LIPOPHILIC TRANSPORT PARTICLES FOR COSMETIC OR PHARMACEUTICAL ACTIVE INGREDIENTS

Abstract

The invention relates to lipophilic transport particles for cosmetic or pharmaceutical active ingredients. The lipophilic transport particles comprise polyglycerol fatty acid ester as a main constituent and, because of the absence of polymorphic transformations, even during long storage, neither have volume changes nor allow the problem of expulsion of the adhering or enclosed active ingredient, due to intense structuring of the crystal lattice and associated compaction, to arise, and therefore the degree of loading with active ingredient and the release profile are stable.

Claims

1. Lipophilic carrier particles for cosmetic or pharmaceutical active ingredients, characterized by one or more polyglycerol fatty acid esters as the main component, respectively obtainable from 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.

2. The lipophilic carrier particles as claimed in claim 1, characterized in that the fatty acids for the synthesis of the polyglycerol fatty acid esters are either saturated or unbranched or both saturated as well as unbranched.

3. The lipophilic carrier particles as claimed in claim 1, characterized in that the fatty acids for the synthesis of the polyglycerol fatty acid esters contain 16, 18, 20 or 22 carbon atoms.

4. The lipophilic carrier particles as claimed in claim 1, characterized in that an investigation of the individual polyglycerol fatty acid ester or polyglycerol fatty acid esters using heat flux differential scanning calorimetry produces, upon heating up, respectively only one endothermic minimum and upon cooling down, respectively only one exothermic maximum.

5. The lipophilic carrier particles as claimed in claim 1, characterized in that the polyglycerol fatty acid ester or polyglycerol fatty acid esters have a stable subcellular form below the solidification temperature with a lamellar separation over at least 6 months at 40° C. which is substantially constant according to an evaluation of the Bragg angle determined by WAXS analysis.

6. The lipophilic carrier particles as claimed in claim 1, characterized in that the polyglycerol fatty acid ester or polyglycerol fatty acid esters have a stable subcellular form below the solidification temperature with a substantially constant thickness of the lamellar-structured crystallites over at least 6 months at 40° C. according to SAXS analysis evaluated using the Scherrer equation.

7. The lipophilic carrier particles as claimed in 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 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.

8. The lipophilic carrier particles as claimed in claim 1, characterized in that the polyglycerol fatty acid ester or individual polyglycerol fatty acid esters have a solidification temperature of below 75° C. preferably between 43° C. and 56° C.

9. The lipophilic carrier particles as claimed in claim 1, characterized in that the contact angle of the polyglycerol fatty acid ester or individual polyglycerol fatty acid esters during the determination of the hydrophobicity differs by less than 10° from the starting value after 16 weeks at 40° C. as well as at 20° C.

10. The lipophilic carrier particles as claimed in claim 1, characterized by post-synthesis mixing of polyglycerol fatty acid esters which are respectively obtainable from esterification reactions which are different because different reaction partners are used or because different reaction conditions are employed.

11. The lipophilic carrier particles as claimed in claim 1, characterized by one or more pharmaceutical active ingredients.

12. The lipophilic carrier particles as claimed in claim 1, characterized by an active ingredient content of more than 10% by weight.

13. The lipophilic carrier particles as claimed in claim 1, characterized by a solid physical state at temperatures of 40° C. or less.

14. The lipophilic carrier particles as claimed in claim 1, characterized by a mass median aerodynamic diameter (MMAD) of 0.5 μm to 5 μm.

15. The lipophilic carrier particles as claimed in claim 1, characterized by a tamped density of less than 0.4 g/cm3.

16. The lipophilic carrier particles as claimed in claim 1, characterized by a water content of less than 2.5%.

17. The lipophilic carrier particles as claimed in claim 1, characterized by an emulsifier, preferably a nonionic surfactant.

18. The lipophilic carrier particles as claimed in claim 1, characterized by one or more incorporated liquid lipids.

19. The lipophilic carrier particles as claimed in claim 12, characterized by at least one pharmaceutical active ingredient from the group formed by glucosteroids.

20. The lipophilic carrier particles as claimed in claim 12, characterized by at least one pharmaceutical active ingredient from the group formed by non-steroidal antirheumatic agents (NSAR).

21. A process for the production of carrier particles as claimed in claim 1, characterized by the following steps: i) dissolving and/or suspending the polyglycerol fatty acid ester or polyglycerol fatty acid esters in an organic solvent, ii) removing the solvent by means of spray drying.

22. The process as claimed in claim 21, characterized in that prior to step ii), at least one pharmaceutical active ingredient is dissolved and/or suspended in the organic solvent.

