Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration.

The aim of this study was the comparison of two different formulations (solid lipid nanoparticles (SLN) and conventional o/w emulsion) as carrier systems for the molecular sunscreen oxybenzone. The influence of the carrier on the rate of release was studied in vitro with a membrane-free model. The release rate could be decreased by up to 50% with the SLN formulation. Further in vitro measurements with static Franz diffusion cells were performed. In vivo, penetration of oxybenzone into stratum corneum on the forearm was investigated by the tape stripping method. It was shown that the rate of release is strongly dependent upon the formulation and could be decreased by 30-60% in SLN formulations. In all test models, oxybenzone was released and penetrated into human skin more quickly and to a greater extent from the emulsions. The rate of release also depends upon the total concentration of oxybenzone in the formulation. In vitro-in vivo correlations could be made qualitatively.     

Ethosomes for skin delivery of ammonium glycyrrhizinate: in vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers.

The aim of this work was the evaluation of various ethosomal suspensions made up of water, phospholipids and ethanol at various concentrations for their potential application in dermal administration of ammonium glycyrrhizinate, a useful drug for the treatment of various inflammatory-based skin diseases. Physicochemical characterization of ethosomes was carried out by photon correlation spectroscopy and freeze fracture electron microscopy. The percutaneous permeation of ammonium glycyrrhizinate/ethosomes was evaluated in vitro through human stratum corneum and epidermis membranes by using Franz's cells and compared with the permeation profiles of drug solutions either in water or in a water-ethanol mixture. Reflectance spectrophotometry was used as a non-invasive technique to evaluate the carrier toxicity, the drug permeation and the anti-inflammatory activity of ammonium glycyrrhizinate in a model of skin erythema in vivo on human volunteers. Ethosomal suspensions had mean sizes ranging from 350 nm to 100 nm as a function of ethanol and lecithin quantities, i.e., high amounts of ethanol and a low lecithin concentration provided ethosome suspensions with a mean size of approximately 100 nm and a narrow size distribution. In vitro and in vivo experiments were carried out by using an ethosome formulation made up of ethanol 45% (v/v) and lecithin 2% (w/v). The ethosome suspension showed a very good skin tolerability in human volunteers, also when applied for a long period (48 h). Ethosomes elicited an increase of the in vitro percutaneous permeation of both methylnicotinate and ammonium glycyrrhizinate. Ethosomes were able to significantly enhance the anti-inflammatory activity of ammonium glycyrrhizinate compared to the ethanolic or aqueous solutions of this drug. Some in vivo experiments also showed the ability of ethosome to ensure a skin accumulation and a sustained release of the ammonium glycyrrhizinate.     

PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties.

The in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties of PLGA-mPEG nanoparticles of cisplatin were investigated. The nanoparticles were prepared by a double emulsion method and characterized with regard to their morphology, size, zeta potential and drug loading. The rate of in vitro degradation of the PLGA-mPEG nanoparticles in PBS (pH 7.4) depended on their composition, increasing when the mPEG content (mPEG:PLGA ratio) of the nanoparticles increased. Sustained cisplatin release over several hours from the PLGA-mPEG nanoparticles in vitro (PBS) was observed. The composition of the nanoparticles affected drug release: the rate of release increased when the mPEG content of the nanoparticles increased. Within the range of drug loadings investigated, the drug loading of the nanoparticles did not have any significant effect on drug release. The loading efficiency was low and needs improvement in order to obtain PLGA-mPEG nanoparticles with a satisfactory cisplatin content for therapeutic application. The i.v. administration of PLGA-mPEG nanoparticles of cisplatin in BALB/c mice resulted in prolonged cisplatin residence in systemic blood circulation. The results appear to justify further investigation of the suitability of the PLGA-mPEG nanoparticles for the controlled i.v. delivery and/or targeting of cisplatin.     

Potential usefulness of solubility index for prediction of the skin permeation rate of 5-ISMN from pressure-sensitive adhesive tape.

