CN115300448A - Achieving nano-amorphous state of materials within nano-porous templates - Google Patents

Abstract

The present invention relates to a method of fabricating nanoscale amorphous materials by solidifying or hardening the material within the nanoscale pores of a porous medium (i.e., a porous template). The porous template may be made by packing nanoscale particles or other means. The invention also relates to a method for manufacturing a porous template of nano-scale amorphous material.

Description

Achieving nano-amorphous state of materials within nano-porous templates

Background

An important problem is faced in the pharmaceutical industry: hydrophobic drugs or drug candidates have poor water solubility, limiting the utilization and absorption of the drug components in the human body. In addition to the problem of poor water solubility, there are problems in the pharmaceutical, catalyst and other industries that arise from poor oil solubility.

Thus, there is a need for a method that enables both hydrophobic materials to be soluble in water and oleophobic ingredients to be soluble in oil, and that can be widely used in many different fields.

Disclosure of Invention

A method of fabricating nanoscale amorphous materials by solidifying or hardening the material within the nanoscale pores of a porous medium (i.e., a porous template) is disclosed. The porous template may be made by packing nanoscale particles or other means. Due to the spatial limitation of the nano-scale pores, the solidification of the interior cannot satisfy the crystallization conditions, thus resulting in a nano-scale amorphous state. This nano-amorphous state has many surprising properties, including but not limited to: compounds are more soluble in various solvents than their crystalline counterparts, and at higher concentrations and faster dissolution rates; higher free energy than the crystalline counterpart; has larger specific surface area and surface energy and can keep stable for a long time; due to its amorphous and nanoscale structure, it has good mechanical or mass transfer properties.

The method of the invention can be applied to insoluble medicine materials to prepare the nano amorphous medicine with obviously improved bioavailability. The aqueous solution concentration can be increased many times compared to the crystalline counterpart and the dissolution rate is also significantly increased. The solubility and dissolution rate can also be widely adjusted by fine tuning the template properties and the curing process.

The process of the invention can be applied to organic solvents in addition to aqueous solutions and is therefore suitable both for oral and topical use. The method of the invention is a physical method, which does not change the chemical components of the material; thus, it can be applied generally to different materials, including but not limited to medical materials.

In some embodiments, the nano-amorphous material produced by the method may comprise only the active ingredient and the porous template, without any other materials, such as co-solvents or surfactants that promote solubility, which are often contained in typical pharmaceutical products. Therefore, the components used in the method of the present invention can suppress adverse effects caused by the additional components. The method of the invention can avoid complex packaging processes, such as soft capsule packaging required by liquid cosolvent, and can significantly reduce the manufacturing cost.

In some embodiments, the nanoporous templates enable the nano-amorphous material to remain stable for a longer period of time. In some embodiments, the compound fails to recrystallize or undergoes any other change in properties over a period of time ranging from several months to over a year. Therefore, it has a long shelf life.

In some embodiments, the method may also be used to prepare amorphous materials other than drugs. Other materials in the nanoporous template may be vitrified, thereby creating a nano-amorphous substance. The method can avoid the rapid cooling quenching method which is usually required when the amorphous material is manufactured, and opens up a new direction for manufacturing the nano-scale amorphous material.

Drawings

FIGS. 1A-1B show Brunauer-Emmett-Teller (BET) adsorption isotherms for a porous template made from 22nm particles, and the pore volume distribution derived from the BET adsorption isotherms.

Figures 2A-2B show X-ray powder diffraction (XRD) and Differential Scanning Calorimetry (DSC) analyses performed on compositions having different loading fractions. Crystalline components begin to appear at a volume fraction of 37% drug loading and grow with increasing drug loading.

Figures 3A-3C show Transmission Electron Microscope (TEM) images and electron diffraction patterns of the template without drug (figure 3A), crystalline fenofibrate (figure 3B), and a combination of both (figure 3C).

Fig. 4A-4B show XRD (fig. 4A) and DSC (fig. 4B) measurements of fenofibrate compositions and crystals. Curves 1 to 5 represent (1) crystalline fenofibrate, respectively; (2) a newly prepared fenofibrate composition with the mass ratio of 20 percent; (3) the same 20% composition stored for 3 weeks; (4) the same 20% composition was stored for 3 months; (5) The profile after recrystallization of the composition in ethanol was stored for 3 months.

Figure 5 shows a solubility comparison between two commercially available fenofibrate products and crystalline fenofibrate, different mass fractions of fenofibrate composition VS, produced using the method of the invention. The solution concentration is proportional to the height of the main peak of the ultraviolet/visible (UV/VIS) spectrum.

Figure 6 shows a solubility comparison between ibuprofen composition VS, two commercially available ibuprofen products and crystalline ibuprofen produced by the wet template technique using the method of the present invention. The solution concentration is proportional to the height of the main peak of the ultraviolet/visible (UV/VIS) spectrum.

FIGS. 7A-7C show Transmission Electron Microscope (TEM) images of templates made with particles of 22nm (FIG. 7A), 12nm (FIG. 7B), and 7nm (FIG. 7C), respectively.

FIGS. 8A-8C show a pH change from a pH having a different initial pH: 10 TEM images of templates made of colloidal suspensions of (fig. 8A), 8 (fig. 8B) and 4 (fig. 8C).

Fig. 9A-9B show TEM images of templates made by rapid evaporation under vacuum (fig. 9A) and slow evaporation in an open air environment (fig. 9B).

FIGS. 10A-10G show the general applicability of the method of the invention to various classes of drugs dissolved in water (FIGS. 10A-10F) and in organic solvents other than water (FIG. 10G).

FIGS. 11A-11G show Differential Scanning Calorimetry (DSC) results for various samples, which reveal the mass ratios of the crystalline components in the samples.

Detailed Description

The present invention relates to the fabrication of a combination of a nano-amorphous form of an active compound and a template to modify the properties of the active compound (e.g., solubility, dissolution rate, and mechanical properties) to enhance the performance of the active compound. In some embodiments, the method generally comprises the following two parts: (1) The nano amorphous active ingredient has good performance due to its amorphous state, nano-scale size, large surface area and controllable solvent preference; (2) A porous template for confining the active ingredient within its pores. The template plays a very important role in increasing the free energy of the ingredients, keeping the ingredients stable, controlling disintegration and inhibiting recrystallization.

Definition of

Ranges provided herein are to be understood as shorthand for all values falling within the range. For example, a range of 1 to 20 should be understood as: including any number, combination of numbers, or subranges from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20, and all intervening fractional values between the above integers, e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. For subranges, "nested subranges" extending from either end of the range are specifically contemplated. For example, nested sub-ranges of the exemplary range 1 to 50 may include 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 another direction.

In this application, "decrease" refers to a negative change, and "increase" refers to a positive change, wherein the negative or positive change 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%.

