COATING MATERIAL FOR USE IN AN HMC METHOD

Abstract

The invention relates to a coating material for use in a hot-melt coating method, said material containing as the main constituent one or more polyglycerol fatty acid, each obtained by way of a complete or partial esterification of a linear or branched polyglycerol containing two to eight glyceryl units with one or more fatty acids, each containing 6 to 22 carbon atoms.

Claims

1. A coating material for use in a hot-melt coating method characterized by one or more polyglycol fatty acid esters, each obtained by way of a complete or partial esterification of a linear or branched polyglycerol containing two to eight glycerol units with one or more fatty acids, each containing 6 to 22 carbon atoms, as the main constituent.

2. The coating material according to claim 1, characterized in that the fatty acids on which the polyglycerol fatty acid ester(s) are based are saturated or unbranched or both saturated and unbranched.

3. The coating material according to claim 1, characterized in that the fatty acids on which the polyglycerol fatty acid ester(s) are based have 16, 18, 20 or 22 carbon atoms.

4. The coating material according to claim 1, characterized in that the examination of the individual polyglycerol fatty acid ester(s) by means of dynamic differential calorimetry for the heat flow during heating respectively only yields an endothermic minimum and during cooling respectively only an exothermic maximum.

5. The coating material according to claim 1, characterized by a subcellular form of the polyglycerol fatty acid ester(s) that is stable below the solidification temperature with a substantially constant lamellar distance at 40° C. for at least 6 months according to evaluation of the Bragg angle determined by means of WAXS analysis.

6. The coating material according to claim 1, characterized by a subcellular form of the polyglycerol fatty acid ester(s) which is stable below the solidification temperature, with a substantially constant thickness of the lamellar-structured crystallites at 40° C. for at least 6 months in accordance with the SAXS analysis evaluated by means of the Scherrer formula.

7. The coating material according to claim 1, characterized by at least one polyglycerol fatty acid ester from the following group: PG(2)-C18 full esters, PG(2)-C22 partial esters with a hydroxyl number of 15 to 100, PG(2)-C22 full esters, PG(3)-C16/C18 partial esters with a hydroxyl number of 100 to 200, PG(3)-C22 partial esters with a hydroxyl number of 100 to 200, PG(3)-C22 full esters, PG(4)-C16 partial esters with a hydroxyl number of 150 to 250, PG(4)-C16 full esters, PG(4)-C16/C18 partial esters with a hydroxyl number of 150 to 250, PG(4)-C16/C18 full esters, PG(4)-C18 partial esters with a hydroxyl number of 100 to 200, PG(4)-C22 partial esters with a hydroxyl number of 100 to 200, PG(6)-C16/C18 partial esters with a hydroxyl number of 200 to 300, PG(6)-C16/C18 full esters, PG(6)-C18 partial esters with a hydroxyl number of 100 to 200, wherein in the polyglycerol fatty acid esters having two fatty acid residues which differ owing to the number of their carbon atoms, those with the smaller number being 35% to 45% present, those with the higher number correspondingly in a complementary manner at 55% to 65%, and the listed full esters preferably having a hydroxyl number less than 5.

8. The coating material according to claim 1, characterized by a viscosity at 80° C. less than 300 mPa.Math.s, preferably less than 200 mPa.Math.s and particularly preferably less than 100 mPa.Math.s.

9. The coating material according to claim 1, characterized by a solidification temperature of the individual polyglycerol fatty acid ester(s) below 75° C., preferably between 43° C. and 56° C.

10. The coating material according to claim 1, characterized in that the contact angle of the individual polyglycerol fatty acid ester(s) determined for determining the hydrophobicity at 40° C. as well as at 20° C. after 16 weeks has less than 10° deviation from the initial value.

11. The coating material according to claim 1, characterized by a post-synthetic mixture of polyglycerol fatty acid esters as the main constituent, which can be obtained from esterification reactions that differ from one another respectively due to the reactants used.

12. The coating material according to claim 1, characterized by a polyglycerol fatty acid ester proportion of at least 98 percent by weight.

