Insulin encapsulation in reinforced alginate microspheres prepared by internal gelation.

Insulin-loaded alginate microspheres prepared by emulsification/internal gelation were reinforced by blending with polyanionic additive polymers and/or chitosan-coating in order to increase the protection of insulin at simulated gastric pH and obtain a sustained release at simulated intestinal pH. Polyanionic additive polymers blended with alginate were cellulose acetate phtalate (CAP), Eudragit L100 (EL100), sodium carboxymethylcellulose (CMC), polyphosphate (PP), dextran sulfate (DS) and cellulose sulfate (CS). Chitosan-coating was applied by using a one-stage procedure. The influence of additive polymers and chitosan-coating on the size distribution of microspheres, encapsulation efficiency and release profile of insulin in simulated gastrointestinal pH conditions was studied. The mean diameter of blended microspheres ranged from 65 to 106 microm and encapsulation efficiency of insulin varied from 14 to 100%, reaching a maximum value when CS and DS were incorporated in the alginate matrix. Insulin release, at pH 1.2, was almost prevented by the incorporation of PP, DS and CS. When uncoated microspheres were transferred to pH 6.8, a fast dissolution occurred, independently of the additive polymer blended with alginate, and insulin was completely released. Increasing the additive polymer concentration in the alginate matrix and/or chitosan-coating the blended alginate microspheres did not promote a sustained release of insulin from microspheres at pH 6.8.     

Sodium alginate microspheres of metoprolol tartrate for intranasal systemic delivery: development and evaluation

Bioadhesive sodium alginate microspheres of Metoprolol tartrate (MT) for intranasal systemic delivery were prepared to avoid the first-pass effect, as an alternative therapy to injection, and to obtain improved therapeutic efficacy in the treatment of hypertension and angina pectoris. The microspheres (Ms) were prepared using emulsification--cross-linking method. The formulation variables were drug loading, polymer concentration, cross-linking agent concentration, and cross-linking time. The Ms were evaluated for characteristics, like particle size, incorporation efficiency, swelling ability, in vitro bioadhesion, in vitro drug release, and in vivo pharmacodynamic performance in rabbits against isoprenaline-induced tachycardia. Treatment of in vitro data to different kinetic equations indicated matrix-diffusion controlled drug delivery from sodium alginate Ms. Polymer concentration, cross-linking agent concentration, and cross-linking time influenced the drug release profiles significantly. In vivo studies indicated significantly improved therapeutic efficacy of MT from Ms with sustained and controlled inhibition of isoprenaline-induced tachycardia as compared with oral and nasal administration of drug solution.     

Sodium alginate microspheres of metformin HCl: formulation and in vitro evaluation

Metformin microspheres with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The prepared microspheres were evaluated for their physico-chemical characteristics like particle size, morphology using SEM, incorporation efficiency, equilibrium water content (swelling) and in vitro drug release. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, crosslinking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration. In case of microspheres containing both sodium alginate and gellan, the mean diameter and the incorporation efficiency were higher than the corresponding microspheres containing only alginate, both increasing with an increase in proportion of gellan. The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drug release for 8 hours. Incorporation of gellan caused a significant decrease in drug release. The release followed a biphasic profile, in all cases, characterized by an initial phase of moderate drug release followed by a phase of higher release. Further, the kinetic treatment of the dissolution data revealed the prevalence of matrix diffusion kinetics.     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6 microm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6?µm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr<alg<pectin<NaCMC<trgh<HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH 7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr < alg < pectin < NaCMC < trgh < HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

A novel impinging aerosols method for production of propranolol hydrochloride-loaded alginate gel microspheres for oral delivery

Propranolol hydrochloride was directly encapsulated in alginate gel microspheres (40-50?μm in diameter) using a novel method involving impinging aerosols of CaCl(2) cross-linking solution and sodium alginate solution containing the drug. Microspheres formulated using 0.1?M CaCl(2) exhibited the highest drug loading (14%, w/w of dry microspheres) with 66.5% encapsulation efficiency. Less than 4% and 35% propranolol release occurred from hydrated and dried microspheres, respectively, in 2?h in simulated gastric fluid (SGF). The majority of the drug load (90%) was released in 5 and 7?h from hydrated and dried microspheres, respectively, in simulated intestinal fluid (SIF). Prior incubation of hydrated microspheres (cross-linked using 0.5?M CaCl(2)) in SGF prolonged the time of release in SIF to 10?h, which has implications for the design of protocols and correlation with in?vivo release behaviour. Restricted propranolol release in SGF and complete extraction in SIF demonstrate the potential of alginate gel microspheres for oral delivery of pharmaceuticals.     

