EP4333817A2 - Realisierung des nanoamorphen zustands von materialien in nanoporösen vorlagen - Google Patents

Realisierung des nanoamorphen zustands von materialien in nanoporösen vorlagen

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Publication number
EP4333817A2
EP4333817A2 EP22799596.6A EP22799596A EP4333817A2 EP 4333817 A2 EP4333817 A2 EP 4333817A2 EP 22799596 A EP22799596 A EP 22799596A EP 4333817 A2 EP4333817 A2 EP 4333817A2
Authority
EP
European Patent Office
Prior art keywords
active compound
porous template
template
porous
templates
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22799596.6A
Other languages
English (en)
French (fr)
Inventor
Lei Xu
David Weitz
Zhuo XU
Changliang Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chinese University of Hong Kong CUHK
Harvard College
Original Assignee
Chinese University of Hong Kong CUHK
Harvard College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US17/313,528 external-priority patent/US20220354796A1/en
Priority claimed from CN202110490559.7A external-priority patent/CN115300448A/zh
Application filed by Chinese University of Hong Kong CUHK, Harvard College filed Critical Chinese University of Hong Kong CUHK
Publication of EP4333817A2 publication Critical patent/EP4333817A2/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the disclosure provides methods to produce amorphous materials at nanometer scale, by solidifying or hardening the materials inside nanometer-sized pores of porous media (i.e., porous templates).
  • porous templates can be made by packing nanometer-sized particles or other means. Due to the spatial constraint of nanometer-sized pores, the solidification inside cannot reach the crystallization condition, and thus leads to an amorphous state at nanometer scale.
  • This nano -amorphous state has many surprising properties, including but not limited to: dissolving compounds more easily with a higher concentration and a faster dissolution rate than the crystalline counterpart in various solvents, having higher free energy than crystalline counterparts, possessing a large specific surface area and surface energy, remaining stable over a long period of time, and exhibiting distinct mechanical or transport properties due to its non crystalline and nanometer-sized structure.
  • the subject method can be applied to insoluble pharmaceutical materials to produce nano-amorphous drugs with significantly improved bioavailability.
  • the aqueous concentrations can increase many times compared with the crystalline counterparts, and the dissolution rates are also greatly increased.
  • the solubility and the dissolution rate may also be broadly adjusted.
  • the subject method can also work for organic solvents and, thus, is suitable for both oral drugs and external ointment medications.
  • the subject method is a physical approach, which does not modify the chemical components of the materials; therefore, it can be generally applied to different materials including, but not limited to, pharmaceutical materials.
  • the nano-amorphous materials produced by this method may only contain the active ingredient and the porous template, without any other materials such as, for example, solubility-promoting cosolvents or surface active agents often found in typical pharmaceutical products. Therefore, the components used in the subject method can inhibit undesirable effects that can be attributed to additional components.
  • the subject method can avoid the complex encapsulation process, such as, for example, softgel capsulation required by liquid cosolvents, which may significantly reduce the manufacturing cost.
  • the nano-porous templates can stabilize the nano -amorphous materials over a long time interval.
  • the compounds cannot recrystallize nor have any other change in properties from several months to more than one year. Therefore, it has a long storage shelf life.
  • the method can also be used to make amorphous materials other than drugs. It can vitrify other materials inside nano-porous templates, to produce nano- amorphous matter. Our approach can avoid the fast-temperature-quenching approach typically required for producing amorphous materials, and opens up a new direction to make amorphous materials at nanometer scale.
  • FIGS. 1A - IB show the Brunaucr Emmett Tel 1 er (BET) sorption isotherm of one porous template made from 22 nm particles, and the pore volume distribution derived from the BET sorption isotherm.
  • BET Brunaucr Emmett Tel 1 er
  • FIGS. 2A - 2B include X-ray Powder Diffraction (XRD) and Differential Scanning Calorimetry (DSC) analysis on composites with different loading fractions. Crystalline component starts to appear and grow at 37% of volume fraction.
  • XRD X-ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • FIGS. 3A - 3C show the transmission electron microscopy (TEM) images and the electron diffraction patterns of the template without drug (FIG. 3A), the crystalline fenofibrate (FIG. 3B), and the composite (FIG. 3C).
  • TEM transmission electron microscopy
  • FIGS. 4A - 4B show the XRD (FIG. 4A) and the DSC (FIG. 4B) measurements of fenofibrate composites and crystals.
  • Curves 1 to 5 respectively represent (1) the crystalline fenofibrate, (2) freshly made 20% mass ratio fenofibrate composite, (3) the same 20% composite stored for 3 weeks, (4) the same 20% composite stored for 3 months, and (5) the 3- month composite recrystallized in ethanol.