13. The coating material according to claim 1, characterized by a solvent-free or surfactant-free or both solvent-free and surfactant-free composition.

14. A combination of coating material with a composition according to claim 1, of the disperse material, characterized in that the coating material has a hollow sphere homeomorphic shape obtained by spraying of its melt, with an internal cavity containing the disperse material.

15. The combination according to claim 14, characterized in that the disperse material has at least one active pharmaceutical ingredient.

16. The combination according to claim 14, characterized in that the disperse material consists of crystals of one or more active pharmaceutical ingredients.

17. A hot-melt coating method in which disperse material is coated with a coating material to form a product from surface-stable individual parts, characterized in that the coating material has a composition according to claim 1.

18. The hot-melt coating method according to claim 17, characterized in that the coating material has a hollow sphere homeomorphic shape obtained by spraying of its melt, with an internal cavity containing the disperse material and the disperse material has at least one active pharmaceutical ingredient.

19. The hot-melt coating method according to claim 18, characterized in that the active pharmaceutical ingredient is thermolabile and, after coating and subsequent cooling to room temperature, has more than 98% of its original effective activity.

20. The hot-melt coating method according to claim 18, characterized in that the gas or gas mixture used for spraying the coating material has a temperature during the spraying which is only 3° C. below the solidification temperature of the coating material, preferably only 1° C. to 2° C.

Description

[0027] In the following, it is explained in closer detail by means of illustrations and an example what properties the proposed coating material and combinations of the coating material and disperse material have and what parameters are to be taken into consideration in which way in a hot-melt coating method in which the proposed coating material is used.

[0028] 595 g of PG.sub.4 and 625 g of C18 fatty acid are placed in a glass apparatus with a distillation bridge and melted. The reaction is carried out under vacuum at 200° C. to 240° C. The esterification is carried out until an AN<1.0 mg KOH/g is reached.

[0029] The partial ester PG(4)-C18 synthesized as above shows in the examination by means of gas chromatography coupled with mass spectroscopy (GC-MS) the quantitative main structure shown in FIG. 1.

[0030] FIG. 2 shows the results of the examinations of PG(4)-C18 by means of dynamic differential calorimetry, wherein the temperature values on the X axis of the diagram are 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)-C8, which respectively have exactly one endothermic minimum that can be assigned to the energy-consuming transition from the solid to the liquid phase on melting of the partial ester. The diagram on the right in FIG. 2 shows exactly one exothermic maximum for the partial ester PG(4)-C1n, which can be assigned to the energy-releasing transition from the liquid to the solid phase on solidifying of the partial ester. The measurements were carried out with a DSC 204 F1 Phoenix of Nietzsche Gerätebau GmbH, 95100 Selb, Germany. Here, a sample of 3-4 mg was weighed into an aluminum crucible and the heat flow was recorded continuously at a heating rate of 5K per minute. A second passage Was carried out at the same heating rate.

[0031] FIG. 3 shows, as contrast to the desired behaviour of the polyglycerol fatty acid esters, the typical behaviour of a polymorphic triacylglycerol during an examination by means of dynamic differential calorimetry when heating up. Here, two local endothermic minima with an exothermic maximum lying therebetween can be seen, wherein the first endothermic, left-hand minimum occurs due to the melting of the unstable α-modification, followed by the exothermic maximum on the crystallization into the more stable β-modification, which in turn melts on further temperature increase, recognizable by the second endothermic, right-hand local minimum.

[0032] FIG. 4 shows the PG (4)-C18 partial ester examined by means of dynamic differential calorimetry on heating up after 6 months of storage at room temperature. FIG. 5 shows the PG(4)-018 partial ester examined by means of dynamic differential calorimetry on heating up after storage for 6 months at 40° C. In both cases, there Is still no exothermic maximum to be seen that could indicate the crystallization into a more stable modification after melting.

