Patent Application
20210361581
When manufacturing pharmaceuticals, and also when manufacturing food supplements, there is frequently a need to compress powdered components into shaped articles which are usually cylindrical in shape and are largely used as tablets. In other industrial fields as well, shaped articles are produced from powders; an example is in the detergent industry. Requirements in the pharmaceutical industry are particularly stringent because here, a reproducible release of the pharmaceutical material has to be guaranteed, along with a sufficient breaking strength and low abrasion of the shaped article. Moreover, they are produced in large numbers and the ability to compress the powder to be compressed uniformly on rapid rotary presses is demanded, wherein the pressing tools must neither be damaged by superfluous shear forces, nor can dissolving the shaped article at the point of use be compromised. In addition, uniform feeding of the powder intended for compression is indispensable to smooth running of a rapid succession of compression processes. However, this can only be regularly successful when the powder is sufficiently free-flowing and does not form any agglomerates which could result in problems w the feeding and it being brought to a halt.
In order to obtain a rapid, effective and uniform mechanical compression process with good results and simultaneously with optimized machine downtimes and maintenance cycles for worn parts, it has become standard practice to add what are known as lubricants as an additive to powders intended for compression, which lubricants reduce both the mutual cohesion of the powder components and also the adhesion of the powder to extrinsic surfaces without, however, the properties of the shaped article formed from the powder as regards wettability and consistency being affected too greatly. The use of magnesium distearate, C26H70MgO4, abbreviated to MgSt, has been shown to be particularly advantageous. As an alternative, for example, polyethylene glycols, abbreviated to PEGs, or glyceryl dibehenate, may also be used, wherein the latter is used as a mixture of mono-, di- and tri-esters of behenic acid which contains only the diesters as the main component. Alternatives to MgSt are therefore in great demand because incompatibilities can occur with some powders containing pharmaceuticals, for example when they contain the antiviral acyclovir, the anticoagulant clopidogrel, the antihypertensive captopril, the antibiotics erythromycin or penicillin or the analgesic acetylsalicylic acid. Even the antidiabetic metformin, which is used in its water-soluble form as metformin-HCl, is potentially incompatible with MgSt, because it can be hydrolysed and can react with the MgSt, which is a Lewis acid, in the presence of residual moisture. PEGs, for example, are not compatible with the most widely used anti-inflammatory ibuprofen or with clopidogrel, mentioned above. Regarding the alternative lubricant glyceryl dibehenate, it is not always possible to obtain optimal results as regards the properties of the shaped articles. The powders which are provided for compression into shaped articles, as disperse systems of the “solid in gas” category, may consist of not only the solid particles, with particle sizes of less than 500 μm, but may also include larger components, for example pre-granulated components.
Thus, the objective is to provide other alternatives to the aforementioned lubricants which can provide comparably good results, in order to provide alternatives in the case of problems with incompatibility or quality when using conventional lubricants. This objective is achieved by means of additives according to claim 1, wherein advantageous selections of such additives are defined in the dependent claims 2 to 11, by means of compressed material composed of powder and additive according to claim 12, wherein advantageous compressed materials are defined in the dependent claims 13 to 17, by means of a process according to claim 18, in which an additive according to one of claims 1 to 11 is used and by means of shaped articles according to claim 19, which have the advantageous properties defined in claims 20 to 23.
Surprisingly, it has now been shown for the first time that additives which, according to claim 1, have polyglycerol fatty acid esters, abbreviated to PGFEs, as the major component, are highly suitable for influencing the cohesion and lubrication on extrinsic surfaces of a powder intended for mechanical compression into shaped articles as an alternative to MgSt when such PGFEs are used, which each can be obtained from a complete or partial esterification of a linear or branched polyglycerol containing two to eight glyceryl units with one or more fatty acids respectively containing 6 to 22 carbon atoms.
The simplest polyglycerols which can form the starting materials for an expedient esterification are linear and branched diglycerols with the empirical formula C6O5H14, which can be synthesized on an industrial scale and in a known manner, for example by reacting glycerol with 2,3-epoxy-1-propanol under basic catalysis with the formation of ether bonds, or by thermal condensation under base catalysis, wherein the fraction containing mainly diglycerols can subsequently be separated.