  • FIG. 5 shows the solubility comparison between the fenofibrate composites produced using the subject methods with different mass fractions, two commercial fenofibrate products, and crystalline fenofibrate.
  • the solution concentration is proportional to the main peak height of the UV/VIS spectrum.
  • FIG. 6 shows the solubility comparison between our ibuprofen composite produced using the subject methods via wet template technique, two commercial ibuprofen products, and crystalline ibuprofen.
  • the solution concentration is proportional to the main peak height of the UV/VIS spectrum.
  • FIGS. 7 A 7C show the TEM images of the templates made from 22 nm (FIG. 7A), 12 nm (FIG. 7B), and 7 nm (FIG. 7C) particles respectively.
  • FIGS. 8A - 8C show the TEM images of the templates made from colloidal suspensions with different initial pH values: 10 (FIG. 8A), 8 (FIG. 8B) and 4 (FIG. 8C).
  • FIGS. 9A - 9B show the TEM images of the templates made by the fast evaporation under vacuum (FIG. 9A) and slow evaporation in open-air (FIG. 9B), respectively.
  • FIGS. 10A-10G show the general applicability of the subject method to various drugs dissolved in water (FIG. 10A) - (FIG. 10F), and in organic solvent beyond water (FIG. 10G).
  • FIGS. 11A-11G show the Differential Scanning Calorimetry (DSC) results of various samples, which reveal the mass ratio of the crystalline component.
  • the subject invention concerns the production of composites to achieve a nano- amorphous state of an active compound, which can increase the active compound performance by altering properties such as solubility, dissolution rate, and mechanical properties.
  • the method typically comprises combining two parts: (1) active ingredients in the nano-amorphous state, which can have advantageous properties due to their amorphous state, nanoscale size, large surface area, and controllable solvent preference; (2) porous templates, which physically confine the active ingredients in their pores. Templates play an important role in increasing the ingredients’ free energy, keeping ingredients stable, controlling the disintegration, and suppressing the recrystallization. Definitions
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9.
  • “nested sub-ranges” that extend from either end point of the range are specifically contemplated.
  • a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.
  • a “reduction” means a negative alteration
  • an “increase” means a positive alteration, wherein the negative or positive alteration is at least 0.001%, 0.01%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.
  • transitional term “comprising,” which is synonymous with “including,” or “containing,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim.
  • the transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
  • Use of the term “comprising” contemplates other embodiments that “consist” or “consist essentially of’ the recited component(s).
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01 % of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • the term “porosity” or “f” is a measure of the void spaces in a material, defined as the fraction of the volume of voids over the total volume. It has a value between 0 and 1, or as a percentage between 0% and 100%.
  • the term “mean pore diameter” or “D p ” is the mean pore size of the porous material and “mean particle diameter” or “D e ” are the mean size of the individual particles that are the basic packing elements.
  • ND P is the ratio between the mean pore diameter to the mean particle diameter.
  • permeability or “K” is the ability of fluids to flow through porous material. According to Kozeny-Carman equation, , with a the proportionality factor.
  • SSA specific surface area
  • the active compound that can be used in the subject methods can be any compound stable above its melting temperature in an inert atmosphere, or any solid state compound below its melting temperature.
  • the compounds can then infiltrate into the pores of the porous templates. If oxidization or a reaction with the surrounding atmosphere occurs, protective gases, such as pure nitrogen or argon, may be supplied to insulate the active compound from oxygen or any other reactive component. Additionally, the melting point can be lowered using means such as, for example, adding a modifier and/or applying high pressure.
  • protective gases such as pure nitrogen or argon
  • the active compound can be in the solid state below the melting temperature. Due to the small pore size that produces strong surface effect, even the solid-state active compound can infiltrate into the pore space and turns into the nano-amorphous state. The external stress applied by pressing may also help the compound to infiltrate into pores.
  • the active compound can be soluble in certain preferred solvents.
  • the active compound can be dissolved in a solvent first, particularly compounds that degrade at high temperatures, and then the dissolved compound can subsequently infiltrate the pores in the porous templates.
  • the preferred solvents may be organic or inorganic; a pure solvent or a mixture of solvents; volatile or non-volatile. Even some gases or solids can become solvents under some special conditions such as, for example, liquid carbon dioxide and polyethylene glycol (PEG) at a temperature greater than each’s respective melting point.
  • Common organic solvents that can be used in embodiments of the subject method include, but are not limited to, ethanol, isopropanol, acetone, alkanols, ketones, esters, ethers, and other chemicals that can dissolve hydrophobic ingredients.
