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Biomedical subjects

M Vert

Publications and source records attributed to M Vert.

At least 55 records · Page 3Linked to original sources
PubMed1994

Attempts to map the structure and degradation characteristics of aliphatic polyesters derived from lactic and glycolic acids.

During the past 5 years, important advances have been accomplished in the understanding of the fate of aliphatic polyesters derived from lactic acid (LA) and glycolic acid (GA) in aqueous media. Hydrolysis of solid LA/GA polymers is now regarded as dependent upon a diffusion-reaction mechanism. Faster central degradation, degradation-induced composition, and morphology changes are three of the most important findings which appeared to be composition-dependent as deduced from the behavior of different LA/GA polymers. An attempt is made to generalize these findings to the whole family and to elaborate a map which could be used to predict degradation characteristics of LA/GA polymers from their initial composition and morphology.

Hydrolysis↗
PubMed1993

Biocompatibility and resorbability of a polylactic acid membrane for periodontal guided tissue regeneration.

The biocompatibility and degradation processes of biomembranes made of a mixture of a high molecular weight racemic polylactic acid (PLA50P) with 0, 10, 20 and 30% w/w racemic polylactic acid oligomers (PLA50p) were assessed for morphological changes in subcutaneous abdominal membrane implantations after 15, 21, 30 and 60 d in 45 Wistar rats. These membranes, prepared for periodontal guided tissue regeneration, showed excellent tissue tolerance without an inflammatory reaction. The higher the content in low molecular weight polylactic acid, the higher the degradation rate. At 60 d, the resorption process was almost complete. This process was initiated by outgrowths of short vascular septa, which developed into lobular networks infiltrating the membranes, which were progressively replaced by normal fibrous connective tissue.

Animals↗
PubMed1993

Fate of bioresorbable poly(lactic acid) microbeads implanted in artificial bone defects for cortical bone augmentation in dog mandible.

The fate was examined of poly(lactic acid) microbeads implanted in large artificial defects created in cortical bone of dog mandibles. Two poly(lactic acid) polymers--poly(L-lactic acid) (PLA 100) and poly(DL-lactic acid) (PLA 50)--were used to make microbeads by solvent evaporation with poly(vinyl alcohol) as surfactant. Histological observation of non-decalcified mandibular bone showed that no real bone regeneration existed in the experimental bone defects 18 months after PLA 100 microbeads implantation. The same observation was made 6 months after implantation of PLA 50 microbeads. PLA 100 and PLA 50 microbeads appeared unable to induce regeneration of cortical bone defects of dog mandible, in contrast to previous observations in man for PLA 50 large implants. The failure is tentatively assigned to the presence of poly(vinyl alcohol) at the surface of microbeads.

Animals↗
PubMed1992

In vivo degradation of massive poly(alpha-hydroxy acids): validation of in vitro findings.

The degradation of various high-molecular-weight aliphatic polyesters derived from glycolic acid and/or lactic acid enantiomers was previously investigated in vitro. It was demonstrated that the bulk degradation mechanism proposed in the literature actually proceeds heterogeneously and proceeds faster in the centre than at the surface of large specimens. In order to compare them, similar compression-moulded specimens were implanted intramuscularly in the backs of rabbits, namely PLA50 (poly(DL-lactic acid)), PLA37.5GA25 (75% DL-lactide and 25% glycolide in the feed) and PLA75GA25 (75% L-lactide and 25% glycolide). These three intrinsically amorphous compounds exhibited faster central degradation. Furthermore, preferential degradation of glycolic acid units and induced crystallization of L-lactic acid enriched fragments were observed in the case of PLA75GA25. These findings are comparable to phenomena observed in vitro and are conclusively supported by the re-examination of some old in vivo results. Accordingly, data reported in this paper validate both the in vitro modelling and new understanding of the degradation of lactic acid/glycolic acid-based aliphatic polyesters reported previously.

Animals↗
PubMed1992

New insights on the degradation of bioresorbable polymeric devices based on lactic and glycolic acids.

This contribution recalls some recent advances in the understanding of the mechanisms of degradation of bioresorbable polymers of the poly(beta-hydroxy acid) type derived from lactic and glycolic acids, which are receiving increasing interest for their potential for osteosynthesis. First, the various polymers are introduced and the field of applications is delimited. It is confirmed that degradation proceeds faster in amorphous domains than in crystallites. It is also shown that degradation proceeds faster in the center than at the surface, although this feature is not predominant in the case of semicrystalline lactic acid stereocopolymers. Of special interest are the findings that quenched compounds can crystallize at body temperature during degradation and that highly crystalline degradation residues can remain in situ for several years. Data show that osteosynthesis with bioresorbable plastics might become a reality for reasonably loaded bones, provided the peculiarities of polymers are taken into account by surgeons.

