JP2011225380A - Production method for mesoporous silica material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method for producing a mesoporous silica material substantially uniform in pore diameter and having a regular structure by using a self-organization process.SOLUTION: The production method includes: a step of preparing an aqueous solution A containing a silica precursor; a step of preparing an aqueous solution B containing neither an alkali metal hydroxide nor an alkaline earth metal hydroxide and containing a poly(alkylene oxide) triblock copolymer, an acid whose pKa is in a range of 3-9 and, optionally, an alkali salt of an acid whose pKa is in a range of 3-9; and a step of producing a mesoporous silica material substantially uniform in pore diameter and having a regular structure by supplying the aqueous solution A and the aqueous solution B to a slender mixing vessel in such a way that liquid flows of the solutions A, B directly collide with each other, thereby adjusting the pH of the resulting mixture to >2 to <8, generating a reaction product at a temperature of 10-100°C in the mixing vessel, separating the reaction product by filtration, drying it, and removing the surfactant. The production method does not include an aging step.

Description

  The present invention produces a mesoporous silica material having a regular structure and a mesoporous silica material having a 2D-hexagonal (two-dimensional hexagonal) structure in a reaction mixture under mildly acidic or neutral pH conditions. Relates to an improved method.

BACKGROUND OF THE INVENTION
The synthesis of mesoporous silica materials with a regular structure has been reported using strongly acidic (pH <2) or strongly alkaline (pH> 9) reaction conditions.

  The first mesoporous solid MCM, or silicate, having a regular structure was reported by Mobil in 1992 (although a patent for a similar experimental procedure was filed in 1969). This MCM was synthesized under strongly alkaline conditions. Kresge et al. (Nature 1992, 359, 710-712) describes a material called MCM-41, which exhibits a hexagonal structure consisting of tubular mesopores, the pore diameter of which can be adjusted within a range of 2 nm to 10 nm. The synthesis was reported. The synthesis of MCM-41 was performed under alkaline conditions using a cationic surfactant.

  In 1998, Zhao et al. (Science, 1998, 279, 548-552) used mesoporous silica with a regular structure using a nonionic triblock copolymer surfactant as a structure-introducing agent. A collaborative self-organization approach was introduced to produce a structured SBA. These materials were synthesized in an acidic medium having a pH below the isoelectric point of silica. The synthesis of SBA-15 with uniform pores of 4.6 nm to 10 nm has been reported. The use of surfactants and amphiphilic polymers as structure-introducing agents for mesoporous silica materials having a regular structure is known in the art. The quaternary ammonium cation used in the synthesis procedure acts as a structure-introducing agent, and after removing the template, a porous material with a regular structure showing a narrow pore size distribution is recovered. In a standard synthesis method, a Si metal alkoxide is hydrolyzed in an aqueous hydrochloride solution of a surfactant that is strongly acidic. Zhao et al. According to the above, in order to form a mesoporous material having a regular structure by this method, the synthesis temperature is 35 ° C. at the lowest and should not exceed 80 ° C. Usually, the synthesis of SBA-15 is carried out in two steps. One of the steps is performed at 35 to 40 ° C., and another aging step is performed at an elevated temperature. According to Zhao et al., Standard synthesis takes at least 24 hours from the addition of Si to the filtration step. After the addition of the silica precursor, a 20-hour process is first performed at 35 ° C., and then an aging process is performed at an elevated temperature. Brodie-Linder et al. Found that the temperature used during the first 10 minutes of silica polymerization had an effect on the surface silanol groups and the volume of the microporous structure of the final material. If microwave irradiation is used in SBA-15, the synthesis time is reduced to 120 minutes.

S. Su Kim et al. In 2001, Journal of Physical Chemistry B, 105, 7663-7670, sodium silicate was used as the silica source (SiO ₂ 27%, NaOH 14%) and pluronic ( MSU-H using either a one-step or two-step assembly process using P123 as a nonionic structure-introducing triblock copolymer surfactant The organization of silica was reported. In the one-step process, mesostructures were formed at a fixed assembly temperature of 308 ° K, 318 ° K, or 333 ° K. A surfactant and an equivalent amount of acetic acid to the hydroxide content of the sodium silicate solution are mixed at ambient temperature and added to the sodium silicate solution to introduce the structure-introducing surfactant. Reactive silica was formed in the presence of. This allows the hexagonal framework to be organized under pH conditions (pH = about 6.5), where both the silica precursor and surfactant are primarily nonionic molecular species. Became. Such pH conditions are outside the range of pH at which the mixture of sodium acetate and acetic acid causes a buffering action (see rules below). In order to obtain a mesoporous material with a highly regular structure, it was necessary to heat the synthesis mixture at 308K. Both surface area and pore volume increased with increasing synthesis temperature. This indicates that the material synthesized at the lowest temperature fails to form a structure well and includes regions with relatively low porosity.

  International Publication No. WO2009 / 133100A discloses a new family of mesoporous silica materials having a regular structure called COK-10. COK-10 is synthesized under mildly acidic or neutral pH conditions using a combination of an amphiphilic block copolymer and an optionally added tetraalkylammonium compound. The mesopores have a substantially uniform pore diameter in the range of 4 nm to 30 nm, and can be finely adjusted by adjusting the synthesis conditions. A new family of mesoporous silica materials having a 2D-hexagonal structure, referred to as COK-12, is also an amphiphilic block copolymer and a buffer having a pH greater than 2 and less than 8. Is synthesized under mildly acidic or neutral pH conditions. The mesopores have a substantially uniform pore diameter in the range of 4 nm to 12 nm, and can be finely adjusted by adjusting the synthesis conditions. Mesoporous silica materials having these regular structures are useful as carrier materials for formulating poorly soluble drug molecules and as carrier materials for formulating oral drugs for immediate release applications.

  The production of mesoporous silica with a regular structure using prior art synthesis procedures is relatively slow and the time required for the production reaches 24 hours. In order to make such mesoporous silica commercially attractive, a much faster and more preferably continuous manufacturing process is required. The manufacturing method disclosed in the present invention provides a high-speed process, which allows continuous production of mesoporous silica as described above, or its precursor material having a mesostructure.

  The present invention relates to a mesoporous silica having a regular structure having mesopores having a substantially uniform size exceeding 4 nm, as disclosed in International Publication No. WO2009 / 133100A, and 2D-hexagonal (2 The present invention relates to a production method for producing a mesoporous silica material having a (dimensional hexagonal) structure by reacting an aqueous solution of a silica precursor with an aqueous solution of a surfactant in one step in a continuous production method. Further, in contrast to the 24-hour manufacturing method disclosed in WO2009 / 133100A, the continuous manufacturing method allows the precursor material having a self-assembled mesostructure to be aged. It is manufactured immediately (in less than 10 seconds) without going through a process (in particular, without going through an aging process at 90 ° C. under a highly isothermal temperature condition). On the other hand, according to the continuous production method, this synthesis is realized without using an extremely strong acidic state (pH <2) or an extremely strong alkaline state (pH> 9) in the reaction mixture. .

  In particular, the production method may be applied to a weakly acidic or mesoporous silica material having a regular structure as described above and a mesoporous silica material having a 2D-hexagonal (two-dimensional hexagonal) structure, or a precursor material having a mesostructure. The present invention relates to a production method for production under neutral pH conditions. In this manufacturing method, an elongated mixing container (conduit) receives a first aqueous solution of the surfactant from a first storage member and a second silica precursor from a second storage member. Receive an aqueous solution. Furthermore, both the first aqueous solution and the second aqueous solution are supplied or delivered to the elongated mixing container (groove, tube). And even if the residence time is less than 10 seconds, the mesoporous silica material having the above self-organized regular structure is discharged from the elongated mixing container. The residence time is such that the linear velocity of the aqueous solution of the surfactant from the first storage member and the linear velocity of the second aqueous solution of the silica precursor are in the range of 1000 to 3000 m / h. It is realized by.

  In the synthesis experiments at pH 4.8, 5.0 and 6.0, porous materials having a regular structure with the characteristics shown in Table 1 below were produced at room temperature. Surprisingly, it has been shown that the addition of a sodium silicate solution to a buffered surfactant causes silica polymerization to occur almost immediately. As illustrated in FIGS. 10A and 10B, the TEM micrographs show that the material collected after 1 minute had a regular structure.

  This result was also achieved in the absence of aromatic hydrocarbons such as 1,2,4-trimethylbenzene in the reaction mixture.

  Surprisingly, by mixing a jet of aqueous sodium silicate (water glass) with a buffered aqueous jet of block copolymer P123, a surfactant, at room temperature in a tube, 2 nm Of mesoporous COK-12 silica with a very regular structure with mesopores of approximately uniform size exceeding (for example, in the range of 4 nm to 30 nm) are 2 and 8 in a continuous synthesis process. In the meantime, it can be synthesized at a pH of preferably 5-6. When the jets come into contact with each other, it is easily visible that silica is condensed and particles are formed. The silica particles are immediately recovered and separated, exhibiting mesoscale hexagonal regularity, and uniformly sized mesopores. Thus, mesoporous COK-12 silica with a very regular structure is produced in as little as 1 minute and complete condensation occurs in less than 5 minutes. In contrast, traditional template manufacturing takes 24 hours.

One embodiment of the present invention is realized by a manufacturing method for manufacturing a mesoporous silica material having a substantially uniform pore size and a regular structure by using a self-assembly method,
Preparing an aqueous solution A containing a silica precursor;
Prepare an aqueous solution B containing neither an alkali metal hydroxide nor an alkaline earth metal hydroxide, and containing a poly (alkylene oxide) triblock copolymer and an acid having a pKa in the range of 3-9. And a process of
The aqueous solution A and the aqueous solution B are used as a liquid flow in an elongated mixing container having a first opening and a second opening.
The liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the first opening of the elongated mixing vessel;
Supplying the liquid streams of the aqueous solution A and the aqueous solution B so as to directly collide,
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. Producing a mesoporous silica material having a regular structure,
The manufacturing method does not include an aging step, and the liquid streams of the aqueous solution A and the aqueous solution B are independently and independently supplied to the first opening of the elongated mixing container as necessary. Released at a linear velocity exceeding 5 m / h.

One aspect of the present invention may be realized by the following production method for producing a mesoporous silica material having a substantially uniform pore size and a regular structure by using a self-organization method. ,
Silica precursors such as alkali silicates; silicic acids; or tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), tetrapropyl orthosilicate (TPOS) Preparing an aqueous solution A containing such a tetraalkylorthosilicate,
Does not include any of alkali metal hydroxides and alkaline earth metal hydroxides, poly (alkylene oxide) triblock copolymer, an acid having a pKa in the range of 3 to 9, and, if necessary, preparing an aqueous solution B containing an alkali salt of an acid having a pKa in the range of 3-9;
The aqueous solution A and the aqueous solution B are used as a liquid flow in an elongated mixing container having a first opening and a second opening.
The liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the first opening of the elongated mixing container at a linear velocity exceeding 5 m / h.
Supplying the liquid streams of the aqueous solution A and the aqueous solution B so as to directly collide,
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. Producing a mesoporous silica material having a regular structure,
In the manufacturing method, an aging step is omitted as necessary.