  • Inorganic or aqueous solutions can be used as solvents for hydrophilic and ionic ingredients.
  • cosolvents such as, for example, crystalline excipients (e.g., urea, sugar, and synthetic polymers including povidone (PVP), polyethyleneglycols (PEG), and polymethacrylates); natural polymers including cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), ethylcellulose, and hydroxypropylcellulose) and starch derivatives (e.g., cyclodextrins); and surfactants (e.g., sodium laureth sulfate, inulin, Inutec® SP1 (beneo, Marmheim, Germany), Compritol® 888 ATO (Gattefosse, Saint-Priest, France, and Gelucire 44/14 (Gattefosse)), electrolytes, and some other modifiers can also be added to facilitate solubility and stability.
  • crystalline excipients e.g., urea, sugar, and synthetic polymers including povidone (PVP), polyethyleneglycols (P
  • solvents can be removed or solidified. Solvents removal can be achieved by evaporation, low-pressure drainage, and solidification by cooling under solidifying point or adding solidifying agents, or any other methods. In addition, it is also possible to use solvent vapor to carry the active ingredients into the pore space.
  • the active compound can be a single compound or a mixture of compounds.
  • the active compound is a medication.
  • the drug medication be a fibrate, including fenofibrate, aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, clofibride, gemfibrozil, ronifibrate, simifibrate; nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, dexibuprofen, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, naproxen, dexketoprofen, loxoprofen, aspirin, salicylic acid, diflunisal, salsalate, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac,
  • NSAIDs
  • a template is a porous medium that provides interstitial pore spaces to contain the active ingredients. Template structures are formed by carefully arranging the packing elements such that the interstitial space between the elements is capable and suitable to contain the one or more active compounds.
  • a critical nucleation size must be reached before crystallization can spontaneously proceed. Below or near the critical size, the amorphous state is more stable than the crystalline state. Therefore, it is feasible to achieve and maintain a stable amorphous state if the active ingredients are kept under or near the critical nucleation size.
  • the active compounds are confined inside interstitial porous space with pore size under or near the critical nucleation size, typically at nanometer scale.
  • small-sized ingredients are more active due to their large surface area and surface energy.
  • the porous templates used in the subject methods should be able to provide small enough interstitial spaces with large internal surface area. However, small interstitial spaces also make it difficult to load the compounds into porous templates and may limit the loading capacity of templates. Therefore, templates should be carefully designed to achieve both a high activity of ingredients and a good loading efficiency.
  • interstitial spaces are commonly produced by packing individual particles.
  • a careful consideration on porosity, mean pore size, mean particle size, agglomerate degree, permeability and specific surface area is required.
  • Porosity which is the fraction of the volume of voids over the total volume, may depend on packing architecture, degree of agglomeration, element particles’ homogeneity and morphology.
  • the porosity of the densest regular packing face-centered cubic crystal structure (FCC) or hexagonal closest packed crystal structure (HCP) lattice
  • FCC face-centered cubic crystal structure
  • HCP hexagonal closest packed crystal structure
  • the porosity of the loosest regular packing is 48% and that of the random loose packing is 41%. Therefore, the porosity of homogenous sphere packing ranges between 26%-48%.
  • agglomeration or gelation may increase the porosity to above 99% (e.g., aerogel).
  • element particles’ inhomogeneity or polydispersity also plays an important role on porosity by providing more choices for particle arrangements: small particles may effectively fill the pores between large ones and drastically reduce porosity, and at the same time increase the specific surface area per unit pore volume.
  • well-sorted particles with approximately the same size typically have a higher porosity than poorly-sorted or inhomogeneous counterparts.
  • porous templates with a high porosity are advantageous for their large capacity (40% or more) and easy infiltration of active ingredients into templates; on the other hand, however, small porosity has the advantage of large specific surface area.
  • small pore sizes (D p ) are preferred, which can be obtained by decreasing the value of particle size D e , agglomeration degree ND a , or porosity f.
  • the pore size D p can be adjustable from the smallest size, the molecular size of active ingredients, 0.1 nm to 1 nm, to the largest size, 10-times to 100-times the critical nucleus size of the active ingredients. It is possible to achieve porous templates with D p ranging from about 0.5 nm to about 500 nm, preferably between about 1 nm and about 50 nm, because colloidal particles with D e between 5 nm and 5000 nm are inexpensive, stable, well-sorted and commonly used in various industries. In certain embodiments, the pore size of the porous template is about 10% to about 10000% of the critical nucleus size of the active compound, preferably about 10% to about 1000%. The pore size can be measured using electron microscopy.