The conjunction "comprising," which is synonymous with "including" or "containing," is inclusive or open-ended and does not exclude additional unrecited elements or method steps. Conversely, the conjunction "consisting of 823070, 8230composition" excludes any element, step or ingredient not recited in the claims. The conjunction "consisting essentially of 8230 \8230composition" limits the scope of the claims to the specified materials or steps and those "does not materially affect the basic and novel characteristics of the claimed invention". The use of the term "comprising" encompasses other embodiments that "consist of" or "consist essentially of" the recited components.

As used in this application, the term "or" is to be understood as being inclusive, unless otherwise indicated herein or otherwise apparent from the context. As used in this application, the terms "a", "an" and "the" are to be construed as either singular or plural unless otherwise indicated herein or apparent from the context.

Unless otherwise indicated or apparent from the context, as used herein, the term "about" is to be understood as being within the normal tolerance of the art, e.g., within 2 standard deviations of the mean. "about" can be understood as being within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the above values. All numbers provided herein are modified by the term "about," unless the context clearly dictates otherwise.

In the present application, the term "porosity" or

Represents a measure of the void space in a material, defined as the fraction of the total volume occupied by the void volume. It takes a value between 0 and 1, or a percentage between 0% and 100%.

In the present application, the term "average pore diameter" or "D _p "denotes the average pore size of the porous material, and" average particle size "or" D _e "means the average size of individual particles as the basic packing element. The term "normalized mean pore diameter" or "ND _p ”

The ratio between the average pore diameter and the average particle diameter is indicated.

In this application, the term "permeability" or "κ" denotes the ability of a fluid to flow through a porous material. According to the Kozeny-Carman formula,

where a is a scaling factor.

In the present application, the term "specific surface area" or "SSA" means the total surface area per unit volume of material.

Active compound

The active compound used in the process of the invention according to the process described herein may be any compound which is stable above its melting temperature in an inert atmosphere, or any solid compound below its melting temperature.

In some embodiments, when the compound is at a melting temperature or higher, the compound can penetrate into the pores of the porous template. If oxidation occurs, or reaction with ambient air, a protective inert gas (e.g., pure nitrogen or argon) may be supplied to isolate the reactive compound from oxygen or any other reactive gas. In addition, the melting point can be lowered by means such as addition of a modifier and/or application of high pressure.

In some embodiments, the active compound is below the melting temperature and in the solid state. Even solid active compounds may penetrate into the pore space and change to a nano-amorphous state due to the strong surface effect created by the small pore size. The external stress applied by means of squeezing can also help the compound to penetrate into the pores.

In some embodiments, the active compound is soluble in some preferred solvents. In some embodiments, the active compound may be first dissolved in a solvent, particularly a compound that degrades at elevated temperatures, and the dissolved compound solution is then able to penetrate into the pores within the porous template. Preferably the solvent may be organic or inorganic; pure solvents or solutionsA mixture of agents; volatile or non-volatile. Even certain gases or solids may become solvents under certain specific conditions, for example, liquid carbon dioxide and polyethylene glycol (PEG) at temperatures above the respective melting points. Common organic solvents that may be used in embodiments of the method of the present invention include, but are not limited to, ethanol, isopropanol, acetone, alkanols, ketones, esters, ethers, and other chemicals that can dissolve hydrophobic components. Inorganic solvents or aqueous solutions may be used as solvents for the hydrophilic and ionic components. In addition, cosolvents, such as crystallization excipients (e.g., urea, sugars, and synthetic polymers including povidone (PVP), polyethylene glycol (PEG), and polymethacrylates); natural polymers including cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), ethylcellulose, and hydroxypropylcellulose) and starch derivatives (e.g., cyclodextrins); surfactants (e.g., sodium lauryl sulfate, inulin, and the like),

SP1 (BENEO of Mannheim, germany),

888ATO (Gattefoss, saint-Priest, france, and Gelucire 44/14 (Gattefoss), electrolytes, and other modifiers may also be added to promote solubility and stability. After loading the solution with the active ingredient dissolved in it into the porous template, the solvent can be removed or solidified. Solvent removal can be achieved by evaporation, low pressure venting, and solidification by cooling at freezing point or addition of a curing agent or any other method. In addition, solvent vapors can also be used to carry the active ingredient into the pore space.

In some embodiments, the active compound may be a single compound, or a mixture of compounds. In a preferred form, the active compound is a drug. The medicine is a fibrate medicine, including fenofibrate, aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate, gemfibrozil, clinofibrate, and double fibrate; non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, dexibuprofen, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, naproxen, dexketoprofen, loxoprofen, aspirin, salicylic acid, diflunisal, salsalac acid, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoxib, nonoxib, nimesulide, lonicin, linocine, lincose, lincosalone, and H-harpagin; trimebutine; asimadoline; non-polytotazine; angiotensin Converting Enzyme (ACE) inhibitors including ramipril, alacepril, captopril, zofenopril, enalapril, quinapril, perindopril, lisinopril, benazepril, imidazopril, trandolapril, cilazapril, fosinopril, alfacalcine, casein kinins, lactokinins and lactotripeptides, especially valine-proline (Val-Pro) and isoleucine-proline (Ile-Pro); and antifungal agents including imidazoles such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole, triazoles, thiazoles, allylamines, echinocandins; or any other drug suitable for use in the methods of the invention.

Form panel

The template is a porous medium that holds the active ingredient with interstitial spaces. The template structure is formed by finely arranging packing elements such that interstitial spaces between the elements are capable and suitable for containing one or more reactive compounds.

According to classical nucleation theory, a critical nucleation size must be reached before the crystallization process can automatically start. Below or near the critical dimension, the amorphous state is more stable than the crystalline state. Thus, if the active ingredient is kept below or near the critical nucleation size, it is feasible to achieve and maintain a stable amorphous state. To achieve the above goals, the active compound is confined within interstitial porous spaces having interstitial dimensions less than or about equal to the critical nucleation dimension (typically on the order of nanometers). Furthermore, the nano-sized active ingredient is more active due to its larger surface area and surface energy. Thus, the porous template used in the method of the invention should provide sufficiently small interstitial spaces with a large internal surface area. However, small interstitial spaces can make it difficult to load compounds into porous templates and can limit the loading capacity of the template. Therefore, the template should be carefully designed to produce active ingredients with high activity and achieve good loading efficiency.

As a typical method, interstitial spaces are generally created by stacking individual particles. In order to achieve the desired packing conditions, the porosity, average pore size, average particle size, degree of agglomeration, permeability and specific surface area need to be carefully considered.

