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Brain delivery of neurotrophic factors via the systemic route is limited by the presence of blood brain barrier. Direct infusion into the intraventricular space is currently the mode of administration available clinically. Alternatively, controlled release systems can be the delivery system of choice using bioerodible polymers such as poly(d,l-lactic-co-glycolic acid) (PLGA). To utilize this concept, one has to establish the safety profile of the polymer and degradation products in brain. This report presents the results on the brain biocompatibility of PLGA implant using a rat model. In vitro erosion studies showed that the test PLGA rods eroded almost completely over a period of one month. Upon implantation into the rats' brains, these polymer rods and their breakdown products were well tolerated by the brain tissue. The overall presentation suggested that the brain tissue response to the implanted polymer was typical of those following mechanical trauma and exposure to foreign body. Tissue reaction was more pronounced around 14 days after implantation and largely subsided by day 28 when polymer erosion was near completion. There was no adverse cellular reactions in the parenchymal tissue adjacent to the implanted polymer. These results suggest that the PLGA materials are biocompatible and can be used to construct drug delivery devices for brain implantation.

The degradation of native LHRH in aqueous buffers of pH ∼1–10 obeyed the rate equation, kobs = kH+aH+ + ko + kHO-(aHO-)x, where x at 60–100°C was ∼0.64 and temperature independent. Extrapolation to 25°C using the Arrhenius equation and secondary rate constants showed that native LHRH is reasonably stable at pH 5.4, giving a shelf life (t90) of approximately 5 years. Regarding physical properties, hydrophobic LHRH analogues nafarelin and detirelix were found to be surface active as demonstrated by a decrease in apparent surface tension with increased peptide concentration. The CMC for detirelix at pH 7.4 was determined to be 5.3 × 10−4M (0.88 mg/ml), and that for nafarelin, >2 mg/ml. At higher concentrations (∼4–8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence

RS-49947 ([ d -Nal 6 ,aza-Gly 10 ]-luteinizing hormone releasing hormone)-silicone elastomer implants exhibit one year of therapeutic drug release in the target species, the canine [1]. Twentyone batches of these nonerodible porous matrix implants were studied by in vitro methodology to assess the effects of drug loading level, gamma irradiation dose, drug particle size and implant size on drug release. In vitro release data as a function of drug loading level are consistent with percolation theory [2–4], or modified percolation theory for small implant size [5]. The implants exhibit a percolation threshold [6–8] at ca. 30–35% of drug raw material. Simple geometric considerations are consistent with observed drug particle and implant size effects on in vitro release results. This model is consistent with an RS-49947 drug particle diameter in the implant of 100 μm. The drug raw material used to make these implants exhibits a unique morphology. Each drug powder particle is an agglomerate of sub-μm sized spheroidal primary particles. The sub-structure to each drug powder particle suggests that contacts between drug particles in the implant would occur on two size scales: (1) inter-particle contacts on a tens or hundreds of μm scale, and (2) intra-particle (primary particle) contacts on a sub-μm scale. Consistent in vitro release results are achieved without any control of overall gross drug particle size. Deagglomeration of RS-49947 drug raw material during the implant manufacturing process could explain the consistent implant performance.

A small macroporous nonerodible matrix implant supplying therapeutic levels of the decapeptide drug RS-49947 ([ d -Nal(2) 6 ,aza-Gly 10 ]-luteinizing hormone releasing hormone) for one year is described and analyzed. The implant is indicated for estrus or male sexual behavior suppression (reversible chemical castration), or for the treatment of sex hormone dependent diseases in the canine or feline. These small (55 mg) slab devices are implanted below the ventral surface skin of the animal through a small incision, and can be removed or replaced at the end of one year of therapy. The optimal system contains 41% of water soluble drug raw material (33.6% theoretical of RS-49947 free base) dispersed in Silastic 382 silicone elastomer. Plasma levels of drug and clinical performance parameters in the canine are presented for the optimal formulation and for formulations containing higher (44% drug solubles) and lower (39% drug solubles) percentages of drug raw material. Formulations containing 39% or 41% of drug raw material release in vivo by an unanticipated apparent zero order release mechanism. Comparison of clinical and in vitro data suggests that in vivo itmechanisms may control drug release rates from these systems. In vitro data for these implants are consistent with current knowledge of macroporous implants, while the in vivo data show anomalous drug release durations and profile shapes. Hypotheses for the differences between in vitro and in vivo drug release are presented. The drug raw material used to manufacture these implants exhibits a unique morphology, which may further complicate understanding of the in vivo release results. In vitro data for these systems give some insight into in vivo release, although the mechanisms of in vitro and in vivo drug release apparently differ.

