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PubMed2005

Effects of cryoprotectants on the viability and activity of freeze dried recombinant yeasts as novel oral drug delivery systems assessed by an artificial digestive system.

The aim of this study was to investigate, in a gastric-small intestinal system TIM-1, the effect of cryoprotectants on the survival of freeze-dried Saccharomyces cerevisiae expressing the heterologous P450 73A1 and their ability to convert trans-cinnamic acid into p-coumaric acid. Yeasts were lyophilized in suspensions of trehalose, maltose, lactose, or a milk proteins/trehalose mix. Freeze-dried or native yeasts and trans-cinnamic acid were introduced simultaneously into TIM-1 at the beginning of digestion. Yeast survival rate was evaluated by cell counting in the ileal effluents. P450 73A1 activity was followed by HPLC assay of p-coumaric acid. Freeze-dried yeasts showed high tolerance to digestive conditions. Nevertheless, their survival rate was lower than that of non-dried cells (around 80% whatever the protective agent vs. 96%). The ability of recombinant freeze-dried S. cerevisiae to perform a bioconversion reaction in the digestive tract was shown with all the protectants. The highest trans-cinnamic acid conversion rate (24 vs. 41% for native yeasts) was obtained with the milk proteins/trehalose mix. These results show that freeze-drying might be considered for the pharmaceutical formulation of new drug delivery systems based on orally administered recombinant yeasts and that TIM-1 could be a helpful tool for the pre-screening of oral dosage forms.

Cryoprotective Agents↗
PubMed2004

Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling.

This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an "ice fog," thereby facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1 degrees C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scale-up drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization.

Cold Temperature↗
PubMed2001

Characterization of murine monoclonal antibody to tumor necrosis factor (TNF-MAb) formulation for freeze-drying cycle development.

PURPOSE: This study was designed to characterize the formulation of protein pharmaceuticals for freeze-drying cycle development. Thermal properties of a protein formulation in a freezing temperature range are important in the development of freezing and primary drying phases. Moisture sorption properties and the relationship between moisture and stability are the bases for the design of the secondary drying phase. METHODS: We have characterized the formulation of TNF-MAb for the purpose of freeze-drying cycle development. The methods include: DTA with ER probes, freeze-drying microscopy, isothermal water adsorption, and moisture optimization. RESULTS: The DTA/ER work demonstrated the tendency to "noneutectic" freezing for the TNF-MAb formulation at cooling rates of -1 to -3 degrees C/min. The probability of glycine crystallization during freezing was quite low. A special treatment, either a high subzero temperature holding or annealing could promote the maximum crystallization of glycine, which could dramatically increase the Tg' of the remaining solution. The freeze-drying microscopy further indicated that, after the product was annealed, the cake structure was fully maintained at a Tp below -25 degrees C during primary drying. The moisture optimization study demonstrated that a drier TNF-MAb product had better stability. CONCLUSIONS: An annealing treatment should be implemented in the freezing phase in order for TNF-MAb to be dried at a higher product temperature during primary drying. A secondary drying phase at an elevated temperature was necessary in order to achieve optimum moisture content in the final product.

Antibodies, Monoclonal↗
PubMed1986

Microsurgical application of freeze-dried arterial allografts.

Arterial allografts of 1.0 mm diameter and 1.0 cm length were freeze-dried and placed into the femoral arteries of 15 Sprague-Dawley albino male rats in order to study patency and tissue reactions of the host. Patency in the first three postoperative days was determined by monitoring viability of the epigastric island flap. All grafts were patent during this early postoperative period. Fourteen of the subjects were surgically explored after 2 months of observation. At that time, 13 (93%) remained patent. Histopathological studies, and transmission and scanning electron microscopy were used to analyze the specimens. These data demonstrated that freeze-dried arteries are remodeled by the host, but do not induce a cellular immune reaction. Dependable freeze-dried microarterial allografts have potential future application in clinical microvascular surgery.

Animals↗
PubMed2004

Preparation of DNA dry powder for non-viral gene delivery by spray-freeze drying: effect of protective agents (polyethyleneimine and sugars) on the stability of DNA.