23. A process for the production of lipophilic carrier particles as claimed in claim 1, characterized by the following steps: i) producing a mixture of the polyglycerol fatty acid ester or polyglycerol fatty acid ester mixture with water by stirring at a temperature which is above the melting temperature of the polyglycerol fatty acid ester or the polyglycerol fatty acid ester mixture, ii) spraying the mixture once or multiple times through a high pressure homogenization nozzle to form an O/W emulsion, iii) cooling the lipid phase to form solid particles in water.

24. The process as claimed in claim 23, characterized in that in addition, at least one emulsifier, preferably a nonionic surfactant, is added to the mixture in step i).

25. The process as claimed in claim 23, characterized in that in addition, at least one pharmaceutical active ingredient is added to the mixture in step i).

26. An inhalation preparation, characterized by lipophilic carrier particles as claimed in claim 1.

27. An inhalation preparation, characterized by lipophilic carrier particles which can be produced by the process according to claim 26.

Description

EXAMPLE 1

[0030] Preparation by Means of Spray Drying Micronized, Lipophilic Carrier Particles Loaded with Ibuprofen for a Powder Inhaler:

[0031] A solution of 1.08 g of PG(3)-C22 partial ester-[137], wherein the number in square brackets gives the hydroxyl value, and 0.46 g of ibuprofen was prepared by dissolving the components in 60 g of tetrahydrofuran, in order to subsequently obtain a content of 2.5% by weight of solid. The solution was sprayed in a Procept 4M8-Trix spray dryer in nitrogen, in a closed ring configuration. In this regard, a drying column was used as the drying chamber and a small cyclone separator was used with a pressure difference of 60 mbar. The inlet temperature was set to at least 5° C. above the boiling point of the solvent, and the air flow speed to 0.3 m.sup.3/min. The solution was forced through a 0.2 mm bi-fluid nozzle with a nozzle pressure of 0.9 bar at a rate of 3.5 g/min, corresponding to 3 L/min. The separated carrier particles loaded with ibuprofen were removed from the spray drying unit and stored for 10 hours under vacuum in order to remove residual solvent. Carrier particles loaded with 30% by weight ibuprofen with a theoretical MMAD of 4.10 μm were obtained. The bulk density was 0.215 g/cm.sup.3, the tamped density was 0.342 g/cm.sup.3, the true density was 1.069 g/cm.sup.3, and the water content was 0.45%. The differential scanning calorimetry for the eutectic mixture of ibuprofen and PG(3)-C22 partial ester-[137] provided the values listed below.

1) immediately after preparation of the carrier particles loaded with ibuprofen;
2) after storage for one month at 20° C.;
3) after storage for one month at 40° C.:

TABLE-US-00001 ad 1) ad 2) ad 3) Start of 58.0° C.  (±58.1° C. (±58.1° C. (± melting  0.06° C.)    0.07° C.)    0.07° C.) process: Melting 60.9° C. (±60.8° C. (±60.8° C. (± temperature:  0.12° C.)    0.07° C.)    0.14° C.) Crystallization 57.9° C. (±58.1° C. (±58.0° C. (± temperature:  0.06° C.)    0.07° C.)    0.00° C.) Heat of fusion: 139.2° C.  (±139.2° C.  (±139.8° C.  (±   5.1° C.)     6.2° C.)     5.4° C.)

EXAMPLE 2

[0032] Preparation Using High Pressure Homogenization of Micronized, Lipophilic Carrier Particles Loaded with Dexamethasone as a Suspension for a Nebulizer

[0033] 0.1% by weight of dexamethasone was added to PG(2)-C18 full ester melted at 70° C. and stirred at 750 revolutions per minute for 60 minutes using a magnetic stirrer to form a clear solution. 100 mL of pre-emulsion for the high pressure homogenization was produced at 70° C. by mixing 10% by weight of the clear solution, 2.5% by weight of poloxamer 188 and 87.5% by weight of purified water with an Ultraturrax T25 (Janke & Kunkel, IKA, Germany) for two minutes at 20500 revolutions per minute. The pre-emulsion underwent high pressure homogenizations in three successive passes which were also carried out at 70° C. In this regard, a Panda K2 NS1001L high pressure homogenizer with a splitting valve (GEA NiroSoavi, Germany) was used. The particle size was determined using a Mastersizer 2000 (Malvern, United Kingdom), which is a tool for analysing the deflection of a laser beam on the basis of random light scattering. 10-30 μL of the suspension to be investigated was added to the measuring cell which already contained 20 mL of highly purified water, in order to obtain a turbidity of between 4% and 6%. The particle fraction index was set to 1.55, and the particle absorption index was set to 0.01 in order to obtain a residual value of less than 1 for each measurement. The pump speed was 1750 revolutions per minute. The data analysis was carried out on the basis of the Mie theory. The median particle size (d.sub.50) according to this was 212 nm. The differential scanning calorimetry for the nanosuspension compared with the clear solution of PG(2)-C18 full ester and dexamethasone showed that the addition of polyoxamer 188 produced no indication of a polymorphic transformation of the stable crystal modification of the PGFE.

