EP3870229A1 - Additif pour une poudre destinée à être pressée pour former des pièces moulées - Google Patents

Additif pour une poudre destinée à être pressée pour former des pièces moulées

Info

Publication number
EP3870229A1
EP3870229A1 EP19726304.9A EP19726304A EP3870229A1 EP 3870229 A1 EP3870229 A1 EP 3870229A1 EP 19726304 A EP19726304 A EP 19726304A EP 3870229 A1 EP3870229 A1 EP 3870229A1
Authority
EP
European Patent Office
Prior art keywords
additive
esters
fatty acid
hydroxyl number
marked
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19726304.9A
Other languages
German (de)
English (en)
Inventor
Dirk LOCHMANN
Sebastian REYER
Sharareh SALAR BEHZADI
Michael Stehr
Andreas Zimmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IOI Oleo GmbH
Original Assignee
IOI Oleo GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/DE2018/000302 external-priority patent/WO2020083411A1/fr
Priority claimed from PCT/DE2018/000363 external-priority patent/WO2020119839A1/fr
Application filed by IOI Oleo GmbH filed Critical IOI Oleo GmbH
Publication of EP3870229A1 publication Critical patent/EP3870229A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0245—Specific shapes or structures not provided for by any of the groups of A61K8/0241
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the even supply of the powder intended for compression is also indispensable for a smooth process of rapid successive compression processes. However, this can only be achieved regularly if the powder is sufficiently free-flowing and does not form agglomerates which can result in the supply slowing down on an inclined plane.
  • polyethylene glycols abbreviated to PEGs, or glyceryl dibehenate are used, the latter being used as a mixture of mono-, di- and triesters of behenic acid which only contains diesters as the main constituent.
  • PEGs polyethylene glycols
  • glyceryl dibehenate a polyethylene glycols
  • MgSt are in demand because incompatibilities occur with some powders containing medicinal products, for example if they have the antiviral aciclovir, the anticoagulant clopidogrel, the antihypertensive agent captopril, the antibiotics erythromycin or penicillin or the analgesic active ingredient acetylsalical acid.
  • metformin-HCl water-soluble form
  • MgSt a Lewis acid
  • CONFIRMATION COPY not, for example, with the widely used anti-inflammatory active ingredient ibuprofen or with the clopidogrel already mentioned.
  • glyceryl dibehenate it is not always possible to achieve optimal results with regard to the properties of the moldings.
  • the powders intended for compression into shaped bodies can, as disperse systems in the “solid in gaseous” category, not only consist of solid particles with particle sizes smaller than 500 ⁇ m, but also include larger, for example pre-granulated, components.
  • additives which, according to claim 1, have polyglycerol fatty acid esters, abbreviated PGFEs, are suitable for influencing the cohesion and the lubricity on foreign surfaces of a powder intended for mechanical compression into shaped bodies as an alternative to MgSt are when those PGFEs are used which are each obtainable from a complete or partial esterification of a linear or branched polyglycerol having two to eight glyceryl units with one or more fatty acids each having from 6 to 22 carbon atoms.
  • PGFEs polyglycerol fatty acid esters
  • the simplest polyglycerols that can be used as starting materials for a targeted esterification are linear and branched diglycerols with the empirical formula C 6 0 5 H 14 , which are synthetically provided industrially in a known manner, for example by adding glycerol with 2 , 3-epoxy-1-propanol is base-catalyzed with the formation of ether linkages or base-catalyzed is thermally condensed, it being possible for the fraction mainly containing diglycerols to be subsequently separated.
  • Diglycerols can occur in three different structural isomeric forms, namely in the linear form, in which the ether bridge between the first carbon atoms of the two glycerol molecules used is formed, in the branched form, in the ether bridge between the first carbon atom of the first and the second Carbon atom of the second glycerol molecule used arises, and in a nucleodentrimere form, in which the ether bridge between the second carbon atoms.
  • the alkaline-catalyzed condensation of two glycerol molecules produces about 80% of the linear form and about 20% of the branched form, while the nucleodentrimeric form is only formed to a very small extent.
  • Polyglycerols with more than two and up to eight glyceryl units can also be used for the esterification with fatty acids.