Porosity is the fraction of the total volume of the pore volume and may depend on the packing structure, degree of agglomeration, uniformity and morphology of the elemental particles. For monodisperse spheres without any agglomeration or cross-linking, the porosity of the most densely regularly packed (face-centered cubic crystal structure (FCC) or Hexagonal Closest Packed (HCP) crystal lattice) is 26%, while the porosity of the random close packing is 36%. In contrast, the most loosely regular packed porosity was 48% and the randomly loosely packed porosity was 41%. Thus, the porosity of the uniform ball packing ranges between 26% and 48%. However, caking or gelling can increase the porosity above 99% (e.g., aerogels). Furthermore, the heterogeneity or polydispersity of the elemental particles provides more options for the particle arrangement, which has a significant impact on porosity, namely: the small particles can effectively fill the voids between the large particles and greatly reduce the porosity while increasing the specific surface area per unit pore volume. Thus, particles that are approximately the same size and that are well sorted typically have a higher porosity than particles that are under-sorted or non-uniform. On the one hand, a porous template with high porosity has the following advantages: its capacity is large (40% or more) and the active ingredient easily penetrates into the template; on the other hand, however, the advantage of a small porosity is a large specific surface area.

Normalized mean pore size (ND) for sphere packing _p ) And porosity of the material

Proportional to the degree of agglomeration (ND) _a ) With a similar relationship: that is, as porosity and/or agglomeration increases, the normalized average pore size will correspondingly increase. In some embodiments, the small pore size (D) _p ) Is preferred, which can be obtained by reducing the particle diameter D _e Degree of agglomeration ND _a Or porosity of

The value of (2) is obtained. Pore size D _p It can be adjusted from a minimum size, the molecular size of the active ingredient, 0.1nm to 1nm, to a maximum size, i.e. 10 to 100 times the critical core size of the active ingredient. Can obtain D _p Porous templates at about 0.5nm to about 500nm, preferably in the range of about 1nm to about 50nm, because colloidal particles with a De of between 5nm to 5000nm are relatively inexpensive, stable, well-sorted, and commonly used in various industries. In some embodiments, the pore size of the porous template is from about 10% to about 10000%, typically preferably from about 10% to about 1000%, of the critical core size of the active compound. Pore size can be measured using an electron microscope.

The permeability of the sphere packing can be determined by the Kozeny-Carman formula

Calculated to be mainly dependent on the pore size D _p Second power and porosity of

To the third power of (c). Generally, high permeability will allow better penetration, but at the same time, a smaller pore size D may also be required _p . Therefore, this should be carefully considered and designedA balanced relationship between these parameters.

The Specific Surface Area (SSA) depends on complex parameters. Smaller particle diameter D _e A larger SSA can be achieved. For having the same D _e Particle packing of (SSA) with porosity

And/or degree of agglomeration (ND) _a ) Is increased. A large degree of agglomeration will greatly reduce SSA. Assuming that the majority of the porous volume is filled with active ingredient, then SSA represents the surface area or surface energy per unit product volume. Thus, a larger SSA is crucial to improve the activity of the ingredient.

In addition to spherical particles, other elemental shapes can be used in the template, including but not limited to cubes, pyramids, rods, and/or platelets. Different element shapes may provide more possibilities for the template structure; also, integrating multiple shapes into a sample can achieve better specific surface area and average pore size performance. Thus, particle morphology and combinations thereof can provide a new parameter space for the template for better porosity, surface energy and performance.

The interstitial spaces of the porous template may be initially filled with a gas, liquid, or solid. The active ingredient may then dissolve into the interstitial material under capillary forces and external pressure, by diffusion or by other means into these interstitial spaces.

Successful fabrication of a template and active ingredient composition typically requires two steps: template preparation followed by loading with active ingredient.

Template preparation

In some embodiments, the template may be prepared by stacking dried colloidal particles. In some embodiments, dry porous materials with nanoscale pores can be prepared by means such as acid etching, chemical synthesis, flame pyrolysis, and the like, which can be used directly as porous templates.

In some embodiments, the template may be prepared by stacking particles initially dispersed in a colloidal suspension. Various types of particles may be used, for example dioxygenSilicon oxide, aluminum oxide, calcium carbonate, metal oxide, carbon ² And/or polyester beads. In a preferred embodiment, silica particles may be used in the colloidal suspension. Colloidal suspensions have the advantage of a uniform particle size, with a wide particle size range, typically between 1nm and 100nm. In some embodiments, the particle size is about 1nm, 5nm, about 7nm, about 12nm, about 22nm, about 44nm, about 60nm, about 80nm, or about 100nm. In some embodiments, larger particles may better retain their spherical shape, while smaller particles may fuse together to achieve a greater 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% by mass of solids, with the remainder including solvents and optionally other chemicals, such as pH buffers, co-solvents, and template surface modifiers soluble in the respective solvents. The suspension is usually stabilized by either electrorepulsion or steric repulsion, which inhibits agglomeration of the particles. In some embodiments, a stabilizer is used to inhibit agglomeration of suspended particles. For example, the concentration of the ionic stabilizer may be less than 1%, preferably in the range of about 0.05% to about 0.5%. The concentration of the steric stabilizer is dependent on the particular case at the maximum equilibrium ratio and ranges from about 0.1% to about 99%. The stabilizer may also be, for example, a sodium counter ion, an ammonium counter ion, or other counter ions, such as phosphate counter ions, poly (ethylene oxide), poly (vinyl alcohol), poly (methacrylic acid), and poly (acrylic acid), polyacrylamide. The ammonium counter ion is more bio-friendly and pH stable throughout the template fabrication process.

In some embodiments, the pH of the suspension may also vary within the following ranges: about 2 to about 12, about 4 to about 10, about 6 to about 8, or about 8. Changes in pH, typically a decrease in pH, result in the particles in the template becoming more spherical and intact, while higher pH tends to increase the degree of fusion and agglomeration. In some embodiments, an acid or base may be added to the suspension to alter the pH.

In some embodiments, to pack the colloidally suspended particles into the porous template, various methods can be used, such as sol-gelGel method, centrifugation method, IR or UV-VIS induced gelation and phase separation method. By means of templates produced by sol-gel processes, the different structures need only minor conditions ³ Variations are possible, such as pH, concentration, electrolyte, temperature, etc., and the template is therefore widely used in a variety of situations. For stable colloidal suspensions, centrifugation can be used as a common method of packing particles. In addition, modifying the surface of the particles to be sensitive to light, pH, specific ions and/or temperature can result in crosslinking or gelling triggered by these parameters. In some embodiments, the particles may be agglomerated with phase separation by adding electrolytes, using specific solvents, changing pH or temperature, or by other means.

In some embodiments, the colloidal suspension is spread and/or poured on a surface. The surface may be glass, metal, plastic, wood, ceramic, clay, and/or other surfaces. In some preferred forms, the colloidal suspension is spread into thin layers on a glass petri dish, allowing rapid evaporation. In some embodiments, the suspension may evaporate rapidly in a low pressure chamber or slowly in an open air environment. In some embodiments, the pressure may be from about 0.001atm to about 1atm, or preferably from about 0.01atm to about 0.2atm. In some embodiments, the temperature may be from about 18 ℃ to about 100 ℃, or preferably from about 70 ℃ to about 100 ℃. In some preferred approaches, the initial temperature and pressure may be set at 70 ℃ and 0.2atm, respectively, for about 30 minutes, and then the pressure adjusted as needed to achieve the fastest evaporation rate while avoiding boiling at low pressure. The colloidal suspension may be maintained at 70 deg.C and 0.01atm for an additional 3 hours. Thereafter, the colloidal suspension is heated to at least about 100 ℃ for 1 hour to completely dry the solvent.

