WO2019009827A1

WO2019009827A1 - Porous ceramic material for drug delivery and release applications and drug delivery and release system comprising such porous ceramic material

Info

Publication number: WO2019009827A1
Application number: PCT/TR2017/050308
Authority: WO
Inventors: Çekdar VAKIFAHMETOĞLU
Original assignee: Vakifahmetoglu Cekdar
Priority date: 2017-07-06
Filing date: 2017-07-06
Publication date: 2019-01-10
Also published as: EP3648746A1; EP3648746A4

Abstract

The present invention relates to a porous ceramic material for drug delivery, which is a multimodal porous ceramic material selected among silica based materials, carbon based materials or polymer derived ceramics materials and capable of carrying multiple bioactive agents. The present invention further relates to a controlled release drug delivery system comprising a carrier made of the above mentioned porous ceramic material and one or more bioactive agents carried by it.

Description

POROUS CERAMIC MATERIAL FOR DRUG DELIVERY AND RELEASE APPLICATIONS AND DRUG DELIVERY AND RELEASE SYSTEM COMPRISING SUCH POROUS CERAMIC MATERIAL The present invention relates to a porous silica, carbon based ceramic material and/or to polymer derived ceramics (PDCs) to be used for drug delivery and release applications and, in particular, for controlled drug release applications. The present invention further relates to a drug delivery and release system comprising such porous ceramic material. Drug delivery systems are engineered systems for the targeted delivery and/or controlled release of bioactive agents, i.e. of molecules useful for instance as dietary supplements, therapeutic drugs, nutraceuticals or pharmaceuticals. The most common drug delivery systems comprise carriers, for instance in the form of nanoparticles, microspheres or beads, loaded with bioactive agents for enabling their introduction in the body. The carriers are in particular designed to control the rate, the time and/or the place of release of the bioactive agents in the body so as to improve their efficacy and safety.

In the state of the art numerous materials have been developed to be used as carriers for drug delivery applications and in particular for controlled drug delivery applications, which allow the drug carried by the materials to be released in a predetermined pattern over a fixed period of time.

Ceramic materials are extensively used for this purpose due to their high biocompatibility which allows them to perform a medical therapeutic function without undesirable local or systemic effects in the patient. Such ceramic materials are typically used in a porous form in order to allow the bioactive agent molecules to be adsorbed on their surfaces, i.e in particular on the surface of their pores.

An example of a porous ceramic material widely used for drug delivery applications is a mesoporous silica (MS) known in the market as SBA-15 or another one MCM-41, which has a structure in which mesopores, i.e. pores between 2 nm and 50 nm, uniform in size are arranged regularly, and in particular in an hexagonal configuration. MS particles are generally synthesized in a way to show monomodal porosity. MS nanoparticles are extensively exploited for controlled drug release systems due to their biocompatibility and high adsorption properties.

The adsorption and the release rate of the selected bioactive agent into and from the MS materials are dependent on the specific pore characteristics, such as volume, diameter, surface area, etc., and on the surface functionality, i.e. active sites.

A disadvantage of the MS material resides on the fact that its porosity needs to be tailored for the specific bioactive agent to be carried by it, in order to ensure an adequate delivery rate. Moreover the synthesis process of MS nanoparticles having monomodal controlled porosity, such as SBA-15 or MCM-41 nunoparticles, is not easy to be performed.

In a recent review it has also been underlined that a further disadvantage of MS material used as a carrier for drug delivery systems can be high level of hemolysis, attributed to the surface density of silanol groups interacting with the surface of the phospholipids of the red blood cell membranes. In the same review it has moreover been hypothesized that MS nanoparticles used in target drug delivery system can cause metabolic changes resulting in melanoma promotion.

An objective of the present invention is to provide a porous ceramic material for drug delivery applications and a drug delivery system which are versatile and show an optimal biocompatibility, while ensuring an adequate loading capacity and release rate of the bioactive agents, aiming to overcome the aforementioned drawbacks of the prior art.

This objective has been achieved by the porous ceramic material for drug delivery applications as defined in claim 1 and by the drug delivery system comprising such porous ceramic material as defined in claim 12. Further achievements have been attained by the subject-matters respectively defined in the dependent claims.

