JP2019126667A - Controlled release device - Google Patents

Abstract

To obtain long-term controlled release effect of drug while suppressing the controlled release of highly-concentrated drug in early stage after filling, and to provide a controlled release device which can suppress side effects caused by blood transition of the highly-concentrated drug.SOLUTION: A controlled release device comprises madreporite 100 having continuous holes formed by communication of multiple pores, a drug and a polymer. The drug is kept in the madreporite 100 as a mixture mixed with the polymer. It is preferable that the madreporite 100 comprises an internal space and the drug is filled in the internal space with a condition of forming the mixture.SELECTED DRAWING: Figure 1

Description

  The present invention relates to sustained release devices.

  In recent years, in the treatment of bone infections and prevention of post-operative infections after surgery for filling artificial bones (bone filling materials), for example, artificial bones composed of porous ceramics are retained by impregnating with an antibacterial agent. An antimicrobial device to be used has been proposed (see, for example, Non-Patent Document 1).

  However, in general, in an artificial bone composed of porous ceramics, the pore diameter of pores formed in the artificial bone is large, and due to this, the retained antibacterial agent is an artificial bone (antibacterial device) Therefore, since it tends to elute at a stretch to the human body, it has been difficult to obtain a prolonged release effect of the antibacterial agent.

  Therefore, in Non-Patent Document 2, a space consisting of small holes in a cylindrical shape is provided in the artificial bone, and after filling the space with an antibacterial agent, the space is covered with a lid, so that a large amount in the artificial bone A method of retaining by containing an antimicrobial is proposed, thereby realizing long-term dissolution of the antimicrobial from the artificial bone.

  However, according to the method of Non-patent Document 2, only long-term elution of the antimicrobial agent is realized by increasing the amount of the enclosed antimicrobial agent, and conversely, in the initial stage of compensating the artificial bone, An extremely high concentration of the antibacterial drug may elute into the human body, resulting in cell necrosis. Further, the transfer of the high concentration of the antibacterial drug into the blood may cause side effects.

  In addition, such a problem arises similarly not only to an antibacterial drug but also to other drugs such as a bone morphogenetic protein (BMP), an anti-inflammatory drug, an antithrombotic drug and the like to be held by an artificial bone.

Ken Yayoi et al., Phosphorus Letter, 80, 12-18, 2014. Yasuo Yamashita et al., Orthopedic Ceramic Implants, 17, 45-48, 1997.

  An object of the present invention is to obtain a sustained release effect of a drug for a long period of time while suppressing the sustained release of a high concentration drug in the initial stage after compensation, and further to suppress side effects due to the transfer of the high concentration drug into the blood. It is to provide a releasable device.

Such an object is achieved by the present invention described in the following (1) to (10).
(1) A porous body having a communication hole formed by communicating a plurality of pores, a drug, and a polymer,
The sustained-release device, wherein the drug is held in the porous body in a mixed state with the polymer.

  Thereby, the sustained release effect of the drug for a long period can be obtained while suppressing the sustained release of the high concentration drug in the initial stage after the supplementation.

  (2) The sustained-release device according to (1), wherein the porous body has an internal space, and the drug is filled in the internal space in the state of the mixture.

  Thus, by filling the internal space in the state of the mixture in which the drug is mixed with the polymer, the sustained release of the drug at a high concentration in the initial stage after supplementation is suppressed, and the long-term drug A sustained release effect can be obtained.

  (3) The controlled release device according to (1) or (2), wherein the porous body has a relative porosity of 40% or more and 95% or less.

  Thereby, while preventing the mechanical strength of the porous body from being lowered, the drug can be smoothly released to the outside of the porous body through the communication hole, that is, the sustained release to the filling site filled with the porous body is smoothly performed. be able to.

  (4) The controlled release device according to any one of (1) to (3), wherein the communication hole has an average diameter of 1 μm to 200 μm.

  As a result, the strength required for the porous body can be maintained, and furthermore, the drug can be smoothly moved between the pores through the communication holes, so that the drug is gradually removed from the porous body through the communication holes. Release will be performed more smoothly.

