Patent Application
20090324725
Microparticles for carrying drugs can be effectively used for a variety of drug forms: oral, intravenous, subcutaneous, transpulmonary or transnasal administrations by adjusting their size or by suitably modifying the microparticles. In addition, in terms of function, they can be effectively used to selectively deliver a drug to the liver, lungs or inflammatory site and the like, control drug release, mask unpleasant taste or improve intestinal absorption and the like.
Known examples of such microparticles include liposomes, polymer micelles, protospheres (registered trademark), resins and inorganic particles (inorganic microspheres or nanospheres) such as silica gel, zeolite or hydroxyapatite. The present invention relates to a novel polyethylene glycol-modified hydroxyapatite (abbreviated as PEG-modified HAP) in which the surface of hydroxyapatite is modified with polyethylene glycol (PEG), applications thereof and a production process of the same.
Hydroxyapatite (hereinafter referred to as HAP) is a basic component of bones and teeth, has high bioaffinity and easily adsorbs sugars and proteins. Consequently, HAP is widely used as a pharmaceutical base material such as materials for repairing bones and teeth, column packing material, drug transporter or cell culture substrate. The surface of HAP is being required to be chemically modified with functional polymers and biologically active substances in order to more fully take advantage of its characteristics. However, since the hydroxyl groups on the HAP surface serving as the footholds for such modification have low reactivity, it is difficult to uniformly bond organic compounds such as functional polymers or biologically active substances.
Chemical modification of apatite particles is reported by Liu Qiug, et al. involving the bonding of polyethylene glycol to nanoapatite particles using hexamethylene diisocyanate (Biomaterials (1998), 19(11-12), 1067-1072). In addition, Furuzono, et al. succeeded in developing a transcutaneous device in which a silane coupling agent having amino groups is bonded to apatite particles followed by bonding with a silicone sheet by means of polyacrylic acid using a condensation reaction between carboxylic acid and amino groups (J. Biomed. Mater. Res. (2001), 56(1), 9-16). Moreover, Tanaka, et al. succeeded in introducing highly reactive organic functional groups onto the surface of porous HAP and then covalently bonding an organic substance to the surface of the porous HAP using a silane coupling agent having two or more types of functional groups and an isocyanate compound, and this is indicated as being able to be widely used in applications such as a chromatography column packing material, DDS carrier, ion exchange medium, cell culture substrate or implant (Japanese Unexamined Patent Application, First Publication No. 2003-342011).
However, since a bifunctional linker reagent is used in each of their production processes, crosslinking between hydroxyapatite particles can inevitably not be avoided, resulting in the problem of the crosslinked hydroxyapatite particles being present as by-products. In addition, since highly reactive silane coupling agents and isocyanate compounds are used, the safety of these residual reactive functional groups is also considered to be present problems.
[Patent Document 1] Japanese Unexamined Patent Application, First Publication No. 2003-342011
[Non-Patent Document 1] Biomaterials (1998), 19(11-12), 1067-1072
[Non-Patent Document 2] J. Biomed. Mater. Res. (2001), 56(1), 9-16
An object of the present invention is to provide a PEG-modified HAP having a high degree of safety and novel functions by modifying the surface of hydroxyapatite particles with a polyethylene glycol derivative without using a bifunctional linker, applications using the same, and a production process of the same.
As a result of conducting extensive studies to solve the aforementioned problems, the inventors of the present invention succeeded in introducing polyethylene glycol onto the surface of HAP with —O(CO) bonds using a polyethylene glycol derivative having a carboxyl group as a terminal functional group. Moreover, the inventors of the present invention found that a drug delivery system (DDS), in which various pharmaceuticals are loaded onto the novel PEG-modified HAP, can be effectively used for a variety of drug forms: oral, intravenous, subcutaneous, transpulmonary or transnasal administrations, and can be effectively applied to selectively deliver a drug to the liver, lungs or inflammatory site and the like, control drug release, mask unpleasant taste or improve intestinal absorption and the like.
This PEG-modified HAP can be expected to maintain the high mechanical strength and ability to adsorb various substances, which are characteristics of apatite, while also having properties such as retention in blood. Consequently, it can be widely used as a DDS carrier as well as chromatography column packing material, ion exchange medium, cell culture substrate or implant and the like.
