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PubMed1978

Bioassay of b-TGdR for possible carcinogenicity.

A bioassay of beta-2'-deoxy-6-thioguanosine monohydrate (b-TGdR) for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered b-TGdR in a buffered saline and polysorbate 80 vehicle at one of two doses, either 3.5 or 7 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 26 weeks. Controls consisted of groups of 10 rats of each sex, which were either administered the vehicle alone (matched vehicle controls) or were untreated (matched untreated controls). Pooled controls consisted of the matched vehicle controls of each sex from the current bioassay, combined with 20 corresponding vehicle controls of each sex from similar bioassays of two other test chemicals. All surviving rats were killed at 78 or 79 weeks. Groups of 35 mice of each sex were administered the chemical in a buffered saline and polysorbate 80 vehicle at one of two doses, either 2 or 4 mg/kg, three times per week for 52 weeks, then observed for periods of up to 27 weeks, depending on length of survival. Because of severe toxicity at the high dose, resulting in loss of all mice by week 12 (males) or week 25 (females), additional groups of 35 mice of each sex were administered 1 mg/kg on the same schedule. Controls consisted of groups of 15 mice of each sex, which were either administered the vehicle or were untreated. Pooled controls consisted of groups of 15 vehicle-control animals of each sex from studies using the doses of 2 or 4 mg/kg, combined with corresponding groups of 15 vehicle-control animals of each sex from the study using the dose of 1 mg/kg. b-TGdR was toxic to rats at the doses used in this study. Mean body weights of the high- and low-dose rats of both sexes were lower than those of the corresponding vehicle controls throughout the study. There was also severe early mortality in the high-dose groups of both sexes and positive dose-related trends in mortality over the period of the bioassay. However, 66% of the low-dose males and 77% of the low-dose females survived until termination of the study. In mice, b-TGdR was toxic at the doses originally selected. Mean body weights were not consistently affected; however, at the high dose only three males and seven females lived past week 7, and all were dead by week 25. In the mid-dose group, only 14% of the males and 6% of the females survived until termination of the study at week 79; in the low-dose group, the survival rate was 31% for the males and 29% for the females. Because of the high mortality, time-adjusted statistical analyses were performed for both rats and mice. In rats, the incidence of carcinomas of the ear canal (combined carcinomas and squamous-cell carcinomas) was statistically significant in both sexes. In males, the results of the test for dose-related trend were significant using either matched vehicle (P=0.046) or pooled vehicle (P=0.014) controls, but direct comparisons of dosed male rats with matched vehicle or pooled vehicle controls did not show significant differences (matched vehicle controls 0/10, pooled vehicle controls 0/28, low-dose 1/31, high-dose 2/7). In females, the results of the test for dose-related trend were significant using either matched vehicle (P=0.002) or pooled vehicle (P<0.001) controls, and the incidence in the high-dose group was significantly higher than that in either the matched vehicle (P=0.023) or pooled vehicle (P<0.001) controls (matched vehicle controls 0/9, pooled vehicle controls 0/28, low-dose 2/32, high-dose 6/13). There were no such ear canal tumors among 165 historical vehicle controls of either sex or among 220 female untreated controls at the laboratory, and only two such tumors occurred among 215 male untreated controls. In mice, no tumors appeared in statistically significant incidences in the dosed groups compared with the matched vehicle controls, and there was no significant evidence of dose-related trend for any tumors. The incidences of the combination of lymphoma and leukemia were significantly higher in the matched vehicle controls of each sex than in the corresponding matched untreated controls (males: matched untreated controls 1/30, matched vehicle controls 19/29; females: matched untreated controls 2/30, matched vehicle controls 21/29). This high incidence in the matched vehicle controls may have been due to a systematic procedural problem associated with injection of the drug. It is concluded that under the conditions of this bioassay, the low survival of the dosed and vehicle-control groups of mice, as well as the possible procedural problem that may have affected the incidences of tumors in these groups, does not allow a determination to be made of the carcinogenic potential of b-TGdR in this species. b-TGdR in the vehicle of 0.05% polysorbate 80 was, however, carcinogenic in rats, producing carcinomas of the ear canal in the females and possibly also in the males.

Journal Article↗
PubMed1978

Bioassay of acronycine for possible carcinogenicity.