In some embodiments, a wet template filled with interstitial liquid is used directly to load the active ingredient. The interstitial fluid may promote the mobility of the active ingredient during loading. It may also help the template to avoid collapse and maintain the original structure. However, in some other approaches, the interstitial fluid needs to be removed to achieve the template. Can useVarious drying methods ^4,5 Such as slow evaporation, high temperature, low pressure, freeze drying and/or supercritical drying, etc.

However, some methods may result in excessive agglomeration, which is undesirable for the template. Excessive agglomeration during sol-gel processing can be inhibited by a variety of methods, such as changing the pH, concentration, electrolyte, temperature, evaporation under vacuum, or combinations thereof.

Loading with active ingredients

Several methods of loading active ingredients into the pore spaces of the template are described herein. For ingredients that are stable above the melting temperature, the molten liquid ingredient can be used directly for loading. For ingredients that are unstable at high temperatures, solutions in specific solvents can be used. However, after loading such solutions, it may be necessary to remove the solvent. In addition to liquid solvents, solvent vapors can be used to carry the active ingredient into the pore space. Since the vapors easily leave the system, no further solvent removal is necessary thereafter. The active ingredient in its solid state may also be used directly for loading into the pores.

For loading liquid samples such as melts or solutions, the Lucas-Washburn formula ⁶ The predicted absorption length in the small capillaries is:

where R is the capillary or pore radius, t is the absorption or loading time, σ is the surface tension, θ is the contact angle, and η is the liquid viscosity. In some embodiments, extending the loading time or reducing the viscosity of the liquid may be effective to increase the loading effect, provided that the pore size and wettability of the porous template generally remains fixed. Thus, it may be useful to load the sample under high temperature conditions (to reduce viscosity) for a sufficiently long time (e.g., hours to days).

To facilitate absorption or loading of the composition into the pattern holes, it may also be desirable to increase the contact area. Thus, the solid component and the porous template may be ground to a powder of 0.1 μm to 1000 μm at room temperature below the melting point and mixed together. In some embodiments, modifiers, such as silanes with various functional groups (e.g., amino, halo, hydroxyl, carboxyl, alkyl, thiol, or phenyl) or lubricants, such as minerals (e.g., talc or silica) or fats (e.g., vegetable fat, magnesium stearate, or stearic acid) may also be added to achieve better absorption fluidity or wettability. The mixed powders are then pressed under high pressure to achieve better mutual contact. The temperature may be increased, for example, above the melting point of the particular active ingredient, but below the thermal degradation temperature of the particular active ingredient, during or after compression is complete, to melt the active ingredient, which may effectively load the melted active compound into the pores. In some embodiments, some solvent vapors, such as low molecular weight alcohols (e.g., ethanol or isopropanol), alkanes (e.g., butane), alkenes (e.g., kerosene), ethers (e.g., DME), aromatics (e.g., esters or terpenes), or other organic or inorganic vapors, can flow into the mixture, carrying the ingredients into the pore spaces. The other loading method comprises the following steps: the active ingredient solution or melt is extruded directly into the template by applying a pressure gradient. The impregnation can also be repeated in order to achieve a high loading efficiency.

To load the active compound into the dry template, in some embodiments, the active compound and template can be ground into a powder and then the two powders are uniformly mixed together. The blend may then be compressed into tablets by hydraulic pressure in a die or by other related means at pressures of about 10 to 100Mpa or even higher. The tablets may then be selected to be baked at a temperature above the melting point of the active compound for an appropriate time period of at least about 2 seconds, about 3 seconds, about 5 seconds, about 30 seconds, about 60 seconds, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or longer. During baking, the active compound can melt and wick into the nanopores of the template. After baking was complete, the samples were cooled to room temperature (about 18 ℃ to about 28 ℃) to give the final product: a composition is provided. In some embodiments, the solid active compound and the solid template are simply mixed, sufficient to load the active compound into the template without melting the mixed compound. Under the high capillary pressure of the nanopores (e.g., at least about 1 MPa), the crystalline component may be absorbed into the nanopores and transition from a crystalline structure to an amorphous structure.

The active ingredient reaches a nanoscale amorphous state due to resolidification of the drug within the nanoscale pores below or near the critical nucleation size. This state has a very high free energy and therefore dissolves faster and more soluble than the crystalline state. In view of the fact that many newly developed drugs and drug candidates have very poor water solubility, the present invention provides a method for realizing a nano amorphous material having an extremely high free energy and a large specific surface area in order to solve this significant problem. Further, the composition may maintain this nanoscale amorphous state for months to more than a year.

To load the active ingredient into the wet template, a colloidal suspension of nanoparticles is centrifuged. The nanoparticles can be agglomerated in a colloidal suspension by centrifugation. Removing the supernatant to obtain a wet porous template having void spaces filled with the liquid of the original suspension; the liquid may be water or other solvents, including organic solvents. Subsequently, the active compound can be heated sufficiently to a temperature that the active compound melts. The molten reactive compound can then be directly contacted with the wet porous template. The molten reactive compound and the wet porous template are maintained above the melting temperature of the reactive compound. Higher temperatures can cause the liquid in the interstices of the particles to evaporate. After being maintained at elevated temperatures (e.g., 80 ℃) for several hours, the interstitial liquid completely evaporates, and the active ingredient displaces the liquid and fills the interstitial spaces. The sample is cooled to room temperature and the molten reactive compound resolidifies within the nanopores. Thus, a nano amorphous composition of the active compound is obtained.

In addition, the present invention may enable the composition to disintegrate in a controlled manner in two aspects: a) A fast release in the target solvent, and b) a slow and controlled release over time.

Quick release in target solvent

There may be large differences in the dissolution of the active ingredient in the different templates. In some embodiments, the particles of the template may be hydrophilic or hydrophobic, oleophilic or oleophobic, acid-or base-labile, or even directly soluble in certain solvents. For example, when an oleophobic ingredient is dissolved in an oily solvent for certain industrial or medical purposes, it is often desirable to use template particles made of an oleophilic polymer or modified at their surface with oleophilic groups. In addition, in certain solvents, the chemical bonds between the template particles may be broken. For example, templates prepared by aqueous polymerization reactions dominated by hydrolysis and hydration are extremely sensitive to the pH of the solvent. Such templates may be readily decomposed in solvents of a particular pH, such as the low pH of gastric or intestinal fluid, a pH greater than 11, or a pH less than 4. Thus, by selecting the appropriate template material, our invention provides a method of rapidly dissolving the product in the target solvent.