Diglycerols can occur in three different structurally isomeric forms, namely in the linear form, in which the ether bridge is formed between the respective first carbon atoms of the two glycerol molecules involved, in the branched form, in which the ether bridge is formed between the first carbon atom of the first and the second carbon atom of the second glycerol molecule employed, and in a nucleodendrimeric form, in which the ether bridge is formed between the respective second carbon atoms. In the case of the condensation of two glycerol molecules catalysed by an alkali, up to approximately 80% occurs in the linear form and up to approximately 20% in the branched form, while only a very small quantity of the nucleodendrimeric form is produced.
In the case of esterification with fatty acids, polyglycerols containing more than two glyceryl units may also be used. In general, the polyglycerols are abbreviated to “PG” and an integer n is added as a suffix, which provides the number of polyglyceryl units, i.e. “PGn”. As an example, triglycerols are written as PG3 and have the empirical formula C9O7H2O. Complete esterification with a fatty acid, for example with stearic acid, should now take place at all of the free hydroxyl groups of the PGn molecule. In the case of a linear PG3, then this would take place at the first and second carbon atoms of the first glyceryl unit, at the second carbon atom of the second glyceryl unit and at the second and third carbon atoms of the third glyceryl unit. The empirical formula for this example is therefore given as C9O7H15R5, wherein each R represents a fatty acid residue, in the selected example with the empirical formula C18OH35.
However, the established abbreviation for polyglycerols esterified with saturated unbranched fatty acids is the designation PG(n)-Cm full ester or, as appropriate, PG(n)-Cm partial ester, wherein the “n” in parentheses, in similar manner to the designation for the polyglycerols, gives the number of glyceryl units contained in the molecule and m represents the number of carbon atoms of the saturated fatty acid used for the esterification reaction. Thus, the “n” represents the number of glyceryl units with the empirical formula C3O2H5R or C3O3H5R2 for marginal glyceryl units, wherein R may represent a fatty acid residue or the hydrogen atom of a free hydroxyl group. “PG(2)-C18 full ester” would therefore describe a polyglycerol fatty acid full ester with the empirical formula C78O9H150 as the major component. In the case of the PG partial ester, the number of fatty acid residues is averaged, whereupon at the same time, the empirical formula provides the fraction with the esterification variation which is present in the majority. A more precise designation of the polyglycerol fatty acid partial ester is provided by additionally providing the hydroxyl value, which is a measure of the non-esterified hydroxyl group content and thus provides information regarding the degree of esterification of the partial ester. Presumably for steric reasons, the esterification reactions in this case occur preferentially from the outside to the inside. Thus, initially, the hydroxyl groups which are esterified are those which allow the fatty acid residue the highest degree of freedom. The first esterification reaction at a linear polyglycerol then preferentially takes place at the hydroxyl group of a first carbon atom of a marginal polyglyceryl unit, then the second esterification reaction takes place at a hydroxyl group of the third carbon atom of the marginal polyglyceryl unit at the other end. Next, the hydroxyl groups at carbon atom positions immediately adjacent to positions which have already been esterified are esterified, and so on.
The term “fatty acids” as used here should be understood to mean aliphatic monocarboxylic acids containing 6 to 22 carbon atoms, which are preferably unbranched and saturated and have an even number of carbon atoms, but they may also contain an odd number, or be branched and/or unsaturated. Preferably, for the esterification of the PGFEs used as the major component of the additive, fatty acids which are saturated and/or unbranched are used. More advantageously, unbranched, saturated fatty acids containing 16, 18, 20 or 22 C atoms are used for the esterification, i.e. palmitic, stearic, arachidic or behenic acid.