  • SSA Specific surface area
  • D e particle diameter
  • SSA porosity
  • ND a agglomeration
  • a strong agglomeration will significantly reduce SSA.
  • other element shapes including but not limited to, cubes, pyramids, rods, and/or platelets can also be used in the templates.
  • Different element shapes can provide more possibilities of template structures; and, integrating multiple shapes into one sample may achieve a better performance on specific surface area and mean pore size. Therefore, particle morphologies and their combinations can provide a new parameter space for templates with better porosity, surface energy, and performance.
  • the interstitial spaces of porous templates may initially be filled with a gas, liquid or a solid.
  • the ingredients can subsequently enter these spaces driven by capillary force, external pressure, dissolution into interstitial materials, diffusion, or by other means.
  • the template can be prepared by packed dry colloidal particles.
  • dry porous materials with nanometer scale pores can be made by, for example, acid etch, chemical synthesis, flame pyrolysis, which can be directly used as porous templates.
  • the template can be prepared by packing particles initially dispersed in colloidal suspensions.
  • particles can be used, such as, for example, silica 1 , alumina, calcium carbonate, metal dioxide, carbon 2 , and/or polyester beads.
  • silica particles are used in the colloidal suspensions.
  • Colloidal suspensions have the advantage of uniform particle size and a broad size range from 1 nm to 100 nm in diameter.
  • the particle size is about lnm, 5 nm, about 7 nm, about 12 nm, about 22 nm, about 44 nm, about 60nm, about 80nm, or about lOOnm.
  • larger particles can maintain their spherical shapes better, while smaller particles can merge together and achieve a larger degree of agglomeration.
  • the colloidal suspension can be about 1% to about 99%, about 10% to about 80%, about 10% to about 60%, about 25% to about 50%, or about 30% to about 40% solid mass, with the remaining portion comprising a solvent and, optionally, other chemicals, such as, for example, pH buffers, co-solvents, and surface modifiers for templates which are soluble in the corresponding solvent.
  • the suspensions are typically stabilized by either the electric repulsion or the steric repulsion, which inhibits the agglomeration of particles.
  • stabilizers can be used to inhibit the suspended particles from agglomeration.
  • the concentration of ionic stabilizers can be less than 1%, preferably in the range of about 0.05% to about 0.5%.
  • the concentration of steric stabilizers can depend on the specific situation under the maximum equilibrium proportion, with a range of about 0.1% to about 99%.
  • Stabilizers can also be, for example, sodium counter ions, ammonium counter ions, or other counter ions, such as, for example, phosphate counter ions, polyethylene oxide), poly(vinyl alcohol), poly(methacrylic acid), and poly(acrylic acid), polyacrylamide.
  • the ammonium counter ions can be more bio-friendly and pH stable throughout the template production process.
  • the pH value of the suspension can also be varied in a range of about 2 to about 12, about 4 to about 10, about 6 to about 8, or about 8.
  • a change in pH usually a lowering of pH, can cause the particles in the template to become more spherical and intact, while a higher pH value tends to increase the degree of merge and agglomeration.
  • acids or bases can be added to the suspension to modify the pH.
  • sol-gel process to pack colloidal suspension particles into a porous template
  • various approaches such as sol-gel process, centrifugation, gelation induced by IR or UV-VIS, and phase separation can be used.
  • Templates produced by sol-gel process can achieve different structures with only small changes in conditions 3 , such as the pH, concentration, electrolytes, temperature, and thus may find broad applications under various circumstances.
  • centrifugation is a common method to pack particles.
  • modifying particle surfaces to make them sensitive to light, pH, certain ions, and/or temperature can result in cross-linkage or gelation triggered by these parameters.
  • the particles can be concentrated with phase separation by adding electrolytes, applying specific solvents, changing the pH or temperature, or by other means.
  • the colloidal suspensions are spread and/or poured onto a surface.
  • the surface can be glass, metal, plastic, wood, ceramic, clay and/or other surfaces.
  • the colloidal suspensions are spread onto glass Petri dishes into thin layers, which can allow for fast evaporation.
  • the suspension can evaporate either rapidly inside a low-pressure chamber or slowly in open air.
  • the pressure can be about 0.001 atm to about 1 atm or, preferably, about 0.01 atm to about 0.2 atm.
  • the temperature can be about 18°C to about 100°C or, preferably, about 70°C to about 100°C.
  • the initial temperature and pressure can be set to 70°C and 0.2 atm for about 30 minutes, and the pressure can be adjusted as needed to achieve the fastest evaporation rate while avoiding boiling at low- pressure.