Skin permeation of 5-ISMN from pressure sensitive adhesive (PSA) tape was evaluated using thermodynamic activity of the drug in PSA. Three acrylic adhesives (Gelva 737, Gelva 1430 and Gelva 1753) were used as PSA. Since the drug activity in PSA is difficult to determine, however, a solubility index was defined. Several PSA tapes containing different amounts of 5-ISMN were prepared, and heat of fusion at the dissolution of 5-ISMN in each PSA was determined by DSC. No exothermic peak was found when the drug concentration was less than the solubility in PSA, whereas the heat of fusion increased proportionally with amount of solid drug in the PSA when the drug concentration was above the solubility. The bending point in the profile of heat of fusion versus 5-ISMN content in PSA was defined as the solubility index. In vitro skin permeation was determined using excised hairless rat skin from 5-ISMN-saturated PSA tapes. The obtained skin permeation of the drug decreased with increases in the solubility index. These profiles were confirmed by a theoretical approach using the differential equation corresponding to Fick's second law of diffusion. These results suggested that the solubility index can be utilized for prediction of the skin permeability of drugs from PSA tape.     

Mechanism of the synergic effects of calcium chloride and electroporation on the in vitro enhanced skin permeation of drugs.

We have already reported the substantial synergic effects of CaCl(2) and electroporation (EP) on in vitro skin permeation of calcein and FITC dextrans. In the present paper, we investigated the mechanisms for these effects by considering changes in lamellar structure and barrier recovery time of the biggest skin barrier, the stratum corneum, by this combined treatment. The change in skin lamellar structure was evaluated by lipid mobility in the stratum corneum using ATR-FTIR, calcein release from stratum corneum-lipid liposomes (SCLL), in vitro skin permeation of calcein and transepidermal water loss (TEWL). The ATR-FTIR measurement, in vitro skin permeation and changes in TEWL were also used for examining the barrier recovery time. The C-H stretching band of skin lipids produced with EP was blue-shifted when compared to that without EP. Asymmetric C-H stretching was highest with EP in CaCl(2) solution. Little release of calcein was observed from SCLL without EP, whereas higher releases were observed after EP with or without NaCl or CaCl(2). Particularly high calcein release (>20%) was observed over 60 min with EP in CaCl(2) solution. The in vitro permeation study of calcein was conducted through excised hairless rat skin that was pretreated with EP before skin excision. Permeation rate was highest in skin excised immediately after in vivo EP, and this rate decreased with time after EP treatment. TEWL recovered to control levels within 2 h after EP in distilled water or NaCl solution, whereas high TEWL was maintained after EP in CaCl(2) solution. These results suggest that at least lamellar destruction of stratum corneum must be related to the enhanced skin permeation of drugs by the combination of CaCl(2) and EPF. On the other hand, a prolonged enhancing effect on the skin permeation of calcein by this combination may be due to a high lamellar destruction and/or delayed barrier repair of stratum corneum.     

Enhancement of skin permeation of ketotifen by supersaturation generated by amorphous form of the drug.

Pressure sensitive adhesive (PSA) matrices containing amorphous ketotifen were prepared and evaluated for enhanced skin permeability of the drug. A solvent casting method using silicone-typed PSA was employed, and n-hexane, an original solvent for the PSA and one more solvent, dichloromethane, tetrahydrofuran, acetone, ethyl acetate or toluene, were used for complete dissolution of ketotifen and high dispersion in an amorphous state of the drug. Presence of the amorphous form was judged based on the in vitro drug release rate from the matrix. As a result, dichloromethane and tetrahudrofuran were selected as appropriate dilution solvents. In vitro permeation experiments through excised hairless mouse skin revealed that the steady-state flux from the amorphous ketotifen-dispersed matrices was about five times greater than that of the crystalline ketotifen-dispersed matrices, and that the enhancement ratio was in good agreement with the solubility ratio of the amorphous to crystalline form of the drug. Comparison of the skin permeation profiles of amorphous ketotifen-dispersed matrices between two different drug contents suggested that the steady-state flux was not influenced by the drug content. In addition, at both drug contents, the period of the steady-state permeation coincided with the time until the amorphous drug was depleted from the matrix. These results suggest that the increase in skin permeation of ketotifen from PSA matrix was due to the supersaturation generated by amorphous form, and that the amorphous form was stable during the application period.     

Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9

Recognition of endogenous DNA and RNA by cells expressing TLR7 and TLR9 is an important contributor to the pathogenesis of systemic lupus erythematosus and has been suggested to contribute to cutaneous lupus and to a group of related inflammatory skin diseases termed interface dermatitis. We have developed a mouse model of TLR7- and TLR9-dependent skin inflammation using tape stripping. In normal mice, this resulted in a rapid but transient inflammatory cell infiltration accompanied by induction of type I IFN production by plasmacytoid dendritic cells (PDCs) and release of extracellular traps and proinflammatory cytokines by neutrophils. These responses were strongly reduced in MyD88-deficient mice and in mice treated with a bifunctional inhibitor of TLR7 and TLR9. In contrast, in lupus-prone (NZBxNZW)F(1) mice, tape stripping induced the development of chronic lesions characterized by a persistent type I IFN gene signature and many clinical and histological features of cutaneous lupus. Depletion of PDCs before injury prevented the development of skin lesions, whereas treatment with a bifunctional TLR7/9 inhibitor before tape stripping or after the initial lesion was established led to a significant reduction of the disease. These data suggest that inhibitors of TLR7 and TLR9 signaling have potential therapeutic application for the treatment of interface dermatitis.     

Interrelation of permeation and penetration parameters obtained from in vitro experiments with human skin and skin equivalents.

In a comparative study, two different in vitro cutaneous test systems were examined: (1) The Franz diffusion cell (FD-C), a test system to study drug permeation through the skin and to obtain data like steady state flux and lag time as well as permeability and diffusion coefficients. (2) The Saarbruecken penetration model (SB-M), a test system to investigate drug penetration into different skin layers and after varying incubation times to acquire values about the quasi steady state drug amounts in the stratum corneum (SC). Three drug concentrations (0.9, 0.45 and 0.225%) of a lipophilic model drug preparation, flufenamic acid in wool alcohols ointment, were applied on the skin's surface using 'infinite dose' conditions. Trypsin-isolated SC, heat-separated epidermis, full-thickness skin and reconstructed human skin (RHS) served as skin membranes in the FD-C, while the SB-M experiments were only carried out using full-thickness skin. Increasing steady state flux data and m(ss) values (steady state drug amount in the SC) were detectable after the application of rising drug amounts. Concerning the permeability of the used skin membranes in establishing barrier properties, the following rank order was observed: RHS>SC> or =epidermis>full skin. The flux data of the FD-C experiments for isolated SC, separated epidermis and RHS were linearly related with the m(ss) values of the SB-M investigations, allowing a direct comparison of permeation with penetration parameters. Concerning the drug amount in the SC, previous investigations succeeded in the establishment of an in vivo/in vitro correlation. Based on the results presented here, the prediction of drug amounts present in the SC after different incubation times in vivo is now possible after penetration as well as permeation experiments using the lipophilic model drug preparation, flufenamic acid in wool alcohols ointment.     

Development of polymer film dosage forms of lidocaine for buccal administration. I. Penetration rate and release rate.

We examined the penetration rate of lidocaine (LC) through excised oral mucosa from hamster cheek pouch and the in vitro release rate of LC from film dosage forms with hydroxypropylcellulose (HPC) as a film base. Addition of glycyrrhizic acid (GL) to the HPC films increased the LC release rate almost GL-content-dependently, while an optimum GL content was observed for the LC penetration rate. No LC penetration was observed from an acidic aqueous solution (pH 3.4) of LC, suggesting only unionized LC can substantially penetrate through the mucosa. A significant relationship between the penetration rate of LC and the release rate of unionized LC was found, suggesting that the in vitro dissolution study is a useful tool to predict the penetration rate taking the unionized drug fraction into consideration.     

Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies

A controlled drug release system based on the injectable PLGA microspheres loaded with gestodene and ethinyl estradiol was prepared and evaluated for the feasibility of monthly synchronic delivery of the two hormonal contraceptives. The scanning electron microscopy, light-scattering analyzer and gel permeation chromatography were used to study the morphology, particle size and molecular weight of the polymer microspheres, respectively. HPLC was utilized to determine the drug loading and the drug released, while a LC-MS-MS system was employed to analyze the plasma drug concentration. Result indicated that the PLGA particles obtained were spherical and appropriate in size. The formulation was stable during the test period. In vitro drug release from the microspheres for both drugs was sustained for about 30 days mostly by the diffusion mechanism. The plasma drug concentration-time profiles of the drug-loaded microspheres were relatively smooth after subcutaneous injection to rats for about 1-month, compared with that for drug suspension. In vitro and in vivo correlation was established. One of the most important facts is the synchronicity of the two contraceptives both in the release kinetics in vitro and the pharmacokinetic behaviors in vivo. Therefore, the synchronic delivery of two contraceptives is achieved for about 1 month by using the injectable PLGA-based microspheres.     

New vesicular ampicillin-loaded delivery systems for topical application: characterization, in vitro permeation experiments and antimicrobial activity.

In this paper, the experimental conditions for preparing ampicillin-loaded surfactant vesicles (SVs) are described. Our studies are focused on the potential use of a vesicular polymeric dispersion as ampicillin delivery system for topical application. The main components of the formulation are uncharged and charged SVs loaded with ampicillin and dispersed in a gellan solution. The following issues are addressed: the drug encapsulation efficiency (e.e.), the kinetic of drug release from the delivery systems, the antimicrobial activity of vesicle-entrapped ampicillin. The in vitro permeation experiments through a synthetic lipophilic barrier (Silastic) and through porcine skin are carried out to evaluate the potential use as a dermal formulation. The use of both a synthetic and a biological membrane allows to discriminate between the effects related to variations of thermodynamic parameters and those correlated to biological factors. The release rate of ampicillin is increased by encapsulation in neutral and negatively charged SVs and the permeation rate was slowed by dispersion of drug-loaded SVs in gellan solution. Finally, studies of antimicrobial activity on prepared systems evidenced that ampicillin encapsulated in SVs exhibit a higher activity than the free drug.     

强的松龙纳米微球缓释膜制备及缓释特性

背景：近年来将强的松龙应用于促进周围神经损伤后功能恢复取得了良好效果,但因半衰期短、局部应用血药浓度不稳定及较大的不良反应限制了其临床应用。目的：制备强的松龙纳米微球缓释膜并对其药物缓释特性进行检测。方法：采用反胶束乳化溶剂挥发法制备强的松龙纳米微球,对载药纳米微球的形态、粒径、载药量、包封率和体外释药行为等性质进行研究;同时将纳米微球与胶原、壳聚糖、大豆卵磷脂等膜材相结合,制得复合药膜,考察复合药膜的形貌、膜中材料的相互作用及药膜的体外释药行为。结果与结论：强的松龙纳米微球具有良好的微观结构,药物均匀分布于纳米微球中,纳米微球粒径均一,表面光滑,平均粒径500 nm,包封率达90%以上,体外缓释实验药物释放良好,存在一定的药物突释现象。观察球膜结合方法制得的复合膜,可见纳米微球均匀分散于复合膜中,复合膜微观结构良好,体外缓释实验见复合膜药物释放更加稳定,无明显药物突释现象出现,显示了良好的药物释放效果。表明通过反胶束乳化溶剂挥发法和球膜结合方法制备出的强的松龙缓释膜剂具有良好的药物缓释特性。     

Indomethacin-loaded polymeric nanocarriers based on amphiphilic polyphosphazenes with poly (N-isopropylacrylamide) and ethyl tryptophan as side groups: Preparation, in vitro and in vivo evaluation.

The effects of copolymer composition, drug structure and initial drug feed on drug loading of polymeric micelles based on amphiphilic polyphosphazenes were investigated. It was found that the drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in 0.1 M PBS (pH 7.4) suggested that indomethacin (IND) in the micelles was released through Fickian diffusion, and no significant difference in release rate was observed for micelles based on copolymers with various EtTrp content. Compared with in vitro IND release profile, in vivo pharmacokinetic study after subcutaneous administration provides a more sustained release behavior. Additionally, in comparison with free drug solution at the same dose, IND concentration in rat plasma showed a prolonged retention when the drug was delivered through polymeric micelles. In vivo pharmacodynamic study based on both carrageenan-induced acute and complete Freund's adjuvant-induced adjuvant arthritis model indicated that sustained therapeutic efficacy could be achieved through intraarticular injection of IND-loaded micelles. Most importantly, local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration.     