Advantageously, the PGFEs of this type which are of use are those which, when the PGFEs or individual PGFE is/are investigated using heat flux differential scanning calorimetry, during the investigation, upon heating up, have only one endothermic minimum and upon cooling down, has only one exothermic maximum, because the pressing force of 10 kN and more on the compressed material which is normally employed for compression means that increased temperatures may arise which, when unsuitable additive components are used, could lead to their polymorphic transformation and to properties of the shaped article which are difficult to control. Additional polymorphic forms would be able to be distinguished upon investigation using differential scanning calorimetry by the appearance of a local exothermic maximum upon heating the sample up, as well as a local endothermic minimum upon cooling the sample down. The “blooming” that occurs after some time in storage in which the polymorphism of a component causes a substantial increase in volume which is macroscopically visible, can be avoided by using additives which exhibit no polymorphism. In particular, triglycerides such as glycerol tripalmitate or glycerol tristearate may have polymorphisms, i.e. respectively both a crystalline unstable a-modification as well as a metastable b′-modification or a stable b-modification may be present and transform from one into the other modification. In this regard, the modifications differ in particular in the thickness of the lamellar, packed crystalline subunits which are also described as subcellular units. As an example, for the a-modification of glycerol tristearate, under specific conditions, stacking of an average of 6 lamellar structures per subcellular unit could be detected and after complete transformation into the b-modification, stacking of an average of 10.5 lamellar structures per subcellular unit and an increase in the crystal thickness of approximately 67% was observed. Because in this case, the computed expected increase of 75% is not obtained, this is presumed to be due to the fact that the individual lamellae of the b-modification have a denser lamellar packing because of the inclined position compared with the a-modification (see D G Lopes, K Becker, M Stehr, D Lochmann et al., in the Journal of Pharmaceutical Sciences 104: 4257-4265, 2015).
Because the additives remain in the final product, it is also advantageous for the PGFEs which are used to have a stable subcellular form below their solidification temperature at 40° C. and 75% relative humidity for at least 6 months, i.e. under the storage conditions for an accelerated stability test, an essentially constant thickness of the lamellar-structured crystallites evaluated by employing small angle X ray scattering, abbreviated to SAXS, and applying the Scherrer equation. SAXS enables conclusions to be drawn regarding the size, the shape and the internal surfaces of crystallites. The thickness of the respective crystallites can be calculated here using the Scherrer equation, which is D=Kλ/FWHM cos (θ). Here, D designates the thickness of the crystallites and K the dimensionless Scherrer constant, which enables the shape of the crystallites to be predicted and as a rule, to a good approximation, it can be taken to be 0.9. FWHM stands for “full width at half maximum”, i.e. the width of the peak of an intensity maximum at half the height above the background, measured in radians, and θ is the Bragg angle, i.e. the angle of incidence of radiation onto the lattice plane. While a sample of glycerol tripalmitate stabilized with 10% polysorbate 65 has a crystallite thickness of 31 nm after storage for six months at room temperature, corresponding to seven lamellae, and the crystallite thickness after storage for six months at 40° C. is 52 nm, corresponding to 12 lamellae, is almost double, the aforementioned polyglycerol fatty acid esters usually exhibit crystallite thicknesses of 20 to 30 nm, corresponding to 2 to 4 lamellae, and are stable after six months storage at 40° C., with the modifications unchanged. In contrast, polyglycerol full esters usually exhibit a slightly higher crystallite thickness of 30 to 40 nm, indicating a higher degree of organisation, corresponding to 5 to 8 lamellae, and are also stable with unchanged modifications under the storage conditions of an accelerated stability test.
It is also advantageous if, when the PGFEs are used under the stated conditions, the lamellar separation according to an evaluation of the Bragg angle using wide angle X ray scattering, abbreviated to “WAXS”, is substantially constant. Individual investigations of the proposed polyglycerol fatty acid esters below their respective solidification temperature using WAXS exhibit one maximum intensity for all polyglycerol fatty acid esters which have been investigated, which means that a respective deflection angle of 21.4°, corresponding to approximately 20, i.e. double the Bragg angle, can be deduced, which gives a separation of the lattice planes of 415 μm, which correlates here with the lamellar packing density of the molecules under investigation. This distance can be structurally associated with the a-modification in which the respective lamellar structures are disposed in a hexagonal lattice parallel to each other with molecules stacked on each other and forming planes. Other modifications cannot be identified. The stability of the identified a-modifications was observed both at room temperature and also at 40° C. for 6 months, also using WAXS. Here again, surprisingly, exclusively the respective polyglycerol fatty acid esters under investigation exhibited stable a-modifications.
