Dietary resistant maltodextrin ameliorates testicular function and spermatogenesis in streptozotocin-nicotinamide-induced diabetic rats.

This study investigated the effect of resistant maltodextrin (RMD) on reproduction in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic male rats. Forty male rats were induced with diabetes by a single intraperitoneal injection of STZ (50 mg kg(-1)) and nicotinamide (100 mg kg(-1)). Five groups were analysed in total: normal, diabetic rats without RMD, diabetic rats with RMD 1.2 g per 100 g diet (1×), with RMD 2.4 g per 100 g (2×), and with RMD 6.0 g per 100 g (5×). The groups of diabetic rats with the RMD supplement, compared to those without supplement, showed improved plasma glucose control, attenuated insulin resistance and recovery of testosterone level and spermatogenesis stage. The STZ-nicotinamide-induced diabetes mellitus (DM) caused a significant reduction in serum testosterone, testis androgen receptor (AR), steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) protein, but a statistical recovery in each of these was observed in the 5× group. TUNEL-positive cells were observed in the diabetic without RMD group, and RMD treatment reduced apoptotic germ cells. The expression of Bax/Bcl2 was induced in the diabetic group and also significantly reduced in the 5× group. Dietary RMD may improve metabolic control in STZ-nicotinamide-induced diabetic rats and attenuate hyperglycaemia-related impaired male reproduction and testicular function.

Sexual genetic and simple sequence repeat (SSR) analysis for molecular marker development on the all hermaphrodite papaya.

The papaya (Carica papaya L.) is one of the most important economic tropical fruits in the world, and the hermaphrodite is the preferred type in field cultures. We analyzed the sexual ratio of offspring from the cultivar 'Taiwan Seed Station No. 7' (T7) by a self-cross and its cross with Taichung Sunrise (TS). Female progeny from the T7 self-crossing were not observed. This finding may be caused by a lethal gene that is linked to females. In this study, we selected 192 simple sequence repeats (SSRs) to analyze the polymorphism between T7 and TS. A total of 37 SSRs were identified for T7 and TS. In addition, 14 SSRs served as the molecular makers for identification of T7, TS and their hybrid offsprings. Thus, the results show that the genetic similarity between T7 and TS is rather high. This suggests that T7 may be a mutant of TS. Phylogenetic analysis from the SSR polymorphisms of the above parent strains and 15 F1 offspring revealed the genetic distance of the F1 offspring located between T7 and TS. The results of this study may provide an opportunity for elucidating the genetic characteristics of all hermaphrodites via identification of molecular makers.

Differential effects of high MUFA with high or low P/S ratio (polyunsaturated to saturated fatty acids) on improving hepatic lipolytic enzymes and mediating PPARγ related with lipoprotein lipase and hormone-sensitive lipase of white adipose tissue in diet-induced obese hamster.

OBJECTIVES: The aim of this study was to assess the relationship between high monounsaturated fatty acids (MUFAs) with different levels of polyunsaturated-to-saturated fatty acid (P/S) ratios and body fat loss in diet-induced obesity (DIO) models. DESIGN: Male Golden Syrian hamsters were randomly assigned to the control group (n=12) and obesity group (n=24) for 4 weeks of the high-fat DIO period; afterward, six hamsters from each group were killed. The remaining control hamsters were still fed a low-fat diet. For an additional 8 weeks, the remaining obesity hamsters were switched to a low-fat diet and subdivided into three subgroups (n=6/group): the obesity-control (ObC) group, high MUFA with high P/S ratio oil (HMHR) group and olive oil (OO) group. Serum insulin and leptin concentrations were measured, and hepatic fatty acid metabolic enzymes and adipose differentiation markers were determined using enzyme activities analysis, western blot and semiquantification reverse-transcription PCR. RESULTS: No difference was observed in the mean energy intake through all study periods. After the DIO period, the obesity group increased in weight gain and epididymal fat weight compared with the control group. DIO hamsters in the HMLR group had significant reductions in white adipose tissue deposition and plasma leptin levels, suppression in adipose peroxisome proliferator-activated receptor-γ (PPARγ) and lipoprotein lipase (LPL) mRNA expressions and increases in hepatic acyl-CoA oxidase and carnitine palmitoyltransferase-I activities and mRNA levels compared with those in the ObC group. The HMHR group had upregulated phosphorylation of hormone-sensitive lipase (HSL) relative to total HSL protein levels compared with the OO group. However, the OO group had significantly elevated hepatic de novo lipogenesis compared with the HMHR group. CONCLUSIONS: HMHR seemed to be beneficial in depleting white adipose tissue accumulation by decreasing adipose PPARγ and LPL mRNA expressions and mediating phosphorylation of HSL, and by improving hepatic lipolytic enzyme activities and mRNA expressions involved in ß-oxidation in DIO hamsters.