A bioassay of acronycine for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Initially, groups of 35 rats of each sex were administered acronycine at one of two doses, either 7.5 or 15 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated rats (untreated controls) and 10 rats injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, new dosed groups of 35 rats of each sex were started later at a dose of 3.75 mg/kg. Additional groups of 10 untreated and 10 vehicle controls of each sex were also started. The rats were administered the acronycine or the vehicle for 51 or 52 weeks, then observed for an additional 28-30 weeks. All surviving rats were killed at 80-82 weeks. Initially, groups of 35 mice of each sex were administered acronycine at one of two doses, either 12.5 or 25 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated mice (untreated controls) and 10 mice injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, two additional dosed groups were started later: 35 mice of each sex at 6 mg/kg and 40 mice of each sex at 2 mg/kg, together with 10 untreated controls and 10 vehicle controls of each sex for the groups dosed at 6 mg/kg, and 20 untreated controls and 20 vehicle controls for the groups dosed at 2 mg/kg. Periods of administration of the chemical to the mice varied from 25 weeks to 92 weeks, depending on toxicity or length of time of survival. Surviving control animals were killed at 78-105 weeks. Acronycine was toxic to rats and mice of each sex at the doses used in this bioassay, as shown by the high mortality rates in all but the low-dose groups and by the lower mean body weights in dosed rats and mice at all doses throughout most of the bioassay. Because of this high number of deaths, time-adjusted statistics are used for the analyses of all incidences of tumors. In male rats, the dose-related trend in the mid-and high-dose groups for the incidence of osteosarcoma at all sites was significant (P=0.002) using the respective vehicle-control group (vehicle controls 0/8, mid-dose 13/30, high-dose 12/18). Comparisons of the individual groups with respective control groups were also significant for the mid-dose (P=0.022) and high-dose (P=0.002) groups, but not for the low-dose group. In female rats, osteosarcoma was observed only in 1/8 high-dose animals. Sarcomas and other related tumors of the peritoneum were observed in all three dosed groups of both male and female rats, but in none of the control groups (males: low-dose 5/30, mid-dose 3/26, high-dose 7/16; females: low-dose 1/35, mid-dose 5/30, high-dose 13/28). In both sexes, the dose-related trends were significant (males, P=0.006; females, P=0.002), and the comparison of the incidences in the high-dose females with the vehicle-control group was significant (P=0.016). None of the incidences in the individual dosed groups of males were significant when compared with vehicle controls. However, since the tumors were observed in all dosed groups but did not occur in historical-control animals at this laboratory, they are considered to be related to the administration of the chemical. In female rats, the incidence of all tumors of epithelial origin of the mammary gland was significant only at the low dose (low-dose vehicle controls 1/10, low-dose 22/35, P=0.004). Adenocarcinomas of the mammary gland were observed in seven low-dose, five mid-dose, and two high-dose female rats, but in no cs, but in no control females. The reverse dose relationship of both benign and malignant tumors was probably due to the higher number of early deaths which occurred in the high-dose group. In mice, the low survival in all dosed groups except the low-dose animals precluded an evaluation of the significance of the incidences of tumors. Lymphomas occurred in low-dose groups of both males and females; however, the incidence of lymphoma in different control groups was highly variable. The high incidence in the low-dose vehicle controls may have been due to a procedural problem associated with the possibility of transfer of tumor cells or oncogenic viruses during the intraperitoneal injection of the test chemical. It is concluded that under the conditions of this bioassay, the low survival of the dosed and control mice and the possible procedural problems associated with the intraperitoneal injection of the chemical did not allow a determination to be made of the carcinogenicity of acronycine in this species. In Sprague-Dawley rats, acronycine in the vehicle of 0.05% polysorbate 80 in phosphate-buffered saline was carcinogenic, producing tumors of the mammary gland in females, osteosarcomas in males, and sarcomas and other related tumors of the peritoneum in both males and females.

Journal Article↗
PubMed1996

[Mechanical duodenal stump suture. Report of experiences: metal staples versus resorbable staples].

The main observation criterion of the present retrospective study is the insufficiency rate after machine closing of the duodenal stump (TA-clip seam device, Auto-Suture), as a consequence of gastrectomy, resection of the stomach with Billroth II respective Roux-Y reconstruction, depending on the used type of clip. Between January 1, 1985 and October 2, 1989 the closing of the duodenal stump was routinely carried out with metal clips (n = 253) in the City Hospital Offenbach. Between October 3, 1989 and December 31, 1991 polysorb staples (n = 96) were exclusively used. The patient collectives were comparable regarding age, sex, health status, basic diseases, accompanying diseases and surgical methods. Closing of the duodenal stump by polysorb staples demonstrated with 13.5% more dehiscent seams than with metal clips (4.7%). As a result of the present study, we cannot recommend the use of polysorb clips for the closing of the duodenal stump.

