Method for improving drug solubility and drug composite material having improved solubility

Abstract

A method for improving drug solubility and a drug composite material having improved solubility. The method comprises preparing a silica colloidal suspension from silica nanoparticles having a diameter between 2 nm and 100 nm; rapidly evaporating a solvent by means of controlling the temperature and pressure, so as to obtain a porous surface material with ultra-high density silanol groups retained on the surface; and loading drug molecules. By controlling the size of nanoparticles and the density of silanol groups, drug molecules can be effectively adsorbed under anhydrous conditions, and rapidly desorbed and released in an aqueous environment.

Description

A method for improving drug solubility and a drug composite material with enhanced solubility. Technical Field

[0001] This invention relates to pharmaceutical technology, and in particular to a method for improving drug solubility and a drug composite material with enhanced solubility. Background Technology

[0002] In the pharmaceutical industry, 60%-70% of drug candidates fail to pass clinical trials and commercialize due to low solubility. Furthermore, the number of insoluble drug candidates is increasing due to their lipophilic properties. These drugs exhibit good affinity for receptors and lipid membranes in the human body, but also face the problem of poor dispersion in water. Therefore, developing effective solubility-enhancing methods is crucial for the development of new drugs and the improvement of existing drugs.

[0003] To address this critical issue, various methods have been developed, such as chemical modification, particle size reduction, solid dispersion, lipid-based formulation, or mesoporous confinement. However, each of these methods has its own limitations. Chemical modification involves altering the molecular structure of the drug and is only applicable to certain drugs. Particle size reduction achieved through mechanical forces or precipitation typically only shows minor increases in solubility. Methods such as solid dispersion and lipid-based formulation face limitations related to drug specificity and stability. Although mesoporous structures based on inorganic materials exhibit excellent stability, they often suffer from incomplete drug release. Therefore, current state-of-the-art technologies face a series of challenges, including limited applicability, low efficacy, stability issues, and high cost. Thus, a next-generation technology that is universally applicable, efficient, stable, and cost-effective is needed.

[0004] It should be noted that the information disclosed in the background section above is only for understanding the background of this application, and therefore may include information that does not constitute prior art known to those skilled in the art.

[0005] Summary of the Invention

[0006] The main objective of this invention is to solve the problems existing in the above-mentioned background art and to provide a method for improving drug solubility and a drug composite material with enhanced solubility.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] In a first aspect of the present invention, a method for improving drug solubility includes the following steps:

[0009] S1. Raw material preparation: Prepare colloidal silica uniformly suspended in an aqueous solution, including silica nanoparticles with a diameter between 2 and 100 nm;

[0010] S2. Preparation of high-density silanol group surface material: The silica gel suspension is rapidly evaporated by controlling temperature and pressure to retain ultra-high density silanyl groups on the surface, thereby enhancing the surface affinity for drug molecules and water and forming a porous structure to increase the specific surface area;

[0011] S3. Drug loading: The active pharmaceutical ingredient is mixed with the high-density silanol group surface material, and the drug molecules are loaded into the material through a drug loading process.

[0012] Furthermore, the density of silanol groups on the surface of the silica nanoparticles is 10 OH / nm. 2 The above measures are taken to increase the adsorption capacity of the silica nanoparticles for drug molecules.

[0013] Furthermore, in step S2, the evaporation is carried out using a vacuum evaporation process.

[0014] Furthermore, in step S3, the drug loading process includes grinding, pressing, and baking a mixture of the active drug component and the high-density silanol group surface material.

[0015] Further, in step S3, the pressing and baking process includes placing the ground mixture into a mold and pressing it using a hydraulic press to form tablets, and then baking the tablets at an optimized temperature for a set time.

[0016] Furthermore, the active pharmaceutical ingredient includes any one or more of the following: fenofibrate, rapamycin, diclofenac, isotretinoin, trimetidine, simvastatin, olaprodine, rapaglitazone, indomethacin, felodipine, flurbiprofen, paclitaxel, docetaxel, naproxen, ibuprofen, progesterone, ketoprofen, and ramipril.

[0017] In a second aspect of the invention, a drug composite material with enhanced solubility is prepared by the method described above for improving drug solubility.

[0018] The present invention has the following beneficial effects:

[0019] This invention proposes an innovative method to improve drug solubility. This method utilizes a specially prepared porous silica template with high specific surface area and ultra-high silanol density, thereby significantly enhancing the adsorption capacity for drug molecules. By carefully controlling the size of the nanoparticles and the density of the silanol groups, this invention can effectively adsorb drug molecules under anhydrous conditions and rapidly desorb and release them in an aqueous environment, thus significantly improving drug solubility, potentially by two to three orders of magnitude. Furthermore, the method of this invention is simple, cost-effective, and scalable, and the prepared drug composite material exhibits excellent stability and long-term storage properties, making it a promising next-generation formulation technology in the pharmaceutical industry.