Additional advantages of the porous ceramic material for drug delivery applications and of the drug delivery system comprising such porous ceramic material of the present invention will become more apparent with the detailed description of the embodiments with reference to the accompanying drawings in which: Figure 1(a) shows N₂ adsorption-desorption isotherms recorded on the samples according to the invention before (HIPO) and after HF etching (HIPO-HF).

Figure 1(b) shows the total porosity volume vs pore size curves calculated from the desorption branch of the isotherms.

Figure 2 shows the hemolysis of Human RBCs by samples of material according to the invention after HF etching (HIPO-HF) and by comparative samples of mesoporous silica MCM-41.

Figure 3 shows the amount of protein cargo loading (Vancomycin or BSA) to each samples of material according to the invention (HIPO and HIPO-HF) and to the comparative samples of MCM-41, given as pmole. Figures 4(a) and 4(b) show release curves of (a) BSA, and (b) vancomycin loaded nanoparticles of materials according to the invention (HIPO and HIPO-HF) and of MCM-41 in PBS buffer.

Figures 5(a) and 5(b) show the release profiles of (a) MCM-41, and (b) HIPO-HF when loaded with both BSA and fluorescein molecules simultaneously.

The porous ceramic material for drug delivery according to the present invention is a multimodal porous ceramic material, i.e. a ceramic material having a pore hierarchy, selected among silica based materials, carbon based materials or polymer derived ceramic materials and capable of carrying multiple bioactive agents, i.e. molecules having a biological effect which are useful for instance as dietary supplements, therapeutic drugs, nutraceuticals or pharmaceuticals.

It has been found that, thanks to the presence of pore scales in different size range, the porous ceramic material according to the present invention can carry different bioactive agents. In particular, the multimodal porous ceramic material is capable of carrying multiple bioactive agents of different molecular sizes.

The expression "capable of carrying multiple bioactive agents" it is here used to indicate that the same porous ceramic material can be used in different application to carry different bioactive agents or it can be used to carry different bioactive agents simultaneously.

The porous ceramic material according to the invention is therefore versatile, being able to carry bioactive agents in different ranges of molecular size, without the need to be specifically customized for each range of molecular size.

Moreover silica based materials, carbon based materials or polymer derived ceramic materials have demonstrated an optimal biocompatibility, without inducing undesirable local or systemic effects in the patient upon administering.

According to an embodiment, the porous ceramic material according to the invention comprises interconnected pores having sizes in at least two distinctly different ranges selected between microporosity range, wherein the size of the pores is smaller than 2 nm, mesoporosity range, wherein the size of the pores is between 2 and 50 nm, and macroporosity range, wherein the size of the pores is bigger than 50 nm.

This allows bioactive agents having different molecular sizes to be adsorbed on the surface of the ceramic material, being accommodated in pores of correspondent size range depending on their specific molecular size. The interconnection between pores allows the bioactive agents to penetrate into the ceramic material reaching their final adsorption site.

Moreover the different size ranges of the pores affect the release profile of the bioactive agents.

In a version of this embodiment, the porous ceramic material according to the invention has a gradient porosity within at least one of the ranges of porosity. This allows to better accommodate bioactive agents of different molecular sizes.

According to an embodiment, the porous ceramic material is silicon oxycarbide and, according to another embodiment, it is carbon. Porous silicon oxycarbide and porous carbon according to the invention have demonstrated a low hemolytic activity, in particular lower than the hemolytic activity of mesoporous silica "MCM-41", being particularly suitable for biomedical applications requiring a direct contact with blood. In particular it has been verified upon investigation that in the silicon oxycarbide materials a fewer number of accessible Si-OH groups was present compared to MS particles, i.e. the surface density of silanol groups was lower in the silicon oxycarbide materials according to the invention than in the mesoporous silica particles "MCM-41" used as a comparison.