Animals↗
PubMed1991

Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors.

Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.

Adult↗
PubMed1989

In vitro and in vivo degradation of poly(D,L lactide/glycolide) type microspheres made by solvent evaporation method.

Microspheres of different poly(alpha-hydroxy acids) were prepared by solvent evaporation to study the effects of gamma-sterilization on stability and to establish the degradation process in vitro and in vivo. gamma-Irradiation dramatically decreases polymer molecular weight and this degradation continues on storage. gamma-Irradiation modifies the controlled release pattern of cisplatin-loaded microspheres. After embolization of rat livers by microspheres, a histological study of the inflammatory response was made, along with gel permeation chromatography analysis of degrading polymers. The degradation rate of the polymers increased with the glycolic unit content in the lactic chains. Scanning electron microscopy of microsphere degradation in vitro correlated with the former observations.

Animals↗
PubMed1986

Polyvalent polymeric drug carriers.

A number of drug-carrier systems have been considered, so far, for time-controlled delivery, targeting, and decrease of toxicity of biologically active compounds. Many of these drug carriers are based on synthetic polymers. Prerequisites for polymeric drug carriers and the need for polyvalent systems capable of carrying different drugs are examined from the viewpoint of effective pharmaceutical uses. The cases of microcapsules, microspheres, nanoparticles, and emulsions based on polymers are recalled. Of particular interest are copolymers, such as amphiphilic block-copolymers and partially quaternized polytertiary amines, that can form hydrophobic microdomains in aqueous media. Discussions are focused on the capability of the corresponding microphases to solubilize, carry, and release lipophilic drugs. The present state of the art is illustrated by recent examples.

Ampicillin↗
PubMedDate not supplied

Synthetic poly(beta-hydroxyalkanoates) with carboxylic acid or primary amine pendent groups and their complexes.

Degradable polyelectrolyte complexes were made by mixing a degradable carboxyl-bearing polyacid, namely poly(beta-malic acid), with a degradable primary amine group-bearing polybase, namely poly(amino serinate), derived from serine. Both oppositely charged polyelectrolytes are functional polymers which belong to the family of poly(beta-hydroxy acid)-type aliphatic polyesters. Poly(amino serinate) polymers were synthesized by a new route starting from the N-carbobenzoxy derivative (N-Z) of DL- or L-serine. These derivatives were allowed to react with mesyl chloride to yield in one step corresponding N-protected derivatives of poly(N-Z-amino serinate) with molar masses in the 20000-40000 range after fractionation. Progressive deprotection of pendent primary amino groups was carried out using a HBr/acetic acid mixture and led to PAS with up to 95% deprotected amine repeat units for less than 15% decrease of the initial molar mass, as shown by N-reprotection with Z groups. Poly(beta-malic acid) and poly(amino serinate) were complexed by mixing aqueous solutions of the two polyelectrolytes: 1-1 neutral precipitates were formed regardless of the respective compositions, provided the molecular weights of both components were high enough. When allowed to age in aqueous media, the solid complexes went rapidly back into solution because of the hydrolytic degradation of at least one of the components. Whether the degradation of one component is affected by that of the other is still unknown.

Amines↗
PubMedDate not supplied

In vitro and in vivo degradation of lactic acid-based interference screws used in cruciate ligament reconstruction.

Nowadays, many degradable polymers are being used under the form of interference screws to fix the bone-tendon-bone autograft in anterior cruciate ligament reconstruction. However, little is known about the post-implantation fate of these screws, especially about the formation of crystalline residues which seems to be a critical factor for the success of surgery with temporary implants based on lactic and glycolic acid derived polymers (PLAGA). In an attempt to bring in some new insights, various high molecular weight stereoregular poly(lactide)s (PLAX with X = percentage of L-lactyl units) obtained by ring-opening polymerization of lactides in the presence of zinc-metal (PLA98-Zn), zinc lactate (PLA98-Znlac) or stannous octoate (PLA100-Sn), were processed by injection-molding to make interference screws to be compared. In vivo data were collected from screws implanted in sheep knees with follow ups ranging from 6 months to 5 years. Histology confirmed the heterogeneous degradation mechanism introduced nearly 10 years ago from in vitro investigations of homemade implants having simpler geometry. The effects of the initiator system (zinc- or tin derivatives) used to polymerize the lactide monomer on the properties of injection molded interference screws was also investigated in vitro in a phosphate buffer solution at 37 degrees C. Major differences in terms of hydrophilicity, hydrolysis rate and loss of mechanical properties were observed between PLA-Zinc and PLA-Tin. Discussion of the behavior of interference screws of different compositions was made on the basis of the present understanding of PLAGA morphology and degradation characteristics.