This study investigates the feasibility of using the process of spray-freeze drying (SFD) to produce DNA dry powders for non-viral gene delivery. The effect of protective agents was assessed on the stability of DNA dry powders after SFD. The process of SFD had adverse effects on the tertiary structure of DNA with the protective agents of sucrose, trehalose and mannitol. With the protection of these sugars, a band corresponding to the linear form of DNA was observed during gel electrophoresis between the supercoiled form (SC) and the open circular (OC) form. On the contrary, excess cationic condensing polyethyleneimine (PEI), in conjunction with the above sugars, had the ability to provide protection for DNA from degradation after SFD. This is indicated by the reservation in SC and OC forms of DNA during agarose gel electrophoresis. The electrostatic forces between PEI polymer and DNA are critical for providing protection against various stresses generated by the process of SFD. Furthermore, on rehydration, the particle size and zeta potential of PEI/DNA complexes at weight ratios 3:1 of SFD dry powders were well maintained. Also, no transfection activity loss of PEI/DNA complexes at weight ratios 3:1 on NIH/3T3 cells was observed for reconstituted powders as compared with untreated control solutions. These results give a better understanding of preparing stable DNA dry powders by the process of SFD.

Animals↗
PubMed2006

Freeze-drying of composite core-shell nanoparticles.

The effects of four sugars (glucose, saccharose, maltose, trehalose) and one surfactant (Poloxamer 188), on the freeze-drying of poly(isobutylcyanoacrylate) (PIBCA), poly(epsilon-caprolactone)-poly(ethylene glycol) (PCL-PEG), and novel core (mainly PIBCA)-shell (principally PEG) composite nanoparticles (CNP) obtained by co-precipitation were investigated. The efficiency of the additives against the adverse effect of freeze-drying on the redispersibility of the nanoparticles was evaluated, based on the visual appearance of the nanoparticle suspensions (Tyndall effect and aggregation), and on the determination of the mean diameter ratio of the nanoparticles before and after freeze-drying. The results indicated that the addition of both sugars and surfactant was essential for the good redispersion of freeze-dried nanoparticles displaying hydrophobic (PIBCA) or hydrophilic (PCL-PEG and CNP) surfaces.

Cyanoacrylates↗
PubMed2005

[Application of freeze-dried cancellous allograft in treatment of spinal tuberculosis].

OBJECTIVE: To investigate the efficacy of freeze-dried cancellous allograft in the treatment of spinal tuberculosis. METHODS: From January 1999 to August 2004, there were 31 cases of spinal tuberculosis who underwent surgery. The freeze-dried cancellous allograft was used as grafting material in all the cases. The cancellous allograft was packed in a titanium mesh cage or an artificial vertebrae, and then used as a strut graft anteriorly to implant into the bone defect after the radical debridement, and the instrumentation was done. RESULTS: Twenty-three cases were followed up 1.5 years to 5 years (3.7 years on average), and bony fusion was achieved in 21 cases 6 months later. In 2 cases ceasing antituberculous therapy after 2 months of operation, the local recurrence was obvious. The loosened screw was noticed in one of these two cases, who had tuberculosis in lumbar spine. When antituberculous therapy continued, the bony fusion was observed in these two cases 12 months later. No further position change of the instrument was noticed in the patient carrying loosened screw, but the kyphosis of the thoracolumbar spine aggravated. CONCLUSION: Freeze-dried cancellous allograft could be used in the treatment of spinal tuberculosis. To achieve good results of allograft incorporation and remodeling, the rigid instrumentation should be performed, postoperative antituberculous therapy is also important.

Adolescent↗
PubMed1987

Freeze-drying of respiratory syncytial viruses for transportation and storage.

The stabilities of eight strains of respiratory syncytial virus were compared after the strains were freeze-dried in the presence and absence of the stabilizer SPGA, which contains 218 mM sucrose, 7.1 mM dipotassium hydrogen phosphate, 3.76 mM potassium dihydrogen phosphate, 4.9 mM sodium glutamate, and 1% (wt/vol) bovine albumin. Strains freeze-dried in the presence of SPGA showed only small-to-negligible losses at 4 degrees C and losses of approximately 2.0 log10 infectious units at 25 degrees C when held for 45 weeks. Losses at 37 degrees C for one strain were approximately 10-fold greater when the strain was freeze-dried in the absence of SPGA. These results indicate that respiratory syncytial virus strains freeze-dried in the presence of a suitable stabilizer can be transported as unrefrigerated samples without undue losses in infectivity.