Namely, the present invention provides that described in (1) to (23) below:
(1) a substance in the form of a mixture comprising hydroxyapatite having a particle diameter of 50 μm to 10 nm and a polyethylene glycol derivative having a carboxyl group as a terminal functional group, wherein the carbon content is 10 to 0.1%;
(2) a substance in which hydroxyapatite having a particle diameter of 50 μm to 10 nm is bonded to a polyethylene glycol derivative having a carboxyl group as a terminal functional group through —O(CO) bonds, wherein the carbon content is 10 to 0.1%;
(3) a substance comprising the substance described in (1) above and a pharmaceutical active ingredient, wherein the weight ratio of the pharmaceutical active ingredient is 1 to 30%, or a substance comprising the substance described in (1) above, a pharmaceutical active ingredient and a pharmaceutical additive, wherein the weight ratio of the pharmaceutical active ingredient is 1 to 30%;
(4) a substance comprising the substance described in (2) above and a pharmaceutical active ingredient, wherein the weight ratio of the pharmaceutical active ingredient is 1 to 30%, or a substance comprising the substance described in (2) above, a pharmaceutical active ingredient and a pharmaceutical additive, wherein the weight ratio of the pharmaceutical active ingredient is 1 to 30%;
(5) a pharmaceutical prepared from the substance described in (3) or (4) above;
(6) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is an siRNA, aptamer, RNA, DNA, peptide or protein;
(7) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is clarithromycin;
(8) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is itraconazole;
(9) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is siRNA;
(10) a method for obtaining the substance described in (1) or (2) above of the submicron size by treating submicron-sized hydroxyapatite and an active ester of a polyethylene glycol derivative having a carboxyl group as a terminal functional group in an anhydrous organic solvent;
(11) a method for obtaining the substance described in (3) or (4) above by treating a submicron-sized substance described in (1) or (2) above and a pharmaceutical active ingredient or pharmaceutical additive in an organic solvent;
(12) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is candesartan;
(13) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is candesartan cilexetil;
(14) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is a double-stranded siRNA having the sequence of 5′-GUGAAGUCAACAUGCCUGCTT-3′ (SEQ ID NO. 1) and 5′-GCAGGCAUGUUGACUUCACTT-3′ (SEQ ID NO. 2);
(15) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is a double-stranded siRNA having the sequence of 5′-CUUACGCUGAGUACUUCGATT-3′ (SEQ ID NO. 3) and 5′-UCGAAGUACUCAGCGUAAGTT-3′ (SEQ ID NO. 4);
(16) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is etoposide;
(17) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is nelfinavir mesylate;
(18) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is simvastatin;
(19) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is 7-ethyl-10-hydroxy-camptothecine;
(20) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is paclitaxel;
(21) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is saquinavir mesylate;
(22) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is insulin; and,
(23) the substance described in (3) or (4) above, wherein the pharmaceutical active ingredient is bromocriptine mesylate.
The following effects can be demonstrated by the present invention.
(1) Use of the PEG-modified HAP of the present invention enables even a poorly soluble pharmaceutical substance to be treated in the manner of a soluble substance, facilitating administration of a drug into the body and improving blood retention in the body.
(2) Modifying the surface of HAP with PEG makes it possible to prevent aggregation of HAP particles.
(3) Use of the PEG-modified HAP of the present invention in a base material makes it possible to prevent aggregation of particles even in the case of HAP particles loaded with an active ingredient.
The following provides a detailed explanation of the present invention.
The present invention relates to a PEG-modified HAP having a high degree of safety and novel functions obtained by bonding a polyethylene glycol derivative to the surface of hydroxyapatite particles with a monofunctional polyethylene glycol derivative without using a bifunctional linker, applications thereof, and a production process of the same.
The HAP subjected to PEG modification may be an HAP solid having a large number of pores (air holes) or HAP not having very high porosity.
HAP is a compound having the general formula of Ca5 (PO4)3OH, and includes a group of compounds referred to as calcium phosphates, such as CaHPO4, Ca3(PO4)2, Ca4O(PO4)2, Ca10(PO4)6(OH)2, CaP4O11, Ca(PO3)2, Ca2P2O7 or Ca(H2PO4)2.H2O according to the non-stoichiometric properties of reactions thereof. In addition, since HAP has as a fundamental component thereof a compound represented by the compositional formula Ca5(PO4)3OH or Ca10(PO4)6(OH)2, a portion of the Ca component may be substituted with one or more types of substituents selected from the group consisting of Sr, Ba, Mg, Fe, Al, Y, La, Na, K, H and the like. In addition, a portion of the (PO4) component may be substituted with one or more types of substituents selected from the group consisting of VO4, BO3, SO4, CO3, SiO4 and the like. Moreover, a portion of the (OH) component may be substituted with one or more types of substituents selected from the group consisting of F, Cl, O, CO3 and the like. In addition, a portion of each of these components may also be defective. Since a portion of the PO4 and OH components of apatite of bone in the body are normally substituted with CO3, entrance of CO3 from the air and partial substitution into each component (on the order of 0 to 10% by weight) is permitted during production of the present composite biomaterial.
