COATED MEDICAL PRODUCT

Abstract

The present invention relates to a suspension for coating of medical devices containing at least one tri-O-acylglycerol, at least one limus active agent in the form of microcrystals and at least one solvent in which the at least one tri-O-acylglycerol dissolves and in which the microcrystals of the at least one limus active agent do not dissolve. Furthermore, the present invention relates to a pmethod for preparing said suspension, a p method for coating a medical device with said suspension, and medical devices coated with at least one tri-O-acylglycerol and at least one microcrystalline limus active agent.

Claims

1. A suspension for coating of a medical device selected from a catheter balloon, a balloon catheter, a stent, or a cannula, the suspension containing: a) at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, and triundecanoylglycerol, b) at least one limus active agent in the form of microcrystals, and c) a solvent or a solvent mixture in which the at least one tri-O-acylglycerol dissolves and in which the microcrystals of the at least one limus active agent do not dissolve.

2. The suspension according to claim 1, wherein the at least one limus active agent is selected from the group comprising or consisting of rapamycin, everolimus, zotarolimus, umirolimus, deforolimus, myolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, and temsirolimus.

3. The suspension according to claim 1, wherein the at least one tri-O-acylglycerol and the limus active agent are present in a mass ratio of 10%-30% tri-O-acylglycerol to 90%-70% limus active agent.

4. The suspension according to claim 1, wherein the at least one limus active agent is in the form of microcrystals having a crystal size in the range of 1 m to 300 m.

5. The suspension according to claim 1, wherein at least 70% of the at least one limus active agent is in the form of microcrystals having a crystal size ranging from 10 m to 50 m.

6. The suspension according to claim 1, wherein the at least one limus active agent has a crystallinity of at least 90% by weight.

7. The suspension according to claim 1, wherein the solvent is a non-solvent having a dielectric constant .sub.r at 20 C. of 2.0 or the solvent mixture contains at least 50% by volume of a non-solvent having a dielectric constant .sub.r at 20 C. of 2.0.

8. The suspension according to claim 1, wherein the solvent mixture is a mixture of at least one polar organic solvent having an n-octanol-water partition coefficient log K.sub.OW of 0.5 to +1.5 and a dielectric constant .sub.r at 20 C. of 5.0 to 30, and at least one nonpolar organic solvent having a dielectric constant .sub.r at 20 C. of 3.0 and an n-octanol-water partition coefficient log K.sub.OW of 3.0.

9. A method of preparing the suspension according to claim 1 comprising the following steps: a) dissolving at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, and triundecanoylglycerol in a solvent or a solvent mixture; b) preparing a suspension of at least one limus active agent in the form of microcrystals and the solution from step a), wherein the microcrystals of the at least one limus active agent do not dissolve in the solution of step a).

10. The method according to claim 9, wherein the at least one limus active agent is selected from the group comprising or consisting of rapamycin, everolimus, zotarolimus, umirolimus, deforolimus, myolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, and temsirolimus.

11. The method according to claim 9, wherein the at least one limus active agent is in the form of microcrystals having a crystal size in the range of 1 m to 300 m.

12. The method according to claim 9, wherein at least 70% of the at least one limus active agent is in the form of microcrystals having a crystal size in the range of 10 m to 50 m.

13. The method according to claim 9, wherein the at least one limus active agent has a crystallinity of at least 90% by weight.

14. The method according to claim 9, wherein the solvent is a non-solvent having a dielectric constant .sub.r at 20 C. of 2.0 or the solvent mixture contains at least 50% by volume of a non-solvent having a dielectric constant .sub.r at 20 C. of 2.0.

15. The method according to claim 9, wherein the solvent mixture is a mixture of at least one polar organic solvent having an n-octanol-water partition coefficient log K.sub.OW of 0.5 to +1.5 and a dielectric constant .sub.r at 20 C. of 5.0 to 30, and at least one nonpolar organic solvent having a dielectric constant .sub.r at 20 C. of 3.0 and an n-octanol-water partition coefficient log K.sub.OW of 3.0.

16. A method for coating of a medical device selected from a catheter balloon, a balloon catheter, a stent, or a cannula, comprising the following steps: a) providing the medical device with a medical device surface, b) providing a suspension containing at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, and triundecanoylglycerol, at least one limus active agent in the form of microcrystals, and a solvent or a solvent mixture, in which the at least one tri-O-acylglycerol dissolves and in which the microcrystals of the at least one limus active agent do not dissolve, and c) applying the coating suspension to the surface of the medical device by means of a syringe method, pipetting method, capillary method, fold spraying method, dipping method, spraying method, dragging method, thread dragging method, drop dragging method, or rolling method.

17. The method according to claim 16, further comprising the following step d) drying the coating.

18. (canceled)

19. A medical device selected from a catheter balloon, a balloon catheter, a stent, or a cannula, coated with the suspension according to claim 1 and subsequent drying of the coating.

20. A medical device selected from from a catheter balloon, a balloon catheter, a stent, or a cannula coated with at least one tri-O-acylglycerol selected from the group consisting of trioctanoylglycerol, trinonanoylglycerol, tridecanoylglycerol, and triundecanoylglycerol, and at least one limus active agent in the form of microcrystals.

21. The medical device of claim 20, wherein the limus active agent is selected from the group comprising or consisting of rapamycin, everolimus, biolimus A9, pimecrolimus, zotarolimus, tacrolimus, deforolimus, myolimus, novolimus, ridaforolimus, and temsirolimus.

22. The medical device of claim 20, wherein the at least one tri-O-acylglycerol and the at least one limus active agent are present in a mass ratio of 10%-30% tri-O-acylglycerol to 90%-70% limus active agent.

23. The medical device according to claim 20, wherein the at least one limus active agent is in the form of microcrystals having a crystal size in the range of 1 m to 300 m.

24. The medical device according to claim 20, wherein at least 70% of the at least one limus active agent is in the form of microcrystals having a crystal size in the range of 10 m to 50 m.

25. The medical device according to claim 20, wherein the at least one limus active agent has a crystallinity of at least 90% by weight.

26. The medical device according to claim 20, wherein a biostable or biodegradable, bioactive or bioinert polymeric, metallic or ceramic layer is present beneath the layer of the at least one tri-O-acylglycerol and the at least one limus active agent.

Description

DESCRIPTION OF THE FIGURES

[0952] FIG. 1 a) cross-sectional view of a circumferentially coated and partially folded balloon; b) microcrystalline structure of everolimus coating under SEM at 1000 magnification.

[0953] FIG. 2 shows at 200 magnification rapamycin in the form of microcrystals in rod shape with very narrow particle size distribution mainly in the range of 10 m to 30 m.

[0954] FIG. 3 shows at 1000 magnification rapamycin in the form of microcrystals in regular rod shape with very narrow particle size distribution mainly in the range of 10 m to 30 m.

[0955] FIG. 4 shows at 200 magnification rapamycin in the form of microcrystals in almost identical rod shape with extremely narrow particle size distribution mainly in the range of 15 m to 30 m. No larger crystals or agglomerates are visible.

[0956] FIG. 5 shows at 1000 magnification rapamycin in the form of microcrystals in almost perfectly regular rod shape with very narrow particle size distribution mainly in the range of 15 m to 30 m. The shape of rhombohedral prisms can be seen very clearly.

[0957] FIG. 6 shows at 200 magnification everolimus in the form of microcrystals in needle shape with extremely narrow particle size distribution mainly in the range of 20 m to 40 m. No larger crystals or agglomerates are visible.

[0958] FIG. 7 shows at 1000 magnification everolimus in the form of microcrystals in needle shape with extremely narrow particle size distribution mainly in the range of 20 m to 40 m. The needle shape can be seen very clearly.

[0959] FIG. 8 shows at 1000 magnification rapamycin in the form of microcrystals in almost identical rod shape with extremely narrow particle size distribution mainly in the range of 20 m to 40 m. No larger crystals or agglomerates are visible.

[0960] FIG. 9 shows at 1000 magnification rapamycin in the form of microcrystals in almost perfectly regular rod shape with very narrow particle size distribution mainly in the range of 20 m to 40 m. The shape of rhombohedral prisms can be seen very clearly.