(5) The sustained-release device according to any one of (1) to (4), wherein the porous body includes a calcium phosphate compound as a main material.
Thereby, the porous body can exhibit more excellent biocompatibility.

  (6) The controlled release device according to any one of (1) to (5) above, wherein the polymer contains at least one of polysaccharides and polyethers.

  Polysaccharides and polyethers are preferably used as polymers because they have excellent biocompatibility.

(7) The drug includes a first functional group, and the polymer includes a second functional group that is reactive with the first functional group,
The sustained release property according to any one of the above (1) to (6), wherein a three-dimensional network obtained by the reaction of the first functional group and the second functional group is formed in the mixture. device.

  Thus, by reacting the first functional group with the second functional group, a three-dimensional network composed of a polymer and a drug can be formed in the mixture. Therefore, a drug (drug) that is not involved in the formation of the three-dimensional network is more precisely included in the mixture by the three-dimensional network, and as a result, the drug is firmly held in the porous body. Therefore, the drug can be gradually released over a longer period while more accurately suppressing the sustained release of the high concentration drug in the initial stage after the sustained release device is compensated.

(8) The sustained-release device according to (7), wherein the drug is an antibacterial drug.
By applying the drug to the antibacterial agent, it is possible to obtain a sustained release effect of the antibacterial agent for a long period of time while suppressing the sustained release of the high concentration antibacterial agent in the initial stage after the sustained release device is filled. Therefore, it is possible to properly suppress or prevent the occurrence of cell necrosis at a site where the sustained release device is filled, and to be able to accurately suppress or prevent bacterial growth at such a site over a long period of time, etc. You can get the effect.

  (9) The controlled release device according to (8), wherein the antibacterial agent is an aminoglycoside antibiotic and the polymer is phosphorylated pullulan.

  Thereby, since the amino group as the first functional group and the phosphate group as the second functional group can be reacted with excellent reactivity, a three-dimensional network can be more reliably formed in the mixture. it can.

  (10) The sustained-release device according to any one of (1) to (9), wherein the mixture has a viscosity at 25 ° C. of 15.0 mPa · S or more and 5000 mPa · S or less.

  By setting the viscosity of the mixture within such a range, the sustained release of the drug at a high concentration in the initial stage after the supplementation of the sustained release device can be suppressed more accurately, and the drug can be released gradually over a longer period of time. Can.

  According to the sustained-release device of the present invention, it is possible to obtain a sustained-release effect of the drug for a long period of time while suppressing the sustained release of the high-concentration drug in the initial stage after the compensation, and further, in the blood of the high-concentration drug. Side effects due to migration can be suppressed.

It is a disassembled perspective view which shows the porous body with which 1st Embodiment of the sustained release device of this invention is equipped. It is a perspective view which shows the porous body with which 2nd Embodiment of the sustained release device of this invention is equipped. It is a graph which shows the relationship between the sustained release amount of gentamicin, and time (days) in Examples 1, 2 and Comparative Example 1. It is a graph which shows the relationship between the sustained release amount of gentamicin and time (day) in Example 3 and Comparative Examples 2 and 3.

  Hereinafter, the sustained release device of the present invention will be described in detail based on a preferred embodiment shown in the attached drawings.

<Sustained release device>
<< First Embodiment >>
First, a first embodiment of the sustained release device of the present invention will be described.

  FIG. 1 is an exploded perspective view showing a porous body provided in the first embodiment of the sustained release device of the present invention.

  The sustained-release device of the present invention comprises a porous body 100 having communication holes formed by communicating a plurality of pores, a drug, and a polymer, and the drug is a mixture of a polymer and a polymer. It is characterized in that it is held in the porous body in a state. By holding the drug in the porous body in a state where the mixture is formed in this way, it is possible to suppress the sustained release of the high concentration drug in the initial stage after the filling to the filling site of the sustained release device (bone filling material). And can maintain sustained release of the drug over a long period of time.