Furthermore, HAP may be adopt an ordinary microcrystalline, amorphous or crystalline form, as well as be in the form of an isomorphic solid solution, substituted solid solution or interstitial solid solution, and may contain non-quantum theory defects. In addition, the atomic ratio of calcium and phosphorous (Ca/P) in HAP is preferably within the range of 1.3 to 1.8 and more preferably within the range of 1.5 to 1.7. This is because, if the atomic ratio is within the range of 1.3 to 1.8, bioaffinity is enhanced since the composition and crystal structure of apatite (calcium phosphate compounds) in the product is able to adopt a composition and structure similar to apatite present in vertebrate bone.
Although the HAP subjected to PEG modification can be prepared using a known method, a commercially available product such as Hydroxyapatite nanopowder manufactured by Aldrich may also be used.
Although a commercially available high-purity, monofunctional activated PEG modifier is used for the “monofunctional polyethylene glycol derivative” used in the present invention, it is not limited thereto. Whether or not the PEG moiety is linear or branched, or the molecular weight of the PEG moiety and the like can be arbitrarily selected and adjusted according to the purpose.
Although an anhydrous organic solvent, and particularly dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetic acid, acetone, tetrahydrofuran (THF), ethyl acetate or dichloromethane, can be used for the reaction solvent during modification, dimethylsulfoxide (DMSO) or acetone, which belong to class 2 to 3 as described in residual solvent guidelines for pharmaceuticals, is particularly preferable. The reaction temperature ranges from cooling with ice to 100° C., the reaction time is 2 to 72 hours, and the “monofunctional polyethylene glycol derivative” is used in large excess (1 to 0.1 g) per 1 g of HAP. Following completion of the reaction, residual excess “monofunctional polyethylene glycol derivative” and a by-product in the form of N-hydroxysuccinimide can be removed by washing with the organic solvent used in the reaction and filtering, and insoluble matter is vacuum dried to obtain PEG-modified HAP. Although the carbon content of the PEG-modified HAP can be adjusted to 0.1 to 10% by adjusting the amount of PEG modification reagent, it is preferably about 1 to 3% in particular.
The PEG-modified HAP of the present invention can be used as a DDS carrier by adsorbing a pharmaceutical active ingredient. Since both HAP and PEG have high biocompatibility, they can be used without reservation for delivering drugs into the body (J. Mater. Sci. (2000), 11(2), 67-72).
A drug can be delivered to a target organ more reliably by bonding a specific ligand to the target organ. In addition, in the case a pharmaceutical active ingredient is poorly soluble causing an injection preparation to be unable to or be poorly absorbed in the intestine, adsorbing a pharmaceutical active ingredient to submicron-sized PEG-modified HAP makes it possible to indirectly prepare pharmaceutically active ingredients at the submicron size, enabling them to be widely applied to the development of injection preparations and improvement of oral absorption. Moreover, substances in which pharmaceutical active ingredients in the form of RNA, DNA or a protein and the like are adsorbed to submicron-sized PEG-modified HAP can be applied as promising DDS for these pharmaceutical active ingredients.
A substance composed of PEG-modified HAP and a pharmaceutical active ingredient or pharmaceutical additive can be prepared using the following method. After dissolving the pharmaceutical active ingredient or pharmaceutical additive in a solvent belonging to class 2 to 3 described in residual solvent guidelines for pharmaceuticals, such as DMSO, ethanol (EtOH) or acetone, adding the PEG-modified HAP at a weight ratio of 90%, and subjecting to ultrasonic treatment at room temperature, the entire amount of the suspension is freeze-dried or removed of solvent by distilling under reduced pressure to obtain a substance as described in the claims. The loading ratio of the pharmaceutical active ingredient or pharmaceutical additive to the PEG-modified HAP can be adjusted to 1 to 30%, although dependent upon the pharmaceutical active ingredient or pharmaceutical additive, and is preferably about 10% in particular.
Although the following provides a more detailed explanation of the present invention through examples thereof, the present invention is not limited by these examples.
200 mg of a polyethylene glycol (PEG) modifier (NOF, Sunbright ME-020CS) were added to a 20 ml of an acetone suspension containing 200 mg of Hydroxyapatite nanopowder (Aldrich, 677418) followed by radiating with ultrasonic waves (frequency: 28 kHz, output: 100 W) for 30 minutes. After stirring the suspension for 18 hours at room temperature, the suspension was separated by centrifugation (9000×g, 20° C., 30 minutes) followed by removing the supernatant by decanting. After washing the precipitate twice with acetone (20 ml×2), the precipitate was dried for 18 hours at 50° C. under reduced pressure to obtain 158 mg of PEG-modified HAP in the form of a white powder.