[0961] FIG. 10 shows the microcrystalline structure of the rapamycin coating with microcrystals of rapamycin substantially in rhombohedral prisms under SEM at 1000 magnification.

[0962] FIG. 11 shows the microcrystalline structure of the rapamycin coating with milled microcrystals of rapamycin under SEM at 1000 magnification.

[0963] FIG. 12 shows the model formed from silicone tubing that mimics the natural course of vessels in the organism a) Simulated Peripheral Catheter; b) Simulated Femoral Artery.

[0964] FIG. 13 a) shows a bending test to determine the particle release of a coated catheter balloon; b) shows an edge impact test to determine the particle release of a coated catheter balloon.

[0965] FIG. 14 shows rapamycin coatings not according to the invention prepared according to WO 2015/039969 A1 at 1000 magnification. A too large almost round crystal surrounded by many quite small crystals of irregular shape and broad particle size distribution can be seen.

[0966] FIG. 15 shows rapamycin coatings not according to the invention prepared according to WO 2015/039969 A1 at 1200 magnification. Numerous quite large crystals surrounded by many quite small crystals of irregular shape and broad particle size distribution can be seen.

[0967] FIG. 16 a) shows rapamycin crystal coating with dry crystals not according to the invention; b) shows the coating from a) after solvent bonding. The crystals are no longer intact.

[0968] FIG. 17 a) shows a rapamycin crystal coating not according to the invention with dry crystals and base coating of adhesive and topcoat with trioctanoylglycerol. b) shows a rapamycin crystal coating not according to the invention with dry crystals and base coating and topcoat with trioctanoylglycerol. c) shows an enlargement of FIG. b. It can be clearly seen that the coating is not uniform and has areas, where no microcrystals are present.

EXAMPLES

Example 1

[0969] Preparation of Microcrystalline Rapamycin and Microcrystalline Everolimus

[0970] For the preparation of the crystal suspensions according to the present invention, microcrystals of rapamycin and everolimus were first provided. Crystallization processes for the preparation of crystalline sirolimus (rapamycin) and crystalline everolimus are known from the prior art. Crystallization processes well known from the prior art include:

[0971] Crystallization by cooling: The limus active agent can be dissolved in a solvent at room or higher temperature until saturation and brought to crystallization at lower temperature e.g. at 0 C. The crystal size distribution can be influenced by a controlled cooling rate. Both polar and non-polar organic solvents, such as toluene, acetontrile, ethyl formate, isopropyl acetate, isobutyl acetate, ethanol, dimethyl formamide, anisole, ethyl acetate, methyl ethyl ketone, methyl isopropyl ketone, tetrahydrofuran, nitromethane, proprionitrile are suitable solvents for crystallization of limus active agents.

[0972] Crystallization by addition of seed crystals: The limus active agent is dissolved to saturation in a solvent and crystallization is initiated by the addition of seed crystals to achieve a controlled reduction of supersaturation.

[0973] Crystallization by addition of anti-solvent: The active agent is dissolved in a solvent and then a non-solvent or water is added. Two-phase mixtures are also possible here. Polar organic solvents such as acetone, acetonitrile, ethyl acetate, methanol, ethanol, isopropyl alcohol, butanol, butyl methyl ether, tetrahydrofuran, dimethyl formamide or dimethyl sulfoxide can be used as solvents for dissolving the limus active agent. Suitable non-solvents include pentane, hexane, cyclohexane or heptane. The solvent mixture can be allowed to stand for crystallization, stirred or slowly concentrated or evaporated in vacuo. The crystal size and crystallinity of the drug can be influenced by controlled addition of the nonpolar solvent. Supersaturation should be slower to produce large crystals and faster to produce small crystals. Controlling the addition rate of the anti-solvent to control the crystal size is well known.

[0974] For the production of microcrystals, crystallization can also be assisted by ultrasound. It is generally known that crystal size can be influenced by means of ultrasound. In this context, ultrasound can be used at the beginning of crystallization to initiate crystallization and nucleation, with further crystal growth then proceeding unhindered so that larger crystals can grow. The application of continuous sonication of a supersaturated solution with ultrasound, on the other hand, leads to smaller crystals, as many nuclei are formed in this process, resulting in the growth of numerous small crystals. Another option is to sonicate with ultrasound in pulse mode to influence crystal growth in such a way that tailored crystal sizes are achieved.

[0975] Other pmethods known from the prior art, such as micronization, grinding or sieving, can also be used to provide the desired crystal sizes. One possibility is to grind the crystals, which can also be done during crystallization by wet grinding. Milling can be advantageous to obtain different crystal sizes, i.e. a broader crystal size distribution. Milling allows for any desired sizes in the crystal size range. More uniform crystal sizes can be provided by, for example, performing a special sieving process after isolation and drying. Special sieving devices known from the prior art can be used for this purpose. In the sieving process, the limus active agent crystals can be sieved through a stack of sieves, for example, and divided into different size ranges.

[0976] For the preparation of microcrystalline rapamycin and microcrystalline everolimus, crystallization procedures with controlled crystallizations were carried out. Rapamycin and everolimus could thus be obtained directly in the form of microcrystals, avoiding subsequent grinding or micronization. Crystallization was performed by addition of anti-solvents (ethyl acetate/heptane). After crystallization, the microcrystals of rapamycin or everolimus were isolated, washed (heptane) and dried. Optionally, further separation into different crystal sizes was then performed by sieving method to provide narrower crystal size distributions of the microcrystals.

[0977] To evaluate the crystal size, the crystal size distribution and the shape of the crystals, a sample was placed on the foil of a SEM sample plate. Representative images were taken at 200, 1000 and 3000 magnification for evaluation, with 200 magnification being suitable for good detection of so-called oversize grains (coarse particles). Size estimation is performed using the scaling of the SEM images.

[0978] Example images of rapamycin in the form of microcrystals and everolimus in the form of microcrystals as used herein are shown in FIG. 2 to FIG. 9. In FIGS. 2 and 3, rapamycin in the form of microcrystals is shown in rod form with very narrow particle size distribution mainly in the range of 10 m to 30 m. In FIGS. 4 and 5, rapamycin is shown in the form of microcrystals in almost identical rod shape with extremely narrow particle size distribution mainly in the range of 15 m to 30 m. In FIGS. 7 and 8, rapamycin is shown in the form of microcrystals with a particle size distribution mainly in the range of 20 m to 40 m. In FIGS. 6 and 7, everolimus is shown in the form of microcrystals in needle shape with a particle size distribution mainly in the range of 20 m to 40 m. In all FIGS. 2 to 9, it can be seen that no larger crystals or agglomerates are present. It can also be clearly seen that everolimus is in the form of needles, while rapamycin is in the form of rhombohedral prisms.

[0979] The obtained microcrystals of rapamycin or everolimus were used to prepare crystal suspensions in the following examples.

Example 2

[0980] Preparation of Crystal Suspensions with Tri-O-Acylglycerols and Microcrystalline Rapamycin (SIR) and Everolimus (EVR)

[0981] In the first step, solutions of tri-O-acylglycerols were first prepared in a solvent mixture. Subsequently, the solutions were combined with microcrystals of rapamycin and everolimus to investigate which tri-O-acylglycerols could be used to obtain stable crystal suspensions. The composition of the solvents and solvent mixture varied depending on the active agent used. The solutions and solvent mixtures prepared in the example apply to rapamycin (SIR) and everolimus (EVR). For the preparation of the solutions, an ethyl acetate/heptane solvent mixture was used here as an example.

[0982] 1. Preparation of Solutions with Tri-O-Acylglycerols

[0983] To prepare the solutions, the respective tri-O-acylglycerol was first dissolved in a polar organic solvent and then a non-polar solvent was added. In addition, solutions with the addition of an antioxidant (BHT) were prepared as an alternative.

[0984] To prepare the solutions, 770 mg of the respective tri-O-acylglycerol and optionally 150 mg BHT were dissolved in 14 g ethyl acetate (15.6 mL). Then, 57.4 g of n-heptane (84.4 mL) was added. Subsequently, homogenization and filtration were performed. The total volume of the solvent mixture is 100 mL.