Slow and controlled release with respect to dissolution time

By selecting a suitable template, the method of the invention also allows for slow and controlled release. In some embodiments, the active ingredient inside the template has a high free energy and is therefore capable of dissolving at a high dissolution rate. In some embodiments, the template is characterized such that it can control the rate of disintegration of the composition. Template parameters such as porosity, pore size, degree of agglomeration, specific surface area and wettability can directly affect the disintegration rate of the template. More specifically, if the composition has a specific surface area (about 50 m) ² G to about 250m ² A large pore size (about 0.5nm to about 50 nm) and highly interconnected porous channels, the disintegration rate can be significantly increased, while a strong and semi-closed structure, high degree of agglomeration and low porosity, strongly inhibits disintegration. Careful design of these parameters can achieve the desired rate of template disintegration, ranging from seconds to weeks. The active ingredients are released immediately, and the active ingredients can be released within seconds after being put into a certain solvent, so that quick adsorption and accurate dose control can be realized; prolonged release of the active ingredient, extending the release time of the active ingredient from a few seconds to minutes, hours, days or even weeksThe frequency of administration can be reduced; delayed release of the active ingredient may be achieved by releasing the active ingredient after a certain period of time (e.g., at least 1min, 2min, 5min, 10min, 15min,30min, 45min, 1h, 2h, 3h, 4h or longer (e.g., 4 hours or more) to control the location of the released active ingredient (e.g., in the digestive tract), and delayed release may also control when the active ingredient is absorbed in the subject.

All patents, patent applications, provisional applications, and publications, including all figures and tables, referred to or cited in this application, are incorporated herein by reference, to the extent they are not inconsistent with the explicit specification of this application.

Specific examples of the process of the invention are given below. These examples should not be construed as limiting the scope of the invention. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise indicated.

Examples

Example 1 template preparation by Rapid evaporation under vacuum

Silica colloid suspensions (1 nm to 100nm in diameter) were spread in a thin layer on glass petri dishes for evaporation. These glass petri dishes were then placed in a vacuum oven at a specific temperature and pressure. The initial temperature and pressure were set at 70 ℃ and 0.2atm, respectively, and then the pressure was appropriately adjusted to achieve the fastest evaporation rate while avoiding boiling at low pressure. Within 30 minutes, most of the solvent water had finished evaporating, and we kept the sample under temperature and pressure conditions of 70 ℃ and 0.01atm for another 3 hours. Subsequently, the sample was baked at a temperature of 100 ℃ or higher for one hour to completely evaporate water.

The pore size distribution of the template made by vacuum flash evaporation was then analyzed using a BET (porous surface measurement based on Brunauer-Emmett-Teller theory) instrument. FIGS. 1A-1B show a typical sample made of a 22nm colloid; FIG. 1A shows raw data for nitrogen absorption and desorption curves; shown in FIG. 1BThe peak value is the pore volume distribution diagram of 5nm-7 nm. More specifically, macropores with a particle size of more than 8nm make up about 10% of the total volume of the sample, and micropores with a particle size of less than 8nm make up about 26% of the total volume of the sample. Taken together, we found that about 36% of the total sample volume was porous (i.e., the porosity was about

)。

Example 2 Loading of active ingredients into Dry templates

This example illustrates a method of loading an active ingredient into a dry template. We take the drug fenofibrate as a specific example of the active ingredient. Fenofibrate is used for treating abnormal cholesterol levels, and is a poorly water-soluble drug with a melting point of 80.5 ℃. We loaded fenofibrate (99% crystals) into the porous template by four steps: (1) Grinding the fenofibrate crystals and the porous template into powder; (2) uniformly mixing the two powders together; (3) compressing the mixture into tablets; and (4) baking the tablet at an elevated temperature.

More specifically, we first ground fenofibrate crystals and a template into powders and then uniformly mix the two powders. The mixture is then placed in a mould and compressed into tablets with a hydraulic press at a high pressure above 10 Mpa. The tablets were then baked at high temperature for several hours. During baking, the drug melt is drawn into the nanopores of the template. After the baking is finished, the sample is cooled to room temperature, so as to obtain a final product: a composition is provided.

The active ingredient reaches a nanoscale amorphous state due to the drug re-solidifying within the nanoscale pores near the critical nucleation size. This state has a very high free energy and therefore a faster dissolution rate and better solubility than the crystalline state. In view of the fact that many newly developed drugs and drug candidates have very poor water solubility, the present invention provides a method for realizing a nano amorphous material having an extremely high free energy and a large specific surface area in order to solve this significant problem. Moreover, the composition can retain this nano-amorphous state for long periods of time (from months to over a year) to achieve long shelf life.

To investigate the maximum proportion of nano-amorphous component that can be produced inside the composition, we loaded different doses of fenofibrate into the template formed by 22nm particles. The sample was then measured by XRD (X-ray powder diffraction) to determine its crystallinity, as shown in fig. 2A. For clarity, we move the curve vertically and place the high-score curve higher. The drug loading fraction is defined herein as the volume of fenofibrate divided by the sum of fenofibrate and the volume of the particles. Obviously, when the number of drug substance integrals reaches above 37%, the crystallization peak starts to appear and gradually increases; and a completely amorphous state when the sample is at 32% volume fraction and below.

To quantify the ratio of crystalline component to amorphous component of fenofibrate in a sample, we performed DSC (differential scanning calorimetry) measurements on the sample of figure 2A and the results are given in figure 2B. Obviously, the fenofibrate crystal component begins to appear and grows when the drug loading fraction reaches 37%. However, the fraction of amorphous fraction remains approximately constant around 32% -36%. This fraction is close to the pore volume fraction of the 22nm template shown in FIG. 1A. Thus, the maximum content of amorphous component is limited by the pore space of the template, and solidification outside the pore space may result in crystalline component.

Example 3 microstructure and time stability of the composition

TEM (transmission electron microscope), XRD (X-ray powder diffraction) and DSC (differential scanning calorimetry) measurements were carried out on the composition produced in example 2, and preliminary analyses were carried out on the microstructure and amorphous portion of the active ingredient.

Fig. 3A-3C show TEM images of pure template, pure nofibrate crystals, and composition, respectively. The left side is the real aerial image and the right side is the diffractogram in fourier space. In fig. 3A, the template is explicitly composed of close-packed silica particles (left panel), and these particles are microscopically amorphous, without crystalline peaks (right panel). In fig. 3B, a plurality of diffraction peaks of the pure fenofibrate crystal are shown on the right side. In fig. 3C, the composition was formed by filling the template well with the re-solidified fenofibrate melt (left panel); the drug is now amorphous due to the absence of a crystalline peak (right panel).