One embodiment of the present invention is realized by a manufacturing method for manufacturing a mesoporous silica material having a substantially uniform pore size and a regular structure by using a self-assembly method,
Preparing an aqueous solution A containing a silica precursor;
Prepare an aqueous solution B containing neither an alkali metal hydroxide nor an alkaline earth metal hydroxide, and containing a poly (alkylene oxide) triblock copolymer and an acid having a pKa in the range of 3-9. And a process of
The aqueous solution A and the aqueous solution B are used as a liquid flow in an elongated mixing container having a first opening and a second opening.
The liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the first opening of the elongated mixing vessel;
Supplying the liquid streams of the aqueous solution A and the aqueous solution B so as to directly collide,
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. Producing a mesoporous silica material having a regular structure,
In the manufacturing method, an aging step is omitted as necessary, and the liquid flows of the aqueous solution A and the aqueous solution B are independently discharged to the first opening of the elongated mixing container. And are released independently at a linear velocity exceeding 5 m / h as needed.

  In addition to the above, the scope of the present invention will become apparent from the detailed description given below. However, since various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art from the detailed description, the detailed description and specific examples show preferred embodiments of the present invention. On the other hand, it should be understood that this is provided for illustrative purposes only. It is to be understood that both the foregoing general description and the following detailed description are exemplary only and are intended for purposes of illustration and are not intended to limit the invention as claimed. It is.

The present invention will become more fully understood from the detailed description set forth below and the accompanying drawings. It should be noted that both the description and the drawings are merely given as an explanation and therefore do not limit the present invention.
It is a figure of the equipment configuration for experiment. In the figure, A is an aqueous solution A, AT is a tube carrying the aqueous solution A, B is an aqueous solution B, BT is a tube carrying the aqueous solution B, M is a mixing tube, C is a collector, S is a separator, D is Dryer / burner. The nitrogen adsorption isotherm of COK-12 (baked mesoporous silica material) of Example 1 (square) and the desorption isotherm (black diamond) of the fired material are shown. The pore diameter distribution of BJH calculated from the adsorption branch is shown. 2 is a SEM micrograph of COK-12 (fired mesoporous silica material) of Example 1. Samples were coated with gold. Images were obtained by using a Philips (FEI) SEM XL30 FEG. 2 is a SEM micrograph of COK-12 (fired mesoporous silica material) of Example 1. Samples were coated with gold. Images were obtained by using a Philips (FEI) SEM XL30 FEG. 2 is a SEM micrograph of COK-12 (fired mesoporous silica material) of Example 1. Samples were coated with gold. Images were obtained by using a Philips (FEI) SEM XL30 FEG. The nitrogen adsorption isotherm of COK-12 (baked mesoporous silica material) of Example 2 (square) and the desorption isotherm (black diamond) of the fired material are shown. The pore diameter distribution of BJH calculated from the adsorption branch is shown. The nitrogen adsorption isotherm of COK-12 (baked mesoporous silica material) of Example 3 (black rhombus) and the desorption isotherm (square) of the fired material are shown. The pore diameter distribution of BJH calculated from the adsorption branch is shown. 4 is a SEM micrograph of COK-12 (calcined mesoporous silica material) of Example 3. Samples were coated with gold. Images were obtained by using a Philips (FEI) SEM XL30 FEG. 4 is a SEM micrograph of COK-12 (calcined mesoporous silica material) of Example 3. Samples were coated with gold. Images were obtained by using a Philips (FEI) SEM XL30 FEG. The nitrogen adsorption isotherm of COK-12 (baked mesoporous silica material) of Example 4 (black rhombus) and the desorption isotherm (square) of the fired material are shown. The pore diameter distribution of BJH calculated from the adsorption branch is shown. 4 is a TEM micrograph of COK-12 (calcined mesoporous silica material) of Example 4. Images were obtained by using a Philips (FEI) SEM XL30 FEG. 4 is a TEM micrograph of COK-12 (calcined mesoporous silica material) of Example 4. Images were obtained by using a Philips (FEI) SEM XL30 FEG. 4 is a TEM micrograph of COK-12 (calcined mesoporous silica material) of Example 4. Images were obtained by using a Philips (FEI) SEM XL30 FEG. The nitrogen absorption isotherm of COK-12 (baked mesoporous silica material) of Example 5 (diamond) and the desorption isotherm (black square) of the fired material are shown. 6 is a TEM micrograph of COK-12 (calcined silica material) of Example 5. 6 is a TEM micrograph of COK-12 (calcined silica material) of Example 5.

Detailed Description of the Invention

  The following detailed description of the invention refers to the accompanying drawings. Even if the drawings are different, the same reference numerals indicate the same or similar components. Also, the following detailed description does not limit the invention. The scope of the invention is defined by the appended claims and equivalents thereof.

  Several documents are cited in the text of this specification. The documents (including all manufacturer's specifications, usage notes, etc.) are each cited by reference. However, none of the cited references is recognized by the applicant as actually constituting the prior art of the present invention.

  The present invention will be described with respect to particular embodiments and with reference to the drawings. However, the invention is not limited to this particular embodiment, but only by the claims. The drawings described are illustrative and not limiting. In the drawings, the size of components may be exaggerated and some may not be drawn to scale, but this is for illustrative purposes. The dimensions and relative dimensions do not correspond to the actual implementation of the present invention.

  Furthermore, the use of terms such as “first”, “second”, “third”, etc. in the description and in the claims is for distinguishing similar components, and is not necessarily for explaining the order and the order of time. is not. Terms used in this manner can be interchanged under appropriate circumstances, and embodiments of the present invention described herein can operate in an order other than the order described or illustrated herein. Should be understood.

  Also, the use of terms such as top, bottom, cover, bottom, etc. in the description and in the claims is for illustrative purposes and is not necessarily for describing relative positions. Terms used in this manner can be interchanged under appropriate circumstances, and embodiments of the invention described herein can operate in directions other than those described or illustrated. Should be understood.

  Further, the term “comprising”, used in the claims, should not be interpreted as being restricted to the means listed following the term. The term does not exclude other components or steps. Thus, the term should be interpreted as indicating the presence of the feature, completeness, process, or component / part referred to, and one or more other features, completeness, process, or component. Does not deny the possibility of existence or addition of / parts or combinations thereof. Therefore, the range indicated by the expression “a device including means A and means B” refers to a device composed only of part A and part B (that is, for the present invention, the related parts of the device are only part A and part B). Should not be limited.

  Throughout this specification the description “one embodiment” or “an embodiment” refers to a particular feature, structure, or characteristic described in connection with that embodiment in at least one embodiment of the invention. It means that it is provided. Thus, the phrases “in one embodiment” or “in an embodiment” are used throughout this specification, although all of these phrases do not necessarily refer to the same embodiment, but the same It may also refer to an embodiment. Further, as will be apparent to those skilled in the art from this disclosure, the specific features, structures, or characteristics described above may be combined in any suitable manner in one or more embodiments.

  Similarly, in the description of exemplary embodiments of the present invention, in order to simplify the disclosure of one or more of the various forms having the inventive step, and to assist in understanding the forms, It should be understood that the various features of the invention may be combined into a single embodiment, figure, or a description of that embodiment or figure. However, this method of disclosure should not be interpreted as reflecting the idea that the claimed invention requires features not specified in each claim. Indeed, as reflected in the following claims, no inventive aspect exists in all features of a single embodiment disclosed above. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.

  Further, some embodiments described herein include other features that are included in other embodiments, and do not include additional features. On the other hand, as those skilled in the art will appreciate, the combination of features of the different embodiments is within the scope of the present invention and is another embodiment. For example, in the following claims, any of the embodiments described in the claims can be used in any combination.

  While numerous specific details are set forth in the description herein, it is to be understood that embodiments of the invention may be practiced without these specific details. In some instances, well known methods, structures, and techniques have not been shown in detail in order not to obscure an understanding of this description.

  The following terms are defined only to assist in understanding the present invention.

[Definition]
As used herein, terms such as mesoscale, mesopore, mesoporous, etc. refer to structures having characteristic dimensions in the range of 2 nm to 50 nm. As used herein, the term mesoscale does not imply any particular spatial organization or manufacturing method. According to the IUPAC nomenclature (J. Rouquerol et al., Pure & Appl. Chem, 66 (1994) 1739-1758), microporous materials have a pore size of less than 2 nm, and mesoporous materials are between 2 nm and 50 nm. The macroporous material has a pore diameter of more than 50 nm. The nanoporous material has a pore size in the range of 0.3 nm to 100 nm.

  As used in the disclosure of the present application, the expression that the pore size distribution is narrow and that the pore size is substantially uniform means that a pore volume differential value (dV) as a function of the pore size is a pore volume distribution curve. Is drawn at a point on the curve that is half the maximum of the curve, the width of the curve (ie, the difference between the maximum and minimum pore diameters at half the height) and (as described above). It means that the ratio with the pore diameter at which the height of the curve is maximum does not exceed 0.75. The pore size distribution of the material prepared according to the present invention is determined by plotting nitrogen adsorption and desorption, and a graph of the pore volume differentiated by pore size as a function of pore size from the acquired data. Is done. The nitrogen adsorption and nitrogen desorption data can be used in the technical field of an instrument (for example, Micrometrics ASAP 2010) that can plot a graph of a value obtained by differentiating pore volume with pore diameter as a function of pore diameter. What is necessary is just to obtain by using. In the case of the micropore range, such a graph is obtained by using the Horvath-Kawazoe model slit hole described in G. Horvath, K. Kawazoe, J. Chem. Eng. Japan, 16 [6], [1983] 470. What is necessary is just to plot using a shape. In the range of mesopores, the graph may be plotted by the method described in E. P. Barrett, L. S. Joyner, P. P. Halenda, J. Am. Chem. Soc., 73 (1951), 373-380.

  As used in disclosing the present invention, the term “aqueous” means related to or made with water.

  As used in disclosing the present invention, the term “elongated shaped mixing container” means a container of any shape, such as a tube, pipe, groove, etc., having two openings.

  As used in disclosing the present invention, the term “silica precursor” means any compound with which silica can be synthesized in the production process of the present invention. “Silica precursors” include alkali silicates, silicic acids, and tetraalkyl orthosilicates (eg, tetraethyl orthosilicate (TEOS), tetramethyl orthosilicate (TMOS), and tetrapropyl. Tetrapropyl orthosilicate (TPOS)).