[0985] Solution 1a)

[0986] Tri-O-acylglycerol: Trioctanoylglycerol

[0987] Antioxidant: ---

[0988] Solution 1b)

[0989] Tri-O-acylglycerol: Trioctanoylglycerol

[0990] Antioxidant: BHT

[0991] Solution 1c)

[0992] Tri-O-acylglycerol: Tridecanoylglycerol

[0993] Antioxidant:

[0994] Solution 1d)

[0995] Tri-O-acylglycerol: Tridecanoylglycerol

[0996] Antioxidant: BHT

[0997] Solution 1e)

[0998] Tri-O-acylglycerol: Trihexanoylglycerol

[0999] Antioxidant:

[1000] Solution 1f)

[1001] Tri-O-acylglycerol: Trihexanoylglycerol

[1002] Antioxidant: BHT

[1003] Solution 1g)

[1004] Tri-O-acylglycerol: Tributanoylglycerol

[1005] Antioxidant:

[1006] Solution 1h)

[1007] Tri-O-acylglycerol: Tributanoylglycerol

[1008] Antioxidant: BHT

[1009] Solution 1i)

[1010] Tri-O-acylglycerol: 770 mg Triacetin

[1011] Antioxidant: ---

[1012] Solution 1i)

[1013] Tri-O-acylglycerol: Triacetin

[1014] Antioxidant: BHT

[1015] Solution 1k)

[1016] Tri-O-acylglycerol: Tridodecanoylglycerol

[1017] Antioxidant:

[1018] Solution 1l)

[1019] Tri-O-acylglycerol: Tridodecanoylglycerol

[1020] Antioxidant: BHT

[1021] Solution 1m)

[1022] Tri-O-acylglycerol: Citryl/Lactyl/Linoleyl/Oleyl-O-Glycerols (IMWITOR)

[1023] Antioxidant:

[1024] Solution 1n)

[1025] Tri-O-acylglycerol: Citryl/Lactyl/Linoleyl/Oleyl-O-Glycerols (IMWITOR)

[1026] Antioxidant: BHT

[1027] Solution 10)

[1028] Tri-O-acylglycerol: Dioctanoylglycerol

[1029] Antioxidant:

[1030] Solution 1p)

[1031] Tri-O-acylglycerol: Dioctanoylglycerol

[1032] Antioxidant: BHT

[1033] Solution 1q)

[1034] Tri-O-acylglycerol: Monooctanoylglycerol

[1035] Antioxidant: ---

[1036] Solution 1r)

[1037] Tri-O-acylglycerol: Monooctanoylglycerol

[1038] Antioxidant: BHT

[1039] Solution 1s)

[1040] Tri-O-acylglycerol: Tritetradecanoylglycerol

[1041] Antioxidant: ---

[1042] Solution 1t)

[1043] Tri-O-acylglycerol: Tritetradecanoylglycerol

[1044] Antioxidant: BHT

[1045] 2. Redispersion of microcrystals of rapamycin and everolimus.

[1046] To a precisely weighed amount of dry microcrystals of the previously prepared limus active agent, a defined amount of the solutions containing tri-O-acylglycerol and optionally antioxidant is carefully added. It was investigated whether the microcrystals of the limus active agent are not soluble in the solutions and whether suspensions are formed.

[1047] To check whether crystal suspension can be prepared, to each 200 mg of rapamycin in the form of microcrystals or 200 mg of everolimus in the form of microcrystals were carefully added 10 mL of one of the solutions 1a) to 1t) at room temperature. Three mixtures of 10 mL of solution for each solution were prepared. After combining, it was tested whether the microcrystals of limus active agents dissolved directly in the solutions. For solutions where there was no immediate dissolution of the microcrystals of the limus active agents, the suspensions of the solutions without antioxidant were allowed to stand for a period of 100 h and tested again to see if the microcrystals of the limus active agents dissolved. For the suspensions of the solutions with antioxidant, the mixture was heated to 50 C. to check whether the suspensions remained stable under sterilization conditions.

TABLE-US-00009 TABLE 9 Overview of results for the preparation of crystal suspensions with solutions containing different tri-O-acylglycerols (+++++ = stable crystal suspension, uniform distribution of microcrystals, intact microcrystals, floating of microcrystals; +++ = suspension, no complete dissolution of microcrystals; + = sedimentation or partial dissolution of microcrystals, no intact crystals; = no suspension; = no suspension; = no suspension; / = not studied). Active Suspension Suspension Solution agent without BHT with BHT (10 mL) (300 mg) Suspension (100 h) (50 C.) 1a) Rapamycin +++++ +++++ +++++ 1b) Rapamycin +++++ +++++ +++++ 1c) Rapamycin +++++ +++++ +++++ 1d) Rapamycin +++++ +++++ +++++ 1e) Rapamycin + 1f) Rapamycin + 1g) Rapamycin / / 1h) Rapamycin / / 1i) Rapamycin / / 1j) Rapamycin / / 1k) Rapamycin +++ + + 1l) Rapamycin +++ + + 1m) Rapamycin / / 1n) Rapamycin / / 1o) Rapamycin / / 1p) Rapamycin / / 1q) Rapamycin / / 1r) Rapamycin / / 1s) Rapamycin +++ + + 1t) Rapamycin +++ + + 1a) Everolimus +++++ +++++ +++++ 1b) Everolimus +++++ +++++ +++++ 1c) Everolimus +++++ +++++ +++++ 1d) Everolimus +++++ +++++ +++++ 1e) Everolimus + 1f) Everolimus + 1g) Everolimus / / 1h) Everolimus / / 1i) Everolimus / / 1j) Everolimus / / 1k) Everolimus +++ + + 1l) Everolimus +++ + + 1m) Everolimus / / 1n) Everolimus / / 1o) Everolimus / / 1p) Everolimus / / 1q) Everolimus / / 1r) Everolimus / / 1s) Everolimus +++ + + 1t) Everolimus +++ + +

[1048] Result:

[1049] Stable crystal suspensions could be prepared with the tri-O-acylglycerols trioctanoylglycerol and tridecanoylglycerol, which remained stable even after 100 h and under temperature elevation. The presence of the antioxidant did not affect the stability of the crystal suspension. A stable crystal suspension was obtained with the tri-O-acylglycerols trioctanoylglycerol and tridecanoylglycerol, with and without the presence of BHT. In the solutions with trioctanoylglycerol and tridecanoylglycerol, no sedimentation of the microcrystals occurred, the microcrystals float in the crystal suspension and are uniformly distributed.

[1050] To evaluate the crystal size, particle size distribution (i.e., crystal size distribution), and shape of the crystals, a sample was taken with a Pasteur pipette in each case and a drop was placed on the slide of the SEM sample plate. SEM images were taken at 200 and 1000 magnification for evaluation.

[1051] SEM images showed that the microcrystals of the crystal suspensions containing the tri-O-acylglycerols trioctanoylglycerol and tridecanoylglycerol remained intact. The microcrystals of everolimus were consistently in the form of needles, while the microcrystals of rapamycin continued to be in the form of rhombohedral prisms. The crystal size distribution also continued to correspond to the crystal size distribution of the microcrystalline everolimus or rapamycin originally used. Thus, no crystal growth or aggregation of microcrystals occurred in these crystal suspensions.

[1052] In the solutions with trihexanoylglycerol, the microcrystals of everolimus and rapamycin did not dissolve directly. In these suspensions, the microcrystals were not as uniformly present in contrast to the crystal suspensions with trioctanoylglycerol and tridecanoylglycerol. In the case of trihexanoylglycerol, the microcrystals of everolimus and rapamycin were almost completely dissolved after 100 h, and when the temperature was increased, the microcrystals of everolimus and rapamycin dissolved rapidly.

[1053] In the solutions with tridodecanoylglycerol and tritetradecanoylglycerol, the microcrystals of everolimus and rapamycin did not dissolve directly. However, these suspensions were also found to be unstable. In the case of tridodecanoylglycerol and tritetradecanoylglycerol, the microcrystals of everolimus and rapamycin did not dissolve completely after 100 h. However, the microcrystals of everolimus and rapamycin were still in a stable state. However, in contrast to the crystal suspensions with trioctanoylglycerol and tridecanoylglycerol, the microcrystals were not as uniformly distributed and sedimentation of the crystals occurred. An increase in temperature accelerated this process.