Adolescent↗
PubMedDate not supplied

Comparative mold and yeast recovery analysis (the effect of differing incubation temperature ranges and growth media).

Environmental monitoring methodology for recovering fungal organisms often dictates the use of a selective medium incubated at ambient temperatures (20-25 degrees C) for as many as seven days incubation to ensure reliable recovery. However, these methods (which must remain standardized for identification purposes) are not the only avenue environmental monitoring programs may follow. This study comparatively analyzed recovery rates of fungal organisms cultured on both a general purpose bacteriological nutrient medium (Tryptic Soy Agar supplemented with Lecithin and Polysorbate 80), and on a medium selective for the growth of yeasts and molds (Sabouraud Dextrose Agar). The bacteriologic medium was incubated at elevated temperatures (30-35 degrees C) for 70-72 hours then transferred to ambient temperatures for another 70-72 hours incubation. The control case selective medium was incubated solely at 20-25 degrees C for 110-130 hours. Additionally, in a separate test the selective medium was incubated at the same temperature and time specifications as the bacteriologic medium to analyze recovery capabilities. Equivalent or better recovery was obtained for all test panel organisms of yeasts and molds using Tryptic Soy Agar supplemented with Lecithin and Polysorbate 80 incubated at 30-35 degrees C. Equivalent or better recovery was obtained for eight of the nine test panel organisms of yeasts and molds incubated at elevated temperatures on Sabouraud Dextrose Agar versus recovery on Agar versus recovery on Sabouraud Dextrose Agar incubated solely at 20-25 degrees C. No inhibition of growth was observed at the elevated temperature range of 30-35 degrees C. Three days incubation at elevated temperatures was a sufficient incubation period to detect the test organisms cultured on Tryptic Soy Agar supplemented with Lecithin and Polysorbate 80.

Culture Media↗
PubMed1978

Griseofulvin---phenobarbital interaction: a formulation-dependent phenomenon.

The reported interaction of griseofulvin with phenobarbital was studied in the rat following oral administration of different dosage forms. A single oral dose of 15 mg of phenobarbital/kg 24 hr prior to the oral administration of a suspension of 100 mg og griseofulvin/kg in 0.5% polysorbate 80 significantly reduced plasma griseofulvin levels. An increase in the concentration of polysorbate 80 to 2% reduced the extent of the interaction from 50 to 32%. Phenobarbital did not influence plasma griseofulvin levels when griseofulvin was given in either 70% polyethylene glycol 300 (suspensions of 20 or 100 mg/kg) or 100% polyethylene glycol 600 (solution of 50 mg/kg). It is concluded that the observed interaction is formulation dependent and is a result of diminished dissolution and, consequently, reduced absorption of griseofulvin.

Animals↗
PubMed1983

Effect of different water-soluble additives on water sorption into silicone rubber.

The ability of ethylene glycol; glycerin; polyethylene glycols 200, 400, and 6000; polysorbate 80; and lactose dispersed in silicone rubber, to promote water sorption into the polymer was investigated in water and in isotonic (pH 7.4) phosphate buffer. Polyethylene glycols 200 and 400, lactose, and, especially, glycerin were effective water carriers. Marked differences in the kinetics of rubber swelling were observed, depending on the carrier. The swelling patterns relative to ethylene glycol, glycerin, and polyethylene glycol 200 showed a maximum due to significant leaching of these additives from the polymer. Steady swelling degrees were afforded by polyethylene glycols 400 and 6000 and by polysorbate 80. The interdependent processes of polymer imbibition and carrier release were speeded up without altering their kinetic patterns by increasing the initial surface-volume ratio of the devices. A proportionality resulted between maximal swelling and initial carrier concentration, although the swelling patterns were substantially unaffected by this variable.

Adsorption↗
PubMed1990

Preparation and evaluation of sterically stabilized liposomes: colloidal stability, serum stability, macrophage uptake, and toxicity.