  As used in disclosing the present invention, the term “surfactant removal” means a process step in which the surfactant is removed. This process includes, for example, a baking method performed at 200 ° C. and an extraction method performed using, for example, supercooled carbon dioxide or ethanol.

  As used in the disclosure of the present invention, the term “aging step” means that the reaction product of the solution A and the solution B is further processed, for example, by holding for a period under an isothermal condition, It means an optional step that completes a production method for producing a mesoporous silica material that is substantially uniform and has a regular structure.

  The term “substantially insoluble” as used herein is used for drugs that are essentially completely insoluble in water, or at least sparingly soluble in water. More specifically, the term is used for any drug in which the ratio of dose (mg) to water solubility (mg / ml) exceeds 100 ml. The solubility of a drug is a neutral (eg, free base or free acid) type solubility in unbuffered water. This meaning includes, but is not limited to, drugs that have essentially zero water solubility (less than 1.0 mg / ml).

  Based on BCS, the term “sparingly soluble in water” is defined to refer to a compound whose maximum dose does not dissolve in an aqueous medium of 250 ml or less at 37 ° C. and pH 1.2-7.5. See Cynthia K. Brown, et al., “Acceptable Analytical Practices for Dissolution Testing of Poorly Soluble Compounds”, Pharmaceutical Technology (Dec. 2004).

  According to the manual (Pharmacology (M.E. Aulton)), for any solvent, solubility is defined as the amount of solvent (g) required to dissolve 1 g of compound. According to this definition, the following solubility is defined. That is, 10 g to 30 g (easy to dissolve), 30 g to 100 g (“slightly insoluble”), 100 g to 1000 g (“hard to dissolve”), 1000 g to 10,000 g (“very insoluble” or “slightly soluble”), and 10000 g. Super (substantially insoluble).

  The terms “drug” and “bioactive compound” are widely understood and indicate compounds that have beneficial prophylactic and / or therapeutic properties, for example when administered to humans. Furthermore, the term “drug itself” is used throughout the specification for comparison and means a drug in an aqueous solution / suspension to which no excipients have been added.

  The term “antibody” refers to intact molecules and fragments thereof that can bind to the epitope determinant of the relevant factor, or to the epitope determinant of the domain of the factor. An “Fv” fragment is the smallest antibody fragment that has a complete antigen recognition and binding site. This region is a dimer (VH-VL dimer), and the variable regions of the heavy chain and the light chain are strongly bound by noncovalent bonds. The three CDRs of each variable region interact to form an antigen binding site on the surface of the VH-VL dimer. In other words, a total of six CDRs from the heavy and light chains function together as antibody sites that bind to the antigen. However, it recognizes and binds to the antigen even though the variable region (or half of Fv with only three CDRs specific for the antigen, half of Fv) is lower than the affinity of the entire binding site. It is known that it can be done. Accordingly, one of the preferred antibody fragments of the present invention is an Fv fragment, but is not limited thereto. Such antibody fragments may be polypeptides comprising antibody fragments of heavy or light chain CDRs that are conserved and recognize and bind antigen. The Fab fragment (also referred to as F (ab)) also has a light chain constant region and a heavy chain constant region (CH1). For example, digesting an antibody with papain produces two types of fragments. One is a fragment that binds to an antigen, called a Fab fragment, which has a heavy chain variable region and a light chain variable region that act as a single domain that binds to the antigen. It is the remaining part called “Fc” because it crystallizes. The Fab 'fragment differs from the Fab fragment in that it further comprises a plurality of residues derived from the carboxyl terminus of the CH1 region of the heavy chain. The CH1 region has one or more cysteine residues from the hinge region of the antibody. However, Fab ′ and Fab are both antigen-binding fragments that have a heavy chain variable region and a light chain variable region that act as a single domain that binds to the antigen. It is structurally equivalent to Fab. Here, a fragment that binds to an antigen having a heavy chain variable region and a light chain variable region that act as a single domain that binds to the antigen and is equivalent to a fragment obtained by digestion with papain is, for example, Even though it is not identical to the antibody fragment produced by digestion with protease, it is referred to as “Fab-like antibody”. Fab'-SH is Fab 'having one or more cysteine residues having a free thiol group in the constant region.

  As used in disclosing the present invention, the term “bioactive species” refers to drugs and antibodies.

  The term “solid dispersion” defines a system of solids (in contrast to liquids or gases) that includes at least two components, one of which is approximately uniformly dispersed in the remaining components. is doing. If the dispersion state of this component is such that the entire system is chemically and physically uniform or homogeneous, or if the system consists of one phase defined by thermodynamics, such a solid dispersion is Hereinafter, it is referred to as “solid solution”. Solid solution is a preferred physical system. This is because the component is usually readily bioavailable to the organism to which it is administered. This advantage may be explained by simply forming a liquid solution when the solid solution comes into contact with a liquid medium, such as gastric juice. This simple dissolution is necessary, at least in part, for the energy required to dissolve the component from the solid solution to dissolve the component from the solid phase consisting of crystals or from the solid phase consisting of microcrystals. It can be said that this is due to the fact that the energy is smaller than that.

  The term “solid dispersion” further encompasses a dispersion where the overall homogeneity is less than that of the solid solution. Such a dispersed state is not chemically and physically uniform throughout or comprises more than one phase. For example, the term “solid dispersion” refers to amorphous, microcrystalline, or crystalline (a), or amorphous, microcrystalline, or crystalline (b), or both, (b) or (a ) Or another phase containing a solid solution containing (a) and (b), also associated with particles having domains or small regions that are substantially uniformly distributed. A domain is a region within a particle that can be clearly identified by some physical characteristic, the size of which is small compared to the size of the entire particle, and is uniformly and randomly distributed within the particle. .

  As used in this application, the term “room temperature” means between 12 ° C. and 30 ° C., more preferably between 18 ° C. and 28 ° C., more preferably between 19 ° C. and 27 ° C., most preferably about It means a temperature between 20 ° C. and 26 ° C.

  As used in this application, the term “low temperature” means between 15 ° C. and 40 ° C., more preferably between 18 ° C. and 23 ° C., even more preferably between 20 ° C. and 30 ° C., most preferably It means a temperature between approximately 22 ° C and 28 ° C.

  As used in disclosing the present invention, the term buffer buffer zone is about 1.5 higher in pH units from about 1.5 lower than the pH that is numerically equal to the pKa of the buffer acid component. It means the pH region in the range up to pH.

[Production method for producing a mesoporous silica material having a regular structure with a substantially uniform pore size]
When using an alkali silicate in the aqueous solution A, an acid having a pKa in the range of 3 to 9 in the aqueous solution B is used to obtain a pH of more than 2 and less than 8 when the aqueous solution A and the aqueous solution B are mixed. Is sufficient, and an alkali salt of an acid having a pKa in the range of 3 to 9 is unnecessary. However, when the silica precursor is used in the aqueous solution A instead, when an alkali salt of an acid having a pKa in the range of 3 to 9 is not added, the aqueous solution B is an aqueous solution in the acid having a pKa in the range of 3 to 9. When mixing A and aqueous solution B, it may be insufficient to obtain a pH greater than 2 and less than 8. The acid having a pKa in the range of 3 to 9 may be present in a buffer having a pH in the range of 3 to 8 when the aqueous solution A and the aqueous solution B are mixed. Alternatively, the solution B itself may contain a buffer.

One specific embodiment of the ultra-fast (1 to 100 seconds) reaction of the present invention is to produce a mesoporous silica material having a regular pore structure and a regular structure using a self-assembly method. A manufacturing method, the manufacturing method comprising:
Preparing an aqueous solution A containing a silica precursor;
Does not include any of alkali metal hydroxides and alkaline earth metal hydroxides, poly (alkylene oxide) triblock copolymer, an acid having a pKa in the range of 3 to 9, and, if necessary, preparing an aqueous solution B containing an alkali salt of an acid having a pKa in the range of 3-9;
The aqueous solution A and the aqueous solution B, as a liquid flow, in an elongated mixing container (groove, tube) having a first opening and a second opening,
A linear velocity in which the liquid streams of the aqueous solution A and the aqueous solution B are each independently in the range of 10 m / h to 1000 m / h to the first opening of the elongated mixing vessel (this linear velocity is , More preferably exceeding 30 m / h, more preferably exceeding 100 m / h, particularly preferably exceeding 500 m / h) so that the liquid streams of the aqueous solution A and the aqueous solution B directly collide with each other. To supply and
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. And a step of producing a mesoporous silica material having a regular structure, wherein a preferable residence time in the elongated mixing vessel is 1 second to 100 seconds, and the production method is performed as necessary. The aging process is omitted.

One specific embodiment of the very short (1-10 seconds) reaction of the present invention is to use a self-assembled method to obtain a mesoporous silica material having a generally uniform pore size and a regular structure. A manufacturing method for manufacturing, the manufacturing method comprising:
Preparing an aqueous solution A containing a silica precursor;
Does not include any of alkali metal hydroxides and alkaline earth metal hydroxides, poly (alkylene oxide) triblock copolymer, an acid having a pKa in the range of 3 to 9, and, if necessary, preparing an aqueous solution B containing an alkali salt of an acid having a pKa in the range of 3-9;
The aqueous solution A and the aqueous solution B, as a liquid flow, in an elongated mixing container (groove, tube) having a first opening and a second opening,
The liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the first opening of the elongated mixing container at a linear velocity ranging from 1000 m / h to 3000 m / h, Supplying the liquid streams of the aqueous solution A and the aqueous solution B so as to directly collide,
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. And a step of producing a mesoporous silica material having a regular structure, wherein a preferable residence time in the elongated mixing container is 1 second to 10 seconds, The aging process is omitted.

  According to a preferred embodiment of the production method for producing a mesoporous silica material having a regular structure according to the present invention, the acid having a pKa in the range of 3-9 is a buffer in which the pH is in the range of 3-8. Present in.

  According to a preferred embodiment of the production method of producing a mesoporous silica material having a substantially uniform pore size and a regular structure according to the present invention, the aqueous solution 2 contains a tetraalkylammonium surfactant (preferably , Tetrapropylammonium hydroxide producing a tetrapropylammonium cation, or tetramethylammonium hydroxide producing a tetramethylammonium cation). The presence of the tetraalkylammonium surfactant causes a change in the mesoporous silica having a regular structure that is produced.

  According to another preferred embodiment of the present invention, the liquid streams of the aqueous solution A and the aqueous solution B are each independently fed to the elongated mixing vessel with a linear velocity exceeding 10 m / h, more preferably 30 m / h. It is discharged at a linear velocity exceeding h, more preferably linear velocity exceeding 100 m / h, particularly preferably linear velocity exceeding 1000 m / h.