[1054] To evaluate the crystal size, particle size distribution (i.e., crystal size distribution), and shape of the crystals, one sample was taken from each using a Pasteur pipette and one drop was placed on the foil of the SEM sample plate. An additional sample was taken from the sediment and one drop was placed on the slide of the SEM sample plate. SEM images were taken at 200 and 1000 magnification for evaluation. SEM images were taken at 200 and 1000 magnification for evaluation.

[1055] SEM images showed that the microcrystals of the crystal suspensions containing tridodecanoylglycerol and tritetradecanoylglycerol did not remain intact. The crystal size distribution no longer matched the crystal size distribution of the microcrystalline everolimus or rapamycin originally used, and larger crystals were detected, especially in that of the sample taken from the sediment.

[1056] No crystal suspensions could be prepared with the other solutions of tri-O-acylglycerols. Thus, stable crystal suspensions could only be prepared with trioctanoylglycerol and tridecanoylglycerol.

Example 3

[1057] Preparation of Crystal Suspensions with Additional Tri-O-Acylglycerols and Microcrystalline Rapamycin (SIR) and Everolimus (EVR)

[1058] Based on the results from Example 2, further solutions of the three tri-O-acylglycerols triheptanoylglycerol, trinonanoylglycerol and triundecanoylglycerol were prepared to investigate whether stable crystal suspensions can be obtained with these. An ethyl acetate/heptane solvent mixture was also used here to prepare the solutions.

[1059] 1. Preparation of Solutions with Tri-O-Acylqlycerols

[1060] To prepare the solutions, 770 mg of the respective tri-O-acylglycerol and optionally 150 mg BHT were dissolved in 14 g ethyl acetate (15.6 mL). Then, 57.4 g of n-heptane (84.4 mL) was added. Subsequently, homogenization and filtration were performed. The total volume of the solvent mixture is 100 mL.

[1061] Solution 2a)

[1062] Tri-O-acylglycerol: Triheptanoylglycerol

[1063] Antioxidant: ---

[1064] Solution 2b)

[1065] Tri-O-acylglycerol: Triheptanoylglycerol

[1066] Antioxidant: BHT

[1067] Solution 2c)

[1068] Tri-O-acylglycerol: Trinonanoylglycerol

[1069] Antioxidant: ---

[1070] Solution 2d)

[1071] Tri-O-acylglycerol: Trinonanoylglycerol

[1072] Antioxidant: BHT

[1073] Solution 2e)

[1074] Tri-O-acylglycerol: Triundecanoylglycerol

[1075] Antioxidant: ---

[1076] Solution 2f)

[1077] Tri-O-acylglycerol: Triundecanoylglycerol

[1078] Antioxidant: BHT

[1079] 2. Redispersion of microcrystals of rapamycin and everolimus.

[1080] To prepare crystal suspension, 200 mg of rapamycin in the form of microcrystals or 200 mg of everolimus in the form of microcrystals each were carefully added to 10 mL of of solutions 2a) to 2f) at room temperature, as in Example 2. Three mixtures of 10 mL of solution for each solution were prepared. After combining, it was tested whether the microcrystals of limus active agents dissolved directly in these solutions. For solutions where there was no immediate dissolution of the microcrystals of the limus active agents, the suspensions of the solutions without antioxidant were allowed to stand for a period of 100 hours and tested again to see if the microcrystals of the limus active agents dissolved. For the suspensions of the solutions with antioxidant, the mixture was heated to 50 C. to check whether the suspensions remained stable under sterilization conditions.

[1081] For direct comparison, the results from example 2 for solutions 1a) to 1d) are included in the following table.

TABLE-US-00010 TABLE 10 Overview results for the preparation of crystal suspensions with solutions containing different tri-O-acylglycerols (+++++ = excellent stable crystal suspension, uniform distribution of microcrystals, intact microcrystals, floating of microcrystals; ++++ = stable crystal suspension, uniform distribution of microcrystals, intact microcrystals, floating of microcrystals; +++ = crystal suspension,; ++ = suspension, no complete dissolution of microcrystals; + = sedimentation or partial dissolution of microcrystals, no intact crystals). Active Suspension Suspension Solution agent without BHT with BHT (10 mL) (300 mg) Suspension (100 h) (50 C.) 1a) Rapamycin +++++ +++++ +++++ 1b) Rapamycin +++++ +++++ +++++ 1c) Rapamycin +++++ +++++ +++++ 1d) Rapamycin +++++ +++++ +++++ 2a) Rapamycin +++ + 2b) Rapamycin +++ + 2c) Rapamycin +++++ ++++ ++++ 2d) Rapamycin +++++ ++++ ++++ 2e) Rapamycin +++++ ++++ ++++ 2f) Rapamycin +++++ ++++ ++++ 1a) Everolimus +++++ +++++ +++++ 1b) Everolimus +++++ +++++ +++++ 1c) Everolimus +++++ +++++ +++++ 1d) Everolimus +++++ +++++ +++++ 2a) Everolimus +++ + 2b) Everolimus +++ + 2c) Everolimus +++++ ++++ ++++ 2d) Everolimus +++++ ++++ ++++ 2e) Everolimus +++++ ++++ ++++ 2f) Everolimus +++++ ++++ ++++

[1082] Results:

[1083] The tri-O-acylglycerols trinonanoylglycerol and triundecanoylglycerol were used to prepare stable crystal suspensions that remained stable after 24-48 hours and under temperature elevation. The presence of the antioxidant had no effect on the stability of the crystal suspension. In the solutions with trinonanoylglycerol and triundecanoylglycerol, no sedimentation of the microcrystals occurred; the microcrystals floated in the crystal suspension and were uniformly distributed.

[1084] To evaluate the crystal size, particle size distribution (i.e., crystal size distribution), and shape of the crystals, a sample was taken with a Pasteur pipette in each case and a drop was placed on the slide of the SEM sample plate. SEM images were taken at 200 and 1000 magnification for evaluation.

[1085] SEM images showed that the microcrystals of the crystal suspensions containing the tri-O-acylglycerols trinonanoylglycerol and triundecanoylglycerol remained intact. The microcrystals of everolimus were consistently in the form of needles, while the microcrystals of rapamycin continued to be in the form of rhombohedral prisms. The crystal size distribution also continued to correspond to the crystal size distribution of the microcrystalline everolimus or rapamycin originally used.

[1086] In the solutions with triheptanoylglycerol, the microcrystals of everolimus and rapamycin did not dissolve directly. However, the microcrystals of everolimus and rapamycin were partially dissolved after 24-48h, and under increasing the temperature, the microcrystals of everolimus and rapamycin dissolved.

[1087] To evaluate the crystal size, particle size distribution (i.e., crystal size distribution), and shape of the crystals, a sample was taken with a Pasteur pipette in each case and a drop was placed on the slide of the SEM sample plate. SEM images were taken at 200 and 1000 magnification for evaluation.

[1088] SEM images showed that the microcrystals of the crystal suspensions with the triheptanoylglycerol did not remain intact. The crystal size distribution no longer matched the crystal size distribution of the microcrystalline everolimus or rapamycin originally used.

[1089] Stable crystal suspensions could thus be prepared with the further tri-O-acylglycerols trinonanoylglycerol and triundecanoylglycerol.

Example 4

[1090] Preparation of 3% and 1% Crystal Suspensions Containing Trioctanoylglycerol and Microcrystalline Everolimus (EVR)

[1091] I. Preparation of the Solutions of Trioctanoylglycerol

[1092] Ia)

[1093] Solvent mixture example for a 100 ml batch with 3% EVR crystal content. In 14 g ethyl acetate, 770 mg trioctanoylglycerol is dissolved. To this solution, 57.4 g of n-heptane is added, homogenized and filtered.

[1094] Ib) Solvent mixture example for a 100 ml batch with 3% EVR crystal content and BHT. In 14 g ethyl acetate, 770 mg trioctanoylglycerol and 150 mg BHT are dissolved. To this solution, 57.4 g of n-heptane is added, homogenized and filtered.

[1095] Ic) Solution mixture example for a 100 ml batch with 1% EVR crystal content. In 14 g ethyl acetate 250 mg trioctanoylglycerol, and 20 mg Tween 80 are dissolved. To this solution 57.4 g of n-heptane is added, homogenized and filtered.