Transdermal delivery of zalcitabine: in vitro skin permeation study.

OBJECTIVE: To study the feasibility of transdermal delivery of anti-HIV drugs in order to maintain blood concentration within the therapeutic range for longer duration and to reduce the side-effects associated with high dose administration. DESIGN AND METHODS: The effects of vehicles and enhancers on the skin permeation rate of zalcitabine (ddC) were investigated to determine the maximum permeation rate attainable. In vitro skin permeation of ddC, saturated in various compositions of ethanol/tricaprylin or ethanol/water cosolvent system, with and without enhancer, was studied at 37 degrees C using freshly excised hairless rat skin and human cadaver skin as model skins. RESULTS: The skin permeation rate of ddC from both ethanol/tricaprylin and ethanol/water cosolvent system increased when increasing the volume fraction of ethanol and reached maximum values at 50-60% (vol/vol) of ethanol. Addition of 1.0% (vol/vol) of permeation enhancer, such as oleic acid or N-methyl-2-pyrrolidone, to the ethanol/tricaprylin (50:50) cosolvent system could not significantly increase the permeation rate of ddC. However, addition of 1.0% (vol/vol) of oleic acid in ethanol/water (60:40) cosolvent system dramatically enhanced the skin permeation rate of ddC with reduced lag time. Permeation rate of ddC increased with increasing oleic acid concentration up to 0.7% (vol/vol) in the ethanol/water (60: 40) cosolvent system, and reached a plateau with further addition of oleic acid. Although permeation rate of ddC across human cadaver skin (0.61 mg/cm2/h) was three times lower than that across hairless rat skin (1.88 mg/cm2/h), the maximum permeation rate of ddC attainable, using ddC saturated solution in ethanol/water (60: 40) cosolvent system containing 1.0% (vol/vol) oleic acid, was 4-5 times higher than the target rate (0.14 mg/cm2/h) to maintain the therapeutic blood level. CONCLUSION: The synergistic enhancement effect of ethanol and oleic acid can make transdermal delivery of ddC feasible.

Microsealed drug delivery systems: fabrications and performance.

PIP: The Microsealed Drug Delivery (MDD) system was developed to achieve several objectives: to maximize the bioavailability of a therapeutic agent in a target tissue; to minimize the adverse side effects of a therapeutic agent or its metabolites; to optimize the onset, rate, and duration of drug delivery; to maintain the steady-state plasma drug level within a therapeutic range for as long as required for effective treatment; and to improve the patient compliance to a therapeutic regimen. This drug delivery system is fabricated from a biocompatible elastomer by microdispersion of the drug reservoir, as immobilized microscopic spheres, in the cross-linked polymer matrix. The release of drugs is controlled at a programmed rate for a prolonged time period. Several physical shapes and sizes of controlled-release drug delivery devices can be fabricated from this MDD system for various biomedical applications. For subcutaneous controlled drug administration, a cylinder-shaped subdermal implant was fabricated from the MDD system for easy subcutaneous implantation and the controlled release of deoxycorticosterone acetate in rats at zero-order rates for a duration of up to 129 days for cardiovascular pharmacology studies. This is 1 example of the many controlled-release drug delivery devices that can be fabricated from the patented MDD system. A bandage-type transdermal MDD device was developed to release an androgen, testosterone, at a constant rate. Topical application of this testosterone-releasing transdermal patch over the skin in the umbilical area of monkeys was observed to achieve a relatively constant plasma level of testosterone for a duration of up to 31 days. The encouraging results laid the foundation for the recent development and marketing of Nitrodisc system. A donut-shaped vaginal device can be fabricated from the MDD system for the intravaginal controlled administration of an orally active contraceptive progestin, such as norethindrone, or of a combination of 1 progestin with 1 estrogen. A 7-shaped IUD can be fabricated from the MDD system for intrauterine controlled administration of an estrogen, such as estriol, or a progestin to achieve a localized contraceptive action.^ieng

Enhanced skin permeability for transdermal drug delivery: physiopathological and physicochemical considerations.