  According to another preferred embodiment of the present invention, the liquid streams of the aqueous solution A and the aqueous solution B are each independently less than 10,000 m / h, more preferably 5,000 m, into the elongated shaped mixing vessel. Is released at a linear velocity of less than / h, particularly preferably less than 2500 m / h.

  Most of the acid is removed during the cleaning process associated with the filtration process, and any remaining acid is removed in the calcination process.

  The variation in pH of the reaction mixture can be used as a condition for fine-tuning the pore size of the final mesoporous silica material having a regular structure as well as the reaction time or reaction temperature within the scope of the present invention. . The pore size increases slightly with increasing pH. The pore diameter increases more greatly with the reaction temperature, but the total pore volume is hardly affected. The pH for carrying out the reaction is more preferably in the range of 2.2 to 7.8, further preferably in the range of 2.4 to 7.6, and particularly preferably in the range of 2.6 to 7.4. is there.

  In another embodiment, the pH at which the reaction is carried out is more preferably in the range of 2.8 to 7.2, even more preferably in the range of 3 to 7.2, particularly preferably in the range of 4 to 7. More preferably, it is in the range of 5 to 6.5.

  Examples 1 to 3 are examples in which pore diameters of 5 nm to 6 nm are realized at room temperature. Larger pores are realized as a result of the block copolymer micelles expanding at higher temperatures. The pore diameter also varies depending on the sodium content. When the content of sodium is large, slightly large pores are formed.

  According to a preferred embodiment of the production method of the present invention, the container may be provided with an in-line mixing device, for example, a static mixer, if necessary.

  In the production method for producing a mesoporous silica material having a substantially uniform pore size and a regular structure according to the present invention, the mixture resulting from the collision of the liquid flow of the aqueous solution A and the aqueous solution B is 100 rpm to 700 rpm. You may stir with the stirring speed of the range.

  It has also been shown that COK-10 materials can be produced in reaction mixtures with a pH greater than 2 and less than 8 under room temperature conditions or low temperature conditions.

  The production conditions may be fine-tuned, whereby a range of 4 nm to 30 nm, more preferably a range of 7 nm to 30 nm, still more preferably a range of 10 nm to 30 nm, particularly preferably a range of 10 nm to 30 nm, even more particularly preferable. Can realize a mesoporous silica material having a regular structure having a pore diameter selected from the range of 4 nm to 12 nm.

  The aqueous solution 1 is preferably an aqueous sodium silicate solution containing at least 10% by weight sodium hydroxide and at least 27% by weight silica.

  In the production method of the present invention, the amount of the reagent or intermediate (for example, amphiphilic polymer, especially Pluronic (registered trademark) P123, or, for example, tetraalkylammonium cation, especially the tetrapropylammonium hydroxide) is within the scope of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the spirit. Furthermore, the temperature, mixing speed, or reaction time conditions in the production method of the present invention, and the configuration of the system and method can be variously changed and modified without departing from the scope or spirit of the present invention. Will be apparent to those skilled in the art. These changes can be finely adjusted, whereby the mesoporous material having a narrow pore size distribution of the present invention can be produced in a range of a desired maximum pore size of 7 to 30 nm.

  According to a preferred embodiment of the production method of the present invention, the residence time in the elongated mixing container (groove, tube) is in the range of 1 minute to 100 minutes. The residence time is preferably 1 second to 100 seconds, and particularly preferably 1 second to 10 seconds.

  According to a preferred embodiment of the production method of the present invention, the mesoporous silica material itself having a substantially uniform pore diameter and a regular structure is produced in the absence of irradiation. However, irradiation may be used when the mesoporous silica material having a regular structure is loaded with a bioactive species.

  According to a preferred embodiment of the production method of the present invention, the above-mentioned mesoporous silica material having a uniform pore diameter and a regular structure is produced in the absence of microwave irradiation. However, microwave irradiation may be used when a mesoporous silica material having a regular structure is loaded with a bioactive species.

  According to a preferred embodiment of the production method of the present invention, the production method further comprises loading a bioactive species into the mesoporous silica material having the regular structure.

  According to a preferred embodiment of the production method of the present invention, the production method further comprises dispersing a substantially insoluble drug as a solid in the mesoporous silica material having the regular structure.

  According to another preferred embodiment of the manufacturing method of the present invention, the manufacturing method is a continuous manufacturing method.

[Poly (alkylene oxide) triblock copolymer]
The poly (alkylene oxide) (A) _n (B) _m (A) _n triblock copolymer is preferably a poly (ethylene oxide) -poly (alkylene oxide) -poly (ethylene oxide) triblock copolymer ( For example, Pluronic® surfactant (see table below), or poly (alkylene oxide) -polyethylene oxide) -polyalkylene oxide triblock copolymer (eg reverse pluronic® surfactant (see below) See the table below)). The alkylene oxide component has at least 3 carbon atoms, and is, for example, a propylene oxide component or a butylene oxide component. In the triblock copolymer, more preferably, the number of ethylene oxide components in each block is at least 5 and / or the number of alkylene oxide components is at least 15, particularly preferably at least 30 in the central block. is there.

Pluronic (R) P123 and Pluronic (R) 17R4, which are poly (alkylene oxide) triblock copolymers, are particularly preferred. Pluronic (registered trademark) P123 has a composition represented by EO ₂₀ PO ₇₀ EO ₂₀ (EO represents ethylene oxide, PO represents propylene oxide), and has the formula HO (CH ₂ CH ₂ O) ₂₀ (CH ₂ CH (CH _{3) O)} is represented by _{70 (CH 2 CH 2 O)} 20 H, molecular weight of about 5800. Pluronic® 17R4 has a composition represented by (PO) ₁₄ (EO) ₂₄ (PO) ₁₄ and has the formula HO (CH ₂ CH (CH ₃ ) O) ₁₄ (CH ₂ CH ₂ O) ₂₄ ( It is represented by CH ₂ CH (CH ₃ ) O) ₁₄ H, has a molecular weight of about 2700 and has a terminal secondary hydroxyl group.

Usually, the ratio of SiO ₂ to Pluronic (registered trademark) P123 is set to 65.

〔silica〕
The source of silica for synthesizing the mesoporous material having a regular structure may be a monomer source, such as silicon alkoxide. TEOS and TMOS are typical examples of silicon alkoxides. Alternatively, an alkali silicate solution, such as water glass, may be used as the silicon source. Kosuge et al. Have shown that water-soluble sodium silicate can be used for the synthesis of SBA-15 type materials (Kosuge et al., Chemistry of Materials, (2004), 16,899-905). In a material called Zeotile, silica pre-organizes to form a nanoscale slab similar to zeolite, which assembles into a three-dimensional mosaic structure on the mesoscale (Kremer et al., Adv. Mater). ., 20, (2003), 1705).

[Buffer solution with a pH greater than 2 and less than 8]
The pH above 2 and less than 8 is preferably 1.5 pH lower in pH units than the pH range of the acidic component of the buffer, i.e., the pH numerically equal to the pKa of the acidic component of the buffer. To 1.5 higher pH. Further, particularly preferably, the pH is in a range from 1.2 pH lower in pH units to 1.2 higher pH than the pH that is numerically equal to the pKa of the acidic component, and more particularly preferably the pH of the acidic component. The pH is in the range from 1.0 lower pH to 1.0 higher pH in pH units than the pH that is numerically equal to pKa.

  Suitable acids having a pKa in the range of about 3 to about 9 include those listed in Table 3 below.

  The buffer is a mixture of a weak acid and a salt of the weak acid, or a mixture of salts of weak acids. Preferred buffers are those based on polyacids / salts or salts of polyacids having a plurality of pKa in the range of 2-8. As the buffer solution, for example, a buffer zone is provided in the vicinity of each pKa, and the buffer zones overlap to be between 2.0 and 7.9: 3.14 ± 1.5, 4.77 ± 1. A citrate / citrate buffer covering the entire range of 5, and 6.39 ± 1.5, and a buffer zone near each pKa, with the buffer zones overlapping, 2.66 And 7.1: succinic acid / succinate buffer, etc., covering the entire respective range of 4.16 ± 1.5, 5.61 ± 1.5.

Preferred buffers having a pH greater than 2 and less than 8 include a sodium citrate / citrate buffer having a pH range of 2.5-7.9, a pH range of 3.2-6.2. Sodium acetate / acetic acid buffer, Na ₂ HPO ₄ / citrate buffer with a pH range of 3.0-8.0, HCl / sodium citrate buffer with a pH range of 1-5, and pH Na ₂ HPO ₄ / NaH ₂ PO ₄ buffer solution having a range of 6-9.

  The sodium / citric acid buffer preferably has a weight ratio of sodium citrate to citric acid in the range of 0.1: 1 to 3.3: 1.

[Drug]
The Biopharmaceutical Classification System (BCS) is a framework for drug substance classification based on aqueous solubility and intestinal permeability (Amidon, GL, Lennernaes H., Shah VP, and Crison JR "A Theoretical Basis For a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability", Pharmaceutical Research, 12: 413-420 [1995], and Adkin, DA, Davis, S. S., Sparrow, RA, Huckle, PD, and Wilding, IR, 1995, The effect of mannitol on the oral bioavailability of cimetidine J. Pharm. Sci. 84, pp. 1405-1409 ).

The biopharmaceutical classification system (BCS) was first developed by G. Amidon, and according to the system, drugs for oral administration are divided into four classes depending on water solubility and intestinal cell layer permeability. To be separated. According to BCS, drug substance is classified as follows.
Class I: High permeability, high solubility Class II: High permeability, low solubility Class III: Low permeability, high solubility Class IV: Low permeability, low solubility Most of the interest in this classification system is for early drugs This has arisen from the application side in the development and management of product changes over the lifetime. In the early stages of drug development, knowledge of a particular drug class is an important factor influencing the decision to continue or discontinue development. The delivery forms and preferred methods of the invention can alter this determination by improving the bioavailability of drugs belonging to class II of the BCS.