[0033] For the WAXS and SAXS analyses, a point-focusing camera system, S3-MICRO, formerly Hecus X-ray Systems Gesmbh, 8020 Graz, Austria, now Bruker AXS GmbH, 76187 Karlsruhe, Germany, equipped with two linear position-sensitive detectors with a resolution of 3.3-4.9 angstroms (WAXS) and 10-1500 angstroms (SAXS) was used. The samples were introduced into a glass capilliary 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.

[0034] FIG. 6 shows the results of the WAYS 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 θ 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 α-modification. The intensity maximum remains stable both when stored for b months at room temperature, as shown in FIG. 7, and also when stored for 6 months at 40° C., as shown in FIG. 8.

[0035] 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 0.111 and a Bragg angle 3 of 0.047 (rad). The values of the SASX analysis of PG(4)-C18 partial esters also remained constant after six months of storage both at room temperature and also at 40° C. (not shown).

[0036] A rheometer Physica—Modular Compact Rheometer, MCR 300 of Anton Paar GmbH, 5054 Graz, Austria, was used for the measurement of the viscosity. The measurement was carried out on a CP-50-2 system with a conical plate with constant shear forces. Here, the sample was melted directly on the plate and the viscosity was determined at 80° C. and 100° C. The viscosity for PG(4)-C18 partial esters is accordingly 74.38 mPa.Math.s at 80° C. and 34.46 mPa.Math.s at 100° C. The partial ester can therefore be processed very well in a hot-melt coating method.

[0037] 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 on cooling of the sample rises between 53.4° C. and 57.0° C. with the maximum at 55.2° C., which marks the solidification temperature.

[0038] FIG. 10 shows a diagram which illustrates the measurement of the contact angle (cf. para. [0020]). For PG(4)-C18 partial esters, the contact angle is approximately 84°, which correlates with an HLB value of approximately 5.2. Compared to other polyglycerol fatty acid esters, PG(4)-C18 partial ester is to be assigned to the more hydrophilic polyglycerol fatty acid esters, as can be seen from FIG. 11 (there=PG4-C18), and thus suitable for the coating of active pharmaceutical ingredients for which an immediate release is desired because the HLB value at 5.2 lies above the HLB rapid release limit of about 4. 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 100, the hydrophobicity can thus be described as stable in comparison with monoglycerol fatty acid esters, such as tristearoylglycerol for example. The same applies to the PG3-C16/C18 partial esters also shown in FIG. 12, left diagram, and PG6-C18 partial esters, right diagram.

[0039] FIG. 13 shows the release kinetics for particles coated with PG(4)-C18 partial esters and alternatively with PG(3)-C16/C18 partial esters, each with 600 mg of N-acetylcysteine. The proportion of PG(4)-C18 partial ester was 45%, the proportion of PG(3)-C16/C18 partial ester was 50% of the total weight of the coated particles. The values on the Y-axis stand for the percentage proportions of the released N-acetylcysteine, the values on the X-axis for the time in minutes. The release investigations were carried out with a device that complies with USP-II, a DT820LH of ERWEKA GmbH, 63150 Heusenstamm, Germany, which has an automatic sample collector. The collected samples were analyzed by means of high pressure liquid chromatography, HPLC for short, under the following conditions: Column: Synergi Fusio RP 4 mm, 0 angstroms, 250 mm×4.6 mm; upstream column: Atlantis T3 (5 μm); mobile phase: acetonitrile 5%/water 95% (pH 1.6); Flow rate: 1 mL/min; In section volume: 20 mm; Column temperature: 21° C.; Temperature of the automatic sample collector: 5° C.; Wavelength: 220 nm; Running time: 20 min. The particles coated with PG(4)-C18 partial ester have an immediately releasing profile in which within the first 5 minutes less than 10% and within the first 30 minutes more than 85% of the N-acetylcysteine is released. In order to achieve a more effective taste masking, the HMC method used can in addition be carried out-with a higher temperature of the inlet air used and higher spray rates in order to further reduce the release of the N-acetylcysteine within the first 5 minutes. The taste masking clue to the release kinetics of the particles coated with PG(3-C16/C18 partial ester can be designated as successful. Virtually no release takes place here in the first 5 minutes, which are critical for taste masking.