  • the colloidal suspensions can be maintained at 70°C and 0.01 atm for another 3 hours. After that, the colloidal suspensions can be heated to at least about 100°C for one hour to dry the solvent completely.
  • wet templates filled with interstitial liquid are directly used to load active ingredients.
  • Interstitial liquid may promote the mobility of active ingredients during the loading process. It may also help the templates from collapsing and maintain the initial structures. In some other embodiments, however, interstitial liquid needs to be removed to achieve the templates.
  • Various drying methods 4,5 such as slow vaporization, high temperature, low pressure, freeze dry, and/or supercritical drying can be used.
  • R is the capillary or pore radius
  • t is the imbibition or loading time
  • s is the surface tension
  • Q is the contact angle
  • h is the liquid viscosity.
  • increasing the loading time or decreasing the liquid viscosity can effectively enhance the loading outcome, given that the pore size and wetting properties of a porous template are typically fixed.
  • loading samples under high temperature (to reduce viscosity) with long enough time, such as, for example, several hours to days, can be useful.
  • both the solid ingredients and the porous templates can be ground into 0.1 pm to 1000 pm powders and mixed together.
  • modifiers such as, for example, silanes with various functional groups (e.g., amino-, halo-, hydroxyl, carboxyl, alkyl-, thiol-, or phenyl-) or lubricating agents such as, for example, minerals (e.g., talc or silica) or fats (e.g., vegetable stearin, magnesium stearate, or stearic acid) can also be added for a better imbibition mobility or wetting property.
  • functional groups e.g., amino-, halo-, hydroxyl, carboxyl, alkyl-, thiol-, or phenyl-
  • lubricating agents such as, for example, minerals (e.g., talc or silica) or fats (e.g., vegetable stearin, magnesium stearate, or stearic acid)
  • the mixed powders can then be pressed under high pressure to achieve a better mutual contact.
  • the temperature can be raised, such as, for example, above the melting point but below the thermal degradation temperature of the specific active ingredient during the pressing process or after pressing, to melt the active ingredients, which can effectively load the melted active compounds into the pores.
  • some solvent vapors such as, for example low molecular mass alcohol (e.g., ethanol or isopropanol), alkane (e.g., butane), alkene (e.g., kerosene), ether (e.g., DME), aromatic compound (e.g.
  • esters or terpenes or other organic or inorganic vapors
  • Another loading approach is to directly infiltrate ingredients solutions or melts into templates by applying pressure gradient. To achieve a high loading efficiency, repeated impregnation may also be applied.
  • the active compound and the templates can be ground into powders, and then mix the two types of powders uniformly.
  • the mixture can subsequently be compressed by hydraulic press inside a mold, or by other related means, into tablets at the pressure of about 10 to lOOMPa or even higher.
  • the tablets can, optionally, then be baked at a temperature above the active compound’s melting point for a suitable period of time of at least about 2 s, about 3 s, about 5 s, about 30 s, about 60 s, about 5 min, about 10 min, about 15 min, about 30 min, about 60 min, about 2 h, about 3 h, about 4, about 5 h, or greater.
  • the active compound can melt and imbibe into the nano-pores of the templates.
  • the sample is cooled to room temperature (about 18°C to about 28°C) and becomes the final product: the composite.
  • the mixing of the solid active compound and the solid template is sufficient to load the active compound into the template, without melting the mixed compounds.
  • the high capillary pressure of nano-sized pores e.g., at least about 1 MPa
  • the crystalline ingredients can be absorbed into nano-pores as well as transform from crystalline to an amorphous structure.
  • the active ingredient reaches an amorphous state at nanometer scale.
  • Such a state has an ultra-high free energy and thus a much better dissolution rate and solubility compared with its crystalline counterpart.
  • the present invention can thus solve this important issue by achieving a nano-amorphous material state with very high free energy and large specific surface area.
  • the composite can remain at this nano-amorphous state over a long period, from several months to more than one year.
  • a colloidal suspension of nanoparticles is centrifuged. With centrifugation the nanoparticles can be concentrated in the colloidal suspension. The supernatant can be removed to obtain a wet porous template that has pore spaces filled with the liquid in which the particles were suspended; the liquid can be water or other solvents, including organic solvents.
  • the active compound can then be heated to a temperature sufficient to melt the active compound. The melted active compound can then be placed in direct contact with the wet porous template. The combination of the melted active compound and the wet porous template can be kept at temperature adequate to maintain the active compound in a liquid form (melted). The elevated temperature can also cause the interstitial liquid in which the particles were suspended to evaporate.
  • the interstitial liquid evaporates completely and the active ingredient replaces it and fills the pore space.