  Solubility class boundaries are based on the maximum dosage strength of an immediate release ("IR") formulation and the pH-solubility profile of the test drug in an aqueous medium with a pH in the range of 1-7.5. ing. Solubility can be measured by shake-flask or titration methods, or validated stability-indicating assay analysis. A drug substance is considered highly soluble when it dissolves in a 250 ml or less aqueous medium with a maximum dosage strength in the pH range of 1-7.5. The 250 ml volume assessment is from a typical bioequivalence (BE) test protocol that prescribes the administration of a drug product to a fasting human volunteer with a full glass (approximately 8 ounces) of water. can get. The boundaries of the osmotic class are directly based on measurements of the rate of mass transport across the human intestinal membrane, and indirectly, the extent of absorption of the drug substance in humans (the proportion of dose absorbed). Not based on systemic bioavailability). The degree of absorption in humans is determined by mass balance pharmacokinetic studies, absolute bioavailability studies, intestinal permeability methods, in vivo human perfusion studies in humans, and in vivo Alternatively, it is measured using intestinal perfusion studies in animals. In vitro penetration experiments can be performed using excised human or animal intestinal tissue, and in vitro penetration experiments can be performed using monolayers of epithelial cells. Alternatively, non-human systems that can predict the extent of drug absorption in humans can also be used (eg, in vitro epithelial cell culture methods). A drug is dissolved if more than 90% of the dose dissolves, as determined based on mass determination or based on comparison to a reference intravenous dose, in the absence of evidence of instability in the gastrointestinal tract. Sex is considered very high. The FDA instruction is pH 7.5, and the ICH / EU instruction is pH 6.8. Immediate release drug product is a minimum of the indicated amount of drug substance, measured at 100 rpm using USP Apparatus I (or at 50 rpm using USP Apparatus II) in each medium listed below a volume of 900 ml or less. % Is considered to dissolve rapidly if it dissolves within 30 minutes. The medium includes (1) 0.1N HCl, or simulated gastric fluid USP without enzyme, (2) pH 4.5 buffer, and (3) pH 6.8 buffer, or enzyme. There is no pseudo intestinal fluid USP. Based on the BCS, a low solubility compound is a compound that does not dissolve in 250 ml or less of an aqueous medium at 37 ° C. with a maximum dose in the range of pH 1.2-7.5. See Cynthia K. Brown, et al., “Acceptable Analytical: Practices for Dissolution Testing of Poorly Soluble Compounds”, Pharmaceutical Technology (Dec. 2004). Immediate release (IR) drug products were measured at 100 rpm using the US Pharmacopoeia (USP) Apparatus I (or at 50 rpm using USP Apparatus II) in each of the media listed below volumes of 900 ml or less. If at least 85% or more of the indicated amount of drug substance dissolves within 30 minutes, it is considered to dissolve rapidly. The medium includes (1) 0.1N HCl, or simulated gastric fluid USP without enzyme, (2) pH 4.5 buffer, and (3) pH 6.8 buffer, or enzyme. There is no pseudo intestinal fluid USP.

  The drug substance is very permeable if the degree of absorption in humans is determined to be greater than 90% of the dose based on mass balance or based on comparison to a reference intravenous dose It is regarded. The boundaries of the osmotic class are directly based on measurements of the rate of mass transport across the human intestinal membrane, and indirectly, the extent of absorption of the drug substance in humans (the proportion of dose absorbed). Not based on systemic bioavailability). The degree of absorption in humans is measured using mass balance pharmacokinetic tests, absolute bioavailability tests, intestinal permeability methods, in vivo human intestinal perfusion tests, and in vivo or in situ animal intestinal perfusion tests Is done. In vitro penetration experiments can be performed using excised human or animal intestinal tissue, and in vitro penetration experiments can be performed using monolayers of epithelial cells. Alternatively, non-human systems that can predict the extent of drug I absorption in humans can also be used (eg, in vitro epithelial cell culture methods). The drug substance is very permeable if the degree of absorption in humans is determined to be greater than 90% of the dose based on mass balance or based on comparison to a reference intravenous dose It is regarded. A drug substance is considered to be less permeable when the degree of absorption in humans is determined to be less than 90% of the dose based on mass balance or based on comparison to a reference intravenous dose. It is. IR drug product, drug substance labeling, measured at 100 rpm (or 50 rpm using Apparatus II) in the United States Pharmacopeia (USP) Apparatus I in each medium listed below with a volume of 900 ml or less If at least 85% of the amount dissolves within 30 minutes, it is considered to dissolve rapidly. The medium includes (1) 0.1N HCl, or simulated gastric fluid USP without enzyme, (2) pH 4.5 buffer, and (3) pH 6.8 buffer, or enzyme. There is no pseudo intestinal fluid USP.

  Drugs belonging to BCS class II are drugs that are particularly poorly soluble or slow to dissolve, but are easily absorbed from solution by the stomach and / or intestinal lining. Therefore, in order to absorb, it is necessary to expose the inner layer of the digestive tract for a long time. Such drugs are found in numerous therapeutic classes. Class II drugs are particularly poorly soluble or slow to dissolve, but are easily absorbed from solution by the stomach and / or intestinal lining. In order to absorb, it is necessary to expose the lining of the gastrointestinal tract for a long time. Such drugs are found in numerous therapeutic classes. A class of particular interest is an antifungal agent such as itraconazole. Many of the known class II drugs are hydrophobic and have long been difficult to administer. Also, due to its hydrophobic nature, absorption tends to vary greatly depending on whether the patient is eating or fasting when taking the drug. This affects the peak level of serum concentration and complicates dose calculation and dosing schedules. Since many of these drugs are relatively inexpensive, a simple formulation is required and the yield may be somewhat inefficient.

  In a preferred embodiment of the present invention, the drug is intraconazole or related drugs, such as fluconazole, telconazole, ketoconazole, and saperconazole.

  Itraconazole is a class II drug used to treat fungal infections and is effective against a wide range of fungi including dermatophytes (tinea infection), Candida, Malassezia, and Chromoblast mycosis Is. Itraconazole functions by destroying key enzymes in the cell wall, yeast and other fungal infectious agents. Itraconazole can also lower testosterone levels, and this property makes itraconazole useful in the treatment of prostate cancer, reducing the production of excessive adrenal corticosteroid hormones and in the treatment of Cushing's syndrome. Itraconazole is available in the form of capsules and oral I solutions. For fungal infections, the recommended dosage for oral capsules is 200 mg to 400 mg once a day.

  Itraconazole has been available since 1992 in the form of capsules, since 1997 in the form of oral I solution, and since 1999 in the form of intravenous prescriptions. Because itraconazole is a very lipophilic compound, it achieves high concentrations in adipose tissue and purulent exudates. However, the dissolution of itraconazole into the aqueous fluid occurs only very limitedly. Stomach acidity and food have a profound effect on the absorption of oral prescription drugs (Bailey, et al., Pharmacotherapy, 10: 146-153 (1990)). Despite having 55% bioavailability, the absorption of oral capsules of itraconazole is variable and unpredictable.

  Other suitable drugs include, for example, griseofulvin and related compounds such as glyceoverdin; multiple types of antimalarial drugs (eg, atovacon); immune system modifiers (eg, cyclosporine); cardiovascular drugs (eg, digoxin and spironolactone) And class II anti-infective drugs such as ibuprofen. In addition, sterols or steroids may be used. Drugs such as danazol, carbamazopine, and acyclovir may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

Danazol is a synthetic steroid derived from ethisterone. Danazol is derived from 17a-pregna-2,4-diene-20-ino [2,3-d] -isoxazol-17-ol (17a-Pregna-2,4-dien-20-yno [2,3-d]. -Isoxazol-17-ol), represented by the formula C ₂₂ H ₂₇ NO ₂ and having a molecular weight of 337.46. Danazol is a synthetic steroid hormone, similar to the group of natural hormones (androgens) found in the body. Danazol is used to treat endometriosis and is also useful for the treatment of fibrocystic mammary disease and hereditary angioedema. Danazol has the function of reducing estrogen levels by suppressing the production of a hormone called gonadotropin by the pituitary gland. Gonadotropins usually activate the production of body hormones such as sex hormones, such as estrogens and progestogens, that are responsible for menstruation and ovulation. Danazol is administered orally and has a bioavailability that is not directly related to dosage, with a half-life of 4-5 hours. An increase in danazol dose is not proportional to an increase in plasma concentration. It has been shown that doubling the dose increases the I plasma concentration by only 30% to 40%. The peak concentration of danazol occurs within 2 hours, but the therapeutic effect usually does not occur approximately 6-8 weeks after taking the daily dose.

Acyclovir is a synthetic nucleoside analog that acts as an antiviral agent. Acyclovir is available for oral administration in the form of capsules, tablets, and suspensions. Acyclovir is a white crystalline powder, expressed as 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl] -6H-purin-6-one, and has the empirical formula C ₈ H _11. It is represented by N ₅ O ₃ and has a molecular weight of 225. Acyclovir may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Acyclovir has an absolute bioavailability of 20% when administered at a dose of 200 mg every 4 hours and a half-life of 2.5 to 3.3 hours. Also, its bioavailability decreases with increasing dose. Although low in bioavailability, acyclovir is very specific in viral suppressive activity because it has a high affinity for thymidine kinase (TK) (encoded by the virus). TK converts acyclovir into nucleotide analogues that prevent viral DNA replication. This prevention of replication is achieved by suppressing and / or inactivating the viral DNA polymerase and terminating the growing viral DNA strand.

  Carbamazepine is used in the treatment of psychomotor epilepsy and as an adjunct in the treatment of partial epilepsy. Carbamazepine can also reduce or reduce the pain associated with trigeminal neuralgia. Carbamazepine has been shown to be useful in the treatment of acute mania and in the prevention of bipolar disorder when given as a monotherapy or in combination with lithium or in combination with a neuroleptic. Carbamazepine may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Carbamazepine is a white to yellowish white powder, expressed as 5H dibenzo [b, furazepine-5-carboxamide] (5H dibenz [b, flazepine-5-carboxamide]), and has a molecular weight of 236.77. Carbamazepine is substantially insoluble in water and soluble in alcohol and acetone. The absorption of carbamazepine is relatively slow despite the 89% bioavailability in the tablet form. When taken orally at one time, carbamazepine tablets and chewable tablets show unchanged peak plasma concentrations of carbamazepine within 4 to 24 hours. The therapeutic range of plasma concentrations of carbamazepine at steady state is generally between 4 mcg / ml and 10 mcg / ml.

  Other representative compounds belonging to Class II include antibiotics that kill H. pylori, and therapeutic drugs. Examples of antibiotics that kill H. pylori include amoxicillin, tetraacillin, and metronidazole. The therapeutic drugs include acid inhibitors (H2 blockers such as cimetidine, ranitidine, famotidine, and nizatidine; proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole), enhanced mucosal defense Drugs (bismuth salt; bismuth subsalicylate), and / or mucolytic drugs (megalate). These species may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Many of the known class II drugs are hydrophobic and have been difficult to administer for a long time. Also, due to its hydrophobic nature, absorption tends to vary greatly depending on whether the patient is eating or fasting when taking the drug. This affects the peak level of serum concentration and complicates dose calculation and dosing schedules. Since many of these drugs are relatively inexpensive, a simple formulation is required and the yield may be somewhat inefficient.

