Patent Application
20250228947
The present invention relates to a composition comprising a metal-organic framework, one or more emulsifier(s), one or more lipid(s) and one or more co-emulsifier(s). Furthermore, the present invention relates to a method for preparing a microemulsion in response to a physical- and/or chemical stimulus and to a method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system. Finally, the present invention relates to the use of a composition comprising a metal-organic framework, one or more emulsifier(s), one or more lipid(s) and one or more co-emulsifier(s) for preparing a microemulsion in response to a physical- and/or chemical stimulus and the use of a composition for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system.
Highly potent but poorly water-soluble drug candidates are common and represent a major challenge for new drug development. Poor water solubility leads to poor oral bioavailability however, bioavailability has important clinical implications as both pharmacological and toxic effects are proportional to dose and bioavailability. Numerous physicochemical approaches to improve the oral bioavailability of such drugs have been explored such as particle size reduction, complexation, salt formation and addition of co-solvents. Since these methods have limited applicability for some compounds, formulation optimization approaches have been sought. Lipid-based formulations, such as microemulsions and self-microemulsifying drug delivery systems (SMEDDS) have already been extensively investigated (see non-patent literature 1 and 2).
Microemulsions are mixtures of lipids, one or more emulsifiers, optionally one or more co-emulsifier(s) and water. They form spontaneously, are thermodynamically stable and have a droplet size between 5 and 100 nm, which is why they appear clear to slightly opalescent to the naked eye. A distinction is made between oil-in-water (O/W) and water-in-oil (W/O) microemulsions, where oil or water, respectively, is present as fine droplets distributed in the other phase. This is made possible by the presence of emulsifiers. As a result, they are able to incorporate a wide variety of active ingredients and are used as drug carriers, especially for substances that are difficult to dissolve in water, whereby they are dissolved in an O/W microemulsion and their absorption and permeation can be improved (see non-patent literature 3).
Another form of lipid-based formulations are the so-called self-microemulsifying drug delivery systems (SMEDDS). These serve as preconcentrates for the formation of microemulsions, thus facilitating their delivery. These are isotropic mixtures of lipids, one or more emulsifiers and optionally one or more co-emulsifier(s) which, after oral administration with the aqueous gastrointestinal fluids, form in situ an O/W microemulsion with drug dissolved in the lipid droplets. Liquid SMEDDS can be administered using soft capsules with good compliance. Examples include Novartis' Sandimmun Neoral® finished drug product for formulation of the immunosuppressant cyclosporine A and AbbVie's Norvir® for delivery of the HIV protease inhibitor ritonavir (see non-patent literature 4).
The use of soft gelatin capsules has been established for many years, but manufacturers are confronted with stability and compatibility problems such as capsule leakage, seepage of ingredients into the shell and incompatibilities of the various components (see non-patent literature 5). These factors affect storage, shelf life and adequate release of the active ingredient and excipients, which is essential for the formation of a microemulsion (see non-patent literature 6).
These challenges have already been addressed in academia by converting the liquid SMEDDS into a solid dosage form. Here, methods such as adsorption to a carrier material, joint spray drying or 3D printing processes are used (see non-patent literature 7). For example, a SMEDDS containing cyclosporine A could be converted to a solid dosage form by simple absorption through porous magnesium aluminometasilicate (see non-patent literature 5). Similarly, naproxen as a liquid SMEDDS could be converted into smooth, granular particles by co-drying with maltodextrin, whose microemulsifying properties and dissolution profile were comparable to the liquid SMEDDS (see non-patent literature 8).
There is still a need for improved solid dosage forms for SMEDDS suitable for providing pharmaceutically active ingredients. Moreover, there is still a need for improving the bioavailability of poorly water-soluble pharmaceutically active ingredients.
It is a problem of the present invention to provide a composition which can be used to prepare a microemulsions in response to a stimulus such as a physical and/or chemical stimulus. Specifically, it is a problem of the present invention to provide a composition which can be used as a solid dosage form of a self-microemulsifying drug delivery system, wherein a microemulsion is generated in response to a physical and/or chemical stimulus. Moreover, the composition according to the present invention can be used to provide a SMEDDS wherein any leakage and/or seepage of ingredients of the SMEDDS is avoided. Furthermore, the composition according to the present invention can be used to provide a solid dosage form of a SMEDDS which has excellent storage properties, shelf life and adequate release of the active ingredient(s) and excipient(s).