Stability issues are critical to the shelf life of the drug. For this test, we measured the change in state of the composition over time using XRD and DSC methods in fig. 4A (XRD) and fig. 4B (DSC): the curve 1 is a fenofibrate crystal sample, and has obvious crystallization peaks in XRD and DSC; curve 2 is the freshly prepared composition, with no crystallization peak, indicating that it is nano-amorphous; curve 3 is after 3 weeks; curve 4 is the condition after 3 months, both samples remain nano-amorphous for a long time. Curve 5 is derived from a sample of the composition after 3 months as shown in curve 4, which is first dissolved in ethanol and then recrystallized by evaporating the ethanol. The re-appearance of the fenofibrate crystalline peak confirms that fenofibrate remains intact after long-term storage in the nano-amorphous state. We also note that the DSC plot of curve 5 has a small peak to the left of the main peak, indicating the presence of very small crystalline particles, possibly on the order of nanometers. These time-based systemic measurements show that our compositions remain stable with respect to time and are able to remain amorphous and inhibit recrystallization throughout storage for many months.

Example 4 solubility measurement of the composition

To test the solubility of our product, we dissolved a sample of the composition in deionized water and compared it to the concentration of a commercial product under the same dissolution conditions. Since the concentration is proportional to the UV absorption spectrum, the concentration can be measured by a UV spectrophotometer.

We prepared a sample of the composition as described in example 2, which was then dissolved in deionized water at a mass ratio of 1/1000 (i.e., 1g of the composition dissolved in 1kg of water). The dissolution process took 4 hours: we first applied ultrasound to the suspension for 1 hour and then left it for 3 hours without ultrasound. Finally, the supernatant of the suspension was collected and filtered through a 0.45 μm mce filter. The UV absorption of the organic solution is proportional to its concentration as predicted by Beer-Lambert rule, so we use a UV-VIS spectrophotometer to measure the concentration of our solution.

To evaluate the performance of our product, we compared it with two typical fenofibrate commercial products on the market and 99% pure crystalline fenofibrate products, as shown in fig. 5. The two fenofibrate products are commercially available as 200mg LIPANTHYL Micro (old generation on top left) and 160mg LIPANTHYL Supra (new generation on top right). We compared our composition product samples with the two above products at different fenofibrate mass ratios of 20%, 15%, 10% and 5%, respectively. Note that the mass ratio of the drug in the LIANTHYL Micro 200mg tablet was 54%, and the mass ratio of the drug in the LIANTHYL Supra 160mg tablet was 22%. Although our samples were less active, figure 5 shows that they reached higher concentrations: is 10-100 times higher than the curve (at the bottom of the curve) for the commercial product and the crystal sample. To better illustrate the curves at these bottoms, we have enlarged the vertical scale and have drawn the enlarged bottom area in the lower figure.

In summary, our composition samples can achieve concentrations ten to one hundred times higher than commercial products and pure crystals under the same dissolution conditions, i.e., the same mass of sample dissolved in deionized water. This confirms that our nano amorphous drug has higher water solubility and therefore better bioavailability should be achieved. We have also noted that our samples can produce significantly higher concentrations even with lower levels of active ingredient. This indicates better efficacy, while the quality of the expensive pharmaceutical ingredient required is greatly reduced, which can effectively reduce costs.

Example 5 Loading of active ingredients into Wet templates

The previous examples were all based on loading the active ingredient into a dry template. In addition to this loading technique, we can also load the active ingredient into a wet template. We used the drug ibuprofen as a specific example of this wet templating technique. Ibuprofen is a poorly water soluble non-steroidal anti-inflammatory drug (NSAID) that has many applications. We illustrate how to load it into a wet template made by centrifugation of a colloidal suspension of 22nm particles. By centrifugation, we packed the nanoparticles tightly at the bottom of the vessel. After removing the supernatant, we obtained a wet porous template with the interstitial spaces filled with water. Crystalline ibuprofen (98% from Sigma Aldrich) with a melting point of 76 ℃ was heated to melt and then placed on top of the wet template. We placed the sample at high temperature and allowed the interstitial water to evaporate rapidly. After a few hours, the water has evaporated completely and the active ingredient fills the pores. The sample was then cooled to room temperature and the ibuprofen solution re-solidified within the nanopores. Thus, a nano amorphous composition of ibuprofen may be achieved.

We then compared the solubility of our composition with two commercial products Advil and Zofen and pure crystalline ibuprofen. The Advil sample is a liquid filled capsule containing about 40% by mass of the drug. The Zofen sample is a solid tablet containing about 63% drug by mass. Pure crystalline ibuprofen contains about 98% drug. Our composition made from the wet template contained only about 20% drug by mass. However, as shown in fig. 6, the concentration achieved by this composition is twice as high as Advil, 40 times higher than Zofen, and nearly 1000 times higher than pure crystal. This again indicates that our nano amorphous drug exhibits better solubility and concentration at a lower mass ratio of drug. Therefore, the use efficiency of the active ingredients in the composition is greatly improved, the demand of the active ingredients is greatly reduced, and the cost can be effectively reduced.

Example 6 various Material Properties and conditions for template preparation

We can prepare porous templates based on various material properties and preparation conditions. For example, colloidal suspensions having different particle sizes, initial fractions, pH values, etc., can be used to meet various needs of the pharmaceutical and other industries.

The particle size may range from a few nanometers to hundreds of nanometers and even larger. For example, we can make a template using the following particles: 5nm, 7nm, 12nm, 22nm, 44nm, 60nm, 80nm and 100nm. The TEM images in fig. 7A-7C show the templates formed by 22nm, 12nm and 7nm particles, respectively. It is clear that larger particles can better retain their spherical shape, while smaller particles can fuse together and achieve a greater degree of agglomeration.

The stabilizer that inhibits agglomeration of the suspended particles may also vary. The previously described examples, stabilization is achieved by sodium ions, but this is disadvantageous in certain biological systems due to the presence of sodium ions. To solve this problem, it is also possible to use a suspension stabilized by ammonium or other ions. The ammonium ions are more bio-friendly and the pH is stable throughout the template fabrication process.

The pH of the suspension may also vary. TEM images in fig. 8A-8C show templates made from suspensions with initial pH of 10, 8 and 4, respectively. The pH of the crude sample was 10. We added hydrochloric acid to adjust the initial pH for the different templates. Figures 8A-8C clearly show that as the pH is lowered, the particles in the template will be more spherical and intact, while higher pH may increase the degree of fusion and agglomeration.

The rate of evaporation can also play an important role in the fabrication of the template. The suspension may be rapidly evaporated in a vacuum chamber or slowly evaporated in an open air environment. FIGS. 9A-9B show TEM images of templates made by these two methods: clearly, rapid drying under vacuum can produce templates with more intact particles, while slow drying in an open air environment causes more agglomeration.