  In a preferred embodiment of the invention, the drug is intraconazole and its related fluconazole, terconazole, ketoconazole, and saperconazole. These species may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Itraconazole is a class II drug used to treat fungal infections against a wide range of fungi, including dermatophytes (ringworm infection), Candida, Malassezia, and melanococcal disease And effective. Itraconazole functions by destroying the cell wall, key yeast enzymes, and other fungal infectious agents. Itraconazole can also lower testosterone levels, and this property makes itraconazole useful in treating prostate cancer, reducing excessive adrenal corticosteroid hormone production and in treating Cushing's syndrome . Itraconazole is available in the form of capsules and oral solutions. For fungal infections, the recommended dosage for oral capsules is 200 mg to 400 mg once a day. Itraconazole has been available since 1992 in the form of capsules, since 1997 in the form of oral solutions, and since 1999 in the form of intravenous prescriptions. Because itraconazole is a very lipophilic compound, it achieves high concentrations in adipose tissue and in exudates with purulent properties. However, penetration of itraconazole into aqueous fluids occurs only very limitedly. Stomach acidity and food have a profound effect on the absorption of oral prescription drugs (Bailey, et al., Pharmacotherapy, 10: 146-153 (1990)). Despite having 55% bioavailability, the absorption of oral capsules of itraconazole is variable and unpredictable.

  Other class II drugs include, for example, sulfasalazine, griseofulvin, and related compounds such as griseoverdin; multiple types of antimalarials (eg, atovacon); immune system modifiers (eg, cyclosporine); cardiovascular drugs (eg, Digoxin and spironolactone); and ibuprofen (analgesic); ritonavir, nevirapine, lopinavir (antiviral); clofazine (therapeutic for leprosy); diloxanidofuran carboxylic acid (anti-amoeba); ); Nifedipine (anti-anginal); spironolactone (diuretic); steroidal drugs such as danazol; anti-viral drugs such as carbamazepine and acyclovir Dyeable drugs, and the like. These species may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

Danazol is a synthetic steroid derived from ethisterone. Danazol is derived from 17a-pregna-2,4-diene-20-ino [2,3-d] -isoxazol-17-ol (17a-Pregna-2,4-dien-20-yno [2,3-d]. -Isoxazol-17-ol), represented by the formula C ₂₂ H ₂₇ NO ₂ and having a molecular weight of 337.46. Danazol is used to treat endometriosis, fibrocystic breast disease, and hereditary angioedema. Danazol is administered orally and has a bioavailability that is not directly related to dosage, with a half-life of 4-5 hours. An increase in danazol dose is not proportional to an increase in plasma concentration. It has been shown that doubling the dose increases plasma concentrations by only 30% to 40%. The peak concentration of danazol occurs within 2 hours, but the therapeutic effect usually does not occur approximately 6 to 8 weeks after taking the daily dose.

Acyclovir is a synthetic nucleoside analog that acts as an antiviral agent. Acyclovir is available for oral administration in the form of capsules, tablets, and suspensions. Acyclovir is a white crystalline powder, expressed as 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy) methyl] -6H-purin-6-one, and has the empirical formula C ₈ H _11. It is represented by N ₅ O ₃ and has a molecular weight of 225. Acyclovir has an absolute bioavailability of 20% with a single dose of 200 mg every 4 hours and a half-life of 2.5 to 3.3 hours. Also, its bioavailability decreases with increasing dose. Although low in bioavailability, acyclovir is very specific in viral suppressive activity because it has a high affinity for thymidine kinase (TK) (encoded by the virus). TK converts acyclovir into nucleotide analogues that prevent viral DNA replication. This prevention of replication is achieved by suppressing and / or inactivating the viral DNA polymerase and terminating the growing viral DNA strand. Acyclovir may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Carbamazepine is used in the treatment of psychomotor epilepsy and as an adjunct in the treatment of partial epilepsy. Carbamazepine can also reduce or reduce the pain associated with trigeminal neuralgia. Carbamazepine has been shown to be useful in the treatment of acute mania and in the prevention of bipolar disorder when given as a monotherapy or in combination with lithium or in combination with a neuroleptic. Carbamazepine is a white to yellowish white powder, expressed as 5H-dibenzo [b, f] azepine-5-carboxamide, and has a molecular weight of 236.77. Carbamazepine is substantially insoluble in water and soluble in alcohol and acetone. The absorption of carbamazepine is relatively slow despite the 89% bioavailability in the tablet form. When taken orally at one time, carbamazepine tablets and chewable tablets show unchanged peak plasma concentrations of carbamazepine within 4 to 24 hours. The therapeutic range of plasma concentrations of carbamazepine at steady state is generally between 4 mcg / ml and 10 mcg / ml. Carbamazepine may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Drugs belonging to class IV of BCS (low permeability, low solubility) are drugs that have particularly low or low solubility in water and very low GI permeability.

The majority of class IV drugs are lipophilic drugs and as a result have very low GI penetration. Examples include acetazolamide, furosemide, tobramycin, cefuroxmine, allopurinol, dapsone, doxycycline, paracetamol, nalidixic acid, chlorothiazide, tobramycin, cyclosporin, tacrolimus, and paclitaxel. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Tacrolimus extends host and transplanted graft survival in animal transplantation models of the liver, kidney, heart, bone marrow, small intestine and pancreas, lungs and trachea, skin, cornea, and limbs. Tacrolimus acts as an immunosuppressant by suppressing the activation of T-lymphocytes (the mechanism of suppression is unknown). Tacrolimus is represented by the empirical formula _{C 44 H 69 NO 12 · H} 2 O, formula weight is 822.05. The appearance of tacrolimus is white crystals or crystalline powder. Tacrolimus is substantially insoluble in water, soluble in ethanol, and extremely soluble in methanol and chloroform. Tacrolimus is available for oral administration as a capsule or as a sterile solution for injection. Absorption of tacrolimus from the gastrointestinal tract after oral administration is inadequate and variable. When a single dose is 5 mg, taken twice daily, the absolute bioavailability of tacrolimus is approximately 17%. Paclitaxel is a chemotherapeutic agent that exhibits cytotoxic activity and antitumor activity. Paclitaxel is a natural product obtained from Taxus baccata by a semi-synthetic process. While paclitaxel has a good reputation for its great potential for therapeutic applications, it has several patient-related disadvantages as a therapeutic agent. These disadvantages stem in part from the very low solubility of paclitaxel in water. The low solubility makes it difficult to provide in a suitable dosage form. Due to the poor solubility of paclitaxel in water, currently approved clinical prescription drugs (by the US FDA) include 50% polyoxyethylated castor oil (CREMOPHOL EL®) and 50% absolute alcohol. And 6 mg / ml paclitaxel solution in which paclitaxel is dissolved. Am. J. Hosp. Pharm., 48: 1520-1524 [1991]. In some cases, extremely strong reactions (including hypersensitivity) occur in combination with CREMOPHOR® administered with paclitaxel to compensate for low water solubility. The prescription drug must be infused over several hours because of the hypersensitivity reaction to the commercial paclitaxel prescription drug and the potential for paclitaxel to precipitate in the blood. In addition, patients must receive prior treatment with steroids and antihistamines prior to infusion. Paclitaxel is a white to yellowish white crystalline powder and is available in the form of a non-aqueous solution for injection. Paclitaxel is very lipophilic and insoluble in water. Such lipophilic drugs may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

  Examples of poorly water-soluble compounds include poorly soluble drugs selected from the group listed below. That is, prostaglandins (eg, prostaglandin E2, prostaglandin F2, and prostaglandin E1), proteinase inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir), cytotoxic agents (eg, paclitaxel, Doxorubicin, daunorubicin, epirubicin, idarubicin, zorubicin, mitoxantrone, amsacrine, vinblastine, vincristine, vindesine, dactiomycin, bleomycin), metallocene (eg, titanium dichloride metallocene), and complex of lipid and drug (Eg, diminazen stearate and diminazen oleate), and generally poorly soluble anti-infectives (eg, griseofulvin, ketoconazole, Conazole, itraconazole, clindamycin), especially antiparasitic drugs (eg, chloroquine, mefloquine, primaquine, vancomycin, vecuronium, pentamidine, metronidazole, nimorazole, tinidazole, atovakon, buparvaquone, niflutimox), and anti-inflammatory drugs (For example, cyclosporine, methotrexate, azathioprine) and the like. These bioactive compounds may be loaded into the mesoporous material of the present invention and further processed to form a pharmaceutical composition.

[Pharmaceutical composition]
Mesoporous silica material having a regular structure according to the present invention that retains a biologically active species (for example, a poorly water-soluble drug, a drug substantially insoluble in water, or an antibody fragment or a nucleotide fragment) as a host Can be formulated as a pharmaceutical composition and is selected for a mammalian host (eg, human patient or livestock) (ie, oral route, oral route, topical route, oral route, It can be administered in various forms tailored to the parenteral, rectal, or other delivery routes.

  The mesoporous silica material having the regular structure of the present invention is a host for small oligonucleic acid or peptide molecules, for example to bind specific molecules, such as aptamers (DNA aptamers, RNA aptamers or peptide aptamers). May be. Such oligonucleic acid hybrids may be formed using the mesoporous materials of the present invention that are or are intended to be hosts for small oligonucleic acids.

  The mesoporous material having a regular structure according to the present invention is a host for a poorly water-soluble drug, a BCS class II drug, a BCS class IV drug, or a compound substantially insoluble in water. It is particularly suitable for immediate release in an aqueous environment. For example, itraconazole may be loaded into a mesoporous silica material having the regular structure of the present invention.

  The pharmaceutical composition (formulation) according to the present invention is, for example, from “Guide Book of Japanese Pharmacopoeia”, Ed. Of Editorial Committee of Japanese Pharmacopoeia, Version No. 13, July 10, 1996, Hirokawa publishing company, You may manufacture by the method selected as needed. The novel mesoporous material of the present invention may be used as a host for small fragments of antibodies. Examples of small fragments of antibodies include Fv 'fragments, single chain Fv (scFv) antibodies, antibody Fab fragments, antibody Fab' fragments, heavy chain or light chain CDR antibody fragments, or anobodies, etc. Can be given.

  For COK-10 materials that have been washed, dried, calcined and loaded with water-insoluble bioactive species in the pores, the rate of release of water-insoluble bioactive species into the aqueous medium is increased. Improved.

  According to the present invention, considering the mild conditions under which the production method of the present invention can be implemented, the production method can be used to encapsulate the drug present in the aqueous solution B during the synthesis process. .

