How to photostabilize molsidomine tablets.

Different methods of photostabilization are presented for the very light sensitive molsidomine tablets. The incorporation of photostabilizers such as light absorber or pigments into the tablets considerably improved the photostability. Nevertheless, photodegradation was still detected after 12 h of intense light stress. Pigments are superior to colorants or ultraviolet absorbers. The use of titanium dioxide needs to be considered carefully. Preblending the pigment with the drug substance is very helpful for taking full advantage of its photostabilizing properties. Surface-treated titanium dioxide with reduced photocatalytic activity was less suitable than untreated. That was due to a change of particle agglomeration and adhesion behavior, which was demonstrated by scanning electron microscopy pictures. However, only the protection of the tablets by a cover, either by blistering or film coating, gave a photostable drug product.

Particular features of photolabile substances in tablets.

Nifedipine and molsidomine tablets are extremely photolabile drug preparations, even at cool room light. Compared to solutions the light spectrum responsible for photodegradation is moved towards the long-wavelength range corresponding to the bathochromic shift of light absorption in the solid state. In the case of nifedipine tablets light up to 500 nm, especially the range between 400-420 nm, is degrading. Molsidomine tablets are affected only by ultraviolet light, but not by visible light. In both cases light penetrates less than 1 mm into the tablets. For nifedipine tablets the exact penetration depth could be determined due to the discolouration of the drug substance upon irradiation. It varied from 360 microm to 880 microm depending on the drug content. Since the decomposition products of nifedipine act as photostabilizers by spectral overlay, light penetration and photodegradation in nifedipine tablets are limited. The formation of gaseous and liquid decomposition products in molsidomine tablets enhances photodegradation. Changes of the tablet structure as well as dissolution and migration processes are discussed. Furthermore the degradation products donot photostabilize the drug substance due to the missing light absorption above 300 nm.

ICH guideline for photostability testing: aspects and directions for use.

The ICH guideline Q1B for photostability testing gives guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products. The choice of the irradiation method, although complying with the guideline demands, may effect test results. High irradiances may shorten testing times, but can lead to enforcement of photodegradation, which was demonstrated for molsidomine tablets. The exposure to an artificial light source (xenon lamp) was compared and correlated to natural daylight. Suitable testing methods for nifedipine and molsidomine tablets were developed. Deviating from the guideline recommendations, the presentation of powder samples should be done in tiny aluminium pans, facilitating the test procedure, minimising the risk of falsified test results due to improper sampling and improving reproducibility. When using glass dishes for the presentation of tablets to photostability testing, they should be lined by e. g. aluminium foil to avoid influences of light reflected from the sample tray.

[Alcohol stove as a source of CO poisoning in a camper]. / Spirituskocher als Quelle einer CO-Vergiftung im Wohnmobil.

Although the number of deaths from fatal CO poisoning has strongly declined since the change from coal gas to natural gas, accidental and suicidal carbon monoxide intoxications still have to be expected. In motor vehicles the exhaust gases from the engine and a stationary heating are the major sources of intoxication. In closed campers and caravans the operation of gas and spirit cooking stoves etc. may also lead to an accumulation of carbon monoxide due to incomplete combustion.

Influence of aqueous coatings on the stability of enteric coated pellets and tablets.