Sterically stabilized liposomes were produced by incorporating a nonionic surfactant, polysorbate 80 (Tween 80), into the lipid bilayer. The sterically stabilized liposomes exhibited a superior entrapment stability compared with surfactant-free liposomes (i.e., liposomes prepared with lipids and cholesterol). The sterically stabilized liposomes were stable at high calcium ion concentrations, and liposome-entrapped carboxyfluorescein was retained within the stabilized liposomes in the presence of serum for at least 5 h. The macrophage uptake of the sterically stabilized liposomes was comparable to that of liposomes containing lipids and cholesterol. The sterically stabilized liposomes were non-toxic, in concentrations up to 3.0 mM, to macrophages. These results indicate that polysorbate 80 can be used to produce stable liposomes without changing the unique macrophage distribution of this drug delivery system.

Cells, Cultured↗
PubMed1995

Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles).

Transport of the hexapeptide dalargin across the blood-brain barrier was accomplished using a nanoparticle formulation. The formulation consisted of dalargin bound to poly(butyl cyanoacrylate) nanoparticles by sorption, coated with polysorbate 80. Intravenous injection of this formulation to mice resulted in an analgesic effect. All controls, including a simple mixture of the three components (drugs, nanoparticles, and surfactant) mixed directly before i.v. injection, exhibited no effect. Analgesia was also prevented by pretreatment with naloxone. Fluorescent and electron microscopic studies indicated that the passage of the particle-bound drug occurred by phagocytic uptake of the polysorbate 80-coated nanoparticles by the brain blood vessel endothelial cells.

Animals↗
PubMed1994

Bioavailability of four oral coenzyme Q10 formulations in healthy volunteers.

The bioavailability of four different Coenzyme Q10 (CoQ) formulations was compared in ten healthy volunteers in a four-way randomised cross-over trial. The included formulations were: A hard gelatin capsule containing 100 mg of CoQ and 400 mg of Emcompress. Three soft gelatin capsules containing: 100 mg of CoQ with 400 mg of soy bean oil (Bioquinon); 100 mg of CoQ with 20 mg of polysorbate 80, 100 mg of lecithin and 280 mg of soy bean oil; and 100 mg of CoQ with 20 mg of polysorbate 80 and 380 mg of soy bean oil, respectively. The result suggests that the soya bean oil suspension of CoQ (Bioquinon has the highest bioavailability. A difference in basic AUC and AUC after p.o. administration of CoQ was observed with respect to sex. A characteristic two peak-pattern was observed at the concentration-time profile.

Administration, Oral↗
PubMed2005

The removal of pyroglutamic acid from monoclonal antibodies without denaturation of the protein chains.

Typically, the removal of pyroglutamate from the protein chains of immunoglobulins with the enzyme pyroglutamate aminopeptidase requires the use of chaotropic and reducing agents, quite often with limited success. This article describes a series of optimization experiments using elevated temperatures and detergents to denature and stabilize the heavy chains of immunoglobulins such that the pyroglutamate at the amino terminal was accessible to enzymatic removal using the thermostable protease isolated from Pyrococcus furiosus. The detergent polysorbate 20 (Tween 20) was used successfully to facilitate the removal of pyroglutamate residues. A one-step digestion was developed using elevated temperatures and polysorbate 20, rather than chaotropic and reducing agents, with sample cleanup and preparation for Edman sequencing performed using a commercial cartridge containing the PVDF membrane. All of the immunoglobulins digested with this method yielded heavy chain sequence, but the extent of deblocking was immunglobulin dependent (typically>50%).

Antibodies, Monoclonal↗
PubMed2006

Melt granulation using a twin-screw extruder: a case study.

The purpose of this study was to use a twin-screw extruder for melt granulation. Polyethylene glycols (PEG 400 and 4000) were used as binders for the development of a drinking water formulation with immediate drug release. The effect of drug content, PEG 400/4000-ratio, surfactant (type and concentration) and granulation temperature on granule properties and dissolution characteristics was determined. The granulation temperature had an important influence on the granule formation. High yield (95% of the granules <1400 microm) was obtained only at a temperature near the melting point of PEG 4000. During granulation the drug of BCS class II was finely dispersed in the PEGs, creating a micro-environment around the drug particles enhancing the dissolution rate. To obtain complete drug release within 10 min for a formulation containing 10% drug, the addition of 2% (w/w) surfactant (polysorbate 80 or Cremophor RH40) was required. At a higher drug content (20%), the PEG 4000 concentration had to be increased to 20% to improve granule properties and 4% polysorbate 80 was required to obtain 100% drug release. X-ray diffractograms showed distinct peaks of crystalline drug, the crystallinity of the drug did not change after 50 days, independent of the storage conditions.

Calorimetry, Differential Scanning↗
PubMed2006

Development and stability of semisolid preparations based on a supercritical CO2 Arnica extract.