  • the sample is then cooled to room temperature and the melted active compound re-solidifies inside the nanometer sized pores.
  • the composite with nano -amorphous state of the active compound is thus achieved.
  • this invention makes it possible for composites to disintegrate in a controlled manner, in the following two aspects: a) rapid release in targeted solvents and b) slow and controllable release with respect to time.
  • the dissolution profile of active ingredients may differ significantly.
  • the particles of templates may be hydrophilic or hydrophobic, oleophilic or oleophobic, acid-labile or alkaline-labile, or even directly dissolvable in certain solvents.
  • to dissolve oleophobic ingredients in oleic solvent for some industrial or medical purposes it is desirable to use template particles that are made from oleophilic polymers or have surfaces modified with oleophilic groups.
  • chemical bonds between template particles may be broken in certain solvents. For example, templates made by aqueous polymerization dominated by hydrolysis and hydration are extremely sensitive to the pH value of solvents.
  • This type of templates may easily decompose in solvents with specific pH values, such as the low pH of succus gastricus (gastric juice) or succus entericus (intestinal juice), a pH greater than 11, or a pH less than 4. Therefore, by choosing appropriate templates materials, our invention provides an approach to rapidly dissolve the product in targeted solvents.
  • the subject methods can also realize slow and controllable release by choosing the appropriate template.
  • active ingredients inside templates have high free energy and are thus soluble with a high dissolution rate.
  • the properties of templates can control disintegration rate of the composites. Template parameters, such as, for example, porosity, pore size, agglomerate degree, specific surface area, and wetting properties, can directly influence the disintegration rate of templates.
  • composites with large specific surface area about 50 m 2 /g to about 250 m 2 /g
  • small pore size about 0.5 nm to about 50 nm
  • highly connected porous channels significantly increase disintegration rate, while strong and semi-closed structures with high agglomeration degree and low porosity may strongly suppress disintegration.
  • Careful designs on these parameters can achieve ideal disintegration rate of templates ranging from seconds to a few weeks.
  • the active ingredients can achieve immediate release, which can release the active ingredient within a few seconds after putting the active ingredient into a solvent for fast adsorption and accurate dosage control; extended release, which can prolong the release time of the active ingredient from a few seconds to minutes, hours, days, or even for weeks to reduce dosing frequency; or delayed release, which can release the active ingredient after a certain amount of time (e.g., at least 1 min, 2 mins, 5 mins, 10 mins, 15 min, 30 mins, 45 mins, 1 h, 2 h, 3 h, 4 h, or a greater amount of time) to control where to release the active ingredient, such as, for example, in the digestive tract, and the delayed release can also control when the active ingredient is absorbed in a subject.
  • a hierarchical architecture of templates may also be designed, which can steadily release ingredients as macro- and microstructures which decompose in an ordered manner.
  • Silica colloidal suspensions (1 nm to 100 nm in diameter), are spread on glass Petri dishes into thin layers for evaporation. These glass Petri dishes are then put inside a vacuum oven with controlled temperature and pressure. The initial temperature and pressure were set to 70°C and 0.2 atm, and appropriate adjustment on pressure is needed to achieve the fastest evaporation rate while avoiding boiling at low-pressure. Within 30 minutes, most of the solvent water has evaporated and we keep the samples at 70°C and 0.01 atm for another 3 hours. After that, we bake the samples above 100°C for one hour to dry the water completely.
  • FIGS. 1A- 1B One typical sample made from 22 nm colloids is shown in FIGS. 1A- 1B.
  • FIG. 1A illustrates the raw data of nitrogen absorption and desorption curves
  • This example describes the method of loading the active ingredients into dry templates.
  • Fenofibrate is used to treat abnormal cholesterol level, which is a poorly water-soluble medicine with the melting temperature of 80.5°C.
  • Fenofibrate (99% crystal) into porous templates in four steps: (1) grinding the Fenofibrate crystal and the porous template into powders, (2) mixing the two types of powders uniformly, (3) pressing the mixture into tablets, and (4) baking the tablets at high temperature. More specifically, we first grind the Fenofibrate crystal and the templates into powders, and then mix the two types of powders uniformly.
  • the mixture is subsequently put into a mold and compressed by hydraulic press into tablets, at a high pressure above 10 MPa.
  • the tablets are then baked at a high temperature for multiple hours. During the baking period, the drug melt is imbibed into the nano-pores of the templates. After the baking period, the sample is cooled to room temperature and becomes the final product: the composite.
  • the active ingredient reaches an amorphous state at nanometer scale.
  • Such a state has an ultra-high free energy and thus a much better dissolution rate and solubility compared with its crystalline counterpart.