For the preparation of the additives, PGFEs from the following group are preferably selected: PG(2)-C18 full esters, PG(2)-C22 partial esters with a hydroxyl value of 15 to 100, PG(2)-C22 full esters, PG(3)-C16/C18 partial esters with a hydroxyl value of 100 to 200, PG(3)-C22 partial esters with a hydroxyl value of 100 to 200, PG(3)-C22 full esters, PG(4)-C16 partial esters with a hydroxyl value of 150 to 250, PG(4)-C16 full esters, PG(4)-C16/C18 partial esters with a hydroxyl value of 150 to 250, PG(4)-C16/C18 full esters, PG(4)-C18 partial esters with a hydroxyl value of 100 to 200, PG(4)-C22 partial esters with a hydroxyl value of 100 to 200, PG(6)-C16/C18 partial esters with a hydroxyl value of 200 to 300, PG(6)-C16/C18 full esters, PG(6)-C18 partial esters with a hydroxyl value of 100 to 200, wherein in the polyglycerol fatty acid esters containing two fatty acid residues which are different because of the number of their carbon atoms, those with a lower number are present in an amount of 35% to 45%, those with a corresponding, complementary higher number are present in an amount of 55% to 65% and the specified full esters preferably have a hydroxyl value of less than 5.
An advantageous property of the PGFEs for an additive in accordance with claim 1 which should be considered is the hydrophobicity, which can be determined by determining the contact angle. The determination of the hydrophobicity is carried out by determining the contact angle between the PGFE in the solid physical state and a droplet of purified water. According to Young's equation, cos θ=(γSV−γSL)/γLV, wherein γSL is the interfacial tension between the PGFE and water, γLV is the interfacial tension of the water droplet and γSV is the surface tension between the PGFE and the surrounding air. θ is the contact angle. Thus, the larger the contact angle θ, the higher is the surface tension between the PGFE and the water and the higher is the hydrophobicity of the PGFE under investigation. The contact angles for the proposed polyglycerol fatty acid esters also correlate with the HLB value which is often used in pharmaceutical technology, which is on a scale of 0 to 20 and provides information regarding the ratio of lipophilic to hydrophilic molecular fractions, wherein the hydrophilic fraction increases with increasing HLB value. For the compression of a powder comprising one or more pharmaceutical substances, the contact angle of the PGFEs used as the additive under storage conditions should undergo only moderate changes, so that the stability of the release kinetics of the pharmaceutical substance or substances produced from the finished shaped article is not compromised. Thus, preferably, those polyglycerol fatty acid esters which have a contact angle with water at 40° C. and also at 20° C. after 16 weeks which deviates by less than 10° from the starting value are preferably used as the major component of the additive. As an example, glycerol tristearate has a comparatively high contact angle deviation with water of 40° under the stated conditions and therefore deviates from the desired release kinetics stability; this can be attributed to a transformation from the a- into the b-modification during storage. The solidification temperature for the PGFEs used as additives is preferably below 75° C., but above 40° C. Here, the solidification temperature is defined as the value for the temperature at which the maximum of the highest exothermic peak of the heat flux occurs during analysis of a sample using differential scanning calorimetry.
Because of the conditions for their synthesis, PGFEs are always mixtures of different molecules, in particular in the case of partial esters. It is, however, also possible for a suitable additive in accordance with claim 1 to be provided after synthesis by mixing those PGFEs which can respectively be obtained by esterification reactions which are different because different reaction partners or different reaction conditions are employed.
The size of the particles of additive has an influence on the total surface area of the additive, and therefore on the properties of the composition formed by the powder for compression and the additive. In principle, it has been shown to be advantageous for the particle size of the additive to be 1 to 300 μm, preferably 5 μm to 15 μm. Correspondingly, the proportion of additives in the composition also has an influence on their behaviour when mechanically compressing into shaped articles and should advantageously not exceed 5% by weight; preferably, it is only 0.05% to 0.5% by weight. Too much additive is associated with increased hydrophobicity of the composition and could have negative effects on the wettability of the prepared shaped article; its dissolution behaviour could then be slowed down in an undesirable manner.
For applications in the pharmaceutical industry, the compressed material formed from the powder provided for mechanical compression into a shaped article and the additive comprises at least one pharmaceutical substance, such as metformin-HCl, for example. The term “pharmaceutical substance” should be understood to mean both directly pharmacologically effective substances and also substances which are only effective after in vivo transformation into an active form. In addition, the powder preferably contains microcrystalline cellulose as a filler; the proportion of this in the compressed material enables the volume of the shaped article to be controlled.