In addition, it is a problem of the present invention to provide a method for preparing a microemulsion in response to a stimulus such as a physical and/or chemical stimulus. Moreover, it is a problem of the present invention to provide a method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system.
Finally, it is a problem of the present invention to provide the use of a composition for preparing a microemulsion in response to a physical- and/or chemical stimulus, for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system.
It has now been found that these and other problems can be solved by the composition and the methods of the present invention. The present invention relates to a composition comprising:
Moreover, the present invention relates to a method for preparing a microemulsion in response to a physical- and/or chemical stimulus comprising the following steps:
Furthermore, the present invention provides the use of a composition comprising:
The present invention further relates to a method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system comprising the following steps:
Finally, the present invention provides the use of a composition comprising:
The present invention is based on the recognition that in the composition of the present invention the one or more emulsifier(s), the one or more lipid(s), the one or more pharmaceutically active ingredient(s) and the one or more co-emulsifier(s) are adsorbed to the metal-organic framework (MOF) and can be desorbed from the MOF in response to a physical and/or chemical stimulus (e.g. light, temperature, change in pH-value). Therefore, the composition of the present invention can be used to efficiently generate a microemulsion such as a water-in-oil or an oil-in-water microemulsion in response to a physical and/or chemical stimulus. Consequently, the composition according to the present invention can be used efficiently as a solid dosage form of a SMEDDS wherein the microemulsion is generated in response to a physical and/or chemical stimulus. The method for preparing a microemulsion in response to a physical- and/or chemical stimulus according to the present invention can efficiently be used to provide any microemulsion containing poorly soluble ingredients (such as pharmaceutically active ingredients). Finally, the present invention is based on the recognition that an efficient and reliable method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system is provided, wherein a solid composition having excellent storage properties and shelf life is used which is capable of being triggered by a physical and/or chemical stimulus.
According to the present invention the term “about” means±10% of the specified numeric value, preferably ±5% and most preferably ±2%.
According to the present invention the terms “SMEDDS”, “liquid SMEDDS”, “self-microemulsifying drug delivery systems” and “liquid self-microemulsifying drug delivery systems” have the meaning of preconcentrates for the formation of microemulsions, wherein these preconcentrates are isotropic mixtures of one or more lipids, one or more emulsifier(s) and optionally one or more co-emulsifier(s) and one or more pharmaceutically active ingredient(s) which, after oral administration with the aqueous gastrointestinal fluids, form in situ an O/W microemulsion with drug dissolved in the lipid droplets.
According to the present invention the terms “solid SMEDDS”, “solid dosage form of a SMEDDS”, “solid self-microemulsifying drug delivery system” and “solid dosage form of a self-microemulsifying drug delivery system” have the meaning of a solid composition wherein the one or more emulsifier(s), the one or more lipid(s) and optionally the one or more co-emulsifier(s) and the one or more pharmaceutically active ingredients are adsorbed to a solid compound such as a MOF.
The term “physical stimulus” means any physical stimulus such as electricity, temperature, pressure, light, sonic waves, x-rays, magnetic field, mechanical stress and so on.
The term “chemical stimulus” means any chemical stimulus such as changes in pH-value, initiating redox-processes, the presence of solvents, metals and enzymes and so on.
The term “co-emulsifier” means any compound capable of stabilizing a water-in-oil or oil-in-water microemulsion comprising an oil, water and one or more emulsifier(s).
The present invention relates to a composition comprising:
The metal-organic framework may be any metal-organic framework known in the art. Preferably, the metal-organic framework is a pharmaceutically acceptable metal-organic framework. Preferably, the metal-organic framework is selected from the group consisting of: UiO-MOFs, ZIF-MOFs, MIL-MOFs, IRMOFs, HKUST-MOFs, COF-MOFs, BAF-MOFs, MFU-MOFs, ZJU-MOFs, TOF-MOFs, CAU-MOFs, MOF-Zr(DTBA) (the term “DTBA” means dithiobisbenzoic acid), MOF-5 and MOF-177. More preferably, the metal-organic framework is selected from the group consisting of: ZIF-MOFs, UiO-AZB (the term “AZB” means azobenzenedicarboxylate), ZJU-64, ZJU-800 and MOF-Zr(DTBA).
Still more preferably, the metal-organic framework is a zeolitic imidazolate framework (ZIF), which may be any ZIF known in the art. Most preferably, the metal-organic framework is ZIF-8.