Pancreatin pellets, placebo pellets and tablets containing vitamin B2 were coated with various aqueous and organic enteric polymers, HPMCAS, HP, Eudragit L 100-55, Eudragit L 30 D-55, CAP, CAT, CMEC and PVAP, comparatively investigated and tested for storage stability. With the exception of Eudragit L 100-55 and Eudragit L 30 D-55, higher amounts of coating material were needed to achieve gastro-resistance with aqueous coating than with organic coating. Film formation from aqueous dispersions of micronized HP 55 was affected by the degree of micronization and was improved by reducing the particle size of the polymer. Undercoating was another suitable measure to decrease the amount of coating material required. The choice of plasticizer was of special importance in the aqueous dispersions, and type and quantity must be appropriate for the polymer applied. Non-polymeric plasticizers such as triethyl citrate (TEC) evaporated along with water during the spraying or drying process and high temperatures promoted such losses. The moisture-sensitive pancreatic enzymes were damaged both by humidity and heat during aqueous coating. The extent of damage was dependent on the coating equipment used. Upon storage, coatings obtained from aqueous dispersions showed changes in enteric performance or release characteristics as a consequence of three chemical/physical mechanisms: hydrolysis of ester linkages in the polymer or plasticizer, evaporation of the plasticizer, delayed film formation. The active ingredient pancreatin induced hydrolysis of the ester based film-former hydroxypropyl methylcellulose acetate succinate (HPMCAS). However, even without the influence of enzymes, the phthalic ester groups of aqueous hydroxypropyl methylcellulose phthalate (HP) were partly cleaved after 11 months storage. In HPMCAS-coated pancreatin pellets, the plasticizer glyceryl triacetate was almost completely hydrolyzed by the enzymes, whilst triethyl citrate was lost by evaporation through permeable packaging material at elevated temperatures. Open storage at elevated temperatures and humidities caused changes in the surface structure of HPMCAS coatings, consisting of a smoothing of the originally somewhat porous film and sticking. When applied to vitamin B2 tablets, Eudragit L 100-55, Opadry enteric (PVAP) and Aqoat (HPMCAS) proved to be quite stable aqueous enteric coatings, whereas cellulose acetate phthalate CAP or cellulose acetate trimellitate CAT coatings as ammonia-neutralized aqueous solution or as water-based pseudolatex Aquateric were unstable when stored under stress conditions.

Correlation of leucocyte count and erythrocyte sedimentation rate with the day of illness in presumed bacterial pneumonia of childhood.

We investigated the effect of the duration of illness on the white blood cell (WBC) and total neutrophil counts and the erythrocyte sedimentation rate (ESR) in untreated children with clinical and roentgenographic findings compatible with bacterial pneumonia. According to the duration of illness before admission, the patients were divided into: Group I, 48 patients ill for < 24 h; Group II, 39 patients ill for 24-48 h; Group III, 21 patients ill for 48-72 h; and Group IV, eight patients ill for 72-96 h. In children with presumably bacterial pneumonia the number of the WBC was greater during the first 2 days of illness. Thereafter, the leucocyte count declined, reaching the lowest levels on the fourth day. A similar course was followed by the absolute number of total neutrophils. During the second day of illness, 92% and 72% of the patients had leucocyte counts > 10,000 and > 15,000/mm3, respectively, whereas on the fourth day of illness only half of the patients had > 10,000 and one-quarter > 15,000 WBC/mm3. The ESR followed an opposite course to that of the WBC. During the first day of illness it was normal or mildly elevated, increasing steadily thereafter. The validity of the WBC and total neutrophil counts in conjunction with the ESR in the evaluation of bacterial pneumonia is augmented when the day of illness is taken into consideration.

Simultaneous quantification of released succinic acid and a weakly basic drug compound in dissolution media.

A HPLC-method was developed to determine both fenoldopam, a weakly basic drug and succinic acid, a pH-adjuster for this drug in dissolution media. The usual assays for succinic acid were not applicable due to its low UV-absorption, the low pH-value of samples or the presence of buffer salts and fenoldopam. The described method is a simple non-ion-pair reversed phase HPLC-method using a fast scanning UV-detector and a PC software program for the quantification of both components. Succinic acid is detected at 205 nm and fenoldopam at 225 nm. The UV-spectrum is used to determine peak purity and to identify peaks (carried out at a 99.9% match). This is especially important as in some of the investigated samples an unknown peak elutes immediately after succinic acid, resulting in spurious high contents, if mistaken for succinic acid. The simple method accomplished the simultaneous quantification of both, succinic acid and fenoldopam, by an accurate, precise, specific and reproducible assay, with a linear range covering all concentrations relevant for dissolution testing. The method is stability indicating and can also be used for the quantification of fumaric acid, another pH-adjuster in dissolution media together with fenoldopam.

Photostability of dithranol.

The influence of light on the antipsoriatic drug dithranol was investigated. A Suntest CPS with xenon lamp and liquid cooling was used as light source for the test. Solutions of dithranol in different organic solvents and in therapeutical concentrations in excipients for the preparation of topical formulations were tested under defined conditions. The extent and rate of photodegradation was determined and compared with the degradation of light-protected solutions. The drug content in the solutions was measured by HPLC. Degradation products were characterised and identified by diode array technique and HPLC-mass spectrometry coupling. The results showed a strong dependency of the photodegradation on the excipient or solvent used.

The pH-independent release of fenoldopam from pellets with insoluble film coats.