To deliver drugs through the skin for systemic medication, the skin permeability needs enhancing by either modifying the drug molecules, or applying skin permeation enhancers to reduce the barrier property of the skin. Traditionally, the enhancement of skin permeability is considered as the result from the improvement of the lipophilicity of drugs and the partition of drugs into the skin, or from the direct actions of skin permeation enhancers on the chemical structure and/or composition of lipids and proteins in the stratum corneum. However, on the other hand, the skin also responds to drugs and/or skin permeation enhancers physiopathologically via its inflammatory and immune reaction. The physiopathological responses of the skin can also induce the changes in the chemical structure and composition of lipids and proteins in the skin. Therefore, the possible role of physiopathological responses of the skin in the enhanced skin permeability should be concerned.

Transdermal drug delivery: a review of pharmaceutics, pharmacokinetics, and pharmacodynamics.

This article provides a critical literature review on the recent advances in the research and development of rate-controlled transdermal therapeutical systems for systemic medication. The article focuses its discussion on the recent development in the fundamentals, developmental concepts, and biomedical assessment of the transdermal controlled drug administration. The scope of the review consists of the following areas: mechanism of percutaneous absorption; enhancement of skin permeability; in vitro and in vivo evaluations of transdermal permeation kinetics and assessment of in vitro-in vivo relationship; pharmacokinetics and pharmacodynamics of transdermal controlled drug administration and establishment of pharmacokinetic/pharmacodynamic relationship; clinical performance of rate-controlled transdermal therapeutic systems; and potential development in rate-controlled transdermal drug delivery.

Nonparenteral administration of peptide and protein drugs.

Peptides/proteins are an important class of drugs which are usually administered by parenteral route. In recent years, pharmaceutical research has been directed towards developing a nonparenteral route of delivery of peptide/protein drugs. These studies report that it may be possible to administer the peptides/proteins especially insulin, by nasal, buccal, rectal, or even transdermal route. Therefore, there is a great potential for future development of a nonparenteral route of delivery of peptide/protein drugs. The primary objective of this review is to report the present status of research involving nonparenteral administration of macromolecular peptides/proteins, with special emphasis on insulin.

Intranasal drug delivery for systemic medications.

This article is designed to provide a critical literature review on the scientific advances in intra- and transnasal drug delivery for systemic medication. The article discusses the fundamentals, developmental concepts, and biomedical assessment of the transnasal administration of systemically effective drugs which are either easily inactivated when taken orally, due to the extensive hepatic first-pass elimination, or too large in molecular size to be absorbed efficiently, except by i.v. administration.

Systemic delivery of peptides and proteins across absorptive mucosae.

As therapeutic peptides and proteins become readily available through rapid advances in recombinant technology, and because rapid presystemic elimination renders them ineffective when administered orally, pharmaceutical scientists are faced with the challenge of delivering these macromolecules systemically; therefore, alternative routes of delivery need to be investigated. Transmucosal delivery through absorptive mucosae represents one of these alternatives. This route has the advantage of being noninvasive and of bypassing hepatogastrointestinal clearance. The absorptive mucosae that have been investigated for delivery of peptides and proteins include buccal, nasal, pulmonary, rectal, and vaginal. Nasal delivery has been studied extensively and has been the most successful--nasal sprays for buserelin, desmopressin, oxytocin, and calcitonin are already available commercially. In general, enzyme inhibitors and permeation enhancers need to be coadministered for successful delivery of these biopharmaceuticals. Classes of enhancers used for transmucosal delivery include bile salts, dihydrofusidates, cyclodextrins, surfactants, and chelating agents. Each of these agents exerts its enhancing effects by a different mechanism, and each has been associated with adverse effects. This article discusses the physiology of each of the mucosae used, the fundamentals of transmucosal delivery, and recent progress in systemic delivery of therapeutic peptides and proteins across each of the mucosae; in an effort to highlight principles of transmucosal delivery, it also discusses the transmucosal delivery of enkephalin, calcitonin, and insulin as case studies.

Pulmonary drug delivery: physiologic and mechanistic aspects.

Peptide and protein drugs are being used increasingly in major research and development programs in the pharmaceutical industry and are also an important class of therapeutic agents due to advances in genetic engineering and biotechnology. Systemic delivery of these macromolecular drugs, however, has been limited to the parenteral route largely because of their extensive presystemic elimination when taken orally. Faced with this dilemma concerning the systemic delivery of these macromolecules with their unique conformational complexity for therapeutic activity, pharmaceutical scientists have evaluated the potential of various non-oral routes of administration as alternatives. Despite the tremendous efforts that have been devoted to this problem, only limited success has been achieved--mostly with small peptides. Growing attention has been given to the potential of a pulmonary route as an alternative non-invasive means for systemic delivery of peptide/protein-based therapeutic agents due to the fact that the lung provides a huge but extremely thin absorptive mucosal membrane. Although current studies show great promise, pulmonary delivery of therapeutic peptides and proteins is complicated by the complexity of the anatomic structure of the human respiratory system and the influence on drug deposition exerted by respiration. This review discusses the fundamental structure and physiology of the human respiratory system, current methodology used to study pulmonary drug absorption, approaches of drug delivery to the distal lung, and recent progress in pulmonary drug delivery by case studies. The mechanisms of pulmonary drug absorption are also discussed.