[Porous body 100]
As shown in FIG. 1, the porous body 100 includes a main body portion 10 including a hole portion 15 and a lid body 20 that covers the hole portion 15 in the present embodiment. By covering 15, an internal space is formed in the porous body 100, and the internal space is filled (contained) in a state where a mixture in which a drug is mixed with a polymer is formed.

  The main body portion 10 includes a hole portion 15 provided in the center portion in the vertical direction and having an opening on the upper surface, and the entire shape thereof is a bottomed cylindrical shape.

  The overall shape of the lid 20 is a truncated cone, the outer diameter of the lid 20 gradually decreases from the upper end to the lower end, and the radius of the circular upper surface is larger than the radius of the lower surface.

  Thereby, when the hole 15 of the main body 10 is covered with the lid 20, the outer peripheral surface of the lid 20 is locked in the middle of the opening of the hole 15. As a result, the hole 15 is covered with the lid 15. By covering with the body 20, an inner space defined by the inner peripheral surface of the hole 15 of the main body 10 and the lower surface of the hole 15 is formed.

The volume of the internal space varies slightly depending on the filling amount of the drug filled to form a mixture, and also the size (volume) of the sustained-release device (porous body 100), but is 0.01 cm ³ or more and 1 cm. preferably ³ or less, more preferably 0.05 cm ³ or more 0.5 cm ³ or less. Thereby, it is possible to fill the internal space with a sufficient amount of the drug (mixture) for gradual release of the drug over a long period of time.

  In this embodiment, the porous body 100 has a plurality of spherical pores (pores) together with the main body portion 10 and the lid 20, and the communication pores are formed by communicating the spherical pores with each other. There is.

  The relative porosity of the porous body 100 is preferably 40% or more, and more preferably 65% or more. By setting the relative porosity within such a range, the spherical pores are reliably communicated with each other to form a communication hole. As a result, a pore structure in which the communication holes are in three-dimensional communication is formed. Therefore, the sustained release of the drug filled in the internal space to the outside of the porous body 100 through this communication hole, that is, the sustained release to the filling site supplemented with the porous body 100 (bone filling material) is smoothly performed. Will be able to. Further, the upper limit of the relative porosity is not particularly limited, but is preferably 95% or less from the viewpoint of the mechanical strength of the porous body 100 (bone filler).

  The average pore diameter of the spherical pores is preferably 120 μm or more and 150 μm or less, and more preferably 130 μm or more and 150 μm or less. Furthermore, its standard deviation is preferably 55 μm or less, more preferably 50 μm or less.

  By setting the average pore diameter within such a range, the drug can be gradually released to the outside of the porous body 100 through the spherical pores, that is, the communicating pores, while suppressing passage through the spherical pores as a mixture. Furthermore, by setting the standard deviation within this range, it can be said that the spherical pores are more uniform, more uniform drug release, and more uniform using the porous body 100 as a scaffold. Bone regeneration can be realized.

  In the present specification, “relative porosity” represents a ratio (%) of pores in the porous body 100 (main body portion 10, lid body 20), for example, (1-W / D / V) X 100, [wherein W is a dry weight, V is a volume, and D is a relationship of theoretical density.

  In the present specification, “spherical pores” are spherical pores formed in the porous body 100 derived from bubbles, polymer spherical beads, and the like. The pore diameter can be obtained, for example, by obtaining a cross-sectional image of a predetermined portion of the porous body 100 using a micro CT apparatus or the like and measuring the pore diameter based on the cross-sectional image. And the average pore diameter and standard deviation can be calculated | required from the pore diameter of each measured spherical pore.

  The image analysis for determining the pore diameter of the spherical pores is performed, for example, by measuring the pore diameter from the SEM image as the equivalent circle diameter.

  In addition, the pores provided in the porous body 100 do not have to be spherical pores as in the present embodiment, and may be, for example, an elliptical shape or an irregular shape having a flat shape.