The results of quantifying the residual solvent present in the prepared PEG-modified HAP by gas chromatography (GC) and quantifying the PEG modification rate in the form of the carbon content as determined by CHN reduction analysis are shown below.
Residual solvent (acetone) concentration: <100 μg/g
Carbon content: 2.01%<
<GC Analysis Conditions>
Apparatus: HP-589011 System (Hewlett Packard)
Column: DB-624, 75 mm×0.53 mm, membrane thickness: 0.3 μm
Column temperature: 40° C.→260° C.
Carrier gas: Helium, 7 psi
Detector: Hydrogen flame ionization detector (FID) 250° C.
<CHN Reduction Analysis Conditions>
Analyzer: Vario EL III (Elementar Analysensysteme GmbH)
Combustion oven temperature: 950° C.
Reduction oven temperature: 500° C.
Helium flow rate: 200 ml/min
Oxygen flow rate: 30 ml/min
Combustion time: 90 sec
1 mg of the prepared PEG-modified HAP was suspended in Milli-Q water (15 ml) and irradiated for 5 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W) followed by measurement of particle diameter (measuring instrument: Horiba Laser Diffraction/Scattering Particle Diameter Distribution Measuring System LA-950) The results are shown in
A DMSO solution (2 ml) of clarithromycin (8 mg) was added to PEG-modified HAP (100 mg) followed by radiating for 2 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W). The suspension was freeze-dried to obtain 108.6 mg of a white powder. This was further dried for 36 hours at 50° C. under reduced pressure to obtain 108.1 mg of the target substance in the form of a white powder.
1 ml of acetonitrile was added to 10 mg of the product followed by irradiating for 5 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W). The suspension was centrifuged (9000×g, 20° C., 3 minutes) and the supernatant was filtered with a 0.22 μm filter to obtain an HPLC sample. As a result of HPLC analysis, 0.74 mg of clarithromycin was confirmed to be contained in 10 mg of the product. Yield: 7.4% (w/w).
<HPLC Analysis Conditions>
1 mg of the product was suspended in Milli-Q water (15 ml) and irradiated for 5 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W) followed by measurement of particle diameter. The results are shown in
A DMSO solution (4.8 ml) of itraconazole (24 mg) was added to PEG-modified HAP (300 mg) followed by irradiating for 2 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W). This suspension was freeze-dried to obtain 324.3 mg of a white powder. After suspending this in Milli-Q water (15 ml), an aqueous solution of sodium chondroitin sulfate (10 mg/ml) (0.3 ml) was added followed by irradiating for 2 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W). This suspension was then freeze-dried to obtain 322.6 mg of a white powder.
1 ml of acetonitrile was added to 10 mg of the product followed by irradiating for 5 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W). The suspension was centrifuged (9000×g, 20° C., 3 minutes) and the supernatant was filtered with a 0.22 μm filter to obtain an HPLC sample. As a result of HPLC analysis, 0.74 mg of itraconazole was confirmed to be contained in 10 mg of the product. Yield: 7.4% (w/w).
<HPLC Analysis Conditions>
1 mg of the product was suspended in Milli-Q water (15 ml) and irradiated for 5 minutes with ultrasonic waves (frequency: 28 kHz, output: 100 W) followed by measurement of particle diameter. The results are shown in
(1) Preparation of Substance Composed of PEG-Modified HAP and Fluorescently Labeled siRNA
6 mg of PEG-modified HAP were weighed out followed by the addition of 10 ml of pure water. The mixture was transferred to an emulsifier-disperser and treated for 1 minute at 16000 rpm to obtain a homogeneous suspension. 18 μl of an aqueous solution of 10 mg/ml fluorescently labeled siRNA were added to 3 ml of the suspension and mixed well.
6 ml of glycerin were added to 3 ml of the product. The sample was observed with a fluorescence microscope. The fluorescence excitation wavelength was set to 490 nm for a fluorescein-labeled sample and 550 nm for a rhodamine-labeled sample. The results are shown in
Observation by fluorescence microscopy revealed the siRNA to be coated onto the surface of the PEG-modified HAP.
Changes in blood concentrations of a substance composed of PEG-modified HAP and itraconazole were confirmed by intravenous and oral administration to rats followed by calculation of bioavailability.