  • the polyglycerols are abbreviated to "PG" and provided with a lower natural number n, which indicates the number of polyglyceryl units, ie "PG n ".
  • PG n the number of polyglyceryl units
  • triglycerols would be given as PG 3 and have the empirical formula C9O7H20.
  • the complete esterification with a fatty acid, for example with stearic acid, would now take place on all free hydroxyl groups of the PG n molecule, i.e.
  • PG (n) -Cm full ester or optionally PG (n) -Cm partial ester has also been established, the parenthesized "n", similar to that in Name of the polyglycerols, the number of glyceryl units contained in the molecule and m stands for the number of carbon atoms of the saturated fatty acid used for the esterification reaction.
  • n stands for the number of glyceryl units with the empirical formula C 3 0 2 H 5 R or C 3 0 3 H 5 R 2 for marginal glyceryl units, where R can represent a fatty acid residue or the hydrogen atom of a free hydroxy group.
  • PG (2) -C18 full esters would thus refer to full polyglycerol fatty acid esters with the empirical formula C / eOgHiso of the main constituent.
  • the number of fatty acid residues is averaged, with the sum formula also indicating the fraction with the most frequently available esterification variants.
  • a more precise description of the polyglycerol fatty acid partial esters results from the additional specification of the hydroxyl number, which is a measure of the content of unesterified hydroxy groups and thus provides information about the degree of esterification of the partial ester.
  • the esterification reactions preferably proceed from the outside in, presumably for steric reasons.
  • the hydroxyl groups which allow the highest degrees of freedom for the fatty acid residue are esterified first.
  • the first esterification reaction on a linear polyglycerol therefore preferably takes place at the hydroxyl group of the first carbon atom of a polyglyceryl unit on the edge, the second esterification reaction then on the hydroxyl group of the third carbon atom of the polyglyceryl unit on the other side. Furthermore, the hydroxyl groups are esterified at positions which are already esterified and immediately adjacent carbon positions, and so on.
  • Fatty acids are understood here to mean aliphatic monocarboxylic acids having 6 to 22 carbon atoms, which are preferably unbranched and saturated and have an even number of carbon atoms, but can also be odd, branched and / or unsaturated. Fatty acids which are saturated and / or unbranched are preferably used for the esterification to the PGFEs used as the main constituent of the additive. It is also advantageous to use unbranched, saturated fatty acids with 16, 18, 20 or 22 carbon atoms for the esterification, that is to say palmitic, stearic, arachic or behenic acid.
  • PGFEs are advantageously used which, when examining the individual PGFE (s) by means of dynamic differential calometry for the heat flow in the course of the investigation, each have only an endothermic minimum and each have only one exothermic maximum during cooling, because of the for the pressing force of 10 kN and more which is usually to be applied to the pressed material, elevated temperatures can occur which, in the case of unsuitable additive components, can lead to their polymorphic transformation and difficult-to-control properties of the shaped body. Additional polymorphic forms would be noticeable in an examination using dynamic differential calorimetry by the occurrence of a local exothermic maximum when the sample was heated and a local endothermic minimum when the sample was cooling.
  • a stratification of on average 6 lamellar structures per subcellular unit could be determined under certain conditions, after complete conversion into the ß-modification then a stratification of on average 10.5 lamellar structures per subcellular unit and an increase in crystal thickness of about 67%.
  • the fact that the mathematically expected increase of 75% is not achieved here is probably due to the fact that the individual lamellae of the ß-modification have a denser lamellar packing due to an inclination compared to the a-modification (see DG Lopes, K. Becker, M. Stehr, D. Lochmann et al. In Journal of Pharmaceutical Sciences 104: 4257-4265, 2015).
  • the PGFEs used have a stable subcellular form below their solidification temperature with at 40 ° C and 75% relative humidity for at least 6 months, i.e. under the storage conditions of an accelerated shelf life test, essentially constant thickness of the lamellar structured crystallites according to small-angle X-ray scattering, abbreviated to SAXS, evaluated using the Scherrer formula.
  • SAXS allows conclusions to be drawn about the size, shape and inner surface of crystallites.