  Furthermore, in such a porous body 100, communication holes are formed when adjacent spherical pores communicate with each other. The average diameter of the communication holes is preferably 1 μm or more and 200 μm or less, and more preferably 10 μm or more and 100 μm or less. By setting the average diameter of the communication holes in such a range, the strength required for the porous body 100 can be maintained. Moreover, since the movement of the drug between the spherical pores through the communication hole is smoothly performed, the sustained release of the drug from the porous body 100 through the communication hole is more smoothly performed.

  Such a porous body 100 may be either an inorganic porous body composed of a ceramic compound or a titanium based compound or an organic porous body composed of a resin material such as polyetheretherketone (PEEK). However, it is preferable that it is an inorganic porous body. Thereby, the porous body 100 can exhibit excellent biocompatibility.

  The inorganic porous body is preferably a ceramic porous body composed of a ceramic based compound, and more preferably a calcium phosphate porous body composed of a calcium phosphate based compound. Thereby, the said effect can be exhibited more notably.

  Examples of calcium phosphate compounds include apatites such as hydroxyapatite (HAP), fluoroapatite, carbonated apatite, etc., dicalcium phosphate, tricalcium phosphate (TCP), tetracalcium phosphate, octacalcium phosphate, etc. These can be used alone or in combination of two or more. Among these calcium phosphate compounds, those having a Ca / P ratio of 1.0 to 2.0 are preferable, and those of 1.5 to 2.0 are more preferably used.

  Examples of titanium compounds include titanium (titanium powder), titanium oxide, titanium carbide, titanium nitride, titanium chloride, barium titanate, and the like, and one or more of these are used in combination. be able to. Of these titanium compounds, titanium is preferably used.

[High molecular]
The polymer is filled in an internal space formed by the main body 10 and the lid 20 included in the porous body 100 in a state where a mixture mixed with a drug is formed. By forming this mixture, the mixture To provide a viscosity with an appropriate range of viscosities, to suppress the sustained release of a high concentration of drug in the initial stage after the sustained release device (bone substitute material) is filled, and for a long period of time Exerts the function of releasing the drug slowly.

  The polymer is not particularly limited, but is preferably, for example, polysaccharides and polyethers, and one or more of them may be used in combination. Polysaccharides and polyethers are preferably used as polymers because they have excellent biocompatibility.

  Examples of polysaccharides include pullulan, alginic acid, dextrin, dextran, cellulose, chondroitin, hyaluronic acid, maltodextrin, starch (amylose, amylopectin) or derivatives thereof, and one or more of them may be used. It can be used in combination.

  Moreover, as a polyether, polyethyleneglycol, polypropylene glycol, or these derivatives etc. are mentioned, for example, It can use combining 1 type, or 2 or more types among these.

  Moreover, as a derivative | guide_body of polysaccharide or polyether, when the drug mentioned later is a thing provided with the 1st functional group, the 2nd functional group reactive with this 1st functional group may be introduced. preferable. Thereby, in the mixture, the first functional group and the second functional group react to form a three-dimensional network composed of a polymer (polysaccharide or polyether) and a drug. The effects obtained by the formation of the network will be described in detail later in the explanation of the drug.

  Furthermore, the weight average molecular weight of the polymer varies depending on the type of the polymer, and is not particularly limited, but for example, it is preferably 10,000 or more and 3,000,000 or less, and 500,000 or more It is more preferable that it is, 000,000 or less. Thereby, since the viscosity of a more suitable range can be given to the mixture obtained by mixing the polymer and the drug, the effect obtained by filling the mixture in the internal space of the porous body 100 is more remarkable. Can be The range of the viscosity of the mixture will be described later.

  In addition, the polymer filling amount in the mixture is such that when the polymer filling amount is A [mg] and the drug filling amount in the mixture is B [mg], A / B is more than 1.0. It is preferably 0 or less, more preferably 3.0 or more and 30.0 or less. Thereby, the viscosity of the mixture can be set in an appropriate range, and the drug can be reliably retained in the mixture.