[0020] The porous template of this invention is made using silica nanoparticles with diameters between 2 and 100 nanometers. The high curvature convex surfaces of these particles help reduce the interaction between silanol groups, thereby achieving a high silanol density. By precisely controlling solvent evaporation under temperature and pressure conditions, particle aggregation is induced, forming a stable porous structure. Furthermore, by changing the type of solvent and evaporation conditions, the properties of the porous template can be further tuned to meet the needs of different drug molecules.

[0021] In terms of drug loading, this invention provides flexible methods for loading drug molecules into porous templates, including injecting molten drug into the template or mixing drug powder with template powder. These methods are simple and easy to scale up, helping to reduce costs and improve production efficiency.

[0022] Furthermore, this invention validated the effectiveness of its solubilizing formulation through in vitro and in vivo experiments, demonstrating the significant advantages of its composite material in terms of dissolution rate and bioavailability. Long-term stability testing showed that its drug composite material retains its performance even after years of storage, which is crucial for the commercialization and clinical application of drugs.

[0023] The versatility of this invention offers broad prospects for future applications in drug delivery, catalysis, controlled drug release, environmental remediation, and sensor development. Its method, based on physical adsorption and desorption mechanisms, avoids chemical modification of drug molecules, thus enabling wider applicability and enhanced safety. In summary, this invention provides a novel, efficient, stable, economical, and widely applicable drug solubility enhancement technology.

[0024] Other beneficial effects of the embodiments of the present invention will be further described below. Attached Figure Description

[0025] Figure 1A shows the physical properties, in vitro and in vivo solubility performance, and long-term stability of the solubilizing formulation PE-07 based on nanoscale silica particles, as well as its effectiveness in improving drug solubility.

[0026] Figure 1B evaluates the solubilizing effect of the PE-07 formulation on 18 poorly soluble active pharmaceutical ingredients (APIs) using UV-VIS spectroscopy, demonstrating its broad applicability to different drug molecules and its significant solubility enhancement capability.

[0027] Figure 2 shows the adsorption isotherm and desorption kinetics, as well as a schematic diagram of APIs on the PE-07 silica surface.

[0028] Figure 3 shows the experimental evaluation of the effect of silanol density, examining the solubilization effect of materials with different silanol densities, and measuring the energy change from API-silanol to water-silanol through simulation. Detailed Implementation

[0029] The embodiments of the present invention will be described in detail below. It should be emphasized that the following description is merely exemplary and not intended to limit the scope and application of the present invention.

[0030] Common silica surfaces typically possess silanol groups (Si-OH). These silanol groups exhibit an affinity for water and organic functional groups, including carboxyl, carbonyl, hydroxyl, and amide groups, which are ubiquitous in pharmaceutical compounds. However, the typical density of silanol groups is 4-6 OH / nm. 2 It has a stronger affinity for active pharmaceutical ingredients (APIs) than water, causing the APIs to adhere to the surface instead of being released into the water.

[0031] This invention proposes a novel solubility enhancement method based on a novel adsorption and desorption mechanism of silica surfaces with ultra-high silanol group density. This method is applicable to various drugs and has the potential to become a next-generation formulation technology. By increasing the density of silanol groups, the affinity of the material surface for both APIs and water is enhanced. However, the increase in surface-to-water interaction is more significant. Therefore, a surface designed with ultra-high density silanols can strongly adsorb various drug molecules under anhydrous conditions. When introduced into an aqueous environment, such a surface preferentially binds water molecules, leading to the desorption and release of previously adsorbed drug molecules. This adsorption-desorption cycle can significantly enhance the dispersion of drug molecules in water, potentially increasing solubility by two to three orders of magnitude.

[0032] This invention provides a method for improving drug solubility, comprising the following steps:

[0033] Step S1. Raw material preparation: Prepare silica nanoparticles with a diameter between 2 and 100 nm as raw materials.

[0034] To ensure biocompatibility, silica, which has been recognized as Generally Recognized As Safe (GRAS) by the FDA, can be selected as the raw material. In a preferred embodiment, the density of silanol groups on the surface of the silica nanoparticles is 10 OH / nm. 2 The above measures are taken to increase the adsorption capacity of the silica nanoparticles for drug molecules.

[0035] Step S2. Preparation of porous template: The silica nanoparticles are dispersed in a solvent to form a colloidal suspension. The solvent is rapidly evaporated by controlling the temperature and pressure to induce the silica nanoparticles to aggregate and form a porous matrix with a large specific surface area, which serves as a porous template.

[0036] In a preferred embodiment, in step S2, the evaporation is performed using a vacuum evaporation process.

[0037] Step S3. Drug loading: The active drug component is mixed with the porous template, and the drug molecules are loaded into the porous template through a drug loading process to form a drug composite material.

[0038] In a preferred embodiment, step S3, the drug loading process includes grinding, pressing, and baking the mixture of the active pharmaceutical ingredient and the porous template. Further, in step S3, the pressing and baking process includes placing the ground mixture into a mold and pressing it using a hydraulic press to form a tablet, followed by baking the tablet at an optimized temperature for a set time.