  • D denotes the thickness of the crystallite and K the dimensionless so-called Scherrer constant, which allows statements about the shape of the crystallite and can usually be assumed to be 0.9 in good approximation.
  • FWHM stands for "full width at half maximum", ie the width of the peak of an intensity maximum at half height compared to the background measured in radians (rad) and Q is the Bragg angle, i.e. the angle of incidence of the radiation on the network plane.
  • polyglycerol full esters usually show a slightly increased crystallite thickness of 30 to 40 nm, corresponding to 5 to 8 lamellae, which indicates a higher degree of organization, and are likewise stable under the storage conditions of an accelerated durability test in unchanged modification.
  • the lamellar distance under the conditions mentioned is essentially constant according to the evaluation of the Bragg angle determined by means of wide-angle X-ray scattering, "WAXS" for short, “WAXS” for short.
  • WAXS wide-angle X-ray scattering
  • Polyglycerol fatty acid ester surprisingly stable a-modification.
  • C16 / C18 full esters PG (4) -C18 partial esters with a hydroxyl number from 100 to 200, PG (4) - C22 partial esters with a hydroxyl number from 100 to 200, PG (6) -C16 / C18 partial esters with a Hydroxyl number from 200 to 300, PG (6) -C16 / C18 full esters, PG (6) -C18 partial esters with a hydroxyl number from 100 to 200, wherein in the polyglycerol fatty acid esters with two different fatty acid residues due to the number of their carbon atoms, those with the a lower number of 35% to 45%, those with a higher number, correspondingly complementary, 55% to 65% and the listed full esters preferably have a hydroxyl number less than 5.
  • the polyglycerol fatty acid esters are therefore preferably used as the main constituent of the additive, the contact angle of which with water at 40 ° C. and at 20 ° C. after 16 weeks has a deviation of less than 10 ° from the initial value. Comparatively high at 40 ° and thus detrimental to a desirable constancy of the release kinetics would be, for example, the deviation of the contact angle under the named conditions for glycerol tristearin with water, which is due to a rearrangement during storage from the a- to the ß-modification.
  • the solidification temperature of the PGFEs used for the additive is preferably below 75 ° C, but above 40 ° C.
  • the solidification temperature is defined here as the temperature value at which the maximum of the highest exothermic peak of the heat flow occurs during cooling during a sample analysis by means of dynamic differential calorimetry.
  • PGFEs are always mixtures of different molecules, especially in the case of the partial esters.
  • a suitable additive according to claim 1 it is also possible for the preparation of a suitable additive according to claim 1 to post-synthetically mix PGFEs which are obtainable from esterification reactions which differ from one another on the basis of the reactants used or the reaction conditions.
  • the size of the particles of the additive has an influence on the total surface of the additive and thus on the properties of the composition of the powder intended for compression and the additive. In principle, it has proven to be advantageous if the size of the particles of the additive is 1 to 300 pm, preferably 5 pm to 15 pm.
  • the proportion of the additive in the composition of the Press good influence on their behavior in the mechanical pressing to form bodies and should advantageously not exceed 5 percent by weight, preferably it is only 0.05 to 0.5 percent by weight. Too much additive is associated with an increased hydrophobicity of the composition and can have negative effects on the wettability of the finished molded article, the dissolution behavior of which can be undesirably slowed down.
  • the material to be pressed from the powder intended for machine compression into a shaped body and the additive also comprises at least one active pharmaceutical ingredient, such as, for example, metformin-HCl, in applications in the pharmaceutical industry.
  • a pharmaceutical active substance is understood here to mean pharmacologically active substances both immediately and only after conversion into an active form in vivo.
  • the powder preferably has microcrystalline cellulose as a filler, the proportion of which in the pressed material can be used to control the volume of the shaped body.
  • the pressed material composed of the additive and the powder has only 0.05 to 0.5 percent by weight of additive and 99.5 to 99.95 percent by weight of powder, the additive consisting of a mixture of each 50% by weight of PG (3) C22 full esters and PG (3) C22 partial esters with a hydroxyl number of 100-200 or entirely of PG (3) C22 partial esters of the same hydroxyl number.
  • the material to be pressed may contain, for example, 15% by weight of metformin-HCl and 84.5 to 84.95% by weight of microcrystalline cellulose.