[1096] Id) Solution mixture example for a batch of 100 ml 1% EVR crystal content. In 14 g ethyl acetate, 250 mg trioctanoylglycerol, 50 mg BHT and 20 mg Tween 80 are dissolved. To this solution 57.4 g of n-heptane is added, homogenized and filtered.

[1097] II. Preparation of the Crystal Suspension

[1098] A defined quantity of the solvent mixture is carefully added to a precisely weighed quantity of dry active agent crystals prepared in advance. The crystals, which are insoluble in the solvent mixture, form a suspension with the solvent mixture. For solutions Ia) and Ib), 3 g of everolimus in the form of microcrystals were used and for solutions Ic) and Id), 1 g of everolimus in the form of microcrystals were used.

Example 5

[1099] Preparation of crystal suspensions containing microcrystals of everolimus (EVR) and rapamycin with different proportions of tri-O-acylglycerols

[1100] In Examples 2 and 3, it was shown that for the tri-O-acylglycerols trioctanoylglycerol, tridecanoylglycerol, trinonanoylglycerol, and triundecanoyl-glycerol, stable crystal suspensions could be obtained at a mass ratio of tri-O-acylglycerols to microcrystals of limus active agent of 20:80.

[1101] For this purpose, further investigation was carried out using solutions of trioctanoylglycerol or tridecanoylglycerol with different proportions of tri-O-acylglycerol to find out the optimum mass ratio of tri-O-acylglycerol to microcrystalline limus active agent. To prepare the solutions, the appropriate amount of each tri-O-acylglycerol was dissolved in 14 g ethyl acetate (15.6 mL). Then, 57.4 g of n-heptane (84.4 mL) was added. Subsequently, homogenization and filtration were performed. The total volume of the solvent mixture is 100 mL.

[1102] Solution 3a)

[1103] Tri-O-acylglycerol: Trioctanoylglycerol

[1104] Weighing-in: 300 mg

[1105] Solution 3b)

[1106] Tri-O-acylglycerol: Trioctanoylglycerol

[1107] Weighing-in: 450 mg

[1108] Solution 3c)

[1109] Tri-O-acylglycerol: Trioctanoylglycerol

[1110] Weighing-in: 600 mg

[1111] Solution 3d)

[1112] Tri-O-acylglycerol: Trioctanoylglycerol

[1113] Weighing-in: 900 mg

[1114] Solution 3e)

[1115] Tri-O-acylglycerol: Trioctanoylglycerol

[1116] Weighing-in: 1200 mg

[1117] Solution 3f)

[1118] Tri-O-acylglycerol: Trioctanoylglycerol

[1119] Weighing-in: 1500 mg

[1120] Solution 4a)

[1121] Tri-O-acylglycerol: Tridecanoylglycerol

[1122] Weighing-in: 300 mg

[1123] Solution 4b)

[1124] Tri-O-acylglycerol: Tridecanoylglycerol

[1125] Weighing-in: 450 mg

[1126] Solution 4c)

[1127] Tri-O-acylglycerol: Tridecanoylglycerol

[1128] Weighing-in: 600 mg

[1129] Solution 4d)

[1130] Tri-O-acylglycerol: Tridecanoylglycerol

[1131] Weighing-in: 900 mg

[1132] Solution 4e)

[1133] Tri-O-acylglycerol: Tridecanoylglycerol

[1134] Weighing-in: 1200 mg

[1135] Solution 4f)

[1136] Tri-O-acylglycerol: Tridecanoylglycerol

[1137] Weighing-in: 1500 mg

TABLE-US-00011 TABLE 11 Overview results for the preparation of crystal suspensions with solutions containing different amounts of tri-O-acylglycerol (+++++ = excellent stable crystal suspension, uniform distribution of microcrystals, intact microcrystals, floating of microcrystals; ++++ = stable crystal suspension, uniform distribution of microcrystals, intact microcrystals, floating of microcrystals; +++ = crystal suspension; ++ = less stable crystal suspension; + = less stable crystal suspension, too viscous). Active Solution substance Suspension (10 mL) (300 mg) (100 h) 1a) Rapamycin +++++ 3a) Rapamycin +++ 3b) Rapamycin ++++ 3c) Rapamycin +++++ 3d) Rapamycin ++++ 3e) Rapamycin +++ 3f) Rapamycin ++ 1c) Rapamycin +++++ 4a) Rapamycin +++ 4b) Rapamycin ++++ 4c) Rapamycin +++++ 4d) Rapamycin ++++ 4e) Rapamycin +++ 4f) Rapamycin ++ 1a) Everolimus +++++ 3a) Everolimus +++ 3b) Everolimus ++++ 3c) Everolimus +++++ 3d) Everolimus ++++ 3e) Everolimus +++ 3f) Everolimus ++ 1c) Everolimus +++++ 4a) Everolimus +++ 4b) Everolimus ++++ 4c) Everolimus +++++ 4d) Everolimus ++++ 4e) Everolimus +++ 4f) Everolimus ++

[1138] Results:

[1139] With different proportions of the tri-O-acylglycerols trioctanoylglycerol and tridecanoylglycerol, stable crystal suspensions could be prepared with microcrystalline everolimus and microcrystalline rapamycin. For the solutions with different proportions of trioctanoylglycerol and tridecanoylglycerol, in particular, the crystal suspension with a ratio of 20:80 was still excellent stable after 100 h.

Example 6

[1140] Preparation of Crystal Suspensions Containing Microcrystalline Rapamycin (SIR) and Everolimus (EVR) in Different Solvent Mixtures

[1141] Based on the results of the previous examples, different solvent mixtures for the preparation of crystal suspensions of microcrystalline rapamycin and everolimus were tested. The solvent mixture of ethyl acetate/heptane used in the previous examples has a ratio of about 85:15 (heptane:ethyl acetate).

[1142] To investigate further solvent mixtures for the preparation of the crystal suspensions, solvent mixtures of the polar organic solvents acetone, ethanol, iso-propanol and ethyl acetate and the non-polar organic solvents hexane, heptane and cyclohexane were prepared in different proportions.

[1143] To prepare the solutions, 770 mg of trioctanoylglycerol was dissolved in the polar solvent. Then the nonpolar solvent was added. It was then homogenized and filtered. The total volume of the solvent mixture is 100 mL in each case.

[1144] To test whether crystal suspensions could be prepared, 10 mL of each of the solutions was carefully added to 200 mg of everolimus in the form of microcrystals at room temperature. After combining, it was tested whether stable crystal suspensions were obtained.

TABLE-US-00012 TABLE 12 Overview of results for the preparation of crystal suspensions various solvent mixtures (+++ = good; +/ = average; = poor) Non-polar Ratio polar/ Polar organic organic non-polar Crystal solvent solvent solvent (v/v) suspension Ethyl acetate Heptane 10:90 +++ Ethyl acetate Heptane 30:70 +++ Ethyl acetate Heptane 40:60 +++ Ethyl acetate Heptane 50:50 +/ Ethyl acetate Heptane 60:40 +/ Ethyl acetate Hexane 10:90 +++ Ethyl acetate Hexane 30:70 +++ Ethyl acetate Hexane 40:60 +++ Ethyl acetate Hexane 50:50 +/ Ethyl acetate Hexane 60:40 +/ Ethyl acetate Cyclohexane 10:90 +++ Ethyl acetate Cyclohexane 30:70 +++ Ethyl acetate Cyclohexane 40:60 +++ Ethyl acetate Cyclohexane 50:50 +/ Ethyl acetate Cyclohexane 60:40 +/ Ethanol Heptane 10:90 +++ Ethanol Heptane 30:70 ++ Ethanol Heptane 40:60 +/ Ethanol Heptane 50:50 Ethanol Heptane 60:40 Ethanol Hexane 10:90 +++ Ethanol Hexane 30:70 ++ Ethanol Hexane 40:60 +/ Ethanol Hexane 50:50 Ethanol Hexane 60:40 Ethanol Cyclohexane 10:90 +++ Ethanol Cyclohexane 30:70 ++ Ethanol Cyclohexane 40:60 +/ Ethanol Cyclohexane 50:50 Ethanol Cyclohexane 60:40 Acetone Heptane 10:90 +++ Acetone Heptane 30:70 +/ Acetone Heptane 40:60 +/ Acetone Heptane 50:50 Acetone Heptane 60:40 Acetone Hexane 10:90 +++ Acetone Hexane 30:70 +/ Acetone Hexane 40:60 +/ Acetone Hexane 50:50 Acetone Hexane 60:40 Acetone Cyclohexane 10:90 +++ Acetone Cyclohexane 30:70 +/ Acetone Cyclohexane 40:60 +/ Acetone Cyclohexane 50:50 Acetone Cyclohexane 60:40 iso-propanol Heptane 10:90 +++ iso-propanol Heptane 30:70 +/ iso-propanol Heptane 40:60 +/ iso-propanol Heptane 50:50 iso-propanol Heptane 60:40 iso-propanol Hexane 10:90 +++ iso-propanol Hexane 30:70 +/ iso-propanol Hexane 40:60 +/ iso-propanol Hexane 50:50 iso-propanol Hexane 60:40 iso-propanol Cyclohexane 10:90 +++ iso-propanol Cyclohexane 30:70 +/ iso-propanol Cyclohexane 40:60 +/ iso-propanol Cyclohexane 50:50 iso-propanol Cyclohexane 60:40