Preferably, the metal-organic framework is present in the composition in an amount of from about 40 wt % to about 99.90 wt % based on the total weight of the composition, more preferably the MOF is present in the composition in an amount of from about 50 wt % to about 99.50 wt %, still more preferably of from about 55 wt % to about 99.00 wt %, even more preferably of from about 60 wt % to about 95 wt %, still even more preferably of from about 65 wt % to about 90 wt %, still even more preferably of from about 70 wt % to about 85 wt %, still even more preferably of from about 70 wt % to about 80 wt %, most preferably of from about 75 wt % based on the total weight of the composition.
The one or more emulsifier(s) may be any non-ionic emulsifier(s) known in the art. Preferably, the one or more emulsifier(s) are pharmaceutically acceptable emulsifier(s). More preferably, the one or more emulsifier(s) are selected from the group consisting of: Kolliphor® RH40, Kolliphor® EL, Capmul® MCM, Captex® 355, Labrafil® M1944 CS; most preferably the one or more emulsifier(s) is Kolliphor® RH40.
Preferably, the one or more emulsifier(s) are present in the composition in an amount of from about 0.01 wt % to about 35 wt % based on the total weight of the composition, more preferably of from about 0.02 wt % to about 30 wt %, still more preferably of from 0.05 wt % to about 25 wt %; even more preferably of from about 0.1 wt % to about 20 wt %, still even more preferably of from about 0.5 wt % to about 17.5 wt %, still even more preferably of from about 1.0 wt % to about 17 wt %; still even more preferably of from about 2 wt to about 16.5 wt %; still even more preferably of from about 2.5 wt % to about 16 wt %; most preferably of from about 5.0 wt % to about 15 wt % based on the total weight of the composition.
Preferably, the one or more emulsifier(s) are of from 1 to 5 emulsifier(s), more preferably of from 1 to 4 emulsifier(s), even more preferably of from 1 to 3 emulsifier(s), still more preferably 1 to 2 emulsifier(s), most preferably 1 emulsifier.
As defined above, the one or more emulsifier(s) may be lipid(s) which are known in the art to act as emulsifier(s). In case no emulsifier is present in the composition which is not a lipid, at least two or more lipid(s) must be present in the composition according to the present invention, wherein at least one of these lipids must be an emulsifier known in the art. In this case, at least one lipid which is an emulsifier known in the art will account as a component according to b) one or more emulsifier(s) and at least one of the other lipid(s) accounts as a component according to c) one or more lipid(s).
Preferably, the composition according to the present invention is a composition, wherein the one or more emulsifier(s) and the one or more lipid(s) are adsorbed to the metal-organic framework, and wherein the one or more emulsifier(s) and the one or more lipid(s) can be desorbed from the metal-organic framework in response to a physical and/or chemical stimulus. More preferably, the physical stimulus is selected from the group consisting of: temperature, pressure, light, sonic waves, x-rays, magnetic field and mechanical stress. More preferably, the chemical stimulus is selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme.
The one or more lipid(s) may be any lipids known in the art. Preferably, the one or more lipid(s) are pharmaceutically acceptable lipids. Preferably, the one or more lipids are selected from the group consisting of: sesame oil, mono-, di- and triglycerides of C10-26 fatty acids, PEG mono- and diesters of C10-26 fatty acids.
Preferably, in the composition according to the present invention the one or more lipid(s) are present in amount of from about 0.01 wt % to about 35 wt % based on the total weight of the composition, more preferably of from about 0.02 wt % to about 30 wt %, still more preferably of from 0.05 wt % to about 25 wt %; even more preferably of from about 0.10 wt % to about 20 wt %, still even more preferably of from about 1.0 wt % to about 17.5 wt %, still even more preferably of from about 1.5 wt % to about 17 wt %; still even more preferably of from about 2.0 wt to about 15 wt %; still even more preferably of from about 2.5 wt % to about 12.5 wt %; most preferably of from about 5.0 wt % to about 10 wt % based on the total weight of the composition.
Preferably, the composition according to the present invention further comprises:
The one or more pharmaceutically active ingredient(s) may be any pharmaceutically active ingredient(s) known in the art. Preferably, the pharmaceutically active ingredient(s) are poorly water-soluble. More preferably, the one or more pharmaceutically active ingredient(s) are selected from the group consisting of: Cyclosporin A, Ritonavir, Probucol, Vitamin K, Lapatinib and Fenofibrate.