[0039] In some embodiments, the active pharmaceutical ingredient includes (but is not limited to): fenofibrate, rapamycin, diclofenac, isotretinoin, trimetidine, simvastatin, olaprodine, rapaglitazone, indomethacin, felodipine, flurbiprofen, paclitaxel, docetaxel, naproxen, ibuprofen, progesterone, ketoprofen, and ramipril.

[0040] This invention also provides a drug composite material with enhanced solubility, prepared by any of the methods for improving drug solubility described in the foregoing embodiments.

[0041] The following further describes specific embodiments and experimental verifications of the present invention.

[0042] To achieve high silanol density while preventing interactions between adjacent silanol groups, silica nanoparticles with diameters between 2 and 100 nm were used as the raw material. These nanoparticles possess highly convex surfaces, effectively increasing the distance between adjacent silanol groups located on the curved surfaces, thereby reducing their mutual influence. Starting from an initial aqueous colloidal suspension, the aggregation of these particles was induced by rapid solvent evaporation under precisely controlled temperature and pressure conditions. The resulting dried particles adhered firmly together via Si-O-Si bonds, while the pores were able to accommodate drug molecules.

[0043] Figure 1A illustrates a solubilized formulation of PE-07 based on nanoscale silica particles, demonstrating advantages in market competitiveness, in vivo validation, stability, and versatility. (a) Actual photograph of the PE-07 excipient and (b) Microscopic TEM image showing the nanoscale silica particles firmly bonded together to form millimeter-sized solid blocks. (c) TEM image of the PE-07 formulation composite, demonstrating the binding of fenofibrate within the particle-filled porous template. The PE-07 formulation of ibuprofen (red triangle) was compared in vitro (d) and in vivo (e). The solubility of (blue inverted triangle) and crystalline ibuprofen (yellow circle) was compared, with equal amounts of ibuprofen in each group. Stability was assessed by comparing UV-VIS absorption of the original formulation (solid line) and after storage (dashed line). Four APIs were tested: flurbiprofen (blue), ketoprofen (red), ibuprofen (black), and fenofibrate (purple). Flurbiprofen, ketoprofen, and ibuprofen were stored for six months, while fenofibrate was stored for two years.

[0044] Figure 1B shows the solubilizing effect of 18 poorly soluble APIs evaluated using UV-VIS spectroscopy by comparing the equilibrium concentrations of the crystalline form (black) and the PE-07 formulation (red). The peak size of the spectra was linearly correlated with the solution concentration. Measurements were performed 6 hours after the dissolution period to ensure complete API release, using DI water as the solvent.

[0045] As shown in Figure 1A(a)-(b), this porous matrix, referred to as a "template," possesses a large specific surface area and an extremely high silanol density, reaching up to 10-30 OH / nm. 2The surface area is 2-6 times that of traditional mesoporous silica surfaces. The synergistic effect of the large surface area and ultra-high silanol density results in excellent adsorption capacity for a large number of drug molecules. Drug molecules can be loaded into the porous template by various methods, such as injecting molten drug into the template or mixing drug powder with template powder (method). By preparing the template and then loading the drug, the final drug composite material is produced, as shown in Figure 1A(c). The drug composite material prepared by the method of the present invention exhibits extremely high solubility in water, low production cost, and long-term stability—three key attributes of next-generation formulation technology. The exact performance and potential mechanism of the method of the present invention will be described in detail below.

[0046] To evaluate the method of the present invention, ibuprofen as the active pharmaceutical ingredient (API) was incorporated into a template (named PE-07) constructed from 7 nm silica particles. Commercial ibuprofen products were then tested using in vitro and in vivo experiments. Comparative analysis.

[0047] For in vitro dissolution testing, a standard dissolution testing apparatus is used, and pure water is used as the dissolution medium to obtain a more controlled testing environment. This invention relates to pharmaceutical composite materials and commercial products. The dissolution curves for the crystalline form of API are shown in Figure 1A(d). The results indicate that the composite material of the present invention achieves rapid dissolution, with a solubility exceeding 90% within the first hour, while the solubility of the crystalline API is less than 20% after 6 hours. Notably, the formulation of the present invention exhibits superior performance compared to established... The formula yielded twice the solubility results.

[0048] To evaluate in vivo effects, pharmacokinetic (PK) studies were conducted using mice as test subjects (method). Specifically, four groups of mice (n=6 per group) were administered the composite material (PE-07) of this invention, respectively. The API and template were crystallized, and their plasma concentrations were then measured at different time points. As shown in Figure 1A(e), the PE-07 sample of the present invention exhibited significantly enhanced pharmacokinetic properties: it achieved almost [missing information - likely referring to a specific effect or characteristic] with the same amount of API. The peak plasma concentration (Cmax) was twice that of crystalline API and the total exposure (i.e., area under the curve) was more than 1.5 times higher. These data highlight the superior performance of the composite material of the present invention. Furthermore, the elevated plasma concentration was rapidly reached within 15 minutes, indicating the rapid action of the composite material of the present invention. Unsurprisingly, the template sample showed zero concentration, as it did not contain API.