Excipients↗
PubMed2004

Investigation of the stabilisation of freeze-dried lysozyme and the physical properties of the formulations.

The long-term stability of a protein formulation requires that the glass transition temperature (Tg) of the formulation should be maximised and the perturbation of the protein native structure in the dried form after processing minimised. In the present study, the stabilisation of lysozyme structure conferred by excipients was monitored using second derivative Fourier transform infrared spectroscopy and the physical properties of protein formulations were investigated using differential scanning calorimetry. The results showed that the preservation of protein native structure during freeze-drying and the Tg of freeze-dried formulations were excipient- and excipient to enzyme mass ratio-dependent. The freeze-dried lysozyme appeared to be less effectively stabilised compared with the spray-dried enzyme when the excipients and the excipient to enzyme mass ratios were the same. In terms of the preservation of the secondary structure of lysozyme, glycerol and sucrose seemed to be more efficient than trehalose, although the Tg of trehalose-containing formulations were found to be higher than the Tg of the equivalent sucrose-based ones. With adding either trehalose or dextran to sucrose-containing formulations, the stabilisation of lysozyme native structure could be as effective as with sucrose alone, whilst the Tg could be enhanced. The results in this study suggested that lysozyme, processed by freeze-drying, is stabilised primarily by the water substitution mechanism.

Chemistry, Pharmaceutical↗
PubMed2006

Impact of freeze-drying on ionization of sulfonephthalein probe molecules in trehalose-citrate systems.

"pH memory," i.e., correlation between pH of solution before freeze-drying and chemical reactivity in the freeze-dried state, has been reported in many systems. In this study, the "pH memory" is explored by comparing the extent of protonation of sulfonephthalein probe molecules, bromophenol blue, bromocresol green, and chlorophenol red, in aqueous solution in the pH range of 3.4-6.0 and in the resulting freeze-dried amorphous matrix (lyophile) containing trehalose and sodium citrate buffer. The protonation of the probe molecules was measured in the lyophiles by diffuse reflectance visible spectroscopy, and compared with that in the solution before drying. The protonation of the indicators in the amorphous matrix correlated with solution pH, that is, an increase in solution pH resulted in a progressive decrease in the indicator protonation in the corresponding lyophile. However, the protonation was consistently higher in the lyophile than in the corresponding solution. The Hammett acidity function of lyophiles was calculated based on the extent of protonation of the probe molecules. Protonation of the probe molecules and the Hammett acidity function depended not only on prelyophilization solution pH, but also on the residual water content and the presence of amorphous sugar in the lyophile.

Bromcresol Green↗
PubMedDate not supplied

Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique.

In this study, the purification by cross-flow filtration (CFF) and freeze drying of poly(D,L-lactic acid) (PLA) nanoparticles prepared by an emulsion-diffusion technique using poly(vinyl alcohol) (PVAL) or poloxamer 188 (P-188) were investigated. The stability of the suspensions was correlated to the affinity of the stabilizers for the nanoparticle surface, the resistance of the coating layer to continuous filtration and to freeze-thawing procedures. The results indicated a clear difference between the two stabilizers, suggesting that the nature of the coating layer has a very important role during CFF and freeze-drying. Nanoparticles prepared with PVAL were filtered and freeze-dried without nanoparticle fusion. This behaviour was attributed to the formation of a stable thick layer (similar to that found for polystyrene latex). In contrast, aggregation of nanoparticles was observed during CFF for the batches prepared with P-188, indicating that the polypropylene oxide blocks present in the copolymer have little affinity for the PLA surface. However, these suspensions were successfully recovered when using stabilizer solutions as diafiltration media, suggesting a dynamic exchange between the P-188-adsorbed chains and those of the identical polymer remaining in the bulk solution. The presence of P-188 did not prevent nanoparticle aggregation after freeze-drying. Therefore, the use of cryoprotectants was necessary. Aggregation may have been due to an increase in the solubility of P-188 in the bulk solution, which provokes a destabilization of the suspension by desorption and partial coverage of the surface. The best cryoprotectants were found to be sugars containing glucose units. The cryoprotective effect was related to the hydrogen bonding capability of these sugars, which prevented aggregation by dehydration of P-188 forcing it to the PLA surface.