Example 7 in vitro dissolution Studies of various drugs and solvents

(1) Dissolution test of fenofibrate and ibuprofen

In vitro dissolution tests are essential to demonstrate the oral bioavailability of poorly soluble drugs. The time dependent dissolution profiles of fenofibrate and ibuprofen are shown in fig. 10A-10B, while the final stable concentrations of these two drugs are shown in the previous fig. 5 and 6. The total drug dose was about 50mg dissolved in 1L deionized water at room temperature. To obtain a concentration versus time plot, a series of samples (3 mL) were taken at predetermined time points and the same volume of deionized water was added back to maintain a constant volume (1L). These extracted samples were filtered through a 0.22 μm MCE filter and the concentration was determined by UV spectrophotometer.

The drug release profiles of fenofibrate and ibuprofen are shown in fig. 10A and 10B. For fenofibrate, the ultraviolet absorbance of pure crystals, physical mixtures (i.e. without pressurization and heating) and two commercial products (LIPANTHYL Supra and LIPANTHYL Micro) is extremely small, exceeding the calibration curve of the concentration vs absorbance, so we can only report their absorbance data and not the release percentage curve. Clearly our composition can reach concentrations of more than 100 times that of all other samples (including commercial drugs) and it releases all active ingredients rapidly within 1 minute. This comparison provides sufficient evidence that our method provides an effective means of breaking the solubility limit for insoluble drug candidates. For ibuprofen shown in figure 10B, our composition exceeded all other samples again by 50% in 1 minute, and by as much as 99% at the end of 6 hours, with the fastest dissolution rate and highest final release percentage.

(2) General applicability to other poorly soluble drugs in water

To demonstrate the general applicability of the present invention, we have applied our technique to 4 other insoluble drugs. We have found that our method can improve the solubility and dissolution of all these drugs. However, the mixing, compression and heating processes may affect the dissolution to varying degrees, and combinations of processes suitable for a particular drug may be used. Fig. 10C, 10D, 10E and 10F show the release profiles of four drugs dissolved in water, respectively: flurbiprofen, trimebutine, ramipril and ketoprofen.

For flurbiprofen, merely mixing the drug powder with the silica template powder is sufficient to break through the solubility limit. As shown in fig. 10C, the pure flurbiprofen crystals, due to their poor solubility, showed a relatively low release amount, i.e., 9.5%, within 6 hours. However, by merely mixing the flurbiprofen crystal and the silica template powder, complete drug release can be achieved within 1 minute, and the concentration thereof is increased by about 10 times after 6 hours. By DSC measurement, we confirmed that the drug in the mixture sample has an amorphous state. The heated composition also exhibited a similar solubility improvement as the simple mixture of the unheated sample, as shown by the blue curve in FIG. 10C. Thus, a simple mixing process is sufficient to convert the flurbiprofen crystals into the nano-amorphous state, which provides a relatively simple, inexpensive manufacturing process for improving the performance of a drug.

However, in another example for trimebutine, pressing and heating become necessary steps. As shown in fig. 10D, the pure trimebutine crystals were insoluble in water and released only 1.18% over the entire 6 hours. Mixing trimebutine crystals with the template powder increased the solubility by a factor of four, reaching a release of about 4.72% after 6 hours, but this was still very low. DSC measurements showed that a sample of the mixture still contained some amount of crystalline drug (see figure 11B). However, after compressing the blended powder into tablets and heating, the heated composition may release more than 70% of the drug in less than 1 minute, and about 95% of the drug in only 5 minutes. DSC measurements indicated that the drug became completely amorphous after heating (see fig. 11B). Thus, the pressing and heating process becomes an important procedure in case the mixing process itself only slightly increases the solubility.

Our approach can improve the less soluble drugs such as ramipril and ketoprofen shown in figures 10E-10F. In both cases, simple mixing can significantly improve dissolution, releasing over 75% and 50% of the drug within 1 minute, respectively. In addition, pressing and heating can further improve performance, releasing nearly 90% and 60% in 1 minute. This shows that the mixing, pressing and heating process can play different roles for achieving the nano-amorphous state of the drug, depending on the drug. For optimal effect, we should select the appropriate step or combination of steps for different drugs by balancing the improvement in solubility with the additional cost of each step.

(3) Generalizing our process to organic solvents

In addition to oral drugs that are soluble in water, topical drugs such as ointments have also taken up a considerable proportion of the commercial drug market. However, some drugs are not well released in organic solvents, which severely limits their bioavailability. Therefore, the product has great market potential by improving the solubility of the product in organic solvents. Fortunately, in vitro dissolution tests demonstrated that our method can also be used to improve solubility in organic solvents.

Econazole nitrate (ECZ) is an antifungal drug used primarily for the treatment of a variety of fungal skin infections and was selected as our model drug due to its low solubility in organic solvents. We chose the organic solvent 2-propanol as our dissolution medium. By simply mixing the drug with the silica template to form a physical mixture, the final concentration of the mixture in 2-propanol has been increased more than two-fold over the pure crystalline counterpart, as shown in fig. 10G. After compression and heating, the composition achieves better dissolution performance, releasing more than 95% of the drug in less than 1 minute. In this example, some improvement was achieved with the physical mixture; the additional pressurization and heating steps facilitate further improvements.

Example 8 analysis of different samples Using Differential Scanning Calorimetry (DSC)

To explore the mechanism of enhanced solubility, we investigated the mass ratio of the pure drug crystals, physical mixture and crystalline components of the heated sample (i.e., degree of amorphization) in fig. 11A-G using Differential Scanning Calorimetry (DSC). The presence of an endothermic peak caused by crystal melting indicates the presence of a crystalline component of the drug. We can calculate the area of this peak and thus quantify the mass ratio of the crystalline component in the entire drug mass loaded in the sample.

A certain mass of sample was accurately weighed and then placed in an aluminum container and a nitrogen gas stream was introduced. The scanning temperature range we chose includes the drug melting point and heats the sample at a heating rate of 10 deg.C/min. While we used the same but empty container as a reference. We observed the following behavior:

(1) Mixing, compression and heating are combined to achieve good dissolution.

For fenofibrate in fig. 11A, the pure drug exhibits a strong and sharp endothermic peak at an onset temperature of 80.8 ℃, corresponding to its melting point. A melting peak still exists in the physical mixture sample. Although the strength was reduced, the residual amount of the crystals was 45.53%, indicating amorphization of a part of the drug. However, the sample heated after the pressurization in fig. 11A did not show any endothermic peak, indicating that it was completely amorphized. As shown in fig. 10A, such heated samples showed better solubility and faster dissolution rates. Therefore, mixing can only achieve partial amorphization of fenofibrate; whereas a further step of pressing and heating is necessary to achieve complete amorphization.

Similar properties were also found in other samples: the trimebutine drug in fig. 11B showed 25.05% crystalline residue after physical mixing; after further pressure and heat processes, the crystalline component completely disappeared. Thus, as shown in fig. 10D, there was only a slight improvement in solubility after the mixing process, and the improvement was more pronounced in the heated sample. Thus, we have found that for certain drugs, such as fenofibrate and trimebutine, simple mixing still leaves a significant fraction of the crystalline component. Therefore, further pressurization and heating are required to achieve the desired properties.