Various ratios of succinic acid to fenoldopam mesylate, ranging from 0:1 to 18:1 were incorporated in pellets and coated with 1.5-12% w/w Surelease. Even though the coating level did influence the rate and amount of fenoldopam release, the influence of the succinic acid to drug ratio was much more important and evident at all coating levels. Being a weakly basic drug, fenoldopam release ceased when testing in SIF for succinic acid to drug ratios of 0:1-4:1, with the end of release being more abrupt for the 0:1 than for the 4:1 ratio. Only for a succinic acid to drug ratio of > or =5 was fenoldopam release constant for 6-8 h and independent of the pH-value of dissolution media. For a thin coat of about 2.5% w/w Surelease, those pellets showed an ideal controlled release behaviour with release rates of about 5-10%/h and a total release of almost 80% in 8 h. The dissolution profiles of Surelease coated pellets with high succinic acid to drug ratios (> or =5) and different coating levels, were evaluated for best fits to commonly used kinetic models. Sustained release mechanisms are discussed according to best fit models. The quantification of the pH-adjuster succinic acid, released from pellets with an acid to drug ratio of < or =1 showed, that despite their failure as a controlled release system for fenoldopam, the investigated coats could control the release of succinic acid effectively at optimized coating levels. For increasing succinic acid to drug ratios (< or =4) succinic acid was released at an ever more constant rate and release rates, though still faster than the release rates of fenoldopam, decreased steadily for increasing ratios. At a 5:1 ratio finally release rates of succinic acid and fenoldopam were almost identical. Therefore those pellet cores were almost completely emptied during dissolution testing, with both fenoldopam and succinic acid leaving at a constant rate and a total release of about 80% each for a 2.5% Surelease coat, while lower succinic acid to drug ratios had failed to show any sustained release for such thin Surelease coats. A similar formulation with fumaric acid instead of succinic acid failed to show the desired release pattern, indicating that it is the presence of a sufficiently high amount of succinic acid rather than the presence of an acidic compound in general, that ensures fenoldopam solubility at higher pH-values.

Investigations on the influence of the type of extruder for pelletization by extrusion-spheronization. I. Extrusion behavior of formulations.

Three different extruders (the Alexanderwerk gravity feed roll extruder, the Gabler axial, single-screw extruder, and the NICA radial-screw extruder) were compared for their suitability for different placebo formulations and for fenoldopam pellets. A fourth extruder, the experimental ram extruder, was also included in some of the comparisons. Evaluation of the extrusion behavior of the three extruders showed differences as well as similarities among them, depending on the composition of the formulation. Although the NICA and Alexanderwerk units extruded all formulations successfully, the Gabler extruder failed to do so at a content of > 60% of soluble ingredients, such as lactose or mannitol. The extrudate surface improved for all extruders with an increase in water content of formulations, but was generally smoother for the Gabler than for the NICA or the Alexanderwerk units. A formulation with colloidal Avicel as spheronization aid showed an identical extrusion behavior for all of the investigated extruders. Of the three extruders, the Gabler unit showed the highest heat generation during extrusion, especially when extruding formulations with a low water content or high contents of soluble excipients. However, when the loss of water during extrusion or spheronization for various formulations was compared, only a two-way ANOVA test on the differences between the water content after extrusion and after spheronization showed a statistically significant difference between the Alexanderwerk or NICA and the Gabler extruder. The two-way ANOVA also proved that this difference is significant only for some formulations, e.g., lactose + Avicel PH 101 formulations, but not for Avicel PH 101 formulations.

Investigations on the influence of the type of extruder for pelletization by extrusion-spheronization. II. Sphere characteristics.

Three different extruders, the Alexanderwerk gravity-feed roll extruder, the Gabler axial, single-screw extruder, and the NICA radial-screw extruder, were compared for their suitability for different placebo formulations and for fenoldopam pellets. A fourth extruder, the experimental ram extruder, was also included in some of the comparisons. The successful spheronization of extrudates from each of these extruders requires the correct water content. This water content, however, is different for each of the formulations and for each extruder. Generally, the Gabler unit required the highest amounts of water for a successful spheronization, yielding > or = 90% between 710 and 1250 microns. The NICA unit needed much less water for the same formulation, and the Alexanderwerk unit required even less water than the NICA unit. Pellet sphericity was also strongly dependent on the correct water content of formulations, but was generally better for pellets produced with the Alexanderwerk or NICA units. A two-way ANOVA test for the individual formulations showed a significant difference in the mean particle size of batches produced with the NICA or the Alexanderwerk and the Gabler extruder. No significant differences could be found between any of the Alexanderwerk or NICA batches. Both extruders showed a linear dependence of the mean particle size on the water content of formulations, but the Gabler extruder showed an almost unchanged particle size over a wide range of water contents, provided that the formulation could be extruded successfully. Batches that were extruded on the NICA unit showed a significantly lower bulk density than comparable Alexanderwerk or Gabler batches. Comparing the true density of pellets, we found that significant differences could only be stated for Avicel PH 101 + water batches and only for the NICA/Gabler interaction. True density increased for all three extruders with increasing amounts of soluble components and with increasing water content. The NICA batches also exhibited a significant difference of the Hausner factor from the other two extruders, but no differences could be found in the friability of pellets.