In particular, in an embodiment, the porous silicon oxycarbide is a polymer derived ceramic material obtained starting from at least one preceramic polymer such as polysiloxane, polycarbosilane, etc. The use of preceramic polymers simplifies the production process used to obtain the porous ceramic silicon oxycarbide according to the invention and allows a better control on the morphology of the final ceramic material. In particular, the typical low pyrolysis temperatures employed in the production process can minimize the damage of the nano- structures of the final material preserving the desired porosity profile.

In an embodiment, the porous ceramic material according to the invention is obtained by a process comprising at least an etching phase. The etching phase allows modifying the chemical, physical and morphological properties of the surface of the ceramic material. In particular by means of the etching phase pores on a further range of porosity can be introduced in the material. This allows for instance to generate microporosity in a material which initially does not comprise microporosity by means of such etching phase, as shown in the following examples.

In a version of this embodiment wherein the porous ceramic material is silicon oxycarbide, the latter is obtained by a process comprising an etching phase with hydrofluoric acid. In particular, in a version of this embodiment, the porous ceramic material is polymer derived silicon oxycarbide etched by hydrofluoric acid.

It has been in fact verified that by etching the porous silicon oxycarbide with hydrofluoric acid, silica phase (SiO_x) is removed from the material, leaving a carbon enriched zones on the pores. This enhances the hemocompatibility of the material, reducing the surface density of silanol groups. In particular the etched silicon oxycarbide material according to the present invention shows much less hemolytic activity compared to mesoporous silica particles "MCM-41" used as a comparison. It has been herein moreover demonstrated that the etching phase with hydrofluoric acid creates additional micro-mesoporosity via removal of silica phase, and so new surfaces richer in carbon are being created. Such etching phase allows tailoring surface area, surface energy and nano-rugosity of the final porous material and it eventually enhances the interaction between the bio-active agent molecules (i.e. for instance the drug molecules to be carried by the material) and the hosting surface.

In a different version of this embodiment wherein the porous ceramic material is carbon, the latter is obtained starting from silicon oxycarbide or silicon oxy-carbonitrides or by other polymer derived ceramic by a process comprising at least an etching phase with halogen gas. This allows obtaining by means of an easy process a fully carbonaceous material having an optimal hemocompatibility and tailored porosity.

According to an embodiment, at least part of the pores is obtained by means of sacrificial templates. More in detail in the production process of the ceramic porous material, particles or spheres of a selected material are added to the initial composition and subsequently removed by means of a thermal treatment step, leaving correspondent pores. By using sacrificial templates for obtaining the ceramic material according to the present invention it is possible to control the exact dimensions and at least partially the distribution of the pores in the material, being also possible to obtain also highly regular structures. This is particularly important for controlled drug delivery applications, since the degree of adsorption of the bio-active agent molecules and the release profile of the same are directly influenced by the porosity of the material used as a carrier and by the morphology of the pores, so that a better control on the number, shape, dimensions and distribution of the pores, as reachable by using sacrificial templates, ensures a better and more predictable performance of the material as a carrier for drug delivery applications. According to an embodiment, the porous ceramic material is capable of simultaneously carrying multiple bio-active agents. This is rendered possible by the multimodal porosity of the material, i.e. by the presence in it of pores having different dimensions , so that molecules of different bio-active agents, especially having different dimensions, can be distinctively accommodated in pores of respective different sizes. Preferably the porous ceramic material is aimed to be used for simultaneously carrying multiple bio- active agents having different release kinetics, so that the release process of each of the different bio-active agents would not be hindering or interfering the release process of the remaining bio-active agents.

It is an object of the present invention also a controlled release drug delivery system comprising a carrier made of a porous ceramic material as above specified and one or more bio-active agents carried by it. In particular, the controlled release delivery systems may be in the form of microstructures, like for instance in a powder form or in the form of microparticles or microspheres, or in the form of macrostructures, like for instance tablets, pills, pellets or granules.

As above specified, different drug delivery systems could be obtained by using a substantially identical porous ceramic material as a carrier and different bio-active agents loaded on it. Moreover the drug delivery systems according to the invention can comprise more than one bio-active agent loaded on the carrier at the same time, to be administered contemporarily to a patient.