As shown in fig. 11C-11D, for some drugs such as ramipril and ketoprofen, the mixing process resulted in a significant decrease in crystallinity, leaving only 20.86% and 13.12% crystalline residues. As shown in fig. 10E-10F, dissolution was significantly improved as most of the drug had been converted to the amorphous state. Upon further application of pressure and heat, no endothermic peaks were observed in the DSC measurements (FIGS. 11C-11D), indicating complete conversion to the amorphous state. Accordingly, the dissolution profiles of these drugs showed an increase in the final concentration and a further increase in the dissolution rate (fig. 10E-10F).

For ibuprofen and econazole, in fig. 11E and 11F, the absence of endothermic peaks for simple mixture samples confirms that the mixing process itself achieves a completely amorphous state. However, as shown in fig. 10B and 10G, pressure and heat are still the steps necessary to achieve better dissolution. It is believed that the application of pressure and heat helps to further reduce the particle size of the drug, allowing the drug to better achieve the nano-amorphous state and thus better dissolution characteristics.

(2) The mixing process itself can achieve good dissolution

In contrast, for some drugs, simply mixing the drug with the template can completely transform the drug crystal into the nano amorphous state, thereby greatly improving solubility and dissolution. For example, for the drug flurbiprofen in fig. 11G, neither the physical mixture nor the heated sample showed the presence of an endothermic peak, indicating complete amorphization. Thus, as shown in fig. 10C, both the physical mixture and the heated sample showed good dissolution characteristics, enabling complete drug release within 1 minute.

In this example, we used DSC thermal analysis to study amorphization of the pure crystalline drug, physical mixture and heated sample reported in FIGS. 10A-10G. In some cases, the mixing process itself can only eliminate a portion of the crystalline fraction, and we still need compression and heating to convert the entire drug into the nano-amorphous state. However, there are also some examples in which the mixing process itself can achieve the nano-amorphous state. In order to achieve the best results with a minimum of steps, we should consider the specific properties of the drug and the template.

Conclusion

In summary, we have invented a new approach to the problem of poor drug solubility that allows better bioavailability and therapeutic efficacy. Our method is applicable to a variety of drugs and different solvents, including water and organic solvents. This ensures its general applicability to oral and topical drugs. By using the processing steps/procedures flexibly, the pharmaceutical ingredients can be changed from the crystalline state to the nano-amorphous state, greatly improving their solubility. The typical steps of template making, drying, mixing, pressurizing and heating are common industrial operations, suitable for low cost mass production.

It is to be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. In addition, any element or limitation of any invention or embodiment thereof disclosed in this application may be combined with any and/or all other elements or limitations (alone or in combination) or any other invention or embodiment thereof disclosed in this application and all such combinations are understood to be within the scope of the invention and not to constitute any limitation on the scope of the invention.

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Claims (24)

1. A method of fabricating a nanoscale amorphous material, the method comprising:

i) Providing an active compound;

ii) providing a porous template, wherein the pore size of the porous template is from about 10% to about 10000% of the critical core size of the active compound;

iii) Melting the active compound or suspending or dissolving the active compound in a solution; and

iv) loading the active compound in solid, molten, dissolved or suspended form into the porous template.

2. The method of claim 1, wherein the porous template has a pore size of from about 10% to about 1000% of the critical core size of the active compound.

3. The method of claim 1, wherein the active compound is a drug.

4. The method of claim 3, wherein the drug is any one of the following: fenofibrate, ibuprofen, flurbiprofen, trimebutine, ramipril, ketoprofen, econazole, NSAIDs, asimadoline, non-doxazone, ACE inhibitors of angiotensin converting enzyme, and antifungal compounds.

5. The method of claim 1, wherein the porous template is made from a colloidal suspension.

6. The method of claim 5, wherein the colloidal suspension is a silica particle suspension.

7. The method of claim 5, wherein the colloidal suspension further comprises ammonium or sodium ions.

8. The method of claim 5, wherein the colloidal suspension consists of particles having a diameter of about 1nm to about 100nm.

9. The method of claim 1, wherein the porous template is centrifuged to remove supernatant to obtain a wet porous template.

10. The method of claim 1, wherein the porous template is dried to obtain a dried porous template.

11. The method of claim 10, wherein the porous template is dried at a temperature of about 20 ℃ to about 100 ℃ and a pressure of about 0.01atm to about 1 atm.

12. The method of claim 10, further comprising milling and mixing the dried porous template and the solid active compound into a powder having a particle size of about 0.1 μm to about 1000 μm.

13. The method of claim 12, further comprising compressing or compacting the mixed porous template and the powder of the solid active compound together into a tablet.

14. The method of claim 1, wherein the porous template is homogeneously mixed with the active compound in a solid state, such that the active compound in a solid state is automatically loaded into the porous template.

15. The method of claim 1, wherein the active compound is melted and maintained at a temperature at or above the melting point of the compound during loading of the melted active compound into the porous template.

16. The method of claim 1, wherein after loading the porous template with the active compound in a solid, molten, dissolved, or suspended state, the method further comprises:

v) cooling the solid, molten, dissolved or suspended active compound loaded in the porous template to below the melting point temperature value of the active compound and/or removing the solvent after loading the active compound into the porous template.

17. The method of claim 16, wherein the solid, molten, dissolved or suspended active compound loaded in the porous template is cooled to about 18 ℃ to about 28 ℃ or about room temperature.

18. A method of making a porous template, the method comprising:

i) Providing a colloidal suspension of particles suspended in a solvent;

ii) centrifuging the colloidal suspension and removing the supernatant to obtain a wet template or spreading the colloidal suspension as a thin layer on a surface, and drying the thin layer at a high temperature of about 70 ℃ to about 100 ℃ under a pressure of about 0.01atm to 1atm for about 3 hours or about 3 days to obtain a dry template.

Or

iii) Dry colloidal particles are stacked or nanoporous porous materials are prepared by methods such as acid etching, chemical synthesis, flame pyrolysis or other methods.

19. The method of claim 18, wherein the particle is any one of the following: silica, alumina, calcium carbonate, metal dioxide, carbon, and polyester beads.

20. The method of claim 18, wherein the particles are of uniform size, have a diameter of about 1nm to 100nm, and have an initial concentration of about 1% to about 60% of the colloidal suspension.

21. The method of claim 18, wherein the solvent comprises any one of a buffer, a stabilizer, and a surface modifier.

22. The method of claim 21, wherein the concentration of the stabilizing agent is about 0.05% to about 0.5%.

23. The method of claim 21, wherein the stabilizer is any one of sodium ions, ammonium ions, phosphate ions, polyethylene oxide, polyvinyl alcohol, polymethacrylic acid, polyacrylic acid, and polyacrylamide.

24. The method of claim 18, wherein the surface is made of any one of glass, metal, plastic, wood, ceramic, and clay.

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