[Cooling action of topicals--present results and testing methods in vivo and in vitro]. / Kühlwirkung von Topika--Kenntnisstand und Bestimmungsmöglichkeiten in vivo und in vitro.

The cooling effect of topicals has been used in the dermatological therapy as "physical effect" on the skin for more than hundred years. This effect of dermatologicals releasing free water is widely accepted, but current knowledge does not correspond to today's possibilities of experimental thermographic tests in man. The present paper describes the results published up to now and the current testing methods in vivo and in vitro.

Stabilization of dithranol in topical formulations.

The influence of different factors such as drug concentration, temperature, pH value, humidity, solubility and stabilizers on the antipsoriatic drug dithranol in topical formulations has been investigated. Dithranol was examined in lipophilic, hydrophilic and cream bases under defined conditions. Additionally, stabilizers have been investigated to protect dithranol against degradation. The drug stability in the formulations was measured by a selective HPLC system. The results showed a strong dependency of the degradation on the drug concentration. The influence of temperature is not of the same importance. Besides the pH value also the type of puffer system must be considerated. The most important effect on dithranol stability which has been directed is the solubility of the drug substance in the ointment base. With higher solubility a significantly accelerated degradation occurs. Degradations of dithranol in hydrophilic and lipophilic bases can be reduced by different stabilizers. Among others succinic acid and tartaric acid being most effective.

[The photostability of antimycotics. 3. Photostability of locally acting antimycotics]. / Untersuchung der Photostabilität von Antimykotika. 3. Mittellung: Photostabilität lokal wirksamer Antimykotika.

The photochemical stability of a number of topical antimycotic drugs was tested. The light sensitivity decreases in the order naftifine, sulbentine, cloxiquin, tolnaftate and chlorphenesin. A liquid chromatography-mass spectrometry system was used to identify a number of photodegradation products. Light exposure of sulbentine leads to the formation of benzylisothiocyanate. Chlorphenesine solutions undergo photodehalogenation with the formation of varying photodegradation products depending on the solvent used. The photochemical reactions of naftifine are a cis-trans-isomerization and the formation of a dimer product. Drug preparations are also degraded under light exposure in a simulated topical application. Excipients in the drug preparations strongly influence the photodegradation kinetics and the chemical structure of photodegradation products.

[Photostability of antifungal agents. 2. Photostability of polyene antibiotics]. / Untersuchung der Photostabilität von Antimykotika. 2. Mitteilung: Photostabilität von Polyenantibiotika.

The polyene antibiotics amphotericin B, natamycin and nystatin are rapidly degraded under the influence of light. Amphotericin B as a heptaene has a markedly higher photostability than the tetraenes natamycin and nystatin. With a new HPLC method for the separation of the different polyene components we could perform a quantitative analysis of the photodegradation process. Initially degradation products with unchanged spectrophotometric absorption spectra are formed from each of the three polyene antibiotics. Longer light exposure leads to the subsequent degradation of the polyene structures. This photochemical instability was also detected in various drug products with polyene antibiotics as active ingredient. On direct sun exposure of topically applied polyene antibiotics a pronounced photodeactivation of the drug substances is expected.

Diabetes and nontraumatic lower extremity amputations. Incidence, risk factors, and prevention--a 12-year follow-up study in Nauru.