Luteinizing Hormone Releasing Hormone (LHRH) is a highly potent decapeptide that stimulates the release of luteinizing hormone and follicle stimulating hormone. Although it was initially thought that the LHRH agonists would be useful for the treatment of infertility, continuous administration of agonist resulted in a parodoxical desensitization of pituitary gonadotropes by receptor down regulation, causing suppression of fertility. 1 These suppressive effects, however, may be very useful for the treatment of other diseases, including endometriosis, breast cancer, precocious puberty and prostatic cancer

Nafarelin controlled release injectable (CRI) releases a decapeptide drug for target one month therapy. Nafarelin, a luteinizing hormone releasing hormone agonistic analogue, is microencapsulated in biodegradable poly(lactide-co-glycolide) microspheres and given by intramuscular injection. Clinical data from a human single dose Phase I clinical study are modelled to develop theoretical multiple dose profiles and theoretical single dose profiles from mixtures of two or three formulations. Single dose injections of nafarelin CRI microspheres (4 mg nafarelin) containing 2, 4, or 7 per cent nafarelin all achieve useful plasma drug levels throughout the target 30 day interval. Therapeutic suppression of testosterone levels was observed in all subjects participating in the phase I clinical study. Highest plasma nafarelin levels are achieved in the 0-10 and 20-35 day post-injection intervals. Theoretical multiple dosing profiles generated from the single dose clinical results show significant oscillations in plasma nafarelin levels depending on the particular dosing interval selected. Thirty or forty day dosing intervals yield significant variability in plasma nafarelin levels at steady state; 15 day dosing intervals show less variability. Therapeutic testosterone suppression was observed in the single dose study, so the nafarelin dose per injection can be reduced in multiple dosing therapies. Theoretical plasma nafarelin profiles from certain mixtures of 2 and 4 per cent nafarelin microspheres or 2 and 7 per cent nafarelin microspheres indicate that a 60 day product could be achieved. In general, all three formulations yield their lowest plasma drug levels during the 10-20 day post-injection interval. Therefore any mixture of these formulations will likewise exhibit low plasma drug levels during this interval.

Vehicle effects on the percutaneous absorption of nicardipine base, nicardipine hydrochloride, ketorolac acid, and ketorolac tromethamine were determined using the rhesus monkey as an in vivo model for human skin penetration. Vehicles investigated included blends of propylene glycol, trimethylene glycol, ethanol, Azone, Tween 20, water, and long-chain fatty acids. Formulations were prepared such that the compound dose, application area, and percentage saturation of the compound in the vehicle were held constant. Variations in absorption of the compounds were therefore attributable to vehicle effects. Each formulation was applied to three monkeys for a period of 24 hr using 10 Hill Top Chambers. Plasma samples were taken at appropriate intervals for 36 to 48 hr. The results indicated that trimethylene glycol and Tween 20 did not enhance absorption of the test compounds despite claims by other investigators. Azone and ethanol provided moderate enhancement of both the rate and the extent of absorption, while long-chain fatty acids in combination with propylene glycol significantly enhanced penetration. In general, higher fluxes were observed with the more lipophilic compounds nicardipine base and ketorolac acid as compared to the hydrochloride and tromethamine salts.

Nafarelin, or d -Nal(2)6 LHRH, is an agonistic analogue of luteinising hormone releasing hormone (LHRH). It was designed as a pro-fertility agent, to initiate the cascade of events culminating in the production of the reproductive steroid hormones from the gonads in both females and males. However, it has since become apparent that native LHRH is secreted in a short pulsatile fashion, and administration of nafarelin by other regimens, including continuous administration, results in a suppression of the sequence of events. This provides utility for hormone dependent syndromes, particularly prostatic cancer and endometriosis. Nafarelin has been micro-encapsulated into poly ( d,l -lactic-co-glycolic) acid by a phase separation process. The microspheres are readily administered as an injectable suspension. The release of compound from such microspheres is triphasic, being predominantly erosion-controlled, with an early diffusional component. Adjustment of the system design provides overlap of these two phases. The initial rapid diffusional release of compound providing an immediate pharmacological response, and the abrupt termination of release, are two significant properties of the system. In vitro release of the compound is similarly triphasic, correlating closely with suppression of estrus in the female rat, and correlating quantitatively with plasma levels of compound in primates. The pharmacological effects seen are unique to the controlled release system, being more profound that those provided by intermittent administration.

The present rapid expansion of activity in development of peptide and protein drug compounds has provided a major thrust for development of novel technology for their delivery. These compounds have typically very low oral bioavailability (although this elusive goal is sufficiently attractive for it to remain an active area of exploration).