In particular, in a preferred embodiment, the molecular size of each of the at least a bio- active agent is not higher than the mean size of the pores of the matrix carrier in a correspondent one of the ranges of porosity present in the matrix carrier and selected between microporosity range (<2 nm), mesoporosity range (2-50 nm) and macroporosity range (>50 nm). For instance, in the case where the carrier is a bimodal porous material having micropores and mesopores, the molecular size of a bio-active agent loaded on the carrier is not bigger at least than the mean size of the mesopores so that the molecules of such bio-active agent can be accommodated in the mesopores of the carrier and, eventually it is not also bigger than the mean size of the micropores, so that molecules of such bio-active agent could be accommodated also in the micropores. In the case where two different bio-active agents having different molecular sizes are loaded on the bimodal porous carrier here above specified, preferably one of the bio- active agents has a molecular size not bigger than the mean size of the mesopores while the other bio-active agent has a molecular size not bigger than the mean size of the micropores. In this manner, the loading capacity of the carrier is optimized. In an embodiment of the drug delivery system, at least 70% of the bio-active agent carried by the carrier is released into an aqueous fluid at a pH between 1 and 8, i.e. a pH compatible with a body fluid. This ensures an optimal exploitation of the bio-active agent loaded in the drug delivery system and hence an optimal efficacy of the latter. In another embodiment, 60% of the bio-active agent carried by the carrier is not released into an aqueous fluid at a pH between 1 and 8 before a period of time of 60 minutes. This ensures a controlled release of the bio-active agent over the time.

It is a further object of the invention also the use of a multimodal porous ceramic material as previously described as a carrier for a drug delivery system for carrying multiple bio-active agents, i.e. different bio-active agents either in different applications or simultaneously.

EXAMPLES In the following, examples of ceramic materials according to the invention together with the characterization results obtained for such materials will be provided.

The same characterization tests have been conducted, as a comparative example, also on commercial samples of mesoporous silica particles (MS) of the "MCM-41" type provided by Sigma- Aldrich Co.

It is to be considered that the foregoing descriptions as well as the following examples are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. Example 1:

Polymer derived ceramic particles according to the present invention have been synthesized starting from polymethylhydrosiloxane (PHMS) having Si-H bonds, vinyl- terminated polydimethylsiloxane (PDMS) and a cyclic 2,4,6,8-tetramethyl-2,4,6,8- tetravinlycyclotetrasiloxane (TMTVS) with Si-C=C moieties, which were used as preceramic precursors together with platinium - divinyltetramethyldisiloxane complex, ~Pt 2% in xylene, serving as catalyst for the curing reactions. In particular PDMS has been used as a sacrificial template. Hydrotalcite (LDH) was also added to the formulation.

Synthesis of the polymer derived ceramic particles proceeded as follows.

PHMS, LDH, PDMS and TMTVS were mixed and upon homogenization, Pt was added to act as catalyst. The blend was further mixed and transferred into aluminum molds standing on the hot plate operating at 200°C for curing overnight, followed by pyrolysis at 1300°C with a heating rate of 2°C/min and 1 h dwell time at the maximum temperature under N₂ gas flow.

The particles obtained according to the above described synthesis process have been labeled as HIPO.

Example 2:

Polymer derived ceramic particles according to the present invention have been synthesized as described in Example 1 and have been subsequently submitted to an etching phase. More in detail the etching phase was conducted on ca 250 mg of HIPO bulk sample using 50 ml of HF (48 vol % in H₂0) solution in PE closed containers. The attack was performed by leaving the sample in contact with the etching solution for 4 days at room temperature. After the attack, SiOC particles were filtered, rinsed with distilled water and dried at 65 °C for 24 h for the subsequent analysis.

The particles obtained according to the synthesis process described in Example 2 have been labeled as HIPO-HF.