[Loading into a mesoporous silica material having a regular structure]
Solutions in solvent 50/50 V / V dichloromethane / ethanol can be prepared, for example, for the bioactive species 1) -7) listed below. 1) Itraconazole. 2) Itraconazole derivatives. 3) surface area having a polarity (PSA) is in the range of from 60 Å ² of 200 Å ^2, more preferably from 70 Å ² range 160 Å ^2, more preferably in the range from 80 Å ² of 140 Å ^2, Note preferably from 90 Å ² of 120 Å ² Triazole compounds in the range, and most preferably in the range of 95 ² to 110 ² . 4) A triazole compound having a partition coefficient (XlogP) in the range of 4-9, more preferably in the range of 5-8, and most preferably in the range of 6-7. 5) A triazole compound having 11 or more freely rotating bonds. 6) A triazole compound having a polar surface area (PSA) in the range of 80 to 200, a partition coefficient in the range of 3 to 8, and 8 to 16 freely rotating bonds. Or 7) a triazole compound having a polar surface area of more than 80%. Sonication may be used to speed up the itraconazole dissolution process. A solution that readily dissolves 50 mg of bioactive species per ml of the solvent mixture is impregnated into the mesoporous material of the present invention so that the bioactive species are loaded into the pores of the mesoporous material and dispersed as molecules in the mesoporous material. Suitable for

Another solvent that is generally suitable for dissolving compounds that are substantially insoluble in water or poorly soluble in water is dichloromethane (CH ₂ Cl ₂ ). In order to impregnate the mesoporous material of the present invention and fill the pores with the bioactive species, a solution having 50 mg of the bioactive species dissolved in 1 ml may be used. However, dichloromethane can be used in other organic (carbon-containing) solvents such as solvents inert to the reaction, ie 1,4-dioxane, tetrahydrofuran, 2-propanol, N-methyl-pyrrolidinone, chloroform, hexa It can be replaced by fluoroisopropanol. As being particularly suitable for alternative, 1,4-dioxane _{(/ -CH 2 -CH 2 -O-} CH 2 -CH 2 -O-\), tetrahydrofuran _{(/ -CH 2 -CH 2 -O-} CH ₂ -CH ₂ -\), acetone _{(CH 3 -C (= O)} -CH 3), acetonitrile _(CH 3 -C≡N), dimethylformamide (H-C (= O) N (CH 3) 2) Or a polar aprotic solvent selected from the group consisting of dimethyl sulfoxide (CH ₃ —S (═O) —CH ₃ ), or, for example, hexane (CH ₃ —CH ₂ —CH ₂ —CH ₂₎ -CH ₂ -CH _3), benzene _{(C 6 H 6),} toluene _{(C 6 H 5 -CH 3)} , diethyl ether _{(CH 3 CH 2 -O-CH} 2 -CH 3), chloroform (CHCl _3), Acetic acid Chill _{(CH 3 -C (= O)} -O-CH 2 -CH 3) , such as, a solvent selected from the group consisting of solvent having no polar and the like. In addition, as an organic (carbon-containing) solvent suitable for the meaning of the present invention, a solvent in which a physiologically active species or a drug hardly soluble in water is dissolved, an organic solvent in which a poorly soluble drug is highly soluble, or the like The solvent is mentioned. For example, an organic compound exhibiting strong hydrogen bonding, such as a fluorinated alcohol (for example, hexafluoroisopropanol (HFIP- (CF ₃ ) ₂ CHOH)), acts as a hydrogen bond acceptor and has a poorly water-soluble substance (for example, Amides and ethers) can be used to dissolve. Bioactive species, or amide class drug compounds, are carbonyls (C = O) and ethers (NC) resulting from covalent bonds between electronegative oxygen and nitrogen atoms and electroneutral carbon atoms. Contains a dipole. On the other hand, primary amides and secondary amides also contain two and one NH dipoles, respectively. The presence of the C = O dipole and, to a lesser extent than the C = O dipole, allows the amide to act as a hydrogen bond acceptor, so HFIP is a suitable solvent. It becomes. For example, another group of organic solvents are nonpolar solvents such as halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.). Of these, most preferred are dichloromethane (DCM) or methylene chloride, which are bioactive species or drugs such as diazepam, α-methyl-p-tyrosine, phencyclidine, quinolinic acid, simvastatin, Lovastatin; a suitable solvent for paclitaxel, alkaloids, cannabinoids and the like. For common solvents and drug compounds, files and databases (e.g., Cosmologic Gmbh & Co, GK's COSMOfiles (TM)) are available, and those skilled in the art can use known bioactive species that are sparingly soluble. A suitable solvent can be selected for loading into a mesoporous oxide having a regular structure. For new structures, using thermodynamic criteria including drug solubility in any solvent, including basic physical properties and phase equilibrium relationships, for example, computational chemistry expert systems and fluid dynamics expert systems (T. Bieker, KH Simmrock, Comput. Chem. Eng. 18 [Suppl. 1] [1993] S25-S29; KG Joback, G. Stephanopoulos, Adv. Chem. Eng. 21 [1995] 257-311; Bagherpour, R. Gani, JA Klein, DT Wu, Comput. Chem. Eng. 20 [1996] 685-702; J. Gmehling, C. Moellmann, Ind. Eng. Chem. Res. 37 [1998] 3112-3123 And M. Hostrup, PM Harper, R. Gani, Comput. Chem. Eng. 23 [1999] 1395-1414 and R. Zhao, H. Cabezas, SR Nishtala, Green Chemical Syntheses and Processes, ACS Symposium Series 767, American Chemical Society, Washington, DC, 2000, pp. 230-243). Examples of such expert systems include Cosmologic Gmbh & Co, GK's COSMOfrag / COSMOtherm (trademark), which interacts with a database of multiple molecules whose characteristics have been elucidated. Alternatively, an automated drug solubility tester such as, for example, Biomek® FX of Millipore can be used by one skilled in the art to easily test the water solubility of a selected compound.

〔Example〕
The following examples disclose the synthesis of COK-12 and describe the most preferred synthesis conditions to obtain a narrow mesopore size distribution.

[Preparation of aqueous solutions 1-10]
10 g P123 (BASF, Belgium), 9.2 g citric acid monohydrate (Riedel-de Haen, Germany) and 6.35 g sodium tricitrate (UCB, Belgium) An aqueous solution (surfactant P123) 1 having a pH of 4.0 was prepared by dissolving in deionized water (268.75 g).

4.83 g of sodium silicate solution (extra pure, Na ₂ O: 7.5 wt%, SiO ₂ : 26.5 to 28.5 wt%, manufactured by Merck, Germany), deionized water (13.95 g) An aqueous solution (silicate precursor) 2 with a pH of 11.0 was prepared by diluting with use.

  28.6 g P123 (BASF, Belgium), 25.8 g citric acid monohydrate (Riedel-de Haen, Germany), and 17.8 g sodium tricitrate (UCB, Belgium) A pH 4.0 aqueous solution (surfactant P123) 3 was prepared by dissolving in deionized water (753.8 g).

7.27 g of sodium silicate solution (extra pure, Na ₂ O: 7.5 wt%, SiO ₂ : 26.5 to 28.5 wt%, Merck, Germany), deionized water (20.98 g) A pH 11.0 aqueous solution (silicate precursor) 4 was prepared by diluting with use.

  10.10 g P123 (BASF, Belgium), 7.33 g citric acid monohydrate (Riedel-de Haen, Germany), and 17.8 g sodium tricitrate (UCB, Belgium) An aqueous solution (surfactant P123) 5 having a pH of 4.7 was prepared by dissolving in deionized water (263.41 g).

11.68 g of sodium silicate solution (extra pure, Na ₂ O: 7.5 wt%, SiO ₂ : 26.5 to 28.5 wt%, manufactured by Merck, Germany), deionized water (33.74 g) A pH 11.0 aqueous solution (silicate precursor) 6 was prepared by diluting with use.

  111.28 g P123 (BASF, Belgium), 100.22 g citric acid monohydrate (Riedel-de Haen, Germany), 69.22 g sodium tricitrate (UCB, Belgium), An aqueous solution (surfactant P123) 7 having a pH of 5.0 was prepared by dissolving in deionized water (2928 g).

145.28 g of sodium silicate solution (extra pure, Na ₂ O: 7.5 wt%, SiO ₂ : 26.5 to 28.5 wt%, manufactured by Merck, Germany), deionized water (419.65 g) A pH 11.0 aqueous solution (silicate precursor) 8 was prepared by diluting with use.

  An aqueous solution (surfactant P123) 9 was prepared by dissolving 4 g of P123 (BASF, Belgium) in an aqueous buffer solution overnight. This aqueous buffer was prepared by adding 3.7 g of citric acid monohydrate (Riedel-de Haen, Germany) and 2.54 g of sodium tricitrate (UCB, (Belgium) and an aqueous solution having a pH of 4.9.

By diluting 10.4 g of sodium silicate solution (NaOH: 10 wt%, SiO ₂ : 27 wt%, Merck, Germany) with deionized water (30.0 g), the pH of 11.0 An aqueous solution (silicate precursor) 10 was prepared.

[Example 1]
The experimental setup used is schematically illustrated in FIG. In the figure, A is an aqueous solution A containing a silica precursor; AT is a tube carrying the aqueous solution A; B is a poly (alkylene oxide) triblock copolymer and an acid having a pKa in the range of 3-9. BT is a tube carrying the aqueous solution B; M is a mixing tube; C is a collector; S is a separator; and D is a dryer / burner. The two syringes of the perfusion pump each had a length of 20 cm and an inner diameter of 1.6 mm. Further, the end of the cylindrical portion was connected to a mixing tube having a length of 160 cm and an inner diameter of 1.6 mm by a Swagelok T-shaped coupling tool having an angle of 90 °. One of the two syringes described above was filled with aqueous solution 1 and the other was filled with aqueous solution 2. In addition, the aqueous solution 1 and the aqueous solution 2 are jetted at flow rates of 99.0 ml / h (49.2 m / h) and 37.2 ml / h (18.5 m / h), respectively, collide with each other, and have a length of 160 cm. Entered mixing tube. By doing so, a pH of 5.0 was achieved in the resulting mixture. The linear velocity passing through the mixing pipe was 67.77 m / h. The residence time of the mixture of the aqueous solution 1 and the aqueous solution 2 in the mixing tube was 85 seconds.

  Multiple pumps were started simultaneously. When contacted, silica condensation was easily visible. The particles flowed through the tubing and were collected in a vial. The particles collected using centrifugation and decantation were washed 3 times with deionized water. The resulting material was first dried at 100 ° C. for 2 hours, then heated in an oven at a rate of 1 ° C./m to a temperature of 300 ° C. and held at 300 ° C. for 8 hours, Baked.

  The properties of the resulting material were determined by performing nitrogen adsorption using a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 200 ° C. for 10 hours (temperature rise rate: 5 ° C./m). The isotherm and pore size distribution are shown in FIGS. 2A and 2B, respectively. In addition, in the TEM micrographs of the obtained calcined mesoporous silica shown in FIGS. 3A, 3B, and 3C, a regular structure of hexagonal P6m in the mesophase appears clearly.