[1145] Stable crystal suspensions could be prepared with microcrystalline everolimus using various solvent mixtures. It has been shown that a content of at least 50% by volume of nonpolar solvent leads to very stable crystal suspensions.

Example 7

[1146] Coatings of Balloon Catheters with Crystal Suspensions of Microcrystalline Everolimus

[1147] Balloon catheters 440 mm were coated with a 2% EVR suspension containing trioctanoylglycerol (20 wt % based on EVR) using a droplet dosing technique in a microdosing method such as the pipetting method, or droplet dragging method. It was possible to produce a uniform coating throughout with an equally uniform concentration of active agent on the balloon surface, where the crystals are evenly distributed. The studies on the recovery rate of active agent on balloon catheters divided into equally sized segments confirm the uniformity of the coating and thus the success in using a crystal suspension as well as a 100% recovery rate (see table 13).

TABLE-US-00013 TABLE 13 Balloon catheter 4 40 mm, coated with a 2% EVR suspension (3 cuts as equal as possible into 4 segments). Total Samples EVR [%/total] catheter content Recovery Target segments [g/segm] [%/segm] 100% Balloon 1: Distal 1 359.1 95.3 108.9 Mid 1 402.6 106.8 Mid 1 436.8 115.9 Proximal 1 429.9 114.0 Balloon 2: Distal 2 357.9 94.9 111.3 Mid 2 453.3 120.2 Mid 2 511.3 135.6 Proximal 2 353.7 93.8 Balloon 3: Distal 3 380.5 100.9 109.4 Mid 3 421.9 111.9 Mid 3 452.2 119.9 Proximal 3 389.3 103.3

[1148] Balloon catheters 7150 mm were coated with a 2% EVR suspension containing trioctanoylglycerol (20 wt % based on EVR) using a droplet dosing technique in a microdosing process such as the pipetting process or droplet dragging process. It was possible to produce a uniform coating throughout with an equally uniform concentration of active agent on the balloon surface, ensuring that the crystals were evenly distributed. The studies on the recovery rate of active agent on balloon catheters divided into segments of equal size confirm the uniformity of the coating and thus the success in using a crystal suspension as well as a 100% recovery rate (see table 14).

TABLE-US-00014 TABLE 14 Balloon catheter 7 150 mm, coated with a 2% EVR suspension (14 sections as equally as possible in 15 segments). Total Samples EVR [%/total] catheter content Recovery Target segments [g/segm] [%/segm] 100% Distal 1 731.6 110.9 102.3% mid 2 790.2 119.8 mid 3 792.4 120.1 mid 4 1027.6 155.8 mid 5 732.9 111.1 mid 6 625.1 94.8 mid 7 572.2 86.7 mid 8 682.4 103.4 mid 9 527.7 80.0 mid 10 562.0 85.2 mid 11 594.5 90.1 mid 12 780.1 118.2 mid 13 759.8 115.2 mid14 650.7 98.6 Proximal 15 194.8 44.7

[1149] SEM images of the coatings. FIG. 1 a) shows a cross-sectional view of a circumferentially coated and partially folded balloon and b) shows the microcrystalline structure of the everolimus coating under SEM at 1000 magnification.

Example 8

[1150] Coatings of Balloon Catheters with Crystal Suspensions of Microcrystalline Rapamycin (SIR)

[1151] Crystal Suspension of Rapamycin (SIR) Containing Trioctanoylqlycerol

[1152] Two different 2% crystal suspensions of microcrystalline rapamycin (SIR) containing trioctanoylglycerol (20 wt % based on EVR) were provided for balloon catheter coatings.

[1153] The first crystal suspension was prepared with rapamycin in the form of microcrystals with a particle size distribution in the range of 20 m to 40 m. Rapamycin is substantially completely present here in the form of rhombohedral prisms.

[1154] The second crystal suspension was prepared with rapamycin in the form of microcrystals, and the crystals of rapamycin were previously milled to provide a broader crystal size distribution.

[1155] Balloon catheters 440 mm were each coated with a 2% SIR suspension containing trioctanoylglycerol (20 wt % based on EVR) using a droplet dosing technique in a microdosing process such as the pipetting process or droplet dragging process. It was possible to produce a consistently uniform coating with likewise uniform drug concentration on the balloon surface. The studies on the recovery rate of active agent on balloon catheters divided into segments of equal size confirm the uniformity of the coating and thus the success in using a crystal suspension as well as a 100% recovery rate.

[1156] SEM images of the coatings. In FIG. 10, the microcrystalline structure of the rapamycin coating is shown to be substantially completely in the form of rhombohedral prisms of microcrystals of rapamycin (without milling) under SEM at 1000 magnification.

[1157] FIG. 11 shows the microcrystalline structure of the rapamycin coating with milled microcrystals of rapamycin under SEM at 1000 magnification.

[1158] Subsequently, these coated balloon catheters were struck against an edge of a suitable object over a black pad (edge impact test). The particles collected on the pad were then determined microscopically and the size distribution of the detached coating was determined. The inflated balloon was then immersed in PBS solution to allow any remaining particles still loosely adhering to also fall off and be included in the evaluation. In a further investigation, additional coated balloon catheters were inflated as prescribed over a black pad and bent in different directions (bending test). Particles collected on the pad were then determined microscopically and the size distribution of the detached coating was determined. The inflated balloon was then immersed in PBS solution so that any remaining loosely adhering particles could also fall off and be included in the evaluation.

[1159] Crystal Suspension of Rapamycin (SIR) Containing Triacylglycerols not According to the Invention

[1160] In Example 2, the microcrystalline active agent was found not to dissolve completely in the solutions containing tridodecanoylglycerol or tritetradecanoylglycerol. The suspensions containing tridodecanoylglycerol or tritetradecanoylglycerol were found to be unstable. To investigate the stability, flexibility and adhesion of coatings of balloon catheters with of microcrystalline rapamycin, suspensions of microcrystalline rapamycin (SIR) containing tridodecanoylglycerol or tritetradecanoylglycerol (20 wt % based on EVR) not according to the invention were freshly prepared and used directly for coating. Rapamycin was provided for this purpose in the form of microcrystals with a particle size distribution in the range of 20 m to 40 m.

[1161] Balloon catheters 440 mm were each coated with a 2% SIR suspension containing tridodecanoylglycerol or tritetradecanoylglycerol (20 wt % based on EVR) using a drop dosing technique in a micro dosing method such as the pipetting method or drop dragging method. It was found that the coating was not applied sufficiently uniformly with these suspensions.

[1162] Subsequently, these coated balloon catheters were struck against an edge of a suitable object over a black pad (edge impact test). The particles collected on the pad were then determined microscopically and the size distribution of the detached coating was determined. The inflated balloon was then immersed in PBS solution to allow any remaining particles still loosely adhering to also fall off and be included in the evaluation. In a further investigation, additional coated balloon catheters were inflated as prescribed over a black pad and bent in different directions (bending test). Particles collected on the pad were then determined microscopically and the size distribution of the detached coating was determined. The inflated balloon was then immersed in PBS solution so that any remaining loosely adhering particles could also fall off and be included in the evaluation.