  • the removal of the finished molded article from the respective mold is a process that only takes place without problems if the composition of the molded article ensures sufficient lubricity on foreign surfaces.
  • the molded body should therefore have the same composition as the material to be pressed and no chemical changes occur during the pressing and the associated energy supply. It is advantageous if the force required to eject the shaped body is not more than 150% of the ejection force that is otherwise required under the same conditions for a test shaped body in which at least 40 percent by weight of the additive is obtained from MgSt and the rest, if necessary, from filler used, preferably microcrystalline cellulose, are replaced. To determine the ejection force, the values of 20 molded bodies are averaged.
  • the upper punch is pressed onto the pressing stock resting on the lower punch, while the lower punch is moved in the direction of the upper punch in this step.
  • the maximum pressure at the upper punch which is specific to the respective pressing process, is thus partially transferred to the lower punch via the material to be pressed. It is advantageous to add at least as much additive to the powder intended for pressing that with a punch diameter of 8 mm and the use of 285 mg of pressed material at the time of a maximum pressure of 10 kN on the upper punch, the maximum pressure on the lower punch is 92% to 98% the maximum pressure of the upper stamp.
  • an excessive amount of the additive can result in the shaped bodies obtained by compression not having the hardness required for pharmaceuticals and thus tending to undesirable breakage or excessive abrasion, which leads to unacceptable fluctuations in the desired active substance content of the shaped bodies. It is therefore desirable and advantageous that the amount of additive that is added to the powder intended for compression is correctly measured. This can be determined on the basis of the resulting properties of the molded body, which preferably does not break when subjected to a linear force of up to 100 N, more preferably up to 150 N and particularly preferably up to 200 N. To determine the breaking strength, 10 shaped bodies each of the linear Exposed to force and the average value determined.
  • the moldings according to the invention should advantageously have a disintegration time of 2 to 4 minutes, determined in accordance with European Pharmacopoeia, Edition 8.0.
  • 6 shaped bodies, each deposited in separate baskets, are placed in 1000 ml of purified water, aqua purificata, which has been heated to a temperature of 37 ° C. (+ 2 ° C.).
  • the baskets are then moved up and down 29 to 32 times by 53 to 57 mm per minute and at predetermined times the state of disintegration of the shaped bodies then removed together with the baskets from the water is assessed in accordance with the European Pharmacopoeia, Edition 8.0.
  • the powder consists of a mixture of metformin-HCl and microcrystalline cellulose, the additive of PG (3) C22 partial ester [138], the number in square brackets here indicating the hydroxyl number.
  • PG (3) C22 partial ester [138] the number in square brackets here indicating the hydroxyl number.
  • a second example changes the composition of the pressed material by 84.9 percent by weight of microcrystalline cellulose, 15 percent by weight of metformin-HCl and 0.1 percent by weight of a mixture of PG (3) C22 full ester and PG (3) C22 in equal parts - Partialester- [138] are pressed.
  • This example shows a disintegration time of 4 minutes, an abrasion of only 0.02%, a breaking strength up to a linear load of 200 N and a required ejection force of 175 N.
  • the examination of the RAMAN spectra of a modified pressed material which consists of 95% metformin-HCl and 5% additive or alternatively 50% of metformin-HCl and 50% additive indicates in comparison with the RAMAN spectra of the individual components and in comparison with the RAMAN spectra of the tablets made therefrom, no interaction or incompatibility between the additive and the active pharmaceutical ingredient, even after the tablets had been stored at 40 ° C. for one month.
  • the modification of the composition of the pressed material compared to the aforementioned example was done with the intention of provoking any mutual influences of the components before, during and after the pressing by omitting the filler and making them more visible.
  • the partial ester PG (4) -C18 shows in the investigation by means of gas chromatography coupled with mass spectroscopy (GC-MS) the quantitative main structure shown in FIG. 1.
  • Fig. 2 shows the results of the studies of PG (4) -C18 by means of dynamic differential calorimetry, the temperature values on the X axis of the diagram being assigned to the heat flow in mW / g on the Y axis.