[Example 2]
The same experimental equipment configuration as in Example 1 was used except that the length of the mixing tube was reduced by 30 cm and the inner diameter was increased. One of the two syringes of the perfusion pump (each 20 cm in length and 1.6 mm in inner diameter) was filled with the aqueous solution 3, and the other was filled with the aqueous solution 4. In addition, the aqueous solution 3 and the aqueous solution 4 are jetted at flow rates of 198 ml / h (98.5 m / h) and 74.4 ml / h (37.0 m / h), respectively, collide with each other, have a length of 30 cm, and an inner diameter of Entered 3.2 mm mixing tube. By doing so, a pH of 5.6 was achieved in the resulting mixture. The linear velocity passing through the mixing pipe was 33.89 m / h. Moreover, the residence time of the mixture of the aqueous solution 3 and the aqueous solution 4 in the mixing tube was 31.9 seconds.

  Multiple pumps were started simultaneously. When contacted, silica condensation was easily visible. The particles flowed through the tubing and were collected in a vial. The particles collected using vacuum filtration were washed with 300 ml deionized water. The resulting material was first dried at 100 ° C. for 2 hours, then heated in an oven at a rate of 1 ° C./m to a temperature of 550 ° C. and held at 550 ° C. for 8 hours, Baked.

  The properties of the resulting material were determined by performing nitrogen adsorption using a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 300 ° C. for 10 hours (temperature rise rate: 5 ° C./m). The isotherm and pore size distribution are shown in FIGS. 4A and 4B, respectively.

Example 3
The same experimental equipment configuration as in Example 2 was used. One of the two syringes of the perfusion pump (each 20 cm in length and 1.6 mm in inner diameter) was filled with the aqueous solution 5 and the other was filled with the aqueous solution 6. In addition, the aqueous solution 5 and the aqueous solution 6 are jetted at flow rates of 198.0 ml / h (98.5 m / h) and 74.4 ml / h (37.0 m / h), respectively, collide with each other, and have a length of 30 cm. It entered a mixing tube having an inner diameter of 3.2 mm. By doing so, a pH of 5.6 was achieved in the resulting mixture. The linear velocity passing through the mixing pipe was 33.89 m / h. Moreover, the residence time of the mixture of the aqueous solution 5 and the aqueous solution 6 in the mixing tube was 31.9 seconds.

  Multiple pumps were started simultaneously. When contacted, silica condensation was easily visible. The particles flowed through the tubing and were collected in a vial. The particles collected using vacuum filtration were washed with deionized water. The resulting material was first dried at 100 ° C. for 2 hours, then heated in an oven at a rate of 1 ° C./m to a temperature of 300 ° C., and held at 300 ° C. for 8 hours, further 1 Firing was carried out by heating to a temperature of 550 ° C for 8 hours at a rate of ° C / m.

  The properties of the resulting material were determined by performing nitrogen adsorption using a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 300 ° C. for 10 hours (temperature rise rate: 5 ° C./m). The isotherm and pore size distribution are shown in FIGS. 5A and 5B, respectively. In addition, in the TEM micrograph of the obtained calcined mesoporous silica shown in FIGS. 6A and 6B, a regular structure of a hexagonal shape of P6m in the mesophase clearly appears.

Example 4
The experimental equipment configuration used is schematically illustrated in FIG. In the figure, A is an aqueous solution A; AT is a tube carrying an aqueous solution A; B is an aqueous solution B; BT is a tube carrying an aqueous solution B; M is a mixing tube; C is a collector; S is a separator; Is a dryer / firing oven. The two syringes of the perfusion pump with cylindrical end are Tygon Chemical's Masterflex® I / P 26 tubing with an inner diameter of 6.4 mm and Tygon Chemical's Masterflex with an inner diameter of 4.8 mm. It was connected to (registered trademark) I / P 15 tubing so that the aqueous solution A and the aqueous solution B flowed in, respectively. The two syringes were mixed by a glass Y-shaped coupling tool having an angle of 120 °, the aqueous solution A having a 4 mm inner diameter, the aqueous solution B having a 3 mm inner diameter, and a 180 cm long mixing tube (with an inner diameter of 6 mm). .4 mm, Tygon Chemical's Masterflex® I / P 26) was connected through a 4 mm inner diameter. Syringe A was filled with aqueous solution 7, and syringe B was filled with aqueous solution 8. In addition, the aqueous solution 7 and the aqueous solution 8 are jetted at flow rates of 1130 ml / m (2107.5 m / h) and 420 ml / m (1392.6 m / h), respectively, and collide with each other to form a mixing tube having a length of 180 cm. Has entered. By doing so, a pH of 5.0 was achieved in the resulting mixture. The linear velocity passing through the mixing pipe was 2890 m / h. Moreover, the residence time of the mixture of the aqueous solution 1 and the aqueous solution 2 in the mixing tube was 2.24 seconds.

  The pump used is Cole Palmer Masterflex (registered trademark) “I / P” Precision Brushless Drive (33 rpm to 650 rpm, I / P “Easy-Load” pump head is used in combination, and PSF housing / SS rotor is used for solution 7 ), And Cole Palmer Masterflex® “L / S” Precision Brushless Drive (6 rpm to 600 rpm, using L / S “High-Performance” pump head for solution 8). The two pumps were started simultaneously. When contacted, silica condensation was easily visible. The residence time in the 180 cm tube was about 3 seconds. The product produced in the first 10 seconds was discarded. The particles flowed through the tubing and were collected in a beaker as a white suspension. Ten minutes after collection, the collected particles were washed three times with deionized water. The resulting material is first dried at 60 ° C. overnight, then heated in an oven at a rate of 1 ° C./m to a temperature of 350 ° C. and held at 350 ° C. for 8 hours. Was fired.

  The properties of the resulting material were determined by performing nitrogen adsorption using a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 200 ° C. for 10 hours (temperature rise rate: 5 ° C./m). The isotherm and pore size distribution are shown in FIGS. 7A and 7B, respectively. The pore diameter was 5.8 nm.

  In the TEM micrographs of the calcined mesoporous silica shown in FIGS. 8A, 8B, and 8C, the regular structure of the P6m hexagonal shape of the mesophase is clearly shown.

Example 5
Solution 10 was added to solution 9 and stirred at 150 rpm using a mechanical mixer. Stirring was stopped after 1 minute. Other than this, no aging step was performed. The product was collected by vacuum filtration, washed with 300 ml deionized water and dried at 60 ° C. It was then calcined by heating in an oven at a rate of 1 ° C./m to a temperature of 550 ° C. and holding the temperature at 550 ° C. for 8 hours.

  The properties of the resulting material were determined by performing nitrogen adsorption using a Micromeritics Tristar apparatus. Prior to measurement, the sample was pretreated at 200 ° C. for 10 hours (temperature rise rate: 5 ° C./m). The isotherm is shown in FIG.

  In the TEM micrographs of the calcined mesoporous silica shown in FIGS. 10A and 10B, the regular structure of the hexagonal shape of P6m in the mesophase clearly appears.

  Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples should be considered exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims (19)

A production method for producing a mesoporous silica material having a substantially uniform pore size and a regular structure using a self-organization method, the production method comprising:
Preparing an aqueous solution A containing a silica precursor;
Prepare an aqueous solution B containing neither an alkali metal hydroxide nor an alkaline earth metal hydroxide, and containing a poly (alkylene oxide) triblock copolymer and an acid having a pKa in the range of 3-9. And a process of
The aqueous solution A and the aqueous solution B are used as a liquid flow in an elongated mixing container having a first opening and a second opening.
The liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the first opening of the elongated mixing vessel;
Supplying the liquid streams of the aqueous solution A and the aqueous solution B so as to directly collide,
Thereby, the pH of the resulting mixture is more than 2 and less than 8, and a reaction product is produced at a temperature in the range of 10 ° C. to 100 ° C. in the elongated mixing vessel,
After the reaction product is discharged from the second opening of the elongated mixing container, the reaction product is separated by filtration, dried, the surfactant is removed, and the pore diameter is substantially uniform. Producing a mesoporous silica material having a regular structure;
The manufacturing method which does not include an aging process.   The manufacturing method according to claim 1, wherein the silica precursor is an alkali silicate.   The said aqueous solution B is a manufacturing method of Claim 1 or 2 which further contains the alkali salt of the acid whose pKa is the range of 3-9.   The production method according to any one of claims 1 to 3, wherein the acid having a pKa in the range of 3 to 9 is present in a buffer having a pH in the range of 3 to 8.   The manufacturing method according to claim 1, wherein the aqueous solution B further contains a tetraalkylammonium surfactant.   The said tetraalkylammonium type surfactant is a manufacturing method of Claim 5 which has a C1-C4 alkyl group.   The production method according to claim 5 or 6, wherein the tetraalkylammonium surfactant is tetrapropylammonium hydroxide (TPAOH) or tetramethylammonium hydroxide (TMAOH).   The manufacturing method as described in any one of Claims 1-7 whose said poly (alkylene oxide) triblock copolymer is Pluronic (trademark) P123.   9. The alkali silicate is present as an aqueous sodium silicate solution, the aqueous sodium silicate solution comprising at least 10% by weight sodium hydroxide and at least 27% by weight silica. The manufacturing method according to one item.   The pH of the said aqueous solution B is a manufacturing method as described in any one of Claims 1-9 which is the range of 2-8.   The manufacturing method according to any one of claims 1 to 10, wherein the pore diameter of the mesoporous silica material is substantially uniform and is in a range of 4 nm to 30 nm.   The production method according to any one of claims 1 to 11, wherein a residence time in the elongated mixing container is in a range of 1 second to 100 seconds.   The liquid flow of the aqueous solution A and the aqueous solution B is independently discharged into the first opening of the elongated mixing container independently at a linear velocity exceeding 5 m / h. The manufacturing method as described.   14. Manufacturing according to any one of the preceding claims, wherein the liquid streams of aqueous solution A and aqueous solution B are each independently released into the elongated mixing vessel at a linear velocity exceeding 10 m / h. Method.   15. Production according to any one of the preceding claims, wherein the liquid streams of aqueous solution A and aqueous solution B are each independently released into the elongated shaped mixing vessel at a linear velocity of more than 30 m / h. Method.   16. A liquid stream of aqueous solution A and aqueous solution B, respectively, is independently released into the elongated shaped mixing vessel at a linear velocity of less than 10,000 m / h. The manufacturing method as described.   The production according to any one of claims 1 to 16, wherein the liquid streams of the aqueous solution A and the aqueous solution B are each independently discharged into the elongated mixing vessel at a linear velocity exceeding 1000 m / h. Method.   The production method according to any one of claims 1 to 17, further comprising a step of loading a bioactive species into a mesoporous silica material having a regular structure.   The production method according to any one of claims 1 to 18, further comprising a step of dispersing a substantially insoluble drug as a solid in the mesoporous silica material having a regular structure.