Viscosity of polymer solution phase and other factors controlling the dissolution of theophylline microspheres prepared by the emulsion solvent evaporation method

The objectives of this investigation are to evaluate the effect of the viscosity of polymer solution phase on microsphere properties, especially the drug release characteristics since no studies on this formulation variable have been reported. Also, since it is known that polymer molecular weight affects both the viscosity of the polymer solution and the release properties of microspheres, the interaction of these factors was studied. Microspheres with 33% theoretical drug loading of anhydrous theophylline core material were prepared by the emulsion solvent evaporation method. Two cellulose acetate butyrate polymers, (CAB381-2, CAB381-20), chemically similar but having different molecular weights, were used to prepare different polymer solutions having different apparent viscosities in acetone. A Brookfield viscometer was used to evaluate the viscosities of polymer solutions. Dissolution rates of microspheres prepared from the polymer solutions were inversely related to the initial polymer solution viscosities for both CAB381-2 and CAB381-20. The times for the release of 30 and 50% of the drug from the microspheres have a linear relationship with initial polymer solution viscosity. Initial release was significantly decreased with increasing polymer solution viscosity. Unlike CAB381-2 microspheres which follow Higuchi spherical matrix release kinetics, microspheres prepared from the higher molecular weight polymer (CAB381-20) showed extended release dissolution profiles with near zero order kinetics. It is evident that both the polymer solution viscosity and the molecular weight have an effect on the drug release from microspheres. These results suggest that release rates of matrix microspheres could be predictably optimized by adjusting the viscosity of polymer solutions.     

Release behaviour of diclofenac sodium dispersed in Gelucire® and encapsulated with alginate beads

Sustained release polymeric particles containing diclofenac sodium dispersed in Gelucire® matrix and encapsulated in calcium alginate shell were prepared with different drug-to-polymer ratios and also with different concentrations of sodium alginate for a fixed drug-to-polymer ratio in an aqueous environment. Spherical particles were formed by dropping an emulsion of diclofenac sodium in Gelucire® matrix, emulsified with sodium alginate, into calcium chloride solution. The gelled beads formed by ionotropic gelation of alginate with calcium ions showed sustained release of the water soluble drug in in-vitro release study. Drug release was a function of square-root of time, suggesting a matrix diffusion release pattern. The rate of release was significantly suppressed with increasing proportions of Gelucire® in the mixture. Sustained and complete release was achieved with Gelucire® of low melting point and low HLB value. No significant drug release occurred in a dissolution medium of pH 1.5, whereas complete release was observed at pH 6.8, consistent with considerable swelling of the alginate gel at this pH.     

Novel tamarind seed polysaccharide-alginate mucoadhesive microspheres for oral gliclazide delivery: in vitro-in vivo evaluation

Novel tamarind seed polysaccharide (TSP)-alginate mucoadhesive microspheres were prepared using TSP and alginate as blend in different ratios with different calcium chloride (CaCl(2)) concentration as a cross linker by ionotropic gelation. The prepared microspheres were of spherical shape having rough surfaces, and average particle sizes within the range of 752.12 ± 6.42 to 948.49 ± 20.92 μm. The drug entrapment efficiency of these microspheres were within the range between 58.12 ± 2.42 to 82.78 ± 3.43% w/w. Fourier transform infrared (FTIR) studies indicated that there were no reactions between gliclazide, and polymers (TSP, and sodium alginate) used. Different formulations of gliclazide loaded TSP-alginate microspheres showed prolonged in vitro release profiles of gliclazide over 12 hours in both stomach pH (pH 1.2), and intestinal pH (pH 7.4). It was found that the gliclazide release in gastric pH was comparatively slow and sustained than intestinal pH. These TSP-alginate microspheres also exhibited good mucoadhesivity. The in vivo studies on alloxan-induced diabetic rats (Animal Ethical Committee registration number: IFTM/837ac/0160) demonstrated the significant hypoglycemic effect of selected formulation of TSP-alginate mucoadhesive microspheres containing gliclazide on oral administration. This developed gliclazide loaded new TSP-alginate mucoadhesive microspheres may be very much useful for prolonged systemic absorption of gliclazide for proper maintaining blood glucose level and advanced patient compliance.     

Synthesis of thiolated alginate and evaluation of mucoadhesiveness, cytotoxicity and release retardant properties