Absorbable Implants↗
PubMedDate not supplied

In vitro delivery of a sparingly water soluble compound from PLA50 microparticles.

The administration of a sparingly soluble drug is always problematic, especially when the drug has to be released from the degradable matrix of a polymeric drug delivery system. Attempts were made to achieve the complete release of 1-[2-(fluorobenzoyl) aminoethyl]-4-(7-methoxynaphtyl)piperazine (FAMP), a potential anxiolytic and antidepressor hydrophobic compound, from racemic poly(lactic acid) (PLA50)-based microparticles, 100% release was required at a low rate in order to allow monthly repeated S.C. or I.M. injections of this potent compound. FAMP-polymer combinations were made in the form of microspheres by the solvent evaporation technique. Release profiles were investigated under dynamic conditions by using a constant flow rate of pH 7.4 0.15 M phosphate buffer, used as a model of body fluids. Under these conditions, none of the microsphere compositions led to total release within a month, even when hydrophilic excipients, namely fructose and PEG were added. PLA50-FAMP microparticles with compositions and sizes similar to those of the microspheres, were then made by direct blending in dichloromethane, evaporation of the solvent, grinding and sieving. These formulations also failed in providing total drug release within 30 days, even at a high drug load. FAMP/PLA50/water-soluble additive, ternary grounded particles were finally prepared with fructose, PLA50 oligomers or poly(ethylene glycol) (PEG) as the additive. Only PLA50 grounded particles with percolating FAMP-PEG microdomains allowed 100% release of FAMP over a 30 day period, at a quasi constant rate which depended primarily on solubility and channelling provided the flow was slow enough. Data are discussed in terms of the accessibility of the entrapped drug to the aqueous medium.

Anti-Anxiety Agents↗
PubMedDate not supplied

The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles.

One of the major problems raised by the microencapsulation of drugs which are sparingly soluble in water is the difficulty to achieve a controlled and total release of the drug. It was previously shown that the microencapsulation of a model water insoluble drug, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAMP) with a hydrophilic additive like low molar mass poly(ethylene glycol)s (PEG) can fulfil these requirements, provided all the drug + additive matter is in contact with the surrounding liquid medium via open pores and percolating channels. In this paper, PEG was replaced by other additives, selected because of their potential ability to increase the solubility of FAMP in pH = 7.4 isosomolar phosphate buffer (PBS). The idea was that increasing the solubility locally in microparticles could allow the drug to be released, despite its poor solubility in aqueous media like body fluids, and be absorbed before recrystallization. The solubility in PBS of FAMP mixed with additive, in the form of solid dispersions, was determined for various additives, namely citric acid, dimyristoyl DL-alpha-phosphatidyl choline (DMPC), poloxamer copolymers of different compositions and poly(dodecyl L-lysine citramidate) (PLCAC12(100)), an aggregate-forming hydrophilic polyelectrolyte containing 100%, hydrophobizing ester groups which can accommodate lipophilic compounds in hydrophobic pockets present in the aggregates. PEG was taken as a reference. It was found that DMPC, some poloxamers and the hydrophobized polyelectrolyte do increase the solubility of FAMP in PBS. Investigation was made of the release of FAMP from ground microparticles, whose loads were composed of FAMP combined with these solubilization-promoting additives. It was found that the release rate of FAMP from such systems can be increased and modulated to achieve an in vitro sustained release over a 20-30 day period and secure exhaustion of the particles at the end of this period.

Benzamides↗
PubMedDate not supplied

The use of additives to modulate the release of a sparingly water soluble drug entrapped in PLA50 microparticles: in vivo investigation.