[0049] The long-term stability of the composite material of the present invention was also rigorously evaluated by comparing fresh samples with those that had been stored for extended periods. As shown in Figure 1A(f), freshly prepared samples and samples stored for 6 months and 2 years were evaluated by dissolving them in pure water for 6 hours until a stable concentration was reached. Subsequently, the UV absorption spectra of each solution were measured, where the peak height was directly correlated with the solute concentration. The results revealed a significant consistency between the freshly prepared samples and the long-stored samples, confirming the durable stability of the composite material of the present invention.

[0050] Furthermore, the broad applicability of the method of the present invention was examined by applying it to a variety of 18 insoluble APIs, as shown in Figure 1B. Comparison of ultraviolet spectra showed that the PE-07 composite material of the present invention (i.e., the template made of 7 nm nanoparticles) generally exhibited a 10-fold to 2000-fold increase in solubility compared to crystalline APIs.

[0051] In summary, all these data confirm that the method of the present invention is not only effective and stable, but also broadly applicable to a wide range of pharmaceuticals. Furthermore, the manufacturing process relies on commonly practiced techniques, namely, temperature and pressure adjustments, which are simple, scalable, and cost-effective. Therefore, the technology of the present invention has the potential to become a next-generation formulation platform technology.

[0052] To elucidate the potential mechanism of the solubility-enhancing technology of this invention, a series of composite material samples were prepared, each loaded with an increasing amount of API into a template. Each sample was then dissolved in pure water, and the amount of API dissolved from each composite material was quantified. Experimental results showed that only one layer of drug molecules coated on the template surface dissolved in water. To ensure the broad applicability of the findings of this invention, this analysis was performed using two different types of APIs, ibuprofen and fenofibrate, and the results are presented below.

[0053] Figure 2 shows the adsorption isotherm and desorption kinetics, as well as a schematic diagram of APIs on the PE-07 silica surface. The dissolved API depth is plotted against the API / template mass ratio of two model APIs, ibuprofen (a) and fenofibrate (c). The API / template ratio was adjusted by modifying the number of APIs while controlling the amount of template. The soluble API depth was calculated by dividing the dissolved API volume by the surface area of ​​the template, the API volume being measured after dissolution in water using UV-VIS spectroscopy (Supplementary Material). The inset illustrates individual molecules, ibuprofen (b) and fenofibrate (d), adsorbed onto the raised PE-07 surface via hydrogen bonds (dashed lines), connecting the APIs and Si-OH groups (highlighted in red). The annotation shows the estimated molecular height calculated using Bondi van der Waals radii. e, the kinetics of the percentage of ibuprofen released in water. Data are presented with equations... A satisfactory logarithmic fit to the linearized form of f, where the power of time equals 1. The illustration shows the desorption of ibuprofen into the aqueous medium, attributed to the competitive advantage of water (blue) over the surface.

[0054] As shown in Figures 2(a) and (c), despite the increase in the amount of API loaded, the amount of dissolved API saturates to specific values, with saturation occurring at 11% (Figure 2(a)) and 25% (Figure 2(c)) by mass fraction on the x-axis, corresponding to 24% and 46% by volume fraction, respectively. These saturation points are quite different from the case where the template pore space is completely occupied, approximately at 30% by volume fraction (see measurements in SI). Therefore, it is clear that the maximum amount of soluble API contained in the template is independent of the total pore volume of the template.

[0055] To understand the actual reason for this maximum dissolution, the amount of dissolved API was converted into its corresponding thickness on the template surface. This was achieved by first determining the surface area of ​​the porous template using the Bruno-Emmett-Taylor (BET) method (Method and SI), and then dividing the volume of dissolved API by this surface area. As shown in Figure 2(a), the thickness of the ibuprofen API obtained was 1.05 nm, which is very close to the molecular height of 1.35 nm when ibuprofen molecules are adsorbed on the surface silanol, as shown in Figure 2(b).

[0056] Similar calculations were performed for fenofibrate. Figure 2(c) shows that this corresponds to a surface coating thickness of 0.79 nm, which again matches the molecular height of 0.855 nm when the API is adsorbed onto the surface, as shown in Figure 2(d). Notably, the two types of molecules adopt significantly different orientations during adsorption: ibuprofen “stands up” on the surface (Figure 2(b)), while fenofibrate “lies flat” (Figure 2(d)). Despite these distinct molecular orientations, the obtained thickness consistently corresponds to the molecular height, indicating that only the monolayer of molecules closest to the surface can dissolve in water. This provides strong evidence for a surface adsorption mechanism.

[0057] Next, the dissolution kinetics of water-adsorbed drug molecules were investigated. A very rapid dissolution rate was observed: over 90% of the fenofibrate API dissolved within the first 60 seconds (Figure 2(e)). This rate contrasts sharply with the dissolution times of several hours typically associated with mesoporous silica formulations, as reported by Vallet-Regí (2004), indicating a very different dissolution mechanism.