OBJECTIVE: To measure the 12-year incidence (1982-1994) of nontraumatic lower extremity amputations (LEAs) in Nauruans, a population at high risk for NIDDM, and to determine the risk factors for amputation in Nauruans with diabetes. RESEARCH DESIGN AND METHODS: Amputation data were abstracted from operating theater records in Nauru, hospital databases in Australia, and Nauru government records. Baseline characteristics of a cohort of 1,564 Nauruans aged > or = 20 years examined during a population-based survey in 1982 were used to determine risk factors for first LEAs. RESULTS: Over this 12-year period, 46 first LEAs were performed on people with NIDDM, of whom 30 were members of the 1982 study cohort. The incidence of first LEAs in Nauruans aged > or = 25 years with NIDDM was 8.1 per 1,000 person-years in the study cohort and an estimated 7.6 per 1,000 person-years nationally. Amputations were associated significantly with lower BMI, lower blood pressure, higher fasting plasma glucose (FPG) level, and longer mean duration of diabetes at baseline, but levels of other risk factors, including cigarette smoking, plasma triglycerides, and plasma cholesterol, were also elevated in amputees. There were no amputations among individuals with baseline FPG levels < 7.8 mmol/l, irrespective of diabetes duration. FPG, baseline diabetes duration, and male sex were independent risk factors for first amputation using the Cox proportional hazards model. There was a decrease in the incidence of amputations after the commencement of a national foot care health education and prevention campaign in June 1992. CONCLUSIONS: The incidence of LEAs in diabetic Nauruans was higher than in other populations after adjusting for age and duration. Given the apparent success of the Nauruan footcare program in reducing amputation rates, other populations with high rates of NIDDM and LEAs should consider population-wide prevention strategies.

Determination by interphase-FISH of the clonality of aberrant karyotypes in human hematopoietic neoplasias.

Interphase-FISH (fluorescence in situ hybridization) studies have been devoted to the determination of clonality of aberrant karyotypes in human leukemia. Various levels of its extent have been examined, including the meaning of a single aberrant karyotype as representing a microclone, the use of FISH to confirm clonality in bi- or multiclonal leukemia, the estimation of the residual (aberrant) clone after contrasexual bone marrow transplantation, and the redetectability in interphase of the abl/bcr rearrangement. The quantitative findings of all these lines of interphase FISH analyses were based on the comparison with data from a large-scale "control" study on normal cells using the same DNA probes which have been chosen for the determination of clonality, i.e. centromeric DNA probes for chromosomes #1, #3, from #6 to #12, from #15 to #18, #20, X and Y, and a specific probe for the abl/bcr rearrangement. In addition, the validity of interphase-FISH analysis on classical bone marrow smears was examined. As a common outcome it was concluded that interphase-FISH technique is a valuable tool for defining clonality of karyotypic changes and, as a consequence, yields additional prognostic information in many human leukemias. It is recommended to perform interphase FISH in routine cytogenetics of leukemia, whenever reasonable.

Comparative interphase cytogenetics using FISH on human ovarian carcinomas.

Analyses using fluorescence in situ hybridization (FISH) were performed on cytogenetic slides of 25 human ovarian carcinomas. Biotinylated alphoid DNA probes were used for the monocolor and bicolor detection of chromosomes #1, #7, #8, #11, #12, #17 and #20 in interphase nuclei of the target cell material. Specific loss of chromosomes #17 and #20 was the most significant finding in aberrant cell populations of the tumors, as was gain of chromosomes #7, #1, #8 and #11. By the use of probe combinations, the presence of combined gains and losses of several chromosomes within the same cell subpopulations could be shown in a series of tumors, while in others the significant numerical chromosome abnormalities found characterized various different cell populations. In summary, FISH could be shown to be a powerful tool of interphase cytogenetics, provided that its limitations are considered conscientiously.

[Relationships between manufacturing parameters and pharmaceutical-technological requirements of biodegradable microparticles. 2. Preparation of injectable microparticles in biodegradable polyester]. / Beziehungen zwischen Herstellungsparametern und pharmazeutisch-technologischen Anforderungen an biodegradierbare Mikropartikeln. 2. Mitteilung: Verarbeitung biodegradierbarer Polyester zu injizierbaren Mikropartikeln.

Local anesthetics containing biodegradable polyester microparticles are prepared using a modified solvent-evaporation process and a spray drying technique. The preparation methods are compared critically. The modified solvent-evaporation process is preferred for the preparation of microparticles. Yields of 90% and microparticle size distributions can be influenced in a reproducible manner. Using the spray drying technique yields are only 60%. The product is characterized by a high portion of microparticles under 10 microns, which are responsible for the rapid release of cinchocain in 168 h as well.