[Drug]
The drug is filled in the internal space formed by the main body 10 and the lid 20 included in the porous body 100 in the state of a mixture mixed with the polymer, and the viscosity is imparted in the state of the mixture. Is controlled to be released at a high concentration at an early stage after supplementation with the sustained release device (bone graft material), and is released from the sustained release device in an appropriate concentration range over a long period of time The pharmacological action is exhibited by moving from a sustained-release device to a living body.

  The drug is not particularly limited as long as it has a pharmacological action, and examples thereof include antibacterial drugs, antifungal drugs, antiviral drugs, bone morphogenetic protein (BMP), anti-inflammatory drugs, anti-inflammatory drugs, and the like. Thrombotic agents and the like can be mentioned, and one or two or more of them can be used in combination. Among them, an antibacterial agent is preferable. By using an antibacterial agent as a drug, it is possible to obtain a sustained release effect of the antibacterial agent for a long time while suppressing the sustained release of the high concentration antibacterial agent in the initial stage after the sustained release device is compensated. Therefore, it is possible to properly suppress or prevent the occurrence of cell necrosis at the site to which the sustained release device is filled, and to accurately suppress or prevent the growth of bacteria at such a site over a long period of time. It is possible to obtain remarkable effects such as suppression of side effects due to the transfer of antibacterial drugs at a concentration in the blood.

  Antibacterial agents include, for example, sawashillin, penicillin antibiotics such as paretocin, keflex, kefural, cephem antibiotics such as cefzone, claris, macrolide antibiotics such as claricid, telomycin such as minomycin and redamycin Antibiotics, fosfomycin antibiotics such as phosmicin, aminoglycoside antibiotics such as kanamycin and gentamycin, new quinolone antibiotics such as krabit, talibid and ozex, glycopeptide antibiotics such as vancomycin and teicoplanin It can be mentioned.

  In such an antibacterial drug, the filling amount filled in the internal space of the porous body 100 is preferably 0.1 mg to 50 mg, more preferably 0.1 mg to 30 mg, as a titer. . Thereby, it becomes possible to release the antibacterial drug from the sustained-release device over a long period of time.

  Antifungal agents include, for example, trichomycin, polyene antifungal agents such as nystatin, econazole, imidazole antifungal agents such as miconazole, fluconazole, triazole antifungal agents such as itraconazole, butenafine Examples include allylamine antifungal agents and flucytosine (5-FC) antifungal agents such as flucytosine.

  Examples of antiviral agents include antiviral agents for inhibiting nucleic acid synthesis such as acyclovir, ganciclovir and lamivudine, intracellular entry inhibitory antiviral agents such as zanamivir and oseltamivir, and host infection enhancing type antifungal agents such as interferon. Viral agents etc. may be mentioned.

  Any bone morphogenetic protein (BMP) may be used as long as it has an activity of promoting osteogenesis by inducing differentiation into undifferentiated mesenchymal cells into osteoblasts. For example, BMP-1, BMP -2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-12 (or more, homodimers), or heterodimers or modifications of these BMPs (Ie, a protein having an amino acid sequence in which one or more amino acids are deleted, substituted and / or added in the amino acid sequence of a naturally occurring BMP and having the same activity as that of a naturally occurring BMP), etc. It can be mentioned.

  Examples of anti-inflammatory agents include salicylic acid based analgesics such as aspirin, anthranyl based analgesics such as mefenamic acid, indole acetic acid based analgesics such as indomethacin and acemetacin, phenylacetic acid based analgesics such as diclofenac, Non-steroidal anti-inflammatory analgesics as cyclooxygenase (COX) inhibitors including propion-type analgesics such as ibuprofen, loxoprofen and naproxen Anti-cytokine antibodies such as anti-TNF-α antibody and anti-IL-6 antibody, cytokine binding protein Anti-cytokine drugs and the like.