Chemistry, Pharmaceutical↗
PubMed1992

Methodology for in-process determination of residual water in freeze-dried products.

The integrity of freeze-dried biological products after reconstitution, as well as their stability during storage, is often more sensitive to small variations in residual moisture level than traditional low molecular weight drugs. Susceptibility to over-drying has also been documented for biological products. This places additional demands on the quality of in-process monitoring to achieve the desired level of residual water. This discussion is a critical overview of methodology for in-process moisture determination, including product temperature measurement, comparative pressure measurement, pressure rise, and residual gas analysis. Advantages and limitations of these methods are discussed.

Biological Products↗
PubMed2000

Elimination of volatile chemicals in disinfectant evaluation procedures by freeze drying.

Standard methods for the removal or inactivation of disinfectants from reaction mixtures are often unsatisfactory when dealing with high concentrations of particulate organic matter. A method employing freeze drying was developed to eliminate residual disinfectant activity from reaction mixtures. Following the addition of volatile chemicals to sterilized cattle slurry, samples were removed from the mixture, freeze dried, and the dried material was reconstituted with diluent containing Escherichia coli as the test micro-organism to determine if the volatile chemicals had been removed. Twelve chemicals and one commercial disinfectant (Virkon S) were evaluated at different concentrations. The chemicals selected were acetone, ammonium hydroxide, carbon tetrachloride, chloroform, dichloromethane, ethyl alcohol, formalin, hydrogen peroxide, isopropyl alcohol, peracetic acid, sodium hypochlorite and xylene. Eight chemicals, acetone, ammonium hydroxide, carbon tetrachloride, chloroform, dichloromethane, ethyl alcohol, isopropyl alcohol and xylene were removed by freeze drying. The remaining four chemicals and the commercial disinfectant, which were not removed by freeze drying, could not be evaluated by this method.

Animals↗
PubMed1987

Activity of ATP synthetase complex after low temperature treatment or freeze-drying of mitochondria isolated from skeletal muscles.

The influence of freezing, thawing, or freeze-drying on ATP synthetase complex of isolated skeletal muscle mitochondria was studied. Cooling to -60 or to -196 degrees C and rapid thawing did not change activity significantly. Slow warming stimulated the release of latent ATP-ase activity and decreased ATP synthesis. These changes were more pronounced after freeze-drying.

ATP Synthetase Complexes↗
PubMed2001

[Reconstruction of the common carotid artery with freeze dried arterial allografts in goats].

OBJECTIVE: To observe the patency rate and histopathologic changes at different times after implantation of freeze dried arterial allografts. METHODS: 4 healthy adult goats were used as the experimental models. A segment of the common carotid artery 2 cm in length was surgically removed and bridged with freeze-dried graft of common carotid artery from another goat. The eight necks of 4 animals were divided into A and B group randomly, each containing 4 arteries. In group A, both cut ends of the carotid artery were anastomosed end to end with the arterial allograft. In group B, the proximal end of the carotid artery was anastomosed end to side with the allograft. The patency of the graft was monitored with Laser Doppler Flowmeter within one week and carotid angiography was performed in selected animal. The allografts with anastomoses were harvested at 1 week, 2 weeks, 3 months and 6 months after implantation, respectively. The surgical fresh specimens were prepared and subject to histopathologic evaluation under light microscope, scanning electron microscope and transmission electron microscope. RESULTS: In Group A, 2 grafts were patent at 1 week and 2 weeks, respectively. One graft was not patent at 3 months, one was largely occluded at 6 months, only 1/4 part of the graft was patent. In Group B, 3 grafts were patent at 1 week, 2 weeks, 3 months, respectively. One graft was occluded at 6 months. There was no significant difference in patency rate between the two groups. Histopathologic examinations showed that in freezed dried arterial homograft, the endothelial cells were lost but the matrix was complete. One week after implantation, mononuclear macrophages were infiltrated into the wall in large amount and adventitia of loose connective tissues was formed. After 2 weeks of implantation, intimia was noted, intimal hyperplasia was also noted at the anastomotic sites and migrated toward the central portions of the graft. At 3 months, the homograft displayed a complete endothelial cell coverage with only small areas of fresh fibrin and endothelial disruption. The rejection reaction was diminished prominently. The medial matrix was largely substituted by proliferation of smooth muscle cells, the homograft was near normal in structure. CONCLUSION: Reconstruction of carotid artery defect with freeze dried arterial homografts was feasible. The rejection reaction was not significant. If the endothelial lining does not regenerate within 3 months, long term graft patency is hardly achieved.