[0058] In the area of ​​polymer adsorption, Granick has established the adsorption capacity D. σ (t) follows an exponential decay model:

[0059] The exponent β is primarily influenced by the energy difference between solvent-surface and adsorbent-surface interactions. When β = 1, it indicates that the surface affinity for the solvent exceeds the surface affinity for the adsorbent, leading to the release of the adsorbent from the surface and the attraction of the solvent. In the experiments of this invention, the pharmaceutical API exhibited properties similar to those of short polymers. Undissolved API on the surface conformed to the decay model, where the dissolution kinetic power was exactly 1, as illustrated in the inset of Figure 2(e).

[0060] While measurements of solubility and rate indicate adsorption and desorption behavior, a precise understanding of the underlying mechanisms remains elusive. To elucidate the fundamental mechanisms, first-principles density functional theory simulations were applied to capture the picture of molecular interactions. The simulations of this invention reveal that, in a dry environment, ultra-high density silanol groups on a silica template surface can adsorb drug molecules and promote their desorption upon contact with water.

[0061] First, the adsorption process was depicted in a dry environment, using ibuprofen as an example API. The bulk density of ibuprofen was estimated per nm. 2 The surface area density is 5 molecules. This is consistent with the density of silanol groups on a typical mesoporous silica surface, ranging from 4 to 6 groups per nm. 2 On average, there are approximately 5 groups per nm. 2 Therefore, in standard mesoporous silica, each ibuprofen molecule may form a hydrogen bond with one silanol group. According to DFT calculations, the enthalpy change resulting from this one-to-one adsorption is -58.17 kJ / mol, insufficient to overcome the enthalpy of vaporization required to extract one ibuprofen molecule from its volume, which is 80.3 kJ / mol. Therefore, typical mesoporous silica cannot effectively adsorb ibuprofen to form a stable composite material.

[0062] In contrast, the silica template of this invention features a significantly higher density of silanol groups than normal—up to four times higher. This high density of silanol groups enhances the magnitude of the adsorption enthalpy. When an ibuprofen molecule interacts with two silanol groups, the adsorption enthalpy increases to -71 kJ / mol, approaching the enthalpy of vaporization of ibuprofen. As the interaction intensifies, including three or four silanol groups per ibuprofen molecule, the adsorption enthalpy (-84.82 kJ / mol and -81.00 kJ / mol) becomes sufficiently strong to exceed the enthalpy of vaporization of ibuprofen. This high density of silanol groups creates a “sticky” surface that effectively adsorbs drug molecules from the volume, forming a monolayer, as shown in the data previously presented in Figure 2(a).

[0063] Figure 3 illustrates the experimental evaluation of the effect of silanol density, examining the solubilization effect of materials with different silanol densities, and measuring the energy change from API-silanol to water-silanol through simulation. a) DFT-optimized (B3LYP-D3 / 6-311++G**, SMD) geometry of ibuprofen-silanol and water-silanol interactions at four silanol densities (σ_OH=5, 10, 15, and 20 / nm^2). Silica clusters form hydrogen bonds with different numbers of silanols (blue dashed lines), the first row with one ibuprofen molecule, and the second row with two water molecules. Considering the molecular volumes of ibuprofen, water, and amorphous silica, the silanol density can be averaged in a single silica cluster as follows: σ_OH=5 / nm^2 for an isolated silanol, σ_OH=10 / nm^2 for a pair of twinned silanols, σ_OH=15 / nm^2 for a pair of twinned silanols plus a neighboring silanol, and σ_OH=20 / nm^2 for two pairs of twinned silanols. Atoms are arranged in descending order of size: silicon (dark blue), oxygen (red), carbon (yellow), and blue (green). b. The solubilizing effects of two APIs, ibuprofen (red) and fenofibrate (black), were evaluated using mesoporous silica materials with different σ_OH values. c. The enthalpy change from IBF-silanol to water-silanol as a function of silanol density (σ_OH) is used for the four silanol densities in (a). d. Concentration (dissolved API / solvent) measured by UV-VIS spectroscopy is plotted against the ratio of total API to solvent. The API used here is ibuprofen, formulated with PE-07 at a 40% API to template ratio.

[0064] Figure 3(a) shows the most favorable adsorption configurations at different silanol densities, ranging from one-to-one to one-to-four (ibuprofen to silanol) interactions. Therefore, ultra-high silanol densities are crucial for the stable adsorption of drug molecules to the surface to form robust composite materials.

[0065] Adsorbing drug molecules onto a surface is a crucial initial step, but facilitating their subsequent desorption and dispersion into water is equally important. DFT simulations of this invention again demonstrate that the same ultra-high silanol density, enabling adsorption under dry conditions, is also critical in aqueous environments. When the drug composite is immersed in water, it faces competition between drug molecules and water molecules for adsorption on the silica surface, depending on the difference in adsorption enthalpy. Since the areal density of water is twice that of ibuprofen, it can be inferred that two water molecules should replace one ibuprofen molecule during desorption.