Preferably, in the composition according to the present invention the one or more pharmaceutically active ingredient(s) are present in amount of from of from 1 wt % to about 50 wt % based on the total amount of the composition; more preferably of from about 2 wt % to about 40 wt %; still more preferably of from about 2.5 wt % to about 35 wt %; even more preferably of from about 4 wt % to about 30 wt %; still even more preferably of from about 5 wt % to about 25 wt %; still even more preferably of from about 5 wt % to about 20 wt %; most preferably of from about 5 wt % to about 10 wt % based on the total weight of the composition.
The composition according to the present invention comprises:
The one or more co-emulsifier(s) may be any co-emulsifier suitable for stabilizing a water-in-oil microemulsion or oil-in-water microemulsion known in the art. Preferably, the one or more co-emulsifier(s) are pharmaceutically acceptable co-emulsifier(s). More preferably, the one or more co-emulsifier(s) are selected from the group consisting of: polyethylene glycols, polypropylene glycols, polyethylene glycol mono- and diethers, diethylene glycol mono- and diethers, C2-10 alcohols and C2-10 amines.
Preferably, the one or more co-emulsifier(s) are present in the composition in an amount of from about 0.001 wt % to about 20 wt % based on the total weight of the composition, more preferably of from about 0.002 wt % to about 15 wt %, still more preferably of from 0.005 wt % to about 10 wt %; even more preferably of from about 0.01 wt % to about 10 wt %, still even more preferably of from about 0.05 wt % to about 7.5 wt %, still even more preferably of from about 0.1 wt % to about 5 wt %; still even more preferably of from about 0.2 wt to about 5 wt %; still even more preferably of from about 0.5 wt % to about 5 wt %; most preferably of from about 1.0 wt % to about 2.5 wt % based on the total weight of the composition.
Preferably, the composition according to the present invention as defined herein is a pharmaceutical composition.
The composition according to the present invention may further comprise fillers or any pharmaceutically acceptable excipients known in the art.
Furthermore, the present invention relates to a method for preparing a microemulsion in response to a physical- and/or chemical stimulus comprising the following steps:
In the method for preparing a microemulsion in response to a physical- and/or chemical stimulus in step i) in the provided composition the one or more emulsifier(s) and the one or more lipid(s) are adsorbed to the metal-organic framework and the one or more emulsifier(s) and the one or more lipid(s) can be desorbed from the metal-organic framework in response to a physical and/or chemical stimulus.
In the method for preparing a microemulsion in response to a physical- and/or chemical stimulus in step ii) a physical and/or chemical stimulus is applied to the composition of step i), wherein the physical and/or chemical stimulus leads to the desorption of the one or more emulsifier(s) and the one or more lipid(s) from the metal-organic framework. Upon the desorption of the one or more emulsifier(s) and the one or more lipid(s) a microemulsion is generated in the composition.
Generally, this method can be useful to generate microemulsions in response to a physical and/or chemical stimulus, for example to increase the solubility of poorly soluble ingredients additionally present in the composition.
The MOF in step i) may be any MOF as defined for the composition according to the present invention herein.
The one or more emulsifier(s) in step i) may be any non-ionic emulsifier(s) as defined for the composition of the present invention herein.
The one or more lipid(s) in step i) may be any lipid(s) as defined for the composition of the present invention herein.
The one or more solvent(s) may be any solvent(s) immiscible with the one or more lipid(s). Preferably, in step i) the one or more solvent(s) are immiscible with the one or more lipid(s) and selected from the group consisting of: water, water containing solutions, and animal- or human body fluids such as gastrointestinal fluids.
The one or more co-emulsifier(s) may be any co-emulsifier(s) as defined for the composition according to the present invention herein.
Preferably, in step ii) the physical stimulus is selected from the group consisting of: temperature, pressure, light, sonic waves, x-rays, magnetic field and mechanical stress; more preferably the physical stimulus is selected from the group consisting of temperature, light and pressure. Preferably, in step ii) the chemical stimulus is selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme; more preferably in step ii) the chemical stimulus is a change in pH-value or initiating a redox-process.
More preferably, in step ii) a chemical stimulus is applied to the composition, even more preferably in step ii) a chemical stimulus selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme, is applied to the composition; more preferably the chemical stimulus is a change in pH-value or initiating a redox-process; most preferably, in step ii) a chemical stimulus is applied to the composition wherein the chemical stimulus is a change in pH-value.