Modification of polymers by covalent attachment of thiol bearing pendant groups is reported to impart many beneficial properties to them. Hence in the present study, sodium alginate–cysteine conjugate was synthesized by carbodiimide mediated coupling under varying reaction conditions and the derivatives characterized for thiol content. The thiolated alginate species synthesized had bound thiol content ranging from 247.8±11.03–324.54±10.107 ΅mol/g of polymer depending on the reaction conditions. Matrix tablets based on sodium alginate-cysteine conjugate and native sodium alginate containing tramadol hydrochloride as a model drug were prepared and mucoadhesive strength and in vitro drug release from the tablets were compared. Tablets containing 75 mg sodium alginate-cysteine conjugate could sustain release of 10 mg of model drug for 3 h, whereas 90% of the drug was released within 1 h from corresponding tablets prepared using native sodium alginate. An approximately 2-fold increase in the minimal detachment force of the tablets from an artificial mucin film was observed for sodium alginate–cysteine conjugate as compared to native sodium alginate. In vitro cytotoxicity studies in L-929 mouse fibroblast cells studied using an MTT assay revealed that at low concentrations of polymer, sodium alginate–cysteine conjugate was less toxic to L-929 mouse fibroblast cell line when compared to native sodium alginate. Hence, thiolation is found to be a simple route to improving polymer performance. The combination of improved controlled drug release and mucoadhesive properties coupled with the low toxicity of these new excipients builds up immense scope for the use of thiolated polymers in mucoadhesive drug delivery systems.     

Preparation and Characterisation of Mucoadhesive Nasal Gel of Venlafaxine Hydrochloride for Treatment of Anxiety Disorders

The aim of the present study is to prepare and evaluate mucoadhesive nasal gels of venlafaxine hydrochloride. Mucoadhesive nasal gels were prepared using polymers like carbopol 934 and sodium alginate and characterized in terms of viscosity, texture profile analysis, ex vivo drug permeation profiles and histopathological studies. The results show that values of viscosity, hardness and adhesiveness increase while those of cohesiveness decrease with corresponding increase in concentration of the polymers. Ex vivo drug permeation profiles showed that formulation containing 5% sodium alginate provided a better controlled release of the drug than the other formulations over a period of 12 h. Histopathological studies assured that gels containing different polymers did not produce any significant change in the nasal mucosae of goat even after 12 h permeation study. Mucoadhesive nasal gel of venlafaxine hydrochloride is a novel dosage form which delivers the drug directly into systemic circulation and provides controlled release of the drug.     

In vitro evaluation of floating and drug releasing behaviors of hollow microspheres (microballoons) prepared by the emulsion solvent diffusion method.

Hollow microspheres (microballoons) floatable in JPX III No.1 solution were developed as a dosage form characterized by excellent buoyant properties in the stomach. Microballoons were prepared by the emulsion solvent diffusion method utilizing enteric acrylic polymers codissolved with drug in a mixture of dichloromethane and ethanol. The release properties of five different drugs exhibiting distinct water solubilities (aspirin, salicylic acid, ethoxybenzamide, indomethacin and riboflavin) entrapped within microballoons were investigated. Buoyancy of the microballoons decreased with increasing drug release rate. In the case of aspirin, salicylic acid and ethoxybenzamide, the drug release profiles of microballoons proved a linear relationships by Higuchi plotting. However, indomethacin and riboflavin release profiles did not follow the Higuchi equation. When the loading amount of riboflavin was higher than the solubility in the mixture of dichloromethane and ethanol, the drug release profiles of the microballoons displayed an initial burst release. The insoluble riboflavin in the mixture of dichloromethane and ethanol adsorbed on to the microballoon surface in the crystal state. Such riboflavin crystals were released preferentially at the initial stage of the release test, which was attributable to the initial burst. In addition, by incorporating a polymer such as hydroxypropylmethylcellulose within the shell of microballoons, the release rate of riboflavin from the microballoons could be controlled while maintaining high buoyancy.     

Biphasic release characteristics of dual drug-loaded alginate beads

The dual drug-loaded alginate beads simultaneously containing drug in inner and outer layers were prepared by dropping plain (single-layered) alginate beads into CaCl₂ solution. The release characteristics were evaluated in simulated gastric fluid for 2 h followed by intestinal fluids thereafter for 12 h. The surface morphology and cross section of dual drug-loaded alginate beads was also investigated using scanning electron microscope (SEM). The poorly water-soluble ibuprofen was chosen as a model drug. The surface of single-layered and dual drug-loaded alginate beads showed very crude and roughness, showing aggregated particles, surface cracks and rough crystals. The thickness of dual drug-loaded alginate beads surrounded by outer layer was ranged from about 57 to 329μm. The distinct chasm between inner and outer layers was also observed. In case of single-layered alginate beads, the drug was not released in gastric fluid but was largely released in intestinal fluid. However, the release rate decreased as the reinforcing Eudragit^® polymer contents increased. When the plasticizers were added into polymer, the release rate largely decreased. The release rate of dual drug-loaded alginate beads was stable in gastric fluid for 2 h but largely increased when switched in intestinal fluid. The drug linearly released for 4 h followed by another linear release thereafter, showing a distinct biphasic release characteristics. There was a difference in the release profiles between single-layered and dual drug-loaded alginate beads due to their structural shape. However, this biphasic release profiles were modified by varying formulation compositions of inner and outer layer of alginate beads. The release rate of dual drug-loaded alginate beads slightly decreased when the outer layer was reinforced with Eudragit^® RS100 polymers. In case of dual drug-loaded alginate beads with polymer-reinforced outer layer only, the initial amount of drug released was low but the initial release rate (slope) was higher due to more swellable inner cores when compared to polymer-reinforced inner cores. The current dual drug-loaded alginate beads may be used to deliver the drugs in a time dependent manner.     