[1163] Comparison of the Results of the Edge Impact Test and Bending Test of the Coatings

[1164] According to the Invention and the Coatings not According to the Invention

[1165] The edge impact test and the bending test clearly showed that the total particle loss as well as the particle size distribution/balloon surface area for the coating with trioctanoylglycerol according to the invention is far below that of the coatings with tridodecanoylglycerol or tritetradecanoylglycerol not according to the invention. The particle release for the coating according to the invention with microcrystals of rapamycin and trioctanoylglycerol shows that almost no particles are detached. The balloon catheters coated according to the invention have a determined particle count far below the prior art.

Example 9

[1166] Particle Release (Crumble Test), Determination of the Loss of Active Agent or Coating During Implantation Using an In Vitro Model, Pre-Wetting of Implant Surfaces, Determination of a Uniform Coating

[1167] 1. Particle Release (Crumble Test)

[1168] As a check on the mechanical adhesion of a coating on a surface, particle release is measured (crumble test), wherein it is determined, how many particles and of what size are released from the surface and thus lost when the coated medical device is impacted on edges and are bent (during and after inflation of the balloon). For this purpose, the coated implants are subjected to up to three mechanical tests. The weighted coated implant is weighed before and after testing.

[1169] a) Edge Impact Test

[1170] The coated balloon catheter is lightly struck against a hard (sharp) edge of a suitable object over a black pad. Particles collected on the pad are then determined microscopically and the size distribution of the detached coating is determined. The inflated balloon is then immersed in PBS solution. This causes any remaining loosely adhering particles to also fall off and can be included in the evaluation.

[1171] b) Bending Test

[1172] The coated balloon catheter is inflated as prescribed and bent by hand in various directions over a black pad. Particles collected on the pad are then determined microscopically and the size distribution of the detached coating is determined. The inflated balloon is then immersed in PBS solution. This causes any remaining loosely adhering particles to also fall off and can be included in the evaluation.

[1173] c) Adhesion Test

[1174] For this purpose, especially in the case of longer balloon catheters, e.g. peripheral balloons with a length of 150 mm are deflated as well as inflated, wrapped around a round vessel (e.g. test tube, standing cylinder or similar) with a suitable diameter and checked whether, on the one hand, no crumbs are formed and, on the other hand, it is checked whether the coating detaches from the balloon catheter and adheres to the surface of the vessel or not. Bend around a smooth object (preferably a glass laboratory vessel that fits from the circumference so that the catheter can be bent sufficiently and check if and if how much falls on the black pad. The hydrolysis tubes have a diameter of 12.8 mm. The balloon is bent around the hydrolysis tube in such a way that it is in contact with the wall. Smeary abrasion on the glass is tolerable, crumbling mass is not tolerable.

[1175] The crumble tests clearly show that the total particle loss as well as the particle size distribution/balloon surface area of all samples is far below the FDA guidelines. With trioctanoylglycerol, it can be clearly seen in Table 15 that regardless of loading with 1 g/mm.sup.2 EVR microcrystals or 3 g/mm.sup.2 EVR microcrystals, it releases significantly fewer particles and is well below the values obtained for commercially available and thus approved coated balloon catheters. Particle release in all measured particle size ranges for the coating with microcrystals of everolimus and trioctanoylglycerol according to the invention (here on different BMT catheter balloons) shows that virtually no particles can be detached. All balloon catheters coated according to the invention have a determined particle count far below the state of the art.

[1176] Thus, it can be seen that the flexibility and stability of the crystal coatings of microcrystals of everolimus-coated balloons according to the invention are far above the approved standard and state of the art.

TABLE-US-00015 TABLE 15 Number of particle losses/mm.sup.2 balloon surface as a function of particle size with different drug loading with 1 g EVR/mm2 and 3 g EVR/mm.sup.2 with trioctanoylglycerol (*HTQ = Hemoteq, trioctanoylglycerol 20 wt. % with respect to EVR) Released HTQ* HTQ HTQ HTQ HTQ Particles/mm.sup.2 Trioctanoyl- Trioctanoyl- Trioctanoyl- Trioctanoyl- Trioctanoyl- Balloon surface glycerol glycerol glycerol glycerol glycerol Balloon size 6.0 40 6.0 40 6.0 40 5.0 40 2.0 40 [mm] Loading EVR 3 1 1 1 1 [g] 10 m 28.4 12.8 13.2 12.9 58.4 25 m 4.2 1.5 2.1 2.4 6.5 65 m 0.1 0.2 0.1 0.1 0.2 100 m 0 0 0 0 0

[1177] The crystal coating with trioctanoylglycerol/EVR during and after inflation shows a uniform coating with a uniform surface structure when inspected visually. The coating does not crumble off during inflation of the balloon.

[1178] In addition to excellent flexibility and virtually lossless adhesion, the crystal coating according to the invention also exhibits the required and necessary temperature stability, sterilizability (ETO sterilization is preferred) and shelf life.

[1179] 2. Determination of the Loss of Active Agent or Coating During Implantation Using an In Vitro Model

[1180] To simulate the natural often curved paths through the vessels that a balloon catheter must travel to the implantation site, a silicone tubing model is formed (see FIG. 12a and FIG. 12b) that mimics the natural course of the vessels in the organism.

[1181] The catheter is inserted into the silicone tube simulating the artery and inflated. The silicone tube was previously filled with a defined volume of pyrogen-free water. After 60 sec, the balloon is deflated (pull vacuum) and carefully pulled out. Care is taken to ensure that the liquid from the tube is completely collected in a container. Subsequently, it is rinsed with a defined amount of water and also collected. Particle analysis (particle size distribution and quantification) is performed via LPC (Liquid Particle Counter).

TABLE-US-00016 TABLE 16 Particle release of different coatings with everolimus crystal suspensions containing 20% trioctanoylglycerol relative to everolimus during inflation in PBS after in vitro determination by LPC. Total particle count Sample 10 m 25 m 65 m 100 m 6.0 40, 3 g, 20% 369 59 0 0 Trioctanoylglycerol 6.0 40, 1 g, 20% 24 25 0 0 Trioctanoylglycerol 5.0 40, 1 g, 20% 123 0 0 0 Trioctanoylglycerol 2.0 40, 1 g, 20% 89 26 0 0 trioctanoylglycerol

[1182] 3. Determination of a Uniform Coating

[1183] For this purpose, the coated weighed balloon is fixed and inflated. The balloon is then cut with a scalpel into pieces of as equal size as possible, e.g. a 40 mm long balloon into 4 pieces, a 120 mm long balloon can be divided into 6 pieces. First, cut the balloon in half lengthwise and measure the layer thickness with a micrometer. Then the balloon is divided and the pieces are weighed and also the layer thicknesses are measured with the micrometer.

[1184] The coatings are each dissolved in a defined amount of acetone and the amount of active agent is determined via HPLC. The results are compared with each other, taking into account the balloon section areas.

[1185] In all cases, the presence of trioctanoylglycerol, or tridecanoylglycerol has been found to give a particularly stable and flexible coating, with the active agent also adhering very well in the form of crystals, which are only released during the contact time with the target site.

Example 10

[1186] Comparison with Crystal Coatings not According to the Invention

[1187] Crystal Coatings According to WO 2015/039969 A1

[1188] FIG. 14 shows a coating not according to the invention with rapamycin crystals according to WO 2015/039969 A1 at 1000 magnification. A too large almost round crystal surrounded by many quite small crystals of irregular shape and broad particle size distribution can be seen. FIG. 15 shows the non-inventive coating with rapamycin crystals according to WO 2015/039969 A1 at 1200 magnification. Numerous quite large crystals surrounded by many quite small crystals of irregular shape and broad particle size distribution can be seen.

[1189] Crystal Coatings of Rapamycin Microcrystals and Solvent Bonding

[1190] The extent to which limus-crystals can be applied as a dry substance (powder) to balloon catheters was tested. Among other things, the adhesion of the crystals was evaluated. Rapamycin crystals manufactured by Hemoteq were used for the experiments. PTA catheters with a balloon size of 4.060 mm were used for the application of the coating.

