Poly DL-lactide Research Articles

The effect of an addition of sodium hydrogenphosphate to poly(D,L)lactide--results of in vitro examinations.

Aim of the study was to examine the influence of sodium hydrogenphosphate (NaP) on the pH value and the mechanical characteristics of degrading poly(D,L)lactide (PDLLA). Test rods of PDLLA with or without NaP amounting to 1, 10, 25 or 50 mol per 100 mol lactate, the degradation product of PDLLA, were produced by injection molding. Molecular weight and bending strength of the rods were measured before and after an accelerated in vitro-test (55 degrees C, Ringer's solution (RS)). For a long-time degradation test PDLLA-rods with or without 1 mol% NaP were placed in RS or Soerensen buffer solution (SB, pH 7.4) at 37 +/- 1 degrees C. Measurements of pH and determination of length, volume and weight of the samples were done in 2-4 week intervals up to the 52nd week after incubation. A pH-drop was measured in RS or SB containing pure PDLLA after 28 or 36 weeks respectively. Stabilization of the pH value due to admixed NaP delayed the degradation related pH drop for 8 weeks in RS or SB. A strong increase of length, volume and weight was measured in PDLLA + NaP-rods. In conclusion minimal stabilization of pH but also an increase of outer dimensions of the samples was found due to the admixture of NaP to PDLLA. Thus, an addition of substantially higher amounts than 1 mol% NaP in PDLLA can not be recommended, regardless of the positive effects on pH stabilization.

In vitro degradation and release profiles of poly-DL-lactide-poly(ethylene glycol) microspheres with entrapped proteins

Poly-DL-lactide (PLA) and poly-DL-lactide-poly(ethylene glycol) (PELA) were produced by bulk ring-opening polymerization using stannous chloride as initiator. PLA, PELA microspheres, and PELA microspheres containing the outer membrane protein (OMP) of Leptospira interrogans with the size of 1.5–2 μm were prepared by a solvent evaporation process. In vitro degradation and release tests of PLA, PELA, and OMP-loaded PELA microspheres were performed in pH 7.4 buffer solution at 37°C. Quantitatively, the degree of degradation was monitored by detecting the molecular weight reduction, by evaluating the mass loss and the apparent degradation rate constant, and by determining the intrinsic viscosity and poly(ethylene glycol) content of retrieved polymer, while the release profile was assessed by measuring the amount of protein presented in the release medium at various intervals. Qualitatively, the morphological changes of microspheres were observed with scanning electron micrography. The observed relative rates of mass loss versus molecular weight reduction are consistent with a bulk erosion process rather than surface erosion for PELA microspheres. The introduction of hydrophilic poly(ethylene glycol) domains in copolymer PELA and the presence of OMP within microspheres show critical influences on the degradation profile. The OMP-loaded PELA microspheres present triphasic release profile and a close correlation is observed between the polymer degradation and the OMP release profiles. It is suggested that the polymer degradation rate, protein diffusion coefficient, and the water-swollen structure of microspheres matrix commonly contribute to the OMP release from PELA microspheres. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 140–148, 2000

Polymerization of lactides and lactones 6. Synthesis of polydl-lactide and polyethylene glycol-co-polydl-lactide copolymer with allylmagnesium chloride

Polydl-lactide (PLA) and polydl-lactide-co-polyethylene glycol (PELA) were synthesized by using allylmagnesium chloride as an initiator. The reaction conditions of homo-polymerization of dl-lactide such as reaction time, reaction temperature and monomer/initiator molar ratio are discussed. The polymer was characterized by 1H-NMR, IR, DSC and GPC. The results indicate that allylmagnesium chloride is quite effective for the ring-opening polymerization of LA.

Optimization of preparative conditions for poly-DL-lactide-polyethylene glycol microspheres with entrapped Vibrio Cholera antigens

Poly-dl-lactide-polyethylene glycol (PELA) with different contents of polyethylene glycol(PEG) were synthesized and the PEG content was estimated according to the integral height of hydrogen shown in 1H-NMR. PELA microspheres containing V. cholera antigen, outer membrane protein (OMP) were prepared by a water-in-oil-in-water (W/O/W) based on solvent evaporation procedure. Antigen microspheres with smooth surface, suitable size for oral administration (0.5–5 μm), high loading efficiency (about 60%) and low level of residual solvent (lower than 20ppm) were obtained. Microspheres prepared from PELA with PEG content of about 10% achieved the highest loading efficiency among PELA copolymers and poly-dl-lactide (PLA) homopolymer, which suggested that microspheres size, morphology and the precipitation rate of polymer showed considerable relations with OMP loading efficiency. The regulation of the solvent components of the oil phase contributes to a stable emulsion W/O, and it is concluded that the stable emulsion W/O plays a significant role in improving the protein loading efficiency of obtained microspheres. The addition of stabilizer, such as gelatin and polyvinyl alcohol, into the internal water phase before emulsification produced no significant difference in OMP entrapment and microspheres size. A higher OMP loading efficiency was achieved by adding NaCl or adjusting the pH at the iso-electric point of OMP in the external water phase. It was indicated in vitro that PELA microspheres with smaller size showed larger extent of initial release and higher release rate, whereas microspheres with the diameter of 2.17 μm showed no apparent burst effect.