Porosity characterization:

The samples obtained according to Examples 1 and 2 and the samples of commercial mesoporous silica particles (MS) of the "MCM-41" type were analyzed by Nitrogen (N₂) gas adsorption. The isotherms were collected at 77 K using an ASAP 2010 (Micromeritics, Norcross, GA, USA) after degassing the sample at 200°C for minimum 4 h before analysis. SSA was calculated from a BET (Brunauer, Emmet, and Teller) analysis in the PIPQ range of 0.05-0.30 - using a minimum of five data points. The pore size distributions (PSDs) were obtained from the desorption branch of the isotherm through the BJH (Barret, Joyner, and Halenda) analysis. The porosity in both the SiOC samples (Examples 1-2) was obtained by crosslinking PHMS with PDMS which serves the purpose of "molecular spacer" and promotes the formation of pores in the 5 - 20 nm range after pyrolysis. Only in the sample according to Example 2, HIPO-HF, further porosity, both pores below 2 nm and pores in the mesopore range 2-50 nm size, was induced by a post-pyrolysis HF etching to dissolve the silica clusters present in the SiOC micro structure.

The results of the porosity measurements are reported being 122 m /g for HIPO, 706 m²/g for HIPO-HF, and finally 744 m²/g for MCM-41.

The HF treatment allowed to increase the porosity values, as could be seen from the BET results previously given.

The sorption isotherms recorded on the samples are reported in Figure 1(a). The sample HIPO shows a clear hysteresis loop above 0.8 P/Po indicating the presence of meso- macroporosity in the sample, see Figure 1(a). In HIPO-HF, i.e. after HF etching, the isotherms change, showing a steep increase at P/Po < 0.1 specifying microporosity which additionally formed during acid treatment.

In Figure 1(b) the pore volume vs. pore size curves are given. HIPO sample clearly shows the presence of mesopores in the 10-20 nm (100-200 Angstrom) size range. After HF etching, HIPO-HF sample showed multi-modal pores, namely: micropores below 2 nm, pores having ~ 4-5 nm, and pores with sizes larger than 5 nm up to ~ 50 nm, including the macrochannels with the samples truly demonstrating hierarchical porosity. The N₂ adsorption-desorption isotherms recorded on the reference MCM-41 sample (not shown but the data can be found in several publications) show the typical shape of mesoporous materials with the hysteresis loop close to P/Po = 0.4 suggesting the presence of pores of ~3 nm size. The BET surface area measured for the MCM-41 silica is 744 m²/g.

Hemolysis:

The hemocompatibility of the materials according to the invention has been investigated in order to evaluate potential applications allowed by a blood-compatible behavior. To this aim, the hemolytic activity of particles of materials according to Examples 1 and 2 and of particles of comparative samples of MCM-41 has been determined by Drabkin's haemoglobin quantification method, which is a direct indication of the integrity of Red Blood Cells (RBCs).

In particular, whole human blood was collected and used within 8 h. About 1 mL of whole blood was added to 8 mL of Dulbecco's phosphate buffered saline (D-PBS) and the RBCs were isolated from serum by centrifugation. The RBCs were washed two times with D-PBS solution. Finally, the RBCs were diluted to 1 mL of D-PBS. For each experiment, 50 μΐ_^ of the diluted RBC suspension was added to 50 μΐ_^ of silica or SiOC particle suspension in D-PBS at the concentration of 1.0 mg/mL and incubated for 4 h with shaking. After that, the mixture was centrifuged and the supernatants were assayed for hemoglobin content by Drabkin's method by measuring the absorbance value at 577 nm with the reference wavelength at 655 nm. All samples were prepared in triplicate. The percent of hemolysis was calculated as:

Hemolysis % = [(Sample absorbance - negative control) / (positive control - negative control)] x 100%

The hemolytic activity of the particles according to the Examples 1 and 2 (HIPO and HIPO-HF) was similar to each other, due to that in Figure 2a only HIPO-HF data is given, but both were lower than the hemolytic activity of the particles of comparative material MCM-41 as seen in Figure 2a. In particular HIPO and HIPO-HF demonstrated a hemolytic activity which is around 60% of the hemolytic activity value measured for the comparative mesoporous silica nanoparticles (MCM-41).