  • the diagram on the left in FIG. 2 shows two almost congruent curves of two measurements of the partial ester PG (4) -C18, each of which has exactly one endothermic minimum that the energy-consuming Transition from the solid to the liquid phase during melting of the partial ester can be assigned.
  • the diagram on the right in FIG. 2 shows exactly one exothermic maximum for the partial ester PG (4) -C18, which can be assigned to the energy-releasing transition from the liquid to the solid phase when the partial ester solidifies.
  • the measurements were carried out using a DSC 204 F1 Phoenix from Nietzsch Automaticbau GmbH, 95100 Selb, Germany. A sample of 3 - 4 mg was weighed into an aluminum pan and the heat flow was recorded continuously at a heating rate of 5K per minute. A second run was done at the same rate of warming.
  • FIG. 3 shows, in contrast to the desired behavior of the polyglycerol fatty acid esters, the typical behavior of a polymorphic triacylglycerol during an examination using dynamic differential calorimetry when warming up.
  • two local endothermic minima with an intermediate exothermic maximum can be seen, the first endothermic, left-hand minimum occurring due to the melting of the unstable a-modification, followed by the exothermic maximum during crystallization into the more stable ß-modification, which in turn occurs at further temperature increase melts, recognizable by the second endothermic, right-hand local minimum.
  • Fig. 4 shows the PG (4) -C18 partial ester examined by means of dynamic differential calorimetry when warming up after 6 months of storage at room temperature.
  • 5 shows the PG (4) -C18 partial ester investigated by means of dynamic differential calorimetry during warming up after storage for 6 months at 40 ° C. In both cases, there is still no exothermic maximum that could indicate crystallization into a more stable modification after melting.
  • WAXS For the WAXS and SAXS analyzes, a point-focusing camera system, S3-MICRO, formerly Hecus X-ray Systems Gesmbh, 8020 Graz, Austria, now Bruker AXS GmbH, 76187 Düsseldorf, 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 placed in a glass capillary of approximately 2 mm in diameter, which was subsequently sealed with wax and placed in the capillary rotation unit. The individual measurements were exposed to an x-ray beam with a wavelength of 1,542 angstroms at room temperature for 1300 seconds.
  • WAXS 3.3 - 4.9 angstroms
  • SAXS 10 - 1500 angstroms
  • FIG. 6 shows the results of the WAXS analysis of various polyglycerol fatty acid esters including PG (4) -C18 partial esters (marked) below their solidification temperature, all of which show an intensity maximum at 2 ° C. of 21.4 °.
  • the Bragg angle corresponds to a distance of the network planes of 415 pm, which is typical for the lamellar packing of the a-modification.
  • the intensity maximum remains stable both when stored for 6 months at room temperature, as shown in FIG. 7, and when stored for 6 months at 40 ° C., as shown in FIG. 8.
  • FIG. 9 shows the results of the SAXS analysis of various polyglycerol fatty acid partial esters.
  • a lamellar distance of 65.2 angstroms can be derived for PG (4) -C18 partial esters.
  • the thickness of the crystallites is 12.5 nm according to the Scherrer formula, with a Scherrer constant of 0.9, a wavelength of 1.542 Angstroms, an FWHM value of 0.0111 and a Bragg angle Q of 0.047 ( wheel).
  • the values of the SASX analysis of PG (4) -C18 partial esters remained constant after six months of storage both at room temperature and at 40 ° C. (not shown).
  • the evaluation of the dynamic differential calorimetry also allows statements about the solidification temperature of the PG (4) -C18 partial ester.
  • the peak of the exothermic maximum when the sample cools rises between 53.4 ° C and 57.0 ° C with the maximum at 55.2 ° C, which marks the solidification temperature.
  • FIG. 10 shows a diagram which clarifies the measurement of the contact angle (cf. par.
  • Fig. 12 shows the change in the contact angle for PG (4) - C18 partial esters, middle diagram, compared to the start measurement (left column) after 16 weeks at room temperature (middle column) and after 16 weeks at 40 ° C (right column).
  • the contact angle does not change by more than 10 °, the hydrophobicity can thus be described as stable in comparison with monoglycerol fatty acid esters, such as tristearylglycerol.