[0066] With σOH = 5 / nm 2On a typical silica surface, simulations of this invention show that the adsorption enthalpy (Hw) for two water molecules is -14.73 kJ / mol, which is weaker than the -18.76 kJ / mol for ibuprofen (HIbu) in an aqueous environment. Therefore, the substitution-related enthalpy change Hrep = Hw - HIbu = 4.03 kJ / mol (1.63 kBT) is positive and exceeds the thermal energy at room temperature, indicating that desorption and substitution on standard mesoporous silica is an unlikely event. This may explain why incomplete drug release is commonly observed in typical silica, regardless of its pore structure—whether ordered mesopores, micropores, or aerosols.

[0067] However, as the density of silanol increases, H w and H Ibu Both are increasing, with Hw increasing more significantly. Detailed data in Figure 3(b) show that as the silanol density σOH increases, the substitution enthalpy Hrep decreases, around σ ΟΗ =12 / nm 2 Dissipation k below room temperature B T. This threshold indicates that at or above this silanol density, the desorption and dissolution processes of ibuprofen molecules are significantly promoted. When the density reaches approximately 20 / nm... 2 When Hrep becomes negative, it indicates that desorption and rapid dissolution are thermodynamically more favorable. The bottom row of Figure 3(a) shows the different molecular configurations of water molecules adsorbed at different silanol densities.

[0068] To verify the predictions derived from DFT simulations, a series of experimental studies (methods) were conducted on various surfaces with different silanol densities. Two commercially available mesoporous silica materials and three templates developed in this invention were used. The two commercial products have approximately 5 / nm... 2 Mesoporous silica pharmaceutical excipients with silanol density ( and The three templates developed in this invention exhibit a higher silanol density: 12.69 / nm. 2 15.01 / nm 2 and 17.34 / nm 2 To ensure the general applicability of the results of this invention to different drugs, two different active pharmaceutical ingredients (APIs), ibuprofen and fenofibrate, were selected. The same amount of each drug was loaded into five types of silica materials using the same process. These drug composites were then dissolved in pure water, and the final fraction of dissolution was measured.

[0069] The experimental results, as shown in Figure 3(c), indicate that the silanol density of a typical silicon product is 5 / nm. 2The original template exhibited low solubility, while the template of this invention showed gradually improved solubility after increasing the σOH content. Notably, the solubility was achieved at a silanol density of approximately 12 / nm. 2 A significant increase in solubility was observed. This observation is consistent with Figure 3(b), where the substitution enthalpy (Hrep) equals the room temperature dissipation (k). B The theoretical points of T) are consistent.

[0070] The excellent negative correlation between the solubility data in Figure 3(c) and the substitution enthalpy in Figure 3(b) underscores the validity of the DFT simulation. The results clearly demonstrate that higher silanol density leads to a lower substitution enthalpy, which facilitates drug molecule desorption and enhances drug solubility. Therefore, solubility measurements provide strong experimental support for DFT calculations.

[0071] Furthermore, this invention reveals an additional unique advantage: because the dissolution of drug molecules from the special surface of this invention is driven by thermodynamic substitution enthalpy, more drug composite material can be continuously added to water to continuously increase the drug concentration. This is illustrated in Figure 3(d): the concentration of ibuprofen can be continuously increased to three orders of magnitude higher than its crystalline form, a remarkable result never before seen! Although this ultra-high concentration represents a metastable state, this state remains stable for more than 24 hours, exceeding the typical timeframe for drug efficacy. Therefore, the technology of this invention provides a unique advantage by achieving ultra-high drug concentrations, a property that may find practical potential in pharmaceutical applications.

[0072] In summary, the development of silica templates with ultra-high silanol density has significantly increased drug solubility, easily achieving enhancements of two to three orders of magnitude. This advancement is based on a novel physical mechanism: the inherent adsorption and desorption processes on these engineered silica surfaces. This fundamental mechanism avoids the need for chemical modification of drug molecules and is applicable to a wide range of drug compounds. It is also highly efficient, cost-effective, scalable, and stable—all invaluable in pharmaceutical manufacturing. Therefore, the method of this invention has the potential to become a next-generation solubility enhancement platform technology and replace several state-of-the-art technologies.

[0073] Furthermore, PE-07 provides a high density of interaction sites on its surface due to its abundant stable silanol groups. These sites can be modified with various functional groups to accommodate a wider range of chemical substances. This versatility makes it a promising candidate for applications in drug delivery, catalysis, controlled drug release, environmental remediation, and sensor development.

[0074] Example

[0075] Template preparation and drug loading

[0076] Templates were prepared using aqueous colloidal silica. The silica particles were nanoscale, measuring 7 nm, 12 nm, and 22 nm, corresponding to PE-07, PE-12, and PE-22, respectively. To achieve template formation, these suspensions underwent a vacuum evaporation process at a specific temperature.