These results have demonstrated that, although the increase in surface area enhances the contact with RBC and therefore may rise the hemolytic activity, the lower surface density of silanol groups in HIPO and HIPO-HF compared to comparative MCM-41 particles, led to a better hemocompatibility of the samples according to the invention. It should be underlined that HF treatment creates additional micro-mesoporosity via removal of silica phase, and so new surfaces richer in carbon are being created. Such process is in fact a functionalization of the surfaces while tailoring surface area, surface energy and nanorugosity index which improves the interaction of cargo molecules and samples surface.

Loading capacity: Two different bioactive agent molecules have been loaded on the samples of materials according to the invention. More in detail to this aim two polypeptides with different size has been employed: Bovine Serum Albumin (BSA), which is the major blood serum protein with molecular weight of 66.463 Dalton and having 1.4 x 4.0 x 4.0 nm3 dimensions, and Vancomycin, which is a glycopeptide with antibiotic properties, about 18 times smaller than BSA with dimensions of 0.8 x 1.5 x 1.0 nm and molecular weight of 1449.3 Dalton.

The results reported in Figure 3 show that the particles according to the present invention demonstrate at least a comparable loading capacity with respect to the comparative particles of MCM-41, while having a higher hemocompatibility, both for small peptide, vancomycin and for a large protein, BSA. In particular HIPO-HF particles demonstrated higher loading capacity, compared to the comparative MCM-41 particles. One mg of HIPO particles adsorbed 31 pmol BSA and after HF-etching 180 pmol BSA were loaded. Instead, mesoporous silica control sample MCM-41 adsorbed 47 pmol BSA. Vancomycin adsorption was at lower levels compared to BSA molecules, which can be explained by different interaction opportunities with the surface, resulting from more contact sites in BSA. In summary, HIPO-HF adsorbed about 4 times more BSA and about 1.5 times more vancomycin molecules than mesoporous silica comparative particles MCM-41.

Bioactive agent release:

Bio-active agents release properties of the samples were tested in vitro monitoring BSA or vancomycin release by UV absorbance method. In particular, release of bioactive agent molecules from pores was monitored in a UV/VIS spectrophotometer at 280 nm. The particles loaded with either vancomycin or BSA was incubated in PBS buffer. The particles were placed in a cell holder, such that the particles were not exposed to incidence light. The particles were kept from mixing by trapping them in a compartment created by a dialysis membrane at the top of a spectroscopy cuvette. The solution was stirred continuously to create a homogeneous solution for sampling at various times. The 280 nm absorbance was measured in a well-mixed solution. The cumulative release of cargo (BSA) increased initially and leveled off afterwards. MCM-41 particles released about 80% at the end of one day incubation, as shown in Figure 4(a). For bio particle after etching the release amount was 90% for one day incubation.

Similar to MCM-41, both samples investigated (HIPO and HIPO-HF) have shown comparable release profiles for vancomycin.

Both samples showed similar trends in release behavior, HF treated samples demonstrated -60% release, while MCM-41 was at -80% after one day, Figure 4(b). Molecule related properties such as weight, size, chemistry of the drug, and porosity properties such as surface area, size, interconnectivity, surface chemistry, etc. of the substrate is very important for release kinetics. For example, we have seen that because of the proper interaction with vancomycin molecules and hierarchical porosity and surface chemistry of HIPO-HF, a longer release profile, compared to MCM-41, was observed. This is an important feature of the materials according to the present invention, since diverse cargo molecules having different release kinetics could be delivered at the same time.

In this regard the release capacity of HIPO-HF particles and of the comparative MCM- 41 particles, when loaded with two different bioactive agents simultaneously, has been evaluated.

To this aim fluorescein and BSA molecules were used as examples. In these dual release studies, the drug vancomycin was replaced by fluorescein for facile and sensitive detection properties. Fluorescein was used as model molecules for small size drugs like vancomycin. Fluorescein which frequently used in cargo release experiments has a comparable molecular weight to vancomycin. The HIPO-HF and MCM-41 particles were both loaded with both fluorescein and BSA and the release kinetics of each of the molecules were analyzed, given in Figures 5(a) and 5(b). Mesoporous silica particle MCM-41 demonstrated very different release kinetics for fluorescein when it is loaded together with BSA compared to data for small or large molecules loaded alone. This can be explained by the hindering effect of BSA and thus delayed fluorescein release was observed. However, when hierarchical porosity HIPO-HF particles were tested, the release kinetics of fluorescein and BSA was not affected much whether they are loaded separately or together, allowing the release of both small and large cargo molecules at the same time, see Figure 5(b).