[0034] The properties of some PGFEs will now be illustrated by way of example and with the aid of the figures.

[0035] The partial ester PG(4)-C18 had the quantitative main structure shown in FIG. 1, when investigated using gas chromatography linked with mass spectroscopy (GC-MS).

[0036] FIG. 2 shows the results of the investigation of PG(4)-C18 using differential scanning calorimetry, wherein the temperature values are on the X axis of the diagram and the heat flux in mW/g is on the Y axis. The left hand diagram in FIG. 2 shows two almost coincident curves for two measurements of the partial ester PG(4)-C18, which each exhibit precisely one endothermic minimum which can be assigned to the energy-consuming transition from the solid to the liquid phase upon melting of the partial ester. The right hand diagram for the partial ester PG(4)-C18 in FIG. 2 shows precisely one exothermic maximum which can be assigned to the energy-releasing transition from the liquid to the solid phase upon solidification of the partial ester. The measurements were carried out using a DSC 204 F1 Phoenix from Nietzsch Gerstebau GmbH, 95100 Selb, Germany. In this regard, a sample of 3-4 mg was weighed into an aluminium crucible and the heat flux was continuously recorded at a heating rate of 5K per minute. A second run was carried out using the same heating rate.

[0037] FIG. 3 shows, as a contrast to the desired behaviour of the polyglycerol fatty acid ester, the typical behaviour of a polymorphic triacyl glycerol during an investigation using differential scanning calorimetry and upon heating up. Here, two local endothermic minima with an intermediate exothermic maximum can be seen, wherein the first endothermic minimum on the left hand side is due to melting of the unstable a-modification followed by the exothermic maximum upon crystallization to form the more stable b-modification, which in turn melts as the temperature rises further, as can be seen by the second local endothermic minimum on the right hand side.

[0038] FIG. 4 shows the PG(4)-C18 partial ester investigated using differential scanning calorimetry upon heating up, after storage for 6 months at room temperature. FIG. 5 shows the PG(4)-C18 partial ester investigated using differential scanning calorimetry, upon heating up after storage for 6 months at 40° C. In both cases, as before, there is no exothermic maximum which could indicate crystallization into a more stable modification.

[0039] 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.

[0040] FIG. 6 shows the results of the WAXS analysis for different polyglycerol fatty acid esters including PG(4)-C18 partial ester (labelled) below their solidification temperature, which all exhibit an intensity maximum at a 20 of 21.4°. The Bragg angle corresponds to a separation of the lattice planes of 415 pm, which is typical for the lamellar packing of the a-modification. The maximum intensity was stable both after storage for 6 months at room temperature, as can be seen in FIG. 7, and also after storage for 6 months at 40° C., as can be seen in FIG. 8.

[0041] FIG. 9 shows the results of the SAXS analysis for various polyglycerol fatty acid esters. For PG(4)-C18 partial ester, a lamellar separation of 65.2 Angstroms could be derived. The thickness of the crystallites, calculated from the Scherrer equation, was 12.5 nm with a Scherrer constant of 0.9, a wavelength of 1.542 Angstroms, a FWHM value of 0.0111 and a Bragg angle θ of 0.047 (radians). The values for the SAXS analysis of PG(4)-C18 partial ester remained the same even after storage for six months, both at room temperature and also at 40° C. (not shown).

[0042] 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.

[0043] FIG. 10 shows a diagram illustrating the measurement of the contact angle (see para [0020]). For PG(4)-C18 partial esters, the contact angle is approximately 84°, which correlates to a HLB value of approximately 5.2. Compared with other polyglycerol fatty acid esters, PG(4)-C18 partial esters can be assigned to the hydrophilic polyglycerol fatty acid esters, as can be seen in FIG. 11 (here=PG4-C18). FIG. 12 shows the variation in contact angle for PG(4)-C18 partial esters, see central graph, against the start measurement (left hand column), after 16 weeks at room temperature (central column) and after 16 weeks at 40° C. (right hand column). The contact angle varied by no more than 10°, and so the hydrophobicity can be described as stable compared with monoglycerol fatty acid esters such as tristearyl glycerol, for example. This is also the case for the PG3-C16/C18 partial ester also shown in FIG. 12, left hand graph, and PG6-C18 partial esters, right hand graph.