Conventional herbal drug preparations (HDP) based on Arnica montana L. have a low content of the active principles, sesquiterpene lactones, which show poor stability and low physical compatibility in semisolid formulations. Recently, an innovative supercritical carbon dioxide (CO2) extract with high sesquiterpene content has been marketed. Development of six semisolid preparations (cetomacrogol, polysorbate 60, polawax, anphyphil, natrosol and sepigel) based on this innovative CO2 extract is discussed. Stability of these preparations was investigated according to ICH guidelines. The evaluation of in vitro release of active constituents was performed using the cell method reported in the European Pharmacopoeia. Preliminary data on in vivo permeation of three selected formulations is demonstrated using the "skin stripping" test, according to the FDA, in healthy subjects. Analysis of sesquiterpene lactones within the extract and in vitro and in vivo studies was performed by RP-HPLC-DAD-MS method. The cetomacrogol showed the best release profile in the in vitro test, while in the in vivo test the best preparation resulted polysorbate 60 and polawax.

Administration, Cutaneous↗
PubMed1999

Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules.

Danazol was dissolved in non-aqueous mixtures containing either polyethylene glycol 400 or polysorbate 80, and filled into hard gelatin capsules at 50 mg concentrations. The bioavailability of these formulations was compared with commercial danazol capsules in a two-way crossover study using young female beagle dogs. Both formulations showed greater oral bioavailability when compared with either the 100 or 200 mg commercial brand of danazol. The bioavailability of the polyethylene glycol 400 and polysorbate 80 formulations was enhanced 3.7 and 15.8 times, respectively, when compared at the 100 mg dose level.

Animals↗
PubMed2000

Recombinant factor VIII SQ--the influence of formulation parameters on structure and surface adsorption.

The main aim of this paper was to investigate the influence of temperature, pH and ionic interactions on the structural stability and surface adsorption of a recombinant factor VIII product, r-VIII SQ. The interaction of r-VIII SQ with glass and air interfaces, and possible means of increasing the stability of the formulation, were also investigated. The stability of r-VIII SQ was followed by measuring the biological activity (VIII:C), by circular dichroism (CD) studies and by the measurement of surface tension using the pendant drop method. The results show that the surface tension decreased exponentially with time; this decrease was more pronounced above 20 degrees C, indicating increased conformational flexibility of the protein with increased temperatures. Far UV CD spectra were not influenced in the range 5-55 degrees C and near UV CD measurements did not indicate structural changes below 45 degrees C. During agitation at 25 degrees C, VIII:C was lost rapidly in formulations without a macromolecular additive. Nonionic surfactants such as polysorbate 80 and polysorbate 20 protected VIII:C to an equally high degree against surface adsorption. Albumin was less effective, but it is possible that this is because it is a protein itself and may have been affected by the agitation. The addition of 300 mg/ml of sucrose improved the long term stability of VIII:C, a finding most likely explained by the theory of preferential hydration. Near UV CD spectra at acidic or basic pH mainly indicated changes around 242 nm, especially at low ionic strength. Addition of 10 mM EDTA at pH 7 resulted in similar changes. This effect was completely reversed by the addition of an excess of Ca(2+), Sr(2+) or Mg(2+) ions. In conclusion, CD spectra and surface tension measurements of r-VIII SQ did not reveal any temperature-induced conformational changes in the temperature range 5-20 degrees C; changes were first noted at elevated temperatures. Surface adsorption of r-VIII SQ during agitation was prevented by the addition of a nonionic surfactant. Preferential hydration improved the storage stability of the protein but did not directly prevent its surface adsorption. The structural integrity of the molecule was preserved at pH 7, at an increased ionic strength and in the presence of some divalent metal ions (Ca(2+), Sr(2+) or Mg(2+)).

Adsorption↗
PubMed1999

Physical state of L-histidine after freeze-drying and long-term storage.