[0040] FIG. 14 shows the release kinetics of the N-acetylcysteine particles coated with PG(4)-C18 partial ester at the beginning, after one month, three months and five months of storage at 40° C. The release kinetics do not differ significantly, the product is stable.

[0041] FIG. 15 shows the release kinetics of the N-acetyl cysteine particles coated with PG(3)-C16/C18 partial ester at the beginning, after storage for one month at room temperature and after storage for one month at 40° C. The release kinetics do not differ significantly here either.

[0042] The successful taste masking by coating material having PG(3)-C16/C18 partial ester as main component was able to be achieved not least through the optimizing of the HMC method parameters. An Innojet Ventilus V-2.5/1 laboratory system served as coating device in combination with the Innojet hot melt device IHD-1 of Romaco Holding GmbH, 76227 Karlsruhe, Germany. PG(3)-C16/C18 partial ester was melted at 100° C. and sprayed onto N-acetylcysteine crystals with an average diameter of about 500 μm. The sample size for the HMC runs was respectively 200 g of disperse material. The spray rates and the air inlet temperatures were changed in the various HMC runs in order to determine the optimal setting for the coating. The effectiveness of the coating method was determined here according to the following equation: Effectiveness (%)=actual coating amount/theoretically achievable coating amount×100, wherein the actual coating amount is the percentage proportion of the coating material used in the respective HMC run applied onto the acetylcysteine crystals. At a spray rate of 5 g/min and an air inlet temperature of 35.0° C., the effectiveness was 90.7%. An increase of the air inlet temperature to 40° C. increased the effectiveness to 91.0%. Surprisingly, an increase of the spray rate to 7.5 g/min and of the air inlet temperature to 50° C. resulted ii an effectiveness of 100%. The two effectiveness values of 90.7% and 91.0% mean that 9.3 or respectively 9.0 percent by weight of the coating material are solidified before a spreading and distribution on the surface of the N-acetylcysteine crystals can take place. The solidified droplets, free of active ingredient, were collected as dust at the end of the respective run and weighed. In the case of 90.2% effectiveness it was 18.6 g, in the case of 91.0% effectiveness 13.0 g. The effectiveness of 100% was achieved here with an air inlet temperature of less than 2° C. below the solidification temperature of the coating material, in this case the PG(3)-C16/C18 partial ester, which has a solidification temperature of 51.7° C. The low specific heat capacity of the polyglycerol fatty acid esters used for the proposed coating material compared to conventional HMC coatings may be a reason why greater, advantageous flexibility in the setting of the air inlet temperature is now possible compared to the prior art. In the publication “Solvent-free melting techniques for the preparation of lipid-based solid oral formulations”, K. Becker et al. in Pharmaceutical Research, May 2015, 32(5), 1519-45, air inlet temperatures of 5° C. to 15° C. below the solidification temperature of the HMC coating material are still considered essential.

[0043] In contrast to the release tests with coating material having PG(4)-C18 partial ester, to determine the release kinetics of the N-acetylcysteine crystals coated with PG(3)-C16/C18 partial ester, instead of an automatic sample collector an integrated detection for UV radiation/visible light was used with a Lambda 25 spectrometer of Perkin Elmer Inc., Waltham, Mass., USA. The release tests were carried out at 37° C. in 900 mL of ultrapure water, obtained from Merck KGaA, Darmstadt, Germany, at a paddle stirring speed of 100 revolutions per minute. The release profiles were initially set to 0% and scaled to 100% release for the release level at the end of the release. FIG. 16 shows the release curves for the particles coated with an air inlet temperature of 35° C., 40° 0 and 50° C. in the HMC method. The particles coated a 50° C. with an effectiveness of 100% have virtuality no release of N-acetylcysteine within the first 5 minutes. The HMC method used with the coating material having PG (3)-C16/C18 partial ester as the main component is therefore well suited for taste masking, after optimization of the air inlet temperature, which is surprisingly possible with the proposed coating material in this way.