[0077] The following active pharmaceutical ingredient (API) was used in the drug loading process: ibuprofen. Ketoprofen, flurbiprofen, docetaxel, diclofenac, repaglinide, oxapezil, isotretinoin, rapamycin, indomethacin, naproxen, simvastatin, trimebutine, fenofibrate, lamiprazole, paclitaxel, progesterone, and felodipine (all from J&K) ).

[0078] APIs are manually ground together with a suitable template. The ground mixture is then placed in a mold and pressed using a hydraulic press, applying a pressure of 80 MPa to form tablets. The tablets are then baked at an optimized temperature for a specific time (hours). The baking process helps relax the drug molecules and promotes effective interaction between the template and the APIs.

[0079] Concentration measurement

[0080] In vitro dissolution tests were performed using a self-made apparatus designed according to USP Apparatus 2 specifications, featuring a rotating blade within a cylindrical container at a speed of 50 RPM. The dissolution process began with the introduction of a single tablet into 500 mL of dissolution medium. After drug release, solution samples were collected at planned intervals to assess dissolution kinetics. The solubility profile of 18 active pharmaceutical ingredients (APIs) was evaluated at a 6-hour time point. Experimental validation confirmed that the solution had reached a stable and completely dissolved state at this time point. Subsequently, [the following steps were performed]. The solution sample was filtered using a 0.2μm syringe filter and then... The concentration was determined using an L850 UV / VIS spectrophotometer. To establish absorbance (ε), the linear coefficient linking UV / VIS absorption to concentration, calibration was performed by evaluating the absorbance of a series of solutions with known concentrations.

[0081] Pharmacokinetic studies

[0082] The pharmacokinetic studies used 24 male C57BL / 6J mice weighing 22-24 grams. There were six mice in each of the four study groups. The study included four groups: 20% PE-07 formulation ibuprofen, 98% ibuprofen crystals, and... 45.7% dose grinding Pure PE-07 template was used as a control. Mice were orally administered ibuprofen formulated with PE-07 and pure PE-07 template at concentrations of 50 mg / kg, and pure ibuprofen at 10 mg / kg. 21.9 mg / kg. Mice were administered the same amount of active ibuprofen (10 mg / kg) except for the control group. Blood samples were collected at the following time points after a single administration: 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Plasma concentrations were then measured using LC / MS analysis.

[0083] Silyl alcohol density measurement

[0084] At room temperature, the silanol groups on the template surface form hydrogen bonds and are in equilibrium. However, at high temperatures, these groups undergo condensation and dehydration reactions. This property allows for the quantification of the amount of silanol using thermogravimetric analysis (TGA). The amount of silanol per unit mass of the template was quantified on the TGA550 system. Weight loss of the template was measured under gradually increasing temperature conditions. To eliminate weight loss due to moisture in the pores, weight measurements were started at 200°C. By measuring weight loss over a temperature range of 200–1000°C, most of the silanol groups present on the template surface could be quantified (results are in SI).

[0085] Ibuprofen and fenofibrate were selected as model active pharmaceutical ingredients (APIs), and the template was modified to investigate which template properties played a dominant role in enhancing solubility. To explore this, four materials with different silanol areal densities, PE-05, PE-07, PE-12, and PE-22, were prepared using colloidal suspensions with particle sizes of 5 nm, 7 nm, 12 nm, and 22 nm. These materials were then compared with commercially available mesoporous silica solubilizing excipients Syloid and Silsol. Comparative experiments were conducted, and the material properties and the effect on improving the solubility of ibuprofen and fenofibrate are shown in Table 1.

[0086] Table 1

[0087] The specific surface area, average pore size, and porosity in Table 1 were characterized using Brunauer–Emmett–Teller (BET) analysis of nitrogen volume adsorption isotherms. The silanol areal density was estimated by measuring the mass change of silicon material with temperature using thermogravimetric analysis (TGA). The mass reduction below 200°C is due to the removal of physically adsorbed moisture, while the mass loss above 200°C is due to the removal of surface hydroxyl groups. The Si-OH density was calculated by dividing the mass loss between 200°C and 1000°C by the specific surface area, as shown in the table. It is noteworthy that all nanoscale colloidal filled templates compared to... Mesoporous silica exhibits a significantly higher surface Si-OH density. Furthermore, the results show that smaller template sizes correspond to higher Si-OH densities, in the order 5 nm > 7 nm > 12 nm > 22 nm.

[0088] After characterizing the five silica templates, their ability to enhance the dissolution of ibuprofen and fenofibrate was compared, as shown in the table. Syloid silica showed no significant difference in both APIs compared to pure crystalline drugs. Furthermore, Silsol did not improve the dissolution of ibuprofen but slightly enhanced fenofibrate, consistent with Humbeeck's findings. However, the PE series materials exhibited significantly better performance on both APIs, despite having lower specific surface area and porosity than Grace silica. Additionally, materials with higher silanol areal density showed better performance. This finding suggests that surface properties, rather than pore size, porosity, or specific surface area, play a crucial role in enhancing dissolution. It is reasonable to infer that the significant improvement in API dissolution is attributable to its interaction with the surface.