正辛胺改性海藻酸钠凝胶微球的制备及其性质研究

目的:制备正辛胺改性海藻酸钠凝胶微球,并研究其性质。方法:以超声波辅助氧化法制备多醛基海藻酸钠,通过希夫碱反应制备正辛胺改性海藻酸钠,并表征其结构;以乳化-内部凝胶化技术制备负载小分子抗肿瘤药物β-榄香烯的改性海藻酸钠凝胶微球,采用气相色谱法测定其8、15、24、48h时的累积释放率及海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率。结果:表征并证实了多醛基海藻酸钠和正辛胺改性海藻酸钠的结构;制备得到的改性海藻酸钠凝胶微球中8、15、24、48h时β-榄香烯的累积释放率分别为16%、28%、40%、83%;海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率分别为36%、73%。结论:制备的正辛胺改性海藻酸钠凝胶微球,具有优良的缓释性能,对β-榄香烯的包封率高。     

The study of drug release from microspheres adhered on pig vesical mucosa

The object of our work is the preparation of a mucoadhesive drug delivery system intended for intravesical application. In the present work, microspheres with Eudragit RS matrix polymer and different mucoadhesive polymers, i.e. chitosan hydrochloride (Ch), sodium salt of carboxymethyl cellulose (CMC) and polycarbophil (PC) were prepared to evaluate their influence on the mucoadhesive properties of microspheres. Different parameters were determined and their influence on pipemidic acid release from microspheres adhered on intact and damaged pig vesical mucosa was evaluated: swelling of polymers, mucoadhesion strength of polymeric films and drug dissolution according to USP XXIV method. The dissolution rate from microspheres containing different mucoadhesive polymers decreases as follows: PC>Ch>CMC. PC swelled to the largest volume among all polymers and as a result the fastest release of the drug from PC microspheres was obtained. The release rate of pipemidic acid from microspheres adhered on intact mucosa followed the order PC>CMC>Ch. These results show that both drug dissolution and mucoadhesion strength strongly influence drug release from adhered microspheres. The slowest release from Ch microspheres could be interpreted by the largest mucoadhesion strength of Ch polymeric films. The release rate of pipemidic acid from microspheres adhered on damaged mucosa followed the order PC=Ch>CMC. The results obtained on pathologically changed mucosa model support the indication of the role of glycosaminoglycans and polymer charge in the mucoadhesion process on vesical mucosa. Analysis of release data shows that the drug dissolution profiles follow the Higuchi kinetics better than the release profiles from adhered microspheres and different kinetics might be a consequence of different release mechanisms.     

Preparation of regular sized Ca-alginate microspheres using membrane emulsification method.

Monodisperse Ca-alginate microspheres were prepared using the membrane emulsification method. Three ionic types of drugs (anionic, cationic and non-ionic) were incorporated into the microspheres, and the effects of sodium alginate concentration and the pressure applied during the dispersing process on the properties of the microspheres were examined. Monodisperse microspheres were obtained when the concentration of alginate solution was 2 wt% and the pressure applied was 0.4 x 10(5) Pa. The mean size of microspheres was approximately 4 microm. Lidocaine x HCl (cationic), sodium salicylate (anionic) and 4-acetamidophenol (non-ionic) were selected as ionic model drugs and included in the alginate microspheres. Lidocaine x HCl (cationic drug) release was more retarded than that of the anionic drug, because of the electrostatic attraction between the negative charge of the ionized carboxyl group in the alginate chain and the positive charge of the cationic drug. In acidic release medium, a slow release was observed due to the low swelling characteristic and the increased viscosity of alginate, regardless of ionic type of drug.     

Release kinetics of fluphenazine from biodegradable microspheres.

Fluphenazine-loaded microspheres were prepared using biodegradable lactide and lactide-co-glycolide polymers. Sustained release of fluphenazine was achieved with fluphenazine loadings of up to 30 per cent in both the lactide and lactide-co-glycolide polymers. Fluphenazine release from microspheres was found to increase with increasing drug loading and was most rapid from the poly-L-lactide-co-glycolide microspheres. The release profiles showed a 'lag' period followed by an accelerating release phase and in some cases a decay period, i.e. the release profiles were sigmoidal and fitted the Prout-Tomkins equation (Prout and Tompkins 1944). Consequently it was considered that polymer degradation, the primary rate-determining step controlling drug release, occurred by a mechanism involving propagation of active sites, drug release reflecting the spread of this degradation throughout the polymer.