(1) Intravenous Administration
Aqueous suspension of substance composed of PEG-modified HAP and itraconazole
Storage conditions: Blocked from light, room temperature
(2) Oral Administration
Aqueous suspension of substance composed of PEG-modified HAP and itraconazole
Storage conditions: Blocked from light, room temperature
Plasma collection times: 0.5, 2, 6, 18, 24, 48 and 168 hours after dosing
Plasma collection: Approx. 0.5 ml of blood were drawn from a caudal vein using a capillary tube treated with sodium heparin
Plasma obtained by centrifuging the blood (12000 rpm, 4° C., 3 minutes) was stored frozen at −20° C. until the time of measurement.
(5) Observation of Symptoms: The animals were only observed for general condition, and observation of specific sites or specific tissues was not carried out.
Analysis Method:
The substance composed of PEG-modified HAP and itraconazole was observed to demonstrate effects that improve intestinal absorption, demonstrating high bioavailability of about 57% at 0.5 to 24 hours (Table 1).
Based on the results of an in vivo blood kinetics study on commercially available Itrizole for injection and Itrizole 50 capsules conducted simultaneous to the above study, the bioavailability at 0.5 to 48 hours of oral Itrizole 50 capsules versus Itrizole for injection was about 39%.
On the basis of these results, a substance composed of submicron-sized PEG-modified HAP and a poorly soluble pharmaceutical was indicated to be useful as a novel injection preparation and as a superior oral preparation exhibiting high oral absorption.
Table 1
Changes in blood concentrations of a substance composed of PEG-modified HAP and clarithromycin were confirmed by intravenous and subcutaneous administration to rats.
(1) Intravenous Administration
Aqueous suspension of substance composed of PEG-modified HAP and clarithromycin
Storage conditions: Blocked from light, room temperature
(2) Subcutaneous Administration
Aqueous suspension of substance composed of PEG-modified HAP and clarithromycin
Storage conditions: Blocked from light, room temperature
Plasma collection times: 0.5, 2, 6, 12, 24, 48 and 168 hours after dosing
Plasma collection: Approx. 0.5 ml of blood were drawn from a caudal vein using a Pasteur pipette treated with sodium heparin
Plasma obtained by centrifuging the blood (8000×g, 4° C., 3 minutes) was stored frozen at −20° C. until the time of measurement.
(5) Observation of Symptoms: The animals were only observed for general condition, and observation of specific sites or specific tissues was not carried out.
Analysis Method:
As shown in Table 2, the substance composed of submicron-sized PEG-modified HAP and a poorly soluble pharmaceutical in the form of clarithromycin was indicated to be useful as a novel injection preparation (able to be intravenously or subcutaneously injected using a 27G injection needle).
Table 2
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 7.4% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 6.3% (w/w)
A composition was prepared using a method similar to Example 4.
Drug adsorption rate was confirmed by fluorescence analysis. Adsorption rate: 20% (w/W)
A composition was prepared using a method similar to Example 4.
Drug adsorption rate was confirmed by fluorescence analysis. Adsorption rate: 20% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 8.0% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 7.4% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 7.9% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 6.8% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 7.4% (w/w)
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 8.0% (w/w)
A composition was prepared using a method similar to Example 4.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 12.7% (w/w)
(Results)
As shown in
(Results)
As shown in
(Results)
As shown in
(Results)
As shown in
(Results)
As shown in
(Results)
As shown in
(Results)
Fluorescence micrographs of cells 4 hours after addition of a substance composed of PEG-modified HAP and fluorescently labeled 5′-CUUACGCUGAGUACUUCGATT-3′ (SEQ ID NO. 3) and 5′-UCGAAGUACUCAGCGUAAGTT-3′ (SEQ ID NO. 4) to A549 human lung cancer cells are shown in
(Results)
As shown in Table 3, a substance composed of submicron-sized PEG-modified HAP and a poorly soluble pharmaceutical in the form of etoposide was observed to demonstrate higher accumulation of etoposide in the liver as compared with a commercially available etoposide injection preparation (Vepesid injection).
Table 3
(Results)
A confocal laser micrograph of a substance composed of PEG-modified HAP and simvastatin is shown in
(Results)
A confocal laser micrograph of a substance composed of PEG-modified HAP and nelfinavir mesylate is shown in
A composition was prepared using a method similar to Example 2 or Example 3.
Drug adsorption rate was confirmed using a method similar to Example 2 or Example 3. Adsorption rate: 4.2% (w/w)
Use of the PEG-modified HAP of the present invention as a base material enables even a poorly soluble pharmaceutical substance to be treated in the manner of a soluble substance, facilitating administration of a drug into the body and improving blood retention in the body.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008-015444 | Jan 2008 | JP | national |
| 2008-153764 | Jun 2008 | JP | national |