Moreover, the present invention relates to the use of a composition comprising:
Preferably, the present invention relates to the use of a composition comprising:
Additionally, the present invention relates to a method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system comprising the following steps:
In the method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system in step iii) in the provided composition the one or more emulsifier(s), the one or more lipid(s), the one or more co-emulsifier(s) and the one or more pharmaceutically active ingredient(s) are adsorbed to the metal-organic framework and the one or more emulsifier(s), the one or more lipid(s), the one or more co-emulsifier(s) and the one or more pharmaceutically active ingredient(s) can be desorbed from the metal-organic framework in response to a physical and/or chemical stimulus.
In the method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system in step iv) a physical and/or chemical stimulus is applied to the composition of step iii), wherein the physical and/or chemical stimulus leads to the desorption of the one or more emulsifier(s), the one or more lipid(s), the one or more co-emulsifier(s) and the one or more pharmaceutically active ingredient(s) from the metal-organic framework. Upon the desorption of the one or more emulsifier(s), the one or more lipid(s), the one or more co-emulsifier(s) and the one or more pharmaceutically active ingredient(s) a SMEDDS is generated which leads to the formation of a microemulsion in the composition, thereby increasing the solubility of a poorly soluble pharmaceutically active ingredient in a solvent and/or increasing the bioavailability of a pharmaceutically active ingredient.
The MOF in step iii) may be any MOF as defined for the composition according to the present invention herein.
The one or more emulsifier(s) in step iii) may be any emulsifier(s) as defined for the composition of the present invention herein.
The one or more lipid(s) in step iii) may be any lipid(s) as defined for the composition of the present invention herein.
The one or more co-emulsifier(s) in step iii) may be any co-emulsifier(s) as defined for the composition according to the present invention herein.
The one or more pharmaceutically active ingredient(s) in step iii) may be any pharmaceutically active ingredients as defined for the composition according to the present invention herein.
The one or more solvent(s) may be any solvent(s) immiscible with the one or more lipid(s). Preferably, in step i) the one or more solvent(s) are immiscible with the one or more lipid(s) and selected from the group consisting of: water, water containing solutions, and animal- or human body fluids such as gastrointestinal fluids.
Preferably, in step iv) the physical stimulus is selected from the group consisting of: temperature, pressure, light, sonic waves, x-rays, magnetic field and mechanical stress; more preferably the physical stimulus is selected from the group consisting of: temperature, light and pressure. Preferably, in step iv) the chemical stimulus is selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme; more preferably the chemical stimulus is a change in pH-value or initiating a redox-process; most preferably in step iv) the chemical stimulus is a change in pH-value.
More preferably, in step iv) a chemical stimulus is applied to the composition, even more preferably in step iv) a chemical stimulus selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme, is applied to the composition; even more preferably in step iv) a chemical stimulus is applied to the composition wherein the chemical stimulus is a change in pH-value or initiating a redox-process; most preferably, in step iv) a chemical stimulus is applied to the composition wherein the chemical stimulus is a change in pH-value.
Finally, the present invention relates to the use of a composition comprising:
Preferably, the preset invention relates to the use of a composition comprising:
[1]A composition comprising:
[2] The composition according to [1], wherein the one or more emulsifier(s) and the one or more lipid(s) are adsorbed to the metal-organic framework, and wherein the one or more emulsifier(s) and the one or more lipid(s) can be desorbed from the metal-organic framework in response to a physical and/or chemical stimulus.
[3] The composition according to [2], wherein the physical stimulus is selected from the group consisting of: temperature, pressure, light, sonic waves and mechanical stress.
[4] The composition according to [2], wherein the chemical stimulus is selected from the group consisting of: a change in pH-value, initiating redox-processes and a presence of an enzyme.
[5] The composition according to [1] to [4], wherein the composition further comprises:
[6] The composition according to [1] to [5], wherein the metal-organic framework is a zeolitic imidazolate framework.
[7] The composition according to [6], wherein the metal-organic framework is the zeolitic imidazolate framework ZIF-8.
[8] The composition according to anyone of [1] to [7], wherein the composition further comprises:
[9] The composition according to anyone of [1] to [8], wherein the one or more emulsifier(s) are non-ionic emulsifiers.
[10]A method for preparing a microemulsion in response to a physical- and/or chemical stimulus comprising the following steps:
[11] The method according to [10], wherein in step ii) a chemical stimulus is applied to the composition.
[12] Use of a composition comprising:
[13]A method for increasing the solubility of a pharmaceutically active ingredient in a solvent and/or for improving the bioavailability of a pharmaceutically active ingredient and/or for preparing a self-microemulsifying drug delivery system comprising the following steps:
[14] The method according to [13], wherein in step iv) a chemical stimulus is applied to the composition.