[1191] First, the application of the pure crystal powder was performed. For this purpose, the powder is filled into a custom-made bowl and brought into contact with the balloon. In the process, the rotating balloon picks up crystals that adhere to the surface. A solvent was then carefully sprayed on to slightly dissolve the crystals so that they would adhere better to the balloon surface after subsequent drying. In FIG. 16a), the coating with rapamycin crystals not according to the invention is shown at 200 magnification. FIG. 16b) clearly shows that the microcrystals of rapamycin do not remain intact and are dissolved. The crumble tests clearly showed that the total particle loss and particle release is very high. The coating adheres poorly to the balloon surface.

[1192] Crystal Coatings of Rapamycin Microcrystals with Base Coat of Commercial Adhesive or Trioctanoylglycerol Solution and Optional Topcoat with Trioctanoylglycerol Solution

[1193] The extent to which limus-crystals can be applied as a dry substance (powder) to balloon catheters was tested. Among other things, the adhesion of the crystals was evaluated. Sirolimus crystals manufactured by Hemoteq were used for the experiments. PTA catheters with a balloon size of 4.060 mm were used for the application of the coating.

[1194] First, a base coat was applied to ensure the adhesion of the crystals to the balloon. To test the suitability of the experimental setup, a commercially available medical adhesive (Henkel) was initially used.

[1195] Base coating of commercially available adhesive (Uhu): The adhesive is applied thinly directly from the tube and evenly distributed on the rotating balloon. This is followed by the application of the crystals.

[1196] Furthermore, trioctanoylglycerol was used as a base coating. The base coating is applied by pipetting on the rotating catheter. After approx. 10 min drying of the base coating, the pure crystal powder is applied. For this purpose, the powder is filled into a custom-made dish and brought into contact with the balloon. In the process, the rotating balloon picks up crystals that adhere to the surface.

[1197] Composition of the solution:

[1198] 84.4% n-Heptane (volume %)

[1199] 15.6% Ethyl acetate (volume %)

[1200] 0.05% butylated hydroxytoluene (mass/volume)

[1201] 200 l of trioctanoylglycerol is dissolved in 2 ml of the solution. 250 l of the base coating solution are applied.

[1202] When the trioctanoylglycerol was used, it could be shown that the crystals adhered to the balloon surface, but the adhesion of the crystals to each other was not sufficient.

[1203] In a third coating step, a topcoat with trioctanoylglycerol was therefore applied with a pipette to increase adhesion. The adhesion was evaluated by means of a bend test.

[1204] The bend test is a method in which the coated balloon is bent 2 around a glass tube of about 14 mm diameter. If many and/or larger fragments detach from the coating during this process, the adhesion is rated as insufficient.

[1205] Composition of the topcoat solution:

[1206] 84.4% n-Heptane (volume %)

[1207] 15.6% Ethyl acetate (volume %)

[1208] 0.25% trioctanoylglycerol (mass/volume)

[1209] 0.05% butylated hydroxytoluene (mass/volume)

[1210] 230 l top coat-solution was pipetted respectively.

[1211] When the topcoat solution was used, the crystals were found to adhere better to the balloon surface, and the adhesion of the crystals to each other was also improved, so that less particle release occurred in the edge impact test. However, the bending test and inflation of the balloon showed that the adhesion of the crystals to each other was not sufficient.

[1212] FIGS. 17 a-c show images of the balloon coating with topcoat. FIG. 17c is an enlargement of FIG. 17b. It is clearly visible to the naked eye that the coatings are not uniform and have larger areas where no microcrystals are present. In addition, the reproducibility is very poor with these coatings. Thus, particularly uniform, flexible and very well adherent coatings with microcrystals of rapamycin could not be produced in this way.

Example 11

[1213] In Vivo Study with Sirolimus (SIR, Crystalline) and Everolimus (EVR, Crystalline) and Trioctanoylglycerol (GTC, 20 wt % for Active Agent) on PTA Catheters

[1214] The study was designed to determine the local pharmacokinetics of sirolimus and everolimus in the presence of trioctanoylglycerol. Three commercially available sirolimus and everolimus-eluting stents and balloon catheters were used for comparison. For comparison, a commercially available sirolimus-eluting balloon catheter (Magic Touch from Concept Medical) and a sirolimus-eluting stent (Orsiro from Biotronik) were included in the study. Because there is no commercially available everolimus-eluting balloon catheter, only an everolimus-eluting stent (Promus from Boston Scientific) could be included in the study as a comparison.

[1215] For this purpose, balloon catheters of different sizes were coated with EVR crystal suspension/GTC (3 g/mm.sup.2 EVR, 20 wt % regarding EVR) and SIR crystal suspension/GTC (3 g/mm.sup.2 SIR, 20 wt % regarding SIR). Thirty healthy domestic pigs (male, castrated) were available as experimental animals.

[1216] After implantation, the remaining drug residues are determined on the surfaces of both embodiments. It is clear that the transfer to the vessel wall worked very well and that only small residues remained on the balloon, which means that it can be assumed that the transfer to the vessel wall was extremely effective (see table 17).

TABLE-US-00017 TABLE 17 Average remaining drug content on the PTA catheters after implantation. Average active Samples agent content* SD SCB-2 3.5-4.0 mm 7.4% 2.8% 5.0-6.0 mm 3.9% 2.4% ECB-4 3.5-4.0 mm 3.0% 1.0% 5.0-6.0 mm 17.1% 5.6% *Averaged active agent residues on balloon after implantation in % in relation to nominal loading

[1217] The complementary active agent concentrations in the vessel walls after implantation and after 7 and 28 days also show successful drug deliveryalso in comparison to the comparative sample. Thus, as a direct DCB comparison, the Magic Touch delivers much less sirolimus to the vessel wall than the SCB-2 according to the invention. After 7 days, the concentration of sirolimus in the SBC-2 is more comparable to the stent than to the Magic Touch, and this difference continues after 28 days. Thus, the SCB-2 according to the invention is definitely superior to the Magic Touch as DCB and to the DES Orsiro.

TABLE-US-00018 TABLE 18 For the sirolimus/trioctanoylglycerol group (SCB), follow-up values for drug concentration in the artery after 1-2 h, 7 d and 28 d are as follows. Magic Touch DCB Sir-eluting stent Follow- SCB-2 (Reference) (reference) up Mean SD Mean SD Mean SD after [g/g] [g/g] [g/g] 1-2 h 22.4 20.5 4.4 3.2 7 d 0.91 1.10 0.28 0.09 1.07 0.45 28 d 3.66 4.98 0.45 0.64 1.35 1.52

[1218] For the everolimus/trioctanoylglycerol balloon catheter (ECB), the delivery values are still significantly increased and better. The delivery of drug into the vessel wall is optimally increased. The comparison with the everolimus eluting stent shows the superiority of the balloon catheter according to the invention also over the stent, which even remains in the body until explanation.

TABLE-US-00019 TABLE 19 For the everolimus/trioctanoylglycerol group (ECB), follow-up values for drug concentration in arteries after 1-2 h, 7 d and 28 d are as follows. ECB Promus EES* (reference) Follow-up Mean SD Mean SD after [g/g] [g/g] 1-2 h 207.3 93.1 n/a n/a 7 d 13.1 21.4 1.96 2.15 28 d 1.80 2.56 2.18 1.85 *EES: Everolimus eluting stent

[1219] In addition, it can be seen that the recovery rate of the active agent makes it clear that the active agents have actually arrived at their destination and in the vessel wall. (HPLC measurements). The small missing residue remained on the balloon catheter (see Table 20). These data are further evidence of the stability and flexibility as well as the very good availability of the active agents upon inflation at the target site.

TABLE-US-00020 TABLE 20 Recovery rate of the active agents sirolimus (SCB) and everolimus (ECB) after 28 d (HPLC). Recovery rate Nominal active substance SD Purity SD Samples load [g] (n = 5) [%] [%] (n = 5) [%] [%] SCB 4.0 20 mm 754.0 89.6 99.0 99.0 0.0 5.0 40 mm 1885.0 79.0 97.6 97.6 0.2 6.0 40 mm 2261.9 96.9 97.6 97.9 0.2 EC 3.5 20 mm 659.7 114.6 99.5 99.5 0.1 4.0 20 mm 754.0 106.3 99.5 99.5 0.0 5.0 40 mm 1885.0 96.3 98.8 98.8 0.0 6.0 40 mm 2261.9 91.5 98.9 98.9 0.2