Novel methods of insulin delivery: an update.

Conventional insulin therapies involve multiple daily subcutaneous injections. However, the resultant disposition of insulin and blood glucose differs considerably from that following the physiological secretion of pancreatic insulin. A variety of alternative routes/methods have been investigated to improve systemic insulin delivery. Peroral and nasal insulin administration have demonstrated good potential for the treatment of diabetes. Facilitated transdermal delivery has also enjoyed success in promoting the systemic delivery of insulin. In addition, pulmonary, buccal, and ocular insulin administration have been shown to decrease serum glucose concentrations. Other methods that have been investigated for their potential in systemic insulin delivery include rectal, vaginal, and uterine routes.

Transdermal testosterone delivery in castrated Yucatan minipigs: pharmacokinetics and metabolism.

The feasibility of using the castrated Yucatan minipig as a hypogonadal animal model to investigate the transdermal controlled systemic delivery of testosterone was studied. During a 24 h application of a testosterone transdermal delivery device (T-TDD), serial blood samples were withdrawn from the minipigs, without anesthesia, at predetermined time intervals and the plasma concentrations of testosterone as well as its major metabolites, dihydrotestosterone and estradiol, were assayed by radioimmunoassay. The compartmental pharmacokinetic modeling analysis of the plasma profiles of total testosterone indicated that as much as 92% of the total testosterone dose released from the T-TDD had been delivered transdermally into the systemic circulation during the initial rapid input period (the first 11 h of the application), while only 8% was delivered during the slow input period (up to 23h). Good correlation was observed between the in vivo input doses [1.9 (+/- 0.2), 4.8 (+/- 0.2) and 6.4 (+/- 0.5) mg/day], determined by the Wagner-Nelson equation, and the daily doses released [1.9 +/- (0.2), 4.7 (+/- 0.2) and 6.6 (+/- 0.5) mg/day, respectively, for 1, 2, and 3 units of T-TDD]. While the in vivo rate of input in the castrated minipigs was observed to be similar to that in hypogonadal men treated with the T-TDD during the first 8 h period, the input rate was found to be slower during the last 12 h. The agreement could suggest that the mechanism for the transdermal systemic delivery of testosterone in the castrated minipig could be similar to that in the hypogonadal men. However, the plasma testosterone profiles attained in the castrated minipigs were observed to be similar to, but slightly lower than that in the hypogonadal men reported in the literature. The delta Cmax (baseline normalized peak plasma concentration) and delta Cavg (baseline normalized average plasma concentration) data in the castrated minipigs were 40 and 44%, respectively, of that in hypogonadal men. The approximately 2.4 fold lower values in delta Cmax and delta Cavg data could result from the difference in the clearance rate of testosterone which approximately 2.8 fold higher in minipigs than in the human. Despite the difference in clearance rate, the castrated minipigs could be a suitable large animal model for studying the pharmacokinetics of testosterone delivered transdermally in human with hypogonadism.

Electrochemistry of drug action I: electrooreduction of ferredoxins.

Ferredoxin serves as an electron carrier in the oxidation-reduction system in anaerobic microorganisms, transferring electrons from a low potential donor to electron-accepting biochemicals. The anaerobicidal activity of some drugs may be due to their interference with the electron transport function of ferredoxin. Two types of ferredoxins (isolated from Clostridium pasteurianum and spinach) were studied, and their electrochemical reduction and biochemical properties were analyzed using a sensitive ac polarographic technique. The reduction potential of both ferredoxins was linearly related to pH. The mechanisms of electron transport in ferredoxin molecules were found to be related to their sulfur-iron bonds. The dissociation of the sulfur-iron bonds resulted in the formation of a free sulfhydryl group and the interruption of the electroactivity of ferredoxin. This sulfur-iron dissociation process was found to be pH dependent. The electroreduction of ferredoxins was an energy-requiring, pH-dependent process.

Long-term controlled navel administration of testosterone.