  • the present invention can thus solve this important issue by achieving a nano-amorphous material state with very high free energy and large specific surface area.
  • the composite can remain at this nano-amorphous state over a long period, from several months to more than one year to achieve a long shelf life.
  • EXAMPLE 3 - MICROSCOPIC STRUCTURE AND TEMPORAL STABILITY OF THE COMPOSITES TEM (Transmission electron microscopy), XRD (X-ray Powder Diffraction) and DSC (Differential Scanning Calorimetry) measurements are performed on the composite produced in Example 2 for preliminary analysis on the microscopic structure and amorphous fraction of the active ingredients.
  • FIGS. 3A-3C TEM images of pure template, pure Fenofibrate crystal and the composite are presented respectively in FIGS. 3A-3C.
  • the left panels are the real space images and the right panels are diffraction patterns in the Fourier space.
  • the template is clearly composed by closely-packed silica particles (left panel) and these particles are microscopically amorphous without any crystalline peaks (right panel).
  • the pure Fenofibrate crystal exhibits multiple diffraction peaks in the right panel.
  • FIG. 3C the composite is formed by filling the template pores with re-solidified Fenofibrate melt (left panel), and the drug is now amorphous as indicated by the lack of crystalline peaks (right panel).
  • curve 1 corresponds to the crystalline Fenofibrate sample with obvious crystalline peaks in both XRD and DSC
  • curve 2 is the freshly made composite without any crystalline peaks, indicating its nano-amorphous state
  • curve 3 is after 3 weeks
  • curve 4 is after 3 months and both samples remain in the nano -amorphous state over a long period of time.
  • Curve 5 comes from the 3- month old composite sample shown in curve 4, which is dissolved in ethanol first and then re- crystalized by evaporating the ethanol.
  • Ibuprofen is a poorly water-soluble nonsteroidal anti-inflammatory drug (NSAID) which has many applications.
  • NSAID poorly water-soluble nonsteroidal anti-inflammatory drug
  • Crystalline Ibuprofen (98%, acquired from Sigma Aldrich) with the melting point of 76°C is heated into melt and then placed on top of the wet template. We keep the sample at a high temperature to evaporate the interstitial water rapidly. After several hours water evaporates completely and the active ingredient fills the pore space. The sample is then cooled to room temperature and the Ibuprofen melt re-solidifies inside the nanometer sized pores. The composite with nano-amorphous state of Ibuprofen is thus achieved.
  • the Advil sample is a capsule filled with liquid which contains around 40% mass ratio of the drug.
  • the Zofen sample is a solid tablet which contains around 63% mass ratio of the drug.
  • Crystalline Ibuprofen contains about 98% of the drug.
  • Our composite made from the wet template contains only 20% mass ratio of the drug.
  • FIG. 6 shows that the composite achieves a concentration twice as high as Advil, 40-times higher than Zofen, and close to 1000-times higher than pure crystal.
  • our nano-amorphous state of drug exhibits a much better solubility and concentration with even less mass ratio of drug. The results thus show a much more efficient usage of active ingredient of our composite, and thus much less amount of active ingredient is needed with a significantly- reduced cost.
  • the size of particles can range from a few nanometers to hundreds of nanometers or even larger.
  • templates with the following particles: 5 nm, 7 nm, 12 nm, 22nm, 44 nm, 60nm, 80nm, and lOOnm.
  • the TEM images in FIGS. 7A-7C demonstrate the templates formed by 22 nm, 12 nm and 7 nm particles respectively. Apparently, larger particles can maintain their spherical shapes better while smaller ones tend to merge together and achieve a larger degree of agglomeration.
  • the stabilizers that inhibit the suspended particles from agglomeration can also be varied.
  • the examples mentioned previously are stabilized by sodium counter ions, which are unfavorable in some biological systems due to sodium ions.
  • suspensions stabilized by ammonium or other counter ions can also be used.
  • the ammonium systems are much more bio-friendly and pH stable throughout the template production process.
  • the pH value of the suspension can also be varied.
  • TEM images in FIGS. 8A-8C illustrate templates made from suspensions with initial pH of 10, 8 and 4 respectively.
  • the original sample has the pH value of 10.
  • FIGS. 8A-8C clearly shows that as pH decreases, the particles in the template become more spherical and intact, while a higher pH value tends to increase the degree of merge and agglomeration.
  • FIGS. 9A-9B shows TEM images of templates by these two methods: clearly fast drying under vacuum produces a template with more intact particles, while slow drying in open-air causes more agglomeration.