[15] Use of a composition comprising:
A liquid preconcentrate for a SMEDDS was prepared by mixing the following compounds:
In this Example sesame oil:maisine represent the one or more lipids, Kolliphor® RH40 represents the one or more emulisifier(s), PEG 400 represents the one or more co-emulsifier(s) and the fluorescent dye Nile Red represents an active ingredient, which in practice may be substituted e.g. by a pharmaceutically active ingredient.
A ZIF-8 MOF loaded with the liquid preconcentrate MENIII obtained from Example 1 was prepared according to the following procedure:
The precipitate obtained from Example 2 was analyzed via XRPD (Powder diffractometer) and the results are shown in
The supernatant obtained from Example 2 was analyzed via dynamic light scattering and the Z-average hydrodynamic diameter [nm] of colloids contained in the supernatant was measured. In
The generation of a SMEDDS and the formation of a microemulsion containing the fluorescent dye Nile Red using the MENIII loaded ZIF-8 in response to a pH-value change which is a chemical stimulus was investigated.
The results are shown
In
Therefore, the results displayed in
From the aliquots obtained in Example 3 the contained solids were isolated. In
The components adsorbed to the MOF have been desorbed from the MOF upon irradiation with the light. This led to photoisomerization of AZB linker and breakdown of the MOF and released adsorbed and encapsulated components
The components adsorbed to the MOF have been desorbed from the MOF upon increasing the temperature to 60° C. ZJU-64 degraded at high temperature releasing attached components.
The components adsorbed to the MOF have been desorbed from the MOF upon increasing the pressure to 0, 10 or 30 MPa. Changes in pressure led to “burst release” of adsorbed and encapsulated components from ZJU-800. The lower the pressure the faster the release.
The components adsorbed to the MOF have been desorbed from the MOF upon initiating a redox-process in the presence of DTT/GSH. Disulfide bond in DTBA is GSH sensitive which led to degradation of the MOF and release of attached and encapsulated components.
Three different Microemulsion preconcentrates with the model drugs Nile Red, Lumefantrine and Vitamin K1 (Table 1) were prepared and loaded onto ZIF-8 according to Examples 1 and 2. Sizes of colloids before synthesis and after adsorption to ZIF-8 were determined by dynamic light scattering (Table 2). The solid product was characterized by solid state NMR and XRPD (
After ZIF-8 loading with microemulsion preconcentrates, colloidal structures disappeared for MEN2 and MEN3 and increased to 96±1 nm for MEN1 (Table 2).
Nile Red adsorption to ZIF-8 was lower for MEN1 as compared to MEN2 and MEN3 (
The solid product was dispersed in acidic solution pH 1.2 according to Example 3. Drug concentration and colloidal structure formation was assessed by fluorescence intensity measurement and HPLC and by dynamic light scattering and 1H DOSY experiments.
Nile Red Desorption was lower from MEN1+ZIF-8 as compared to MEN2+ZIF-8 and MEN3+ZIF-8 (
Lower Vitamin K1 and Lumefantrine adsorption to ZIF-8 was observed from MEK/L1 as compared to MEK/L2 and MEK/L3 (
Tablets with a diameter of 12 mm consisting of 40 wt % tableting mixture (88 wt % lactose, 9 wt % cellulose, 2 wt % aluminum oxide and 1 wt % magnesium stearate), 10 wt % microcrystalline cellulose and 50 wt % MEK+ZIF-8 resulting in tablet weights of 201±0.8 mg, 502±1.6 mg, and 705±0.8 mg (average standard deviation, n=3) for MEK1, MEK2, and MEK3, respectively, were prepared. Desorption dynamics was similar to the powder alone (
A 3D powder printed tablet using a mixture of 80 wt % Bentonite, 10 wt % Hydroxypropyl methylcellulose, and 10 wt % MEN3+ZIF-8 powder was prepared. Water was the binding agent. Desorption dynamics was similar to the powder alone (
| Number | Date | Country | Kind |
|---|---|---|---|
| EP 22168387.3 | Apr 2022 | EP | regional |
This application corresponds to the U.S. National phase of International Application No. PCT/EP2023/058309, filed Mar. 30, 2023, which, in turn, claims priority to European Patent Application No. 22168387.3 filed Apr. 14, 2021, the contents of which are incorporated by reference herein in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2023/058309 | 3/30/2023 | WO |