It has been shown to be advantageous for the compressed material formed from the additive and the powder to have only 0.05% to 0.5% by weight of additive and 99.5% to 99.95% by weight of powder, wherein the additive consists of a mixture of respectively 50% by weight of PG(3)-C22 full ester and PG(3)-C22 partial ester with a hydroxyl value of 100-200 or entirely of PG(3)-C22 partial ester with the same hydroxyl value. In addition to the additive, the compressed material may also contain a proportion of 15% by weight of metformin-HCl, for example, and a proportion of 84.5% to 84.95% by weight of microcrystalline cellulose.
For an optimized action of the additive as regards the influence on the cohesion and the lubrication on extrinsic surfaces for a powder intended for mechanical compression into shaped articles, prior to compression, preferably, before being fed to the compression site, the additive is preferably mixed with the powder. This is because correct feeding to the compression site in a shaped article compressing machine, as a rule into the die of a tablet press, is also critically dependent on the flow properties of the powder which are influenced by the additive in a manner such that the feed of the compressed material occurs uniformly and without stoppages.
Furthermore, removal of the prepared shaped article from the respective mould is a process which can only be carried out without problems when the composition of the shaped article guarantees a sufficient lubrication on extrinsic surfaces. Thus, the shaped article should have the same composition as the compressed material and during compression and the supply of energy associated therewith, should not undergo any chemical changes. This is of advantage if the force required for ejecting the shaped article is no more than 150% of the ejection force which is required under otherwise identical conditions for a test shaped article in which at least 40% by weight of the additive has been replaced by MgSt and the remainder optionally by the filler employed, preferably microcrystalline cellulose. In order to determine the ejection force, values for 20 shaped articles are averaged each time.
During compression of the compressed material composed of additive and powder by means of a rotary press, in the final step of the compression process, the upper punch is forced onto the compressed material lying on the lower punch, while in this step, the lower punch is moved in the direction of the upper punch. The specific maximum pressure at the upper punch for the respective compression process is thus transferred to a certain extent onto the lower punch via the compressed material. Advantageously, an amount of additive is added to the powder intended for compression which is such that for a punch diameter of 8 mm and an injection of 285 mg of compressed material, at the time of a maximum pressure of 10 kN at the upper punch, the maximum pressure at the lower punch is 92% to 98% of the maximum pressure of the upper punch.
If a quantity of additive is added to the powder intended for compression into shaped articles which is too small, then there is a risk that the desired effect, namely a reduced cohesion of the powder particles with respect to each other and a reduced adhesion to extrinsic surfaces, is not sufficient, with the consequence that the compressed material could stop flowing even when it is being fed to the compression site, the pressing tools could be blocked by sticking particles or the required pressure could still be so high that the shaped articles obtained dissolve too slowly under physiological conditions, and so the substance would not be taken up quickly enough and the pharmaceutical effect would not occur. On the other hand, too large a quantity of additive could result in the shaped articles obtained by compression not having the hardness required for pharmaceuticals, and so might break up, which is undesirable, or abrade too much, which would lead to unacceptable variations in the targeted uniform active ingredient content of the shaped article. Thus, advantageously and desirably, the quantity of additive which is added to the powder intended for compression is measured correctly. This can be established on the basis of the resulting properties of the shaped article, which preferably exhibit no breakage under a linear effective force of up to 100 N, preferably up to 150 N and particularly preferably up to 200 N. In order to determine the breaking strength, the linear effective force is respectively applied to 10 shaped articles and the average value is determined. Furthermore, the abrasion is determined: in accordance with the European Pharmacopoeia, issue 8.0, a number of shaped articles with a total weight of as close to 6.5 g as possible are placed in a rotating drum after they have been carefully freed from any abraded material or dust already present. The drum is then rotated 100 times at a speed of 25 revolutions per minute. Next, the shaped articles are carefully freed from abraded material and dust once again, weighed and the average weight which is determined is compared with the starting weight. It has been shown to be advantageous for the weight loss by dust using this procedure to be no more than 0.02% to 0.25% by weight.
Finally, according to the European Pharmacopoeia, issue 8.0, the shaped articles in accordance with the invention should advantageously have a disintegration time of 2 to 4 minutes. In this regard, in each case 6 shaped articles, each placed in separate baskets, are placed in 100 mL of purified water, aqua purificata, which has been heated to a temperature of 37° C. (±2° C.). The baskets are then moved 53 to 57 mm back and forth, 29 to 32 times per minute, and at predetermined times the disintegration status of the shaped articles and baskets removed from the water is assessed in accordance with the European Pharmacopoeia, issue 8.0.
