However, the kinetics of oxytocin and vasopressin biosynthesis appeared to be remarkably different, as judged by their differential labeling with different pulse and chase times. Additionally, the use of different chase periods following the pulse of radiolabel has allowed us to determine that oxytocin reaches the spinal cord via the fast component of axonal transport (> 8 mm h −1). Using immunoprecipitation and purification by high performance liquid chromatography, we were also able to purify radiolabeled neurophysins from spinal cord tissue homogenates. These results lend further support to a role for oxytocin and vasopressin in the modulation of autonomic nervous system function and to the role of the paraventricular nucleus as an integration center for endocrine and autonomic function.

Osmotic delivery systems for the beta-adrenoceptor antagonists metoprolol and oxprenolol: design and evaluation of systems for once-daily administration.

The essential features and mode of action of oral osmotic drug delivery systems (Oros) for metoprolol fumarate and oxprenolol succinate are described. Critical aspects in the development of systems for once-daily administration of both drugs are discussed, and methods for evaluating in vitro release characteristics are presented. In vitro testing confirmed that drug delivery corresponded closely to the theoretical release behaviour predicted from the physicochemical and membrane permeability characteristics for both oxprenolol and metoprolol systems. In vitro release rates were also shown to be unaffected by pH, in vitro test procedures, dissolution media and long-term storage at different temperatures.

Pharmacokinetic evaluation of osmotically controlled indomethacin delivery systems in man

Absorption characteristics of two osmotic delivery systems for indomethacin have been evaluated in man following single-dose administration as compared to intravenous and capsule administration of the drug. Fifteen healthy volunteers received all treatments according to a latin square design. Initial appearance rates of indomethacin in the general circulation following oral administration of the osmotically controlled delivery systems mimic their constant delivery rates found in vitro. The renal clearance and urinary recovery of free plus conjugated indomethacin is comparable in all treatments. Compared to intravenous or capsule administration of indomethacin, drug is 84% bioavailable from either controlled-release preparation.

Pharmacokinetics of valproic acid and metabolites in mouse plasma and brain following constant-rate application of the drug and its unsaturated metabolite with an osmotic delivery system.

Human therapeutic valproic acid (VPA) levels could be maintained in the mouse for a period of 1 week by constant rate application via subcutaneously implanted osmotic minipumps. Also, the concentrations of VPA metabolites observed in mouse plasma were similar to those seen in human plasma. The drug application could be prolonged by replacing exhausted pumps with freshly-filled devices. Removal of the implanted pumps and measurement of the decay of the drug levels revealed that the half-life of the main plasma metabolite 2-en(2-propyl-2-pentenoic acid) exceeded that of VPA. This result was confirmed by constant-rate application of this metabolite; the plasma clearance of 2-en (as calculated from the steady-state levels observed) was found to be lower than that of VPA. Brain levels of VPA and 2-en during steady-state were 3-10 per cent of corresponding plasma levels. The blood-brain kinetics of 2-en following administration of VPA were similar to those observed following application of 2-en itself. VPA was cleared faster from the brain than from the plasma, while 2-en was more persistent in the brain than in the plasma. Our results indicate that controlled, constant-rate application of drugs such as VPA, via implantable osmotic minipumps, may be a valuable procedure for a number of pharmacological and toxicological studies, particularly where persistent drug levels must be maintained for extended time periods.

In vivo biosynthesis of hypothalamic luteinizing hormone releasing hormone in individual free-running female rats.

The present studies examined the feasibility of performing in vivo biosynthetic studies of hypothalamic LHRH in preoptic area cannulated individual ovariectomized, estradiol benzoate (EB)-progesterone (P) treated rats. One day after EB treatment, rats were bilaterally cannulated in the anterior ventromedial preoptic area (POA). The following day, rats were treated with P, and a mix of 3H-proline and 3H-leucine (500 muCi) was continuously infused (for 8 hr) into the POA using an Alzet osmotic minipump delivery system at a rate of 1 microliter/h/cannula. 3H-LHRH was acid-extracted from discrete hypothalamic regions (POA, medial basal hypothalamus [MBH]and median eminence [ME]) and was purified to constant specific activity by sequential High Performance Liquid Chromatography. 3H-LHRH accounted for 0.010%, 0.018% and 1.6% of the total tissue 3H recovered in the POA, MBH and ME, respectively. These results demonstrate the feasibility of performing physiological studies on the biosynthesis and transport of hypothalamic LHRH using POA cannulated free-running female rats.

Rectal infusion of the model drug antipyrine with an osmotic delivery system.

An osmotically-powered rectal drug delivery system, was used for the rectal infusion of the model drug antipyrine. The system, which is slightly larger than a normal suppository, has a nominal pumping rate of 43 microliter h-1 over at least 30 h. Four healthy volunteers kept two such systems in their rectum for a sum total of 98 h. Saliva and plasma concentrations were determined at regular intervals and in all cases a very constant steady-state saliva and plasma concentration was reached and maintained. Defecation and reinsertion of the drug delivery system did not cause any irregularities in the concentration profile. The system was very well tolerated by the volunteers.

Experimental Endophthalmitis Treated With an Implantable Osmotic Minipump

A rabbit model of endophthalmitis was used to test the efficacy of an osmotic minipump delivery system as compared to standard intravitreal injection of the antibiotic, Staphylococcus aureus was inoculated into the vitreous cavity, and elimination of microorganisms was compared with use of intravitreal administration of 100 micrograms of gentamicin sulfate by either single pars plana injection or the continuous four-day administration of drugs to the vitreous via pars plana tubing connected to the minipump implanted subcutaneously near the rabbit's ear.

The role of polymers in optimizing therapeutic effectiveness of drugs

AbstractA new class of pharmaceutical dosage forms—therapeutic systems—has been developed. Unlike conventional dosage forms (i.e., pills, capsules, or sustained release preparations), which are specified only by the amount of drug they contain, therapeutic systems are described both by the rate and duration of drug delivery. The first products to embody this technology are: (1) an ocular therapeutic system that delivers the anti‐glaucoma drug, pilocarpine, to the eye for one week; (2) an intrauterine contraceptive system that delivers the fertility controlling hormone, progesterone, to the uterus for one year; and (3) an oral osmotic delivery system for administration of drug to the gastrointestinal tract. Specific furictiQns of polymers as constructional elements of therapeutic systems are discussed and consideration is given to properties critical to the intended performance, test procedures, and parameters for prediction of mechanical and physico‐chemical functionality, stability, and safety.

Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations

Miniature osmotic delivery systems were constructed and tested in various environments according to the design criteria described in the present paper. These devices, when activated by water, can deliver a variety of solutions or suspensions at zero-order rates for periods of hours up to several weeks. The osmotic pumps consist of a cylindrical reservoir for the fluid, surrounded by a layer of an osmotic driving agent which, in turn, is encapsulated by a semipermeable membrane. The reservoir material is chemically inert to most aqueous drug formulations, dilute acids, bases, and alcohols. The outer housing of the pump, which is the membrane, is highly compatible with tissues when the pumps are implanted in animals. Typically, the miniature pumps have a total volume of approximately 0.6 ml, and an internal effective volume of approximately 0.2 ml. The delivery rate can be varied from 0.1 to 3 μl/hr. Devices of this type have been tested successfully as implants in mice for anticancer drug research, in endocrine studies, and in narcotic-drug evaluations. The time course of the pumping ratein vivo is accurately specified by thein vitro pumping rate under conditions that are isotonic and isothermal to extracellular fluid.