The merit of sintered PDLLA/TCP composites in management of bone fracture internal fixation.

Polyesters based on lactic acid have been reported in terms of safety and biodegradation in human beings for 2 decades. The greatest advantage of such material is its degradation conducted only by hydrolysis, whereby the ester backbones are supposed to be unchained in the aqueous condition. The final degradable products are carbon dioxide and water which can be metabolized and digested in the physiological environment. The goal of this study was aimed at developing a composite sintered with poly-DL-lactide (PDLLA) and tricalcium phosphate (TCP) ceramic particles for orthopedic application. The TCP particles in a range of 30-60 wt% with 5 wt% increments were doped into the PDLLA matrix which was prepared by melting and hot pressing techniques for the reinforcement. The basic mechanical strength, biodegradable behavior, and biological response of the composites were investigated in the study. Various techniques such as pH meter, UV, Fourier-transform infrared, and x-ray diffractometer were used to examine and record the degradable process of the composites soaked in saline for 1-16 weeks. The rabbit femur condyle fracture fixation test was used to evaluate tissue compatibility and the effects of bone fracture fixation on the composites. Histological observation and x-ray photography were used for investigating assistance. The mechanical strength of the composites initially increased with TCP additions up to 50wt%, but thereafter they showed no significant difference (p < 0.05). The composite with 50 wt% TCP addition showed greater mechanical strength and had good agreement with cortical bone in terms of its elastic modulus of 30-40 GPa. The weight loss of the pure PDLLA soaked in the saline started at 4 weeks and reached 95% after 16 weeks. The composites compared with pure PDLLA, however, showed no apparent evidence of degradation after soaked for 12 weeks. The possible mechanisms for the delayed degradation of the composites in saline might have been solution penetration retardation by the ceramic particles and chemical bonds formed between the interface of the TCP particles and the PDLLA matrix. In the histological evaluation of the rabbit femur condyle fracture fixation test, the surface of the composite with 50 wt% TCP addition was attached by the newly generated bone without fibrous tissue around 8 weeks after implantation. The fractured bone was gradually healed and the composite firmly and properly fixed on the fracture area during the implanted period, which provided a breeding environment for normal bone remodeling. The developed composite was thought to be an alternative material for orthopedic application in the future, especially for bone screws and bone plates.

In vivo degradation and release kinetics of chloramphenicol-loaded poly(D,L)-lactide sponges.

Poly(d,l)-lactide (PDLLA) homopolymer, with an average molecular weight of 20,000 daltons, was produced by the ring-opening polymerization of d,l-lactide in the presence of SnCl(2).2H(2)O as the catalyst. The PDLLA sponges loaded with chloramphenicol were prepared by a solvent evaporation technique. The drug loadings achieved were 14.84 and 25.23 mg for the PDLLA sponges with 35 and 70 mg total weights, respectively. These sponges were implanted in Wistar rats, and in vivo degradation, drug release, and tissue reactions were followed. The PDLLA sponges carrying no drug degraded with time linearly. Almost 80% of the sponges were degraded in about 180 days. While the drug-loaded PDLLA sponges were degraded much faster in 4 weeks (about 35% of the matrix was degraded), then the degradation slowed down significantly. Drug release from the sponges was parallel to the degradation. Almost 60% of the loaded drug released in 4 weeks. There were no acute inflammatory reactions in the initial period, either for the plain or for the drug-loaded PDLLA sponges. Macrophages and multinuclear giant cells start to appear after 7 days of implantation. The fibroblastic activity also started after the same period. After that, there were decreases in the number of some cells (neutrophils, lymphocytes, and macrophages), while multinuclear giant cells and fibroblastic activities gradually increased. Granulation tissue started at about 1 month, and new connective tissue was gradually formed until 180 days of implantation. There were significant numbers of inflammatory cells after 60 days, which were replaced by fibroblasts after 180 days. There was almost no significant neovascularization after 180 days, but implant fragmentation gradually increased (which slows the degradation) with time. It was concluded that this novel drug release sponge may be safely and effectively used as an active soft tissue-filling material.