English Abstract↗
PubMed1996

Preparation and characterization of freeze-dried chitosan-poly(ethylene oxide) hydrogels for site-specific antibiotic delivery in the stomach.

PURPOSE: The purpose of this study was to develop novel drug delivery systems with pH-sensitive swelling and drug release properties for localized antibiotic delivery in the stomach. METHODS: The drug delivery systems were synthesized by crosslinking chitosan and poly(ethylene oxide) (PEO) in a blend to form semi-interpenetrating polymer network (semi-IPN). Scanning electron microscopy was used to compare the surface and bulk morphology of the freeze-dried and air-dried chitosan-PEO semi-IPN. The hydrogels were allowed to swell and release the antibiotics--amoxicillin and metronidazole--in enzyme-free simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.2) at 37 degrees C. RESULTS: Freeze-dried chitosan-PEO semi-IPN with a porous matrix had swollen extensively as compared to the air-dried hydrogel. The swelling ratio of freeze-dried and air-dried chitosan-PEO semi-IPN after 1 h in SGF was 16.1 and 2.30, respectively. More than 65% of the entrapped amoxicillin and 59% of metronidazole were released from the freeze-dried chitosan-PEO semi-IPN after 2 h in SGF. CONCLUSIONS: The results of this study suggest that freeze-dried chitosan-PEO semi-IPN could be useful for localized delivery of antibiotics in the acidic environment of the gastric fluid.

Amoxicillin↗
PubMed1980

Freeze-dried, plastic-embedded tissue preparation: a review.

The freeze-dried, plastic-embedded specimen is a versatile type of animal soft tissue preparation, with attributes that commend it for some types of analytical and morphological studies. The preparation involves rapid freezing, freeze-drying, osmic acid vapor fixation, and embedding in an epoxy resin. This preparation, though difficult and tedious, offers some advantages for quantification and localization of water-soluble constituents in intracellular spaces. When prepared according to established protocol, there is evidence to suggest that the embedded sample faithfully retains intracellular levels of water-soluble constituents that are present at time of cryofixation. The sample can be stored easily and indefinitely and the tissue can be examined in a variety of ways. Thin sections will accept many stains for light and electron microscopy; the sample can be used for some histochemical procedures; and quantification of intracellular electrolytes is possible with electron probe microanalysis using one of several techniques. A major disadvantage of the method is the lack of satisfactory preservation of normal solute distributions in extracellular spaces. Important considerations for instruments equipped with Si(Li) energy detector systems are the decrease in mass fraction of the elements of interest due to embedding material, and complications in analysis for some elements because of the presence of osmium. This latter problem is of little consequence for analysis by wavelength spectrometers; and the increase in sample density, because of the embedding material, can be used to advantage for thick sample analysis.

Freeze Drying↗
PubMed1983

Comparison of fresh autogenous and freeze-dried allogenic skin for mandibular vestibuloplasty.

This study compared the ability of fresh autogenous and freeze-dried allogenic split-thickness skin grafts to maintain vestibular depth following vestibuloplasty. Both graft systems resulted in covering of the alveolar ridge by firmly attached tissue, which would be expected to enhance prosthetic stability. The appearance of the fresh autogenous grafts was consistent with that of mature skin grafts, whereas the freeze-dried grafts had the appearance of alveolar mucosa. Vestibular depth stabilized at six weeks with both graft systems, and at six months there was no significant difference (P less than 0.05) between the freeze-dried and fresh grafts with respect to their ability to maintain vestibular depth.

Animals↗