Male fertility has reportedly been regulated by the long-term, continuous administration of testosterone. To deliver the testosterone at a controlled rate for a month or longer, a bandage-type, testosterone-releasing, disk-shaped device was developed. In vitro drug elution studies demonstrated that a constant release profile of testosterone was achieved. In vivo studies in rhesus monkeys with the medicated device directly overlaying the navel for 46 d, yielded a fairly steady plasma level and also a constant urinary excretion rate for 32 d. A greater systemic bioavailability (more than twofold) was achieved as compared with drug disposition directly onto the navel or via the placebo device (i.e., drug is deposited onto the prefabricated placebo device). A fairly constant cumulative urinary recovery profile was achieved for longer than 1 month, in which greater than 90% of the dose was administered. The in vitro and in vivo relationship was analyzed and discussed.

A new bioassay for insulin in conscious rabbits by continuous measurement of glycemic responses.

Because of the substantial variability often observed in the determination of insulin potency by the United States Pharmacopeia (USP) bioassay method, a large number of rabbits are required in order to attain an accuracy of +/- 6% and each bioassay needs 2-3 weeks to be completed. In this report, an improved bioassay method has been developed. This bioassay was conducted in conscious healthy rabbits. The decline in blood glucose levels, following intravenous injection of an insulin preparation, was monitored (in uninterrupted manner) by the continuous glucose monitoring system developed. A glucose response curve was generated, and from this response curve, various pharmacodynamic parameters were easily determined. The whole procedure could be completed in 1 day and also achieved an accuracy where upon only one rabbit is needed to determine accurately the insulin potency. To validate the method, a total of nine healthy rabbits were studied to determine the inter- and intra-animal reproducibility. The values of insulin potency determined from four pharmacodynamic parameters were compared, and the potency calculated from the ABGC (area of the blood glucose response curve under baseline) was found to be the most accurate: a mean (+/- SEM) value of 102.3(+/- 1.2)% was determined by inter-animal study (n = 9) and a value of 100.6(+/- 1.3)% by intra-animal study (n = 4). The inter-bioassay variability among the random-dose bioassays was 1.2% for inter-animal and 1.3% for intra-animal studies. The insulin potency in an insulin sample determined by this bioassay had attained an overall mean (+/- SEM) value of 101.6(+/- 0.8)% (n = 17).(ABSTRACT TRUNCATED AT 250 WORDS)

Intestinal absorption of dideoxynucleosides: characterization using a multiloop in situ technique.

The intestinal absorption of dideoxynucleosides was studied in rabbits, using a closed-loop mesenteric-sampling in situ technique developed in this laboratory, and the kinetic profiles were characterized. Each of the dideoxynucleosides exhibited different dependence on the intestinal regions studied: 3'-azido-2',3'-dideoxythymidine was best absorbed from the ileum, while 2',3'-dideoxyinosine and 2',3'-dideoxycytidine were preferentially absorbed from the jejunum. The results were validated by the mass-balance approach; the percent of drug retained in the intestinal lumen and that degraded at the intestinal pH, by colonic flora, in the intestinal tissue, and in plasma were assessed.

Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 2. The effect of vehicle and enhancer on skin permeation.

The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.

Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 1. Stability studies for hairless rat skin permeation.

The stability of dideoxynucleoside-type anti-HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia-Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37 degrees C for at least 30 h. However, DDC and DDI degraded in the extract of the dermis following first-order kinetics at both 25 and 37 degrees C, while AZT was stable at 37 degrees C for at least 30 h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor, i.e., p-chloromercuribenzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin.

Effects of H+ liberated from hydrolytic cleavage of polyester microcapsules on their permeability and degradability.

Microcapsules prepared from blends of poly(d,l-lactide-coglycolide) with a lactide:glycolide ratio of 75:25 (PLGA75:25) and poly-(d,l-lactide) (PLA5000) or poly(d,l-lactic acid-co-glycolic acid) (PLGA5000) were dispersed in phosphate-buffered saline, and their hydrolytic rates were investigated. Using the Henderson-Hasselbalch equation and an L-lactic acid experiment, the concentration of hydrogen ions released into the bulk medium was calculated from the change in buffer pH. The rate of H+ formation was found to be dependent upon the polymer composition of the microcapsules. The incorporation of PLGA5000 or PLA5000 into PLGA75:25 microcapsules drastically enhanced hydrolytic rates of microcapsules and resulted in controlled release of hydrogen ions generated from carboxyl end groups of both intact and degrading polymers. In contrast to microcapsules prepared with PLGA75:25 only, which liberated a negligible amount of H+ ions after a 21-day incubation, the microcapsules prepared from polymer blends released approximately (19.2-42.0) (x10(-3)) mmol of H+ ions. It has been found that the amount of hydrogen ions liberated into the bulk can be used as a qualitative indicator to monitor the change in microcapsule permeability to protein as well as polymer degradation.