[0089] The surface silanol density can be calculated by dividing the amount of silanol per unit mass by the specific surface area of ​​the template. Using... Specific surface area was measured in ASAP2020 (results in SI). Prior to measurement, the template was stored overnight in a vacuum oven at 120°C to remove moisture. The measurement was based on the Bruno-Emmett-Taylor (BET) method via nitrogen adsorption.

[0090] The silanol densities of PE-07, PE-12, and PE-22 were determined, as well as two typical types of silica: WRGrace. and Each has 5OH / nm 2 The density of silanol. It is worth noting that... Specifically designed to enhance solubility.

[0091] First Principles Simulation

[0092] Ab initio simulations were performed using the Gaussian16 software package. The calculations employed a B3LYP-D3 hybrid functional and a 6-311++G(d,p) basis set, which provides a good balance between computational cost and accuracy. D3 dispersion correction was applied because previous studies have shown that dispersion forces play a dominant role in the interaction between ibuprofen and the silica surface.

[0093] The geometry of the silica clusters interacting with ibuprofen was optimized until the total enthalpy was minimized. Enthalpy H was calculated by applying zero-point correction (ΔZPE) and thermal correction (ΔE). TThe electron energy (E) added to the BSSE correction c The calculation is based on: H = E c +ΔZPE+ΔE T

[0094] By the enthalpy (H) of the silica-ibuprofen combination Ibu-Si Subtract ibuprofen (H) from the original text. Ibu ) and silanol clusters (H Si The sum of the enthalpies of ) determines the adsorption enthalpy ΔH. Ibu : ΔH Ibu =H Ibu-Si -H Ibu -H Si

[0095] Similarly, the adsorption enthalpy ΔH of water dimers on silica w : ΔH w =H w-Si -H w -H Si

[0096] The adsorption process was simulated by the interaction of ibuprofen with silica clusters in a vacuum environment. The dissolution process was simulated in water using a density-based solvation model (SMD). This comparison involved analyzing the adsorption enthalpy of water dimer on silica and ibuprofen on silica.

[0097] The above description provides a further detailed explanation of the present invention in conjunction with specific / preferred embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various substitutions or modifications can be made to these described embodiments without departing from the concept of the present invention, and all such substitutions or modifications should be considered within the scope of protection of the present invention. In the description of this specification, the reference to terms such as "an embodiment," "some embodiments," "preferred embodiment," "example," "specific example," or "some examples," etc., indicates that the specific features, structures, materials, or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any suitable manner in one or more embodiments or examples. Without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification and the features of different embodiments or examples. Although the embodiments of the present invention and their advantages have been described in detail, it should be understood that various changes, substitutions, and modifications can be made herein without departing from the scope of protection of the patent application.

Claims

1. A method for improving drug solubility, characterized in that, Includes the following steps: S1. Raw material preparation: Prepare colloidal silica uniformly suspended in an aqueous solution, including silica nanoparticles with a diameter between 2 and 100 nm; S2. Preparation of high-density silanol group surface material: The silica gel suspension is rapidly evaporated by controlling temperature and pressure to retain ultra-high density silanyl groups on the surface, thereby enhancing the surface affinity for drug molecules and water and forming a porous structure to increase the specific surface area; S3. Drug loading: The active pharmaceutical ingredient is mixed with the high-density silanol group surface material, and the drug molecules are loaded into the material through a drug loading process.

2. The method for improving drug solubility as described in claim 1, characterized in that, The density of silanol groups on the surface of the silica nanoparticles is 10 OH / nm. 2 The above measures are taken to increase the adsorption capacity of the silica nanoparticles for drug molecules.

3. The method for improving drug solubility as described in claim 1 or 2, characterized in that, In step S2, the evaporation is carried out using a vacuum evaporation process.

4. The method for improving drug solubility as described in any one of claims 1 to 3, characterized in that, In step S3, the drug loading process includes grinding, pressing, and baking a mixture of the active drug component and the high-density silanol group surface material.

5. The method for improving drug solubility as described in claim 4, characterized in that, In step S3, the pressing and baking process includes placing the ground mixture into a mold and pressing it with a hydraulic press to form tablets, and then baking the tablets at an optimized temperature for a set time.

6. The method for improving drug solubility as described in any one of claims 1 to 5, characterized in that, The active pharmaceutical ingredient includes any one or more of the following: fenofibrate, rapamycin, diclofenac, isotretinoin, trimetidine, simvastatin, olaprodine, rapaglitazone, indomethacin, felodipine, flurbiprofen, paclitaxel, docetaxel, naproxen, ibuprofen, progesterone, ketoprofen, and ramipril.

7. A drug composite material with enhanced solubility, characterized in that, It is prepared by the method for improving drug solubility as described in any one of claims 1 to 6.

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