Sustained and total release of the sparingly water soluble compound, namely 1-[2-(4-fluorobenzoyl)aminoethyl]-4-(7-methoxynaphthyl) piperazine hydrochloride (FAM), from poly (DL-lactic acid) (PLA50) microparticles was previously shown to be feasible if the particles are obtained by grinding a solid mixture composed of the polymer and a percolating array of the compound mixed with an additive. Such microparticles, where the additive was poly (ethylene glycol) (PEG), dimyristoylphosphatidylcholine (DMPC), or Poloxamer 6800, were administrated subcutaneously to rats either as depot or using a liquid vehicle. The variations of the plasma concentration vs time determined by high pressure liquid chromatography and fluorometric detection, were plotted for the various microparticle systems, blood being taken twice from each animal and each measurement being triplicated. Data were analysed by non-compartmental analysis, in order to evaluate the elimination constant, the half-life, the area under the curve and the bioavailability for each system. Kinetics experiments were performed over 24h and also for 7 days. It was found that, for the selected formulations, the release of the sparingly water soluble compound depends on the dissolution rate in vivo and on the physicochemical characteristics of the additive, including solubility and micelle formation. Data correlated well with the results of previous in vitro investigation.

Animals↗
PubMedDate not supplied

Labile conjugation of a hydrophilic drug to PLA oligomers to modify a drug delivery system: cephradin in a PLAGA matrix.

The physical entrapment of a hydrophilic drug within degradable microspheres is generally difficult because of poor entrapment yield and/or fast release, depending on the microsphere fabrication method. In order to counter the effects of drug hydrophilicity, it is proposed to covalently attach the drug to lactic acid oligomers, with the aim of achieving temporary hydrophobization and slower release controlled by the separation of the drug from the degradable link within the polymer matrix. This strategy was tested on microspheres of the antibiotic cephradin. As the prodrug form, the entrapment of the drug was almost quantitative. The prodrug did degrade in an aqueous medium, modelling body fluids, but cleavage did not occur at the drug-oligomer junction and drug molecules bearing two lactyl residual units were released. When the prodrug is entrapped within a PLAGA matrix, no release was observed within the experimental time period. However, data suggest that conjugation via a bond more sensitive to hydrolysis than the main chain PLA ester bonds should make the system work as desired.

Biodegradation, Environmental↗
PubMedDate not supplied

Cephradin-plaga microspheres for sustained delivery to cattle.

In the field of controlled drug delivery, most of the reported work is aimed at introducing new systems, or at providing basic information on the critical parameters which affect release profiles in vitro and occasionally in vivo. The situation is totally different when one wants to fulfil the specific requirements imposed by the marketing of a sustained release device to be used in humans or in animals eaten by human beings. The control of the release characteristics is then a difficult challenge. In this work, attempts were made to combine cephradin, a hydrophilic beta-lactam antibiotic, and bioresorbable polymeric matrices of a poly(alpha-hydroxy acid) in the form of microspheres with the aim of delivering the antibiotic to cattle at a dose rate of 4-5 mg/kg/day over a 3-4 days period after i.m. injection. PLAGA aliphatic polyesters were selected because they are already FDA approved as matrices. The solvent evaporation technique using PVA as the emulsion stabilizer was selected because it is efficient and can be extended to an industrial scale. Various experimental conditions were used in order to obtain the highest encapsulation yields compatible with the desired specifications. Decreasing the volume of the aqueous phase and adding a water-miscible organic solvent/non-solvent of cephradin failed. In contrast, microspheres containing up to 30% cephradin were prepared after addition of sodium chloride to the aqueous dispersing phase. The amount of entrapped drug was raised to 40% by decreasing the temperature and the pressure. Preliminary investigations using dogs showed that 20% cephradin microspheres prepared under these conditions extended the presence of cephradin in the blood circulation up to 48 h. Increasing the load led to higher blood concentrations but shorter sustained release. The fact that the microspheres were for cattle limited the volume of the injection and thus the amount of microspheres to be administered. The other limiting factors were related to microsphere morphology.

Animals↗
PubMedDate not supplied

In vivo sustained release of cisplatin from bioresorbable implants in mice.

Two kinds of cisplatin-containing implants were prepared from polylactic acid (type I) and from lactic acid-glycolic acid copolymer (type II). Type I implants were almost unaffected when inserted in the renal parenchyma of mice. In contrast, type II implants evolved clearly after in vivo implantation. X-ray pictures and platinum concentration measurements showed a continuous release of platinum over at least three weeks. The release resulted in high platinum concentrations in the kidney tissues and low plasma concentrations, compared to systemic injection. Type II implants seem adequate for further clinical trials of local treatment by cisplatin.

Animals↗