  • FIGS. 10A- 10B The time dependent dissolution profiles of Fenofibrate and Ibuprofen, whose stable concentrations are shown in FIG. 5 and FIG. 6, are illustrated in FIGS. 10A- 10B.
  • the total drug dose is about 50mg dissolved in 1L of deionized water at the room temperature.
  • a series of samples (3 mL) are withdrawn at predetermined time points, and the same amount of fresh media is added back to maintain a constant volume (1L). These withdrawn samples are filtered by 0.22 pm MCE filters, and their concentrations are then determined with a UV spectrophotometer.
  • FIGS. 10A and 10B The drug release profiles of Fenofibrate and Ibuprofen are shown in FIGS. 10A and 10B
  • Fenofibrate the UV absorbance for pure crystalline, physical mixture (i.e., without pressing and heating) and two commercial products (LIPANTHYL Supra and LIPANTHYL
  • Micro are extremely small, which are beyond the concentration versus absorbance calibration curve, and thus we can only report their absorbance data rather than the release percentage curve.
  • our composite can reach a concentration over 100-fold than all the other samples (including commercial drugs), and it rapidly releases all of the active ingredient within 1 minute. This comparison provides a well-founded proof that our approach provides an effective technique for insoluble drug candidates to break the solubility limit.
  • the composite again outperforms all other samples, with the fastest dissolution rate and highest ultimate released percentage, which dissolves 50% in 1 minute and up to 99% at the end of 6 hours.
  • FIG. IOC, FIG. 10D, FIG. 10E, and FIG. 10F show the release profiles of four drugs dissolved in water: Flurbiprofen, Trimebutine, Ramipril and Ketoprofen, respectively.
  • Flurbiprofen only mixing drug powder with silica template powder is sufficient to break the solubility limit. As shown in FIG. IOC, pure Flurbiprofen crystal exhibits relatively low release amount, i.e. 9.5% in 6 hours due to poor solubility. However, simply mixing the Flurbiprofen crystal and silica template powders can achieve a complete drug release in only 1 minute, and an approximately 10-fold higher concentration after 6 hours. With DSC measurements, we confirm that the drug in the mixture sample has an amorphous state. The heated composite also exhibits a similar improvement in solubility as the simple mixture without heating sample, as shown by the blue curve in FIG. IOC. Therefore, the simple mixing process is sufficient to change the Flurbiprofen crystal into the nano-amorphous state, which provides a rather simple and cheap manufacturing method to improve this drug’s performance.
  • More poorly-soluble drugs can be improved by our method, such as Ramipril and Ketoprofen shown in FIGS. 10E-10F.
  • simple mixture can improve the dissolution significantly, with more than 75% and 50% of drugs respectively released in 1 minute.
  • pressing and heating can further enhance the performance, with nearly 90% and 60% released in 1 minute. This indicates that depending on different drugs, the steps of mixing, pressing, and heating may make independent contributions to realize the nano- amorphous drug state.
  • Econazole nitrate an antifungal drug primarily used to treat a variety of fungal skin infections, is selected as our model drug due to its relatively low solubility in organic solvents.
  • the organic solvent, 2-Propanol has been chosen as our dissolution medium.
  • 2-Propanol By simply mixing this drug with silica template to form a physical mixture, its ultimate concentration in 2-Propanol already increases by more than 2 times than the pure crystalline counterpart, as shown in FIG. 10G. After pressing and heating, the composite achieves an even better dissolution behavior, with more than 95% of drug released in less than 1 minute. In this case, the physical mixture achieves some improvement; and the additional steps of pressing and heating achieve even further improvement.
  • DSC Differential Scanning Calorimetry
  • the pure drug exhibits a strong and sharp endothermic peak with the onset temperature of 80.8°C, corresponding to its melting point.
  • a melting peak still exists in the physical mixture sample; although, its intensity is decreased with 45.53% of the crystal remaining, which results in a partial amorphization of the drug.
  • the pressed and then heated sample in FIG. 11 A does not show any endothermic peak, which indicates a complete amorphization.
  • Such heated samples also exhibit better solubility and a faster dissolution rate, as shown in FIG. 10A. Therefore, mixing can only achieve partial amorphization for Fenofibrate; and, a further pressing and heating step is necerney for complete amorphization.
  • both the physical mixture and the heated sample do not exhibit any endothermic peak, indicating a complete amorphization. Accordingly, both the physical mixture and the heated samples exhibit excellent dissolution characteristics with complete drug release within 1 minute, as illustrated in FIG. IOC.

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EP22799596.6A 2021-05-06 2022-05-05 Realisierung des nanoamorphen zustands von materialien in nanoporösen vorlagen Pending EP4333817A2 (de)

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