Binding and uptake of biodegradable poly- dl-lactide micro- and nanoparticles in intestinal epithelia

The use of biodegradable particles as oral delivery vehicles for macromolecular drugs was investigated. We evaluated the binding, uptake and absorption of poly- dl-lactide (PLA) micro- and nanoparticles in Caco-2 monolayers and in ileal tissue and gut associated lymphoid tissue (GALT) of anaesthetised rats and rabbits. Using a range of experimental techniques, we found that approximately 10% of administered micro- and nanoparticles were adsorbed to the apical membranes of each of the five intestinal models. Nanoparticles were found to be absorbed better than microparticles. Overall, little discrimination in uptake patterns was evident between Peyer's patch (PP) and non-PP tissue while rat ileum showed a greater uptake capacity than rabbit. Our results show that uptake of PLA particles was low capacity, size-dependent and predominantly transcellular in all systems. A low proportion of the apically-bound particles was absorbed, with uptake exclusion evident for particles >4μm. The affinity of PLA particles for intestinal epithelia and GALT needs to be greatly enhanced in order to achieve improved oral bioavailability of macromolecules.

Influence of Formulation Variables on the Morphology of Biodegradable Micropartieles Prepared by Spray Drying

The preparation of micropartieles of the biodegradable poly-DL-lactide (PLA) and polylactide-co-gtycolide (PLGA) polymers using spray-drying technology was studied. Formulation parameters investigated include polymer type, polymer molecular weight, polymer concentration, and viscosity. Micropartieles were characterized using electron microscopy, particle size analysis, and gel permeation chromatography. Kinematic viscosity was determined for each of the sprayed polymer solutions. Polymer molecular weight and polymer concentration were found to be important parameters when preparing PLA and PLGA micropartieles using spray-drying technology.

Phase behavior of polylactides in solvent (SINGLEBOND) Nonsolvent mixtures

Isothermal phase diagrams for the semicrystalline poly-L-lactide (PLLA) and the amorphous poly-DL-lactide (PDLLA) in combination with several solvent-nonsolvent combinations (dioxane/water, dioxane/methanol, chloroform/methanol, and NMP/water) have been determined. The locations of the liquid-liquid miscibility gap, the solid-liquid miscibility gap and the vitrification boundary in the isothermal phase diagrams at 25°C were identified. The liquid-liquid miscibility gap for the systems with PLLA was located in the same composition range as the corresponding systems with PDLLA. For the systems containing PLLA solid-liquid demixing was thermodynamically preferred over liquid-liquid demixing. Attempts were made to correlate the experimental findings with predictions on the basis of the Flory-Huggins theory for ternary solutions using interaction parameters derived from independent experiments. Qualitative agreement was found between the theoretical predictions and the experimentally obtained liquid-liquid miscibility gap. No good agreement was found for the solid-liquid miscibility gap.

A morphological study of membranes obtained from the systems polylactide-dioxane-methanol, polylactide-dioxane-water and polylactide-N-methyl pyrrolidone-water

The influence of liquid-liquid demixing, solid-liquid demixing, and vitrification on the membrane morphologies obtained from several polylactide-solvent-nonsolvent systems has been investigated. The polymers investigated were the semicrystalline poly-L-lactide (PLLA) and the amorphous poly-DL-lactide (PDLLA). The solvent-nonsolvent systems used were dioxane-water, N-methyl pyrrolidone-water and dioxane-methanol. For each of these systems it was attempted to relate the membrane morphology to the ternary phase diagram at 25°C. It was demonstrated that for the amorphous poly-DL-lactide the intersection of a glass transition and a liquid-liquid miscibility gap in the phase diagram was a prerequisite for the formation of stable membrane structures. For the semicrystalline PLLA a wide variety of morphologies could be obtained ranging from cellular to spherulitical structures. For membrane-forming combinations that show delayed demixing, trends expected on the basis of phase diagrams were in reasonable agreement with the observed membrane morphologies. Only for the rapidly precipitating system PLLA-N-methyl pyrrolidone-water were structures due to liquid-liquid demixing obtained when structures due to solid-liquid demixing were expected. Probably, rapid precipitation conditions promote solid-liquid demixing over liquid-liquid demixing, because the activation energy necessary for liquid-liquid demixing is lower than that for crystallization.