New microemulsion vehicle facilitates percutaneous penetration in vitro and cutaneous drug bioavailability in vivo.

Microemulsion systems possessing a potentially improved skin bioavailability of lidocaine were designed and explored for some characteristics. The existence of microemulsion regions was investigated in quaternary systems composed of glyceryl oleate+polyoxyl 40 fatty acid derivatives (surfactants)/tetraglycol (co-surfactant)/isopropyl palmitate/water by constructing pseudo-ternary phase diagrams at fixed co-surfactant/surfactants (CoS/S) ratios. Light scattering measurements used to determine the diameter of the internal phase revealed that lidocaine in the microemulsions increased the droplet size, implying a drug tendency to accumulate in the interfacial layers. Percutaneous penetration studies using rat skin in vitro showed that the transdermal flux of lidocaine was significantly improved by microemulsion composed of the glyceryl oleate-PEG-40 stearate combination rather than glyceryl oleate-PEG-40 hydroxylated castor oil. Two principal factors were found to govern the transdermal penetration of lidocaine from the microemulsion: water content and the CoS/S ratio. By analyzing skin layers (epidermis and dermis) for lidocaine content, significantly higher concentrations were found after rats were treated in vivo with liquid microemulsions (CoS/S=1.8, 30 wt.% water) or patches compared to those measured after application of EMLA cream. It has been suggested, therefore, that these microemulsions loaded with lidocaine would provide adequate analgesia in relatively shorter periods of time.     

Osmotic drug delivery using swellable-core technology.

Swellable-core technology (SCT) formulations that used osmotic pressure and polymer swelling to deliver drugs to the GI tract in a reliable and reproducible manner were studied. The SCT formulations consisted of a core tablet containing the drug and a water-swellable component, and one or more delivery ports. The in vitro and in vivo performance of two model drugs, tenidap and sildenafil, formulated in four different SCT core configurations: homogeneous-core (single layer), tablet-in-tablet (TNT), bilayer, and trilayer core, were evaluated. In vitro dissolution studies showed that the drug-release rate was relatively independent of the core configuration but the extent of release was somewhat lower for the homogeneous-core formulation, particularly under non-sink conditions. The drug-release rate was slower with increasing coating thickness and decreasing coating permeability, and was relatively independent of the drug loading and the number and size of the delivery ports. The drug-release rates were similar for the two model drugs despite significant differences in their physicochemical properties. Tablet-recovery and pharmacokinetic studies conducted in beagle dogs showed that the in vivo release of drug from SCT formulations was comparable to the in vitro drug release.     

In vivo pharmacokinetics and pharmacodynamics of topical ketoconazole and miconazole in human stratum corneum.

A direct study evaluating whether differential drug uptake of topical 2% miconazole and 2% ketoconazole from cream formulations into human stratum corneum correlated with differential pharmacological activity against Candida albicans was investigated in healthy human subjects. A single 24-h topical dose of 2% ketoconazole cream or 2% miconazole cream was applied unoccluded, at the same dose (2.6 mg of formulation per cm2 of surface area), at four skin sites on both ventral forearms of six human subjects. At the end of the treatment, residual drug was removed with a tissue from all sites and the treated site was tape stripped 11 times, either 1, 4, 8, or 24 h later. The first tape disc was discarded. The remaining tape discs, 2 through 11, were combined and extracted for drug quantification by high-performance liquid chromatography and bioactivity against C. albicans growth in vitro. Topical 2% ketoconazole produced 14-, 10-, and 7-fold greater drug concentrations in stratum corneum than 2% miconazole at 1, 4, and 8 h after a single topical dose. Ketoconazole and miconazole concentrations in the stratum corneum were similar 24 h after drug removal. Tape disc extracts from 2% ketoconazole-treated skin sites demonstrated significantly greater bioactivity in the bioassay than 2% miconazole. The increased efficacy of 2% ketoconazole compared with that of 2% miconazole in vitro reflects their differential uptake into the stratum corneum and inherent pharmacological activity. Tape stripping the drug-treated site in conjunction with a bioassay is therefore a useful approach in the determination of bioavailability of topical antifungal agents.     