The invention will now be illustrated with the aid of an example of the additive in accordance with the invention, the compressed material in accordance with the invention, the process in accordance with the invention and the shaped articles in accordance with the invention.
PG(3)-C22 partial esters with a hydroxyl value of 138 were firstly micronized using supercritical fluid technology, abbreviated to “SCFT”, using carbon dioxide as the fluid; the median particle size for all of the particles was 13.15 μm (±0.05 μm). A proportion of these particles was used as an additive. The pharmaceutical substance was metformin-HCl; the filler was microcrystalline cellulose, known by the trade name Avicel PH102. Prior to mixing, the metformin-HCl was passed through a sieve with a pore size of 200 μm. In this example, the powder was therefore a mixture of metformin-HCl and microcrystalline cellulose, the additive was PG(3)-C22 partial ester-[138], wherein the number in square brackets gives the hydroxyl value here. The compressed material was obtained by mixing these components in a Turbula TC2 mixer from Willy A Bachofen Maschinenfabrik (CH) at 75 revolutions per minute for 10 minutes; the compressed material consisted of 15% by weight of metformin-HCl, 84.75% by weight of microcrystalline cellulose and 0.25% by weight of PG(3)-C22 partial ester-[138]. The compressed material was compressed into flat tablets in a Stylcam 200R compacting simulator from Medelpharm (FR) using punches and dies from Natoli (USA) with a diameter of 8 mm. The subsequent investigations of the prepared tablets in accordance with European Pharmacopoeia issue 8.0 provided a disintegration time of only 2 minutes, an abrasion of 0.12%. The breaking strength of the tablets was strong enough to withstand a linear effective force of up to 140 N; the ejection force to remove the tablets from the die was only 120 N.
In a second example, the composition of the compressed material was varied; 84.9% by weight of microcrystalline cellulose, 15% by weight of metformin-HCl and 0.1% by weight of a blend of equal parts of PG(3)-C22 full ester and PG(3)-C22 partial ester-[138] were compressed. For this example, the disintegration time was 4 minutes, the abrasion was only 0.02%, the breaking strength of the tablets was strong enough to withstand a linear effective force of up to 200 N and the ejection force required was 175 N.
The investigation of the RAMAN spectra of a modified compressed material which consisted of 95% metformin-HCl and 5% additive, or alternatively 50% metformin-HCl and 50% additive, compared with the RAMAN spectra of the individual components and compared with the RAMAN spectra of the tablets prepared from it, indicated that there were no interactions or incompatibilities between the additive and the pharmaceutical substance, even after storage of the tablets for one month at 40° C. The variation in the composition of the compressed material compared with the preceding example was made in order to provoke any opposing influences of the components before, during and after compression by leaving out the filler and to make them more noticeable.
The properties of some PGFEs will now be illustrated by way of example and with the aid of the figures.
The partial ester PG(4)-C18 had the quantitative main structure shown in
For the WAXS and the SAXS analyses, a spot focusing camera system, S3-MICRO, formerly Hecus X ray Systems Gesmbh, 8020 Graz, Austria, now Bruker AXS GmbH, 76187 Karlsruhe, Germany, was equipped with two linear position-sensitive detectors with a resolution of 3.3-4.9 Angstroms (WAXS) and 10-1500 Angstroms (SAXS). The samples were introduced into a glass capillary with a diameter of approximately 2 mm, which was then sealed with wax and placed in the rotary capillary unit. The individual measurements were made at room temperature by exposure to a beam of X rays at a wavelength of 1.542 Angstroms for 1300 sec.
The analysis from the differential scanning calorimetry also enabled predictions to be made about the solidification temperature of the PG(4)-C18 partial ester. The peak of the exothermic maximum upon cooling the sample down was between 53.4° C. and 57.0° C. with the maximum at 55.2° C., which marks the solidification temperature.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/DE2018/000302 | Oct 2018 | DE | national |
| PCT/DE2018/000363 | Dec 2018 | DE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/DE2019/000115 | 4/30/2019 | WO | 00 |