Time-kill curves were used to study the time course of antimicrobial effects against S. aureus bacteria. Time-kill results, i.e. the bacterial susceptibility test results further confirmed that cargo-loaded hierarchical porosity particles according to the invention demonstrate an effective therapeutic efficacy, by inhibiting bacterial growth. A strong and prolonged bactericidal activity was observed as compared to control experiment without antibiotic application. For sake of conciseness such test results are not herein reported.

From the above examples it clearly appears that porous ceramic materials according to the present invention, having hierarchically porosity, in particular obtained by using "molecular spacer" polymer followed by pyrolysis and possibly by an etching phase, show an optimal hemolytic behavior, good loading capabilities with different bioactive agents in particular having different molecular sizes, such as vancomycin (MW=1449.3 g.mol-1) and Bovine Serum Albumin (BSA) (MW=66463 g.mol-1), efficient release behavior and optimal bactericidal activity.

In particular, it is important to underline that the materials according to the invention exhibit lower hemolysis than commercially available mesoporous silica (MCM-41). Due to encapsulation efficiency, release kinetics and biocompatibility, the porous ceramic material according to the present invention provides an alternative drug delivery material with respect to the ones currently available on the market which exhibits in particular a high versatility, being suitable to carry different bioactive agents even simultaneously.

The material according to the present invention provides an ideal carrier for drug delivery and release system used on the treatment of some illnesses that, as known, exhibit resistance to single drug molecule and require the administration of more than one drug, as it occurs for instance in the case of chemotherapeutic drugs, ensuring an optimal therapeutic efficacy. Such types of problems can be overcome by combination therapy using multiple agents producing a synergetic effect as in the case for present invention.

Claims

1. Porous ceramic material for drug delivery, characterized in that it is a multimodal porous ceramic material selected among silica based materials, carbon based materials or polymer derived ceramics materials capable of carrying multiple drugs.

2. The porous ceramic material according to claim 1 comprising interconnected pores having sizes in at least two distinctly different ranges selected between microporosity range, mesoporosity range and macroporosity range.

3. The porous ceramic material according to claim 2 having a gradient porosity within at least one of the ranges of porosity.

4. The porous ceramic material according to any of the preceding claims, which is capable of simultaneously carrying multiple drugs.

5. The porous ceramic material according to any of the preceding claims, at least part of the of which pores are obtained by means of sacrificial template.

6. The porous ceramic material according to any of the preceding claims, which is obtained by a process comprising at least an etching phase.

7. The porous ceramic material according to any of the preceding claims, which is silicon oxy-carbide.

8. The porous ceramic material according to claims 6 and 7, characterized in that it is obtained by a process comprising at least an etching phase by using hydrofluoric acid.

9. The porous ceramic material according to claim 7 or 8, characterized in that it is a polymer derived ceramic material obtained starting from at least one preceramic polymer such as polysiloxane.

10. The porous ceramic material according to any of the claims 1 to 6, characterized in that it is carbon.

11. The porous ceramic material according to claims 6 and 10, characterized in that it is obtained starting from silicon oxycarbide or silicon oxy-carbonitrides by a process comprising at least an etching phase by using halogen gas.

12. A controlled release drug delivery system comprising a carrier made of a porous ceramic material according to any of the preceding claims and at least a bioactive agent carried by it.

13. A controlled release drug delivery system according to claim 11, characterized in that at least 70% of the bioactive agent carried by the carrier is released into an aqueous fluid at a pH between 1 and 8.

14. A controlled release drug delivery system according to claim 12 or 13, characterized in that 60% of the bioactive agent carried by the carrier is not released into an aqueous fluid at a pH between 1 and 8 before a period of time of 60 minutes.

15. Use of a multimodal porous ceramic material according to any of the claims 1 to 11 as a carrier for a drug delivery system for carrying multiple drugs.