Effects of Application Durations and Heat on the Pharmacokinetic Properties of Drug Delivered by a Lidocaine/Tetracaine Patch: A Randomized,Open-Label,Controlled Study in Healthy Volunteers

BackgroundThe lidocaine/tetracaine heated patch is typically applied to the skin for 20 to 30 minutes to provide local dermal analgesia prior to venous access or minor dermatologic procedures. The potential exists for the use of multiple heated patches for longer application times, but the pharmacokinetic properties and tolerability of these multiple and/or longer applications have not been assessed.ObjectiveThe aim of this study was to assess the effects of heat and application time on the pharmacokinetic properties and tolerability of the patch after the application of 4 lidocaine/tetracaine (70/70 mg) heated patches applied at the same time in healthy volunteers for up to 12 hours.MethodsIn this randomized, open-labeled, controlled study, healthy subjects underwent 4 treatment periods (2-, 4-, or 12-hour application of 4 heated patches, or 4-hour application of 4 unheated patches), each separated by a 1-week washout period.ResultsTwelve subjects were enrolled (8 women, 4 men; mean age, 31.8 years; mean body mass index, 24.1 kg/m²). No tetracaine was detected in the plasma of any subject. Plasma concentrations of lidocaine increased rapidly during the first 2 hours of application in each heated-patch group, and with mean (SD) C_max values of 18.2 (5.1), 25.7 (5.9), and 30.3 (8.1) ng/mL in the 2-, 4-, and 12-hour groups, respectively. Estimates of application time–normalized AUC_0–t were not significantly different between the 2- and 4-hour applications of the heated patches, but were 25% lower during the 12-hour application time, suggesting continued but diminished drug delivery between 4 and 12 hours. Compared with subjects who received the unheated patch, those who received the heated patch had plasma lidocaine concentrations 5- and 3-fold higher after 30 and 60 minutes, respectively. Fifteen mild to moderate adverse events (AEs) were reported in 7 subjects, and none of the subjects discontinued the study due to treatment-related AEs.ConclusionThe heated patch continuously delivered drug for up to 12 hours and was generally well tolerated in these healthy subjects. ClinicalTrials.gov identifier: NCT01602757.     

In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS.

Transdermal systems (TDS) are a well-known application form for small, moderately lipophilic molecules. The aim of this study was to investigate the possibility of applying a highly lipophilic drug, the antiestrogen AE (log P=5.82) transdermally by polyacrylate-based matrix TDS. For this purpose, two effects of both drug and enhancer concentration in TDS were investigated: in-vitro release and transdermal permeation of drug and enhancers. In the TDS investigated, in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. The steady-state fluxes observed were low (about 50-100 ng cm(-2) h(-1)). But skin pretreatment with permeation enhancers resulted in a markedly enhanced permeability (1400 ng cm(-2) h(-1)). Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not. In conclusion, it was shown that the highly lipophilic antiestrogen can be administered transdermally by pretreating the skin with the fluid permeation enhancer combination propylene glycol-lauric acid (9+1) and then applying a matrix TDS.     

In vitro and in vivo release of levonorgestrel from poly(ortho esters): II. Crosslinked polymers

The in vitro and in vivo release of levonorgestrel from crosslinked poly(ortho ester) cylindrical devices containing 30 wt.% drug and 7.1 wt.% Mg(OH)₂ was studied. For reasons not entirely understood, hydrolysis rates of crosslinked poly(ortho ester) are faster than hydrolysis of linear polymers. The in vitro release rate of levonorgestrel was about 10 μg/day for 160 days at which point the experiment was discontinued. The in vivo levonorgestrel release rate in rabbits from identical devices was about 20 μg/day. In the in vitro studies polymer erosion leads drug release but in vivo release of levonorgestrel is fast enough so that concomitant polymer erosion and drug release take place. SEM examination of devices explanted from rabbits are consistent with a surface erosion process.