  • monoglycerol fatty acid esters such as tristearylglycerol.

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Abstract

L'invention concerne un additif pour une poudre destinée à être pressée pour former des pièces moulées. L'additif est utilisé pour influencer la poudre pour ce qui concerne sa cohésion et son aptitude au glissement sur des surfaces externes et possède, comme élément constitutif principal, un ou plusieurs esters d'acides gras de polyglycérol pouvant être obtenus respectivement à partir d'une estérification totale ou partielle d'un polyglycérol linéaire ou ramifié, possédant de deux à huit unités glycéryle, avec un ou plusieurs acides gras possédant chacun de 6 à 22 atomes de carbone.
EP19726304.9A 2018-10-22 2019-04-30 Additif pour une poudre destinée à être pressée pour former des pièces moulées Pending EP3870229A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/DE2018/000302 WO2020083411A1 (fr) 2018-10-22 2018-10-22 Matériau de revêtement destiné à être utilisé dans un procédé hmc
PCT/DE2018/000363 WO2020119839A1 (fr) 2018-12-11 2018-12-11 Procédé de préparation d'un ester d'acide gras de polyglycérol
PCT/DE2019/000115 WO2020083412A1 (fr) 2018-10-22 2019-04-30 Additif pour une poudre destinée à être pressée pour former des pièces moulées

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EP19726304.9A Pending EP3870229A1 (fr) 2018-10-22 2019-04-30 Additif pour une poudre destinée à être pressée pour former des pièces moulées
EP19742277.7A Pending EP3870144A1 (fr) 2018-10-22 2019-07-01 Particules de transport lipophile pour principes actifs cosmétiques ou pharmaceutiques

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EP (2) EP3870229A1 (fr)
CN (2) CN113242738A (fr)
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WO (1) WO2020083412A1 (fr)

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JPS6092213A (ja) * 1983-10-25 1985-05-23 Riken Vitamin Co Ltd 錠剤，錠菓の製造法
JPS60105632A (ja) * 1983-11-15 1985-06-11 Taiyo Kagaku Kk 打錠用滑沢剤
US4755387A (en) * 1985-03-21 1988-07-05 The Procter & Gamble Company Therapeutic particles
NZ231281A (en) * 1988-11-08 1991-01-29 Takeda Chemical Industries Ltd Sustained release pharmaceutical preparations comprising the active agent dispersed in a solid matrix of a fatty acid ester of a polyglycerol
TW209174B (fr) * 1991-04-19 1993-07-11 Takeda Pharm Industry Co Ltd
US5612053A (en) * 1995-04-07 1997-03-18 Edward Mendell Co., Inc. Controlled release insufflation carrier for medicaments
US5891476A (en) * 1997-12-22 1999-04-06 Reo; Joe P. Tastemasked pharmaceutical system
US6117451A (en) * 1998-08-25 2000-09-12 Pharmalogix, Inc. Direct compression metformin hydrochloride tablets
MXPA05014194A (es) * 2003-06-27 2006-02-24 Otsuka Pharma Co Ltd Particulas de farmaco de liberacion sostenida y procedimiento para producirla.
JP5292105B2 (ja) * 2007-01-11 2013-09-18 株式会社カネカ 補酵素ｑ１０粒子の製造方法
EP2611438B1 (fr) * 2010-08-30 2020-04-01 Pulmatrix Operating Company, Inc. Formulations de poudre sèche et méthodes de traitement de maladies pulmonaires
WO2013183062A2 (fr) * 2012-06-05 2013-12-12 Rubicon Research Private Limited Formulations d'ibuprofène de goût agréable
WO2018232453A1 (fr) * 2017-06-20 2018-12-27 Respirion Pharmaceuticals Pty Ltd Procédé destiné à réduire les infections pulmonaires

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US20210361581A1 (en) 2021-11-25
CN113242738A (zh) 2021-08-10
US20210361577A1 (en) 2021-11-25
EP3870144A1 (fr) 2021-09-01
WO2020083412A1 (fr) 2020-04-30
CN112867481A (zh) 2021-05-28
BR112021006416A2 (pt) 2021-07-06
BR112021006425A2 (pt) 2021-07-27

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