Liquid samples of L-histidine of varying pH values and mixed with salt, metal ions, polysorbate 80 and sucrose have been analysed by differential scanning calorimetry to evaluate the influence of these additives on the glass transition temperature and crystallisation of L-histidine during freezing and thawing. L-Histidine solutions of varying pH were freeze-dried with and without a thermal cycle and the physical state of the freeze-dried cakes, following long-term storage, were studied by powder X-ray diffraction. Amorphous L-histidine crystallised when it was exposed to moisture, and the identity of the crystalline materials is reported. The crystallisation of L-histidine during freezing and thawing is dependent on the pH of the solution and is shown to be at a minimum at pH 6, which coincides with the pK(a) of the imidazoline function. Sucrose inhibited the crystallisation of L-histidine during thawing, while sodium chloride or polysorbate 80 did not. The addition of metal ions (Ca2+ and Mg2+) up to 10% (w/w) did not depress the glass transition temperature significantly, while the addition of Zn2+ increased it. The physical state of L-histidine after freeze-drying is shown to be dependent on both the pH of the solution and the freezing cycle. The risk of crystallisation of amorphous L-histidine is low if the freeze-dried material is protected from moisture.

Calcium↗
PubMed2000

Influence of surfactants (present in the dissolution media) on the release behaviour of tolbutamide from its inclusion complex with beta-cyclodextrin.

The possible competitive displacement of a drug from its cyclodextrin-based inclusion complex by a third substance was investigated by studying the dissolution behaviour of tolbutamide-beta-cyclodextrin inclusion complex in demineralised water and in aqueous solution of different surfactants. Physical mixtures and kneaded systems were prepared in 1:1 and 1:2 drug-beta-cyclodextrin mol/mol ratios and they were characterised by hot-stage microscopy, differential scanning calorimetry, and X-ray powder diffractometry. The release behaviour of tolbutamide from its inclusion complex was studied by studying the dissolution of the binary systems in water and in aqueous solutions of three surfactants: polysorbate 20, poloxyl 23-lauryl ether, and sodium lauryl sulphate. When demineralised water was used as the dissolution media, the fastest dissolution of tolbutamide was obtained from 1:2 kneaded system followed by 1:1 kneaded system. The presence of poloxyl 23-lauryl ether and sodium lauryl sulphate in the media caused a decrement in the rate and extent of dissolution of the drug from both kneaded systems in comparison with that obtained from the same systems in water. However, the release of tolbutamide from the kneaded systems remains unaffected when polysorbate 20 was present in the dissolution media. Results of this study suggest that the simultaneous presence of beta-cyclodextrin and surfactants of proper molecular structure in a pharmaceutical formulation can give rise to an unexpected dissolution of the drug.

Calorimetry, Differential Scanning↗
PubMed2000

Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system.

A novel non-competitive NMDA receptor antagonist MRZ 2/576 is a potent but rather short-acting (5-15 min) anticonvulsant following intravenous administration to mice as estimated by the prevention of maximal electroshock induced convulsions. This is most probably due to a rapid elimination of the drug from the central nervous system by transport processes that are sensitive to probenecid. Intravenous administration of the drug bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 prolongs the duration of the anticonvulsive activity in mice up to 210 min and after probenecid pre-treatment up to 270 min compared to 150 min with probenecid and MRZ 2/576 alone. The results of this study demonstrate that polysorbate 80 coated poly(butylcyanoacrylate) nanoparticles used so far as a delivery system to the brain for drugs that do not freely penetrate the blood brain barrier can also be used as a parenteral controlled release system to prolong the CNS availability of drugs that have a short duration of action.

Animals↗
PubMed1998

Spray-drying of air-liquid interface sensitive recombinant human growth hormone.

Spray-drying is an attractive method for preparing fine recombinant human growth hormone (rhGH) powders if the detrimental effect of protein degradation at the air-liquid interface on the protein can be minimized. In this study, we demonstrated that rhGH degradation (insoluble and soluble aggregate formation), as the consequence of air-liquid interfacial degradation, could be prevented using the appropriate formulation. Adding polysorbate-20 surfactant into the liquid feed (with no presence of sugar protectant) significantly reduced the formation of insoluble protein aggregates, while adding the divalent metal zinc ion effectively suppressed the formation of soluble protein aggregates. The combination of the two yielded a spray-dried rhGH powder having insignificant protein degradation. Our data suggest that the two components might protect the protein through different mechanisms. Polysorbate molecules occupy the air-liquid interface of spray droplets, thereby reducing the chance for rhGH to form insoluble aggregates by surface denaturation. Two zinc ions associate with two rhGH molecules to form a dimer complex that can resist the formation of soluble protein aggregates. Characterization of spray-dried powders by scanning electron microscopy suggests that both formulation and drying conditions have a strong influence on particle morphology and shape. Overall, spherical rhGH powders of smooth surface and good biochemical quality can be prepared by spray-drying using this formulation with no addition of sugar protectant.

Calorimetry, Differential Scanning↗