Effect of molecular weight and storage times on tolmetin release from poly- d,l-lactide microspheres to lipid model membrane. A calorimetric study

The release of a nonsteroidal antiinflammatory agent (NSAID), 1-methyl-5-p-toluoylpyrrole-2-acetic acid (Tolmetin), from different molecular weight (9000, 16 000 or 109000) poly- d,l-lactide (PDLLA) microspheres was tested at two different storage times (one and 6 months), by measuring the drug transfer from loaded microspheres to void model membranes at temperatures above and below polymer glass transition temperature (T g). Dimyristoylphosphatidylcholine (DMPC) liposomes were selected as the model membrane. At first the effects of drug, in terms of transitional temperature shift (ΔT m), and enthalpy changes (ΔH) on thermotropic behaviour of liposomes were analysed by differential scanning calorimetry (DSC) to determine the release rate of drug [1]. Calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of void and tolmetin loaded microspheres. The samples have been previously incubated at temperatures above and below polymer glass transition temperature. The amount of drug released from the different microparticulate systems to void liposomes was quantified by comparing the T m shift of the lipid bilayer caused by the drug released from polymeric system, to that caused by free drug. Results show how the release processes are affected by molecular weight and storage times of tolmetin loaded PDLLA microspheres as well as by temperature. The release measured by considering the effect on void liposomes and employing DSC technique results to be an in vitro method. This can be applied to detect therapeutic systems stability by studying the slow kinetics directly at the site of drug uptake.

Polylactide macroporous biodegradable implants for cell transplantation. II. Preparation of polylactide foams by liquid-liquid phase separation.

Potential of thermally induced phase separation as a porogen technique has been studied in an effort to produce a surgical implant suitable for cell transplantation. Emphasis has been placed on the liquid-liquid phase separation of solutions of amorphous poly DL-lactide and semicrystalline poly L-lactide in an 87/13 dioxane/water mixture. The related temperature/composition phase diagrams have been set up by turbidimetry, and the possible occurrence of a gel has been discussed. Freeze-drying of some phase-separated polylactide solutions can produce flexible and tough foams with an isotropic morphology. Interconnected pores of 1-10 microns in diameter are expected to result from the spinodal decomposition of the polylactide solutions with formation of co-continuous phases. Thermodynamics of the polymer/solvent pair has a decisive effect on the final macroporous foams, as shown by the dependence of their porosity, density, porous morphology, and mechanical behavior on molecular weight and crystallinity of polylactide and concentration of the original solutions. On the basis of the foam characteristics, potential of the liquid-liquid phase separation (spinodal decomposition) has been compared with the solid/liquid phase separation (solvent crystallization) as a porogen technique.

Formulation and in vitro release study on poly ( dl-lactide) microspheres containing hydrophilic compounds: glycine homopeptides

Poly dl-lactide ( dl-PLA) microspheres containing glycine and its homopeptides viz. diglycine, triglycine, tetraglycine and pentaglycine were prepared using an oil emulsion and solvent evaporation technique. Optimization of processing parameters was studied on glycine and pentaglycine microspheres and it was found that a dl-PLA concentration of 10.3% w/w and an emulsifier (sorbitan sesquioleate) concentration of 0.3% v/v produced yields of microspheres with excellent entrapment when processed under following conditions: emulsions time, 1 min; solvent evaporation time, 2 min; internal phase: external phase ratio, 1:7; stirring speed, 1100 rpm; emulsion temperature, 5°C; and maximumm processing temperature, 35°C. Microspheres prepared as above at four different loadings (2.5, 5.0, 7.5 and 10.0% w/w) were analysed for percent entrapment, in vitro release and morphological characteristics. Gel permeation chromatography established that there was no observable polymer degradation during the 10-day release period with or without the model drug at 37.0 ± 0.5°C. Analysis if glycine or pentaglycine release data using dissolution or diffusion kinetics and scanning electron photographs of the intact and leached microspheres suggested that the release of glycine and its homopeptides from dl-PLA microspheres was mostly by diffusion through the matrix. However, for compounds having low aqueous solubility, e.g., tetra- and pentaglycine, dissolutionm played a rate-limiting role.

Calorimetric studies on tolmetin release from poly- dl-lactide microspheres to lipid model membrane

The aim of this work was to study the rate of release of an NSAI agent from poly- dl-lactide (PDLLA) microspheres, by evaluating the effect of the drug on the thermotropic behaviour of dimyristoylphosphatidylcholine liposomes (DMPC), selected as a model membrane. Polylactide microspheres loaded with 1-methyl-5- p-toluoylpyrrole-2-acetic acid (tolmetin) were prepared by the spray-drying method. Samples made of liposomes charged with free drug and suspensions of blank liposomes added to weighed amounts of tolmetin-loaded microspheres were analyzed by DSC. Calorimetric analyses were performed on samples previously incubated at temperatures below and above the polymer glass transition temperature ( T g ). Free drug was found to interact with the phospholipidic bilayer by modifying its thermotropic behavior. The amount of drug released from the microparticulate to void liposomes was quantified by comparing the T m shift caused by drug release from the polymeric system with that due to free drug. The results demonstrate the extent to which the release process is affected by temperature throughout the polymeric structure. In conclusion, the calorimetric technique detects changes occurring directly on the adsorption sites and can thus be applied to study slow kinetics directly at the site of drug uptake.