  Examples of antithrombotic agents include heparin sodium, heparin such as heparin calcium, warfarin such as warfarin potassium, antithrombin drugs such as argatroban, urokinase, tysokinase, alteplase, thrombolytic agents such as nateplase, ticlopidine hydrochloride, Platelet aggregation inhibitors such as cilostazol, ethyl icosapentate, etc. may be mentioned.

  In addition, the drug preferably has a first functional group. When the drug has a first functional group, a polymer (polysaccharide or polyether derivative) having a second functional group that is reactive with the first functional group is selected as the first functional group. The group and the second functional group can be reacted to form a three-dimensional network composed of a polymer and a drug in the mixture. Therefore, in the mixture, a drug that does not participate in the formation of the three-dimensional network forms an inclusion that is included by the three-dimensional network, and as a result, the drug is held more firmly in the porous body 100. The effects obtained by mixing the polymer and the drug in the mixture can be significantly exhibited. That is, the drug can be gradually released over a longer period while more appropriately suppressing the sustained release of the high-concentration drug at the initial stage after the supplement of the sustained-release device.

  The viscosity of this mixture at 25 ° C. is preferably 15.0 mPa · S or more and 5000 mPa · S or less, and more preferably 20.0 mPa · S or more and 3500 mPa · S or less. By setting the viscosity of the mixture in such a range, the effect obtained by mixing the polymer and the drug in the mixture can be more significantly exhibited.

  Examples of the first functional group included in the drug include a hydroxyl group, a carboxy group, and an amino group. On the other hand, when the first functional group is a hydroxyl group, examples of the second functional group include an alkoxy group. In addition, when the first functional group is a carboxy group, examples of the second functional group include a vinyl group (carbon-carbon double bond), an acetylene group (carbon-carbon triple bond), and an amino group. Further, when the first functional group is an amino group, examples of the second functional group include a phosphoric acid group, a sulfuric acid group, a vinyl group (carbon-carbon double bond), and a carboxy group. Be

  Among these, a combination in which the first functional group is an amino group and the second functional group is a phosphate group is preferable. Since the first functional group and the second functional group can be reacted with excellent reactivity if they are a combination of the first functional group and the second functional group, in the mixture, the three-dimensional network It can be reliably formed into an inclusion state. Specifically, the combination drug and the polymer (the derivative of polysaccharide) in which the first functional group is an amino group and the second functional group is a phosphate group specifically include gentamicin as an aminoglycoside antibiotic, A combination with phosphorylated pullulan can be mentioned.

Second Embodiment
Next, a second embodiment of the sustained release device of the present invention will be described.

FIG. 2 is a perspective view showing a porous body provided in the second embodiment of the sustained-release device of the present invention.
Hereinafter, the sustained-release device of the second embodiment will be described with a focus on differences from the sustained-release device of the first embodiment, and description of similar matters will be omitted.

  The sustained release device of the second embodiment is the same as the sustained release device of the first embodiment except that the configuration of the porous body 100 provided in the sustained release device is different.

  That is, in the sustained-release device of the second embodiment, the porous body 100 is configured by the main body 10 alone, with the lid 20 omitted, and the overall shape of the main body 10 is a rectangular parallelepiped (cubic). None, the formation of the hole 15 is omitted.

  In the main body portion 10, the mixture is impregnated into the spherical pores (communication holes) included in the porous body by impregnation, and the filling site in which the sustained release device is directly filled from the mixture in the communication holes. The drug is released slowly.

  Also by the sustained release device of the second embodiment, the same effect as that of the first embodiment can be obtained.

  As mentioned above, although the sustained-release device of this invention was demonstrated based on embodiment of illustration, this invention is not limited to this.

  For example, in the sustained-release device of the present invention, each component can be replaced with any component that can exhibit the same function, or any component can be added.

  For example, in the present invention, any two or more configurations shown in the first and second embodiments may be combined.

  Furthermore, although the case where the shape of the main-body part 10 made bottomed cylindrical shape or cube shape was demonstrated in the sustained-release device of the said embodiment, it is not limited to the thing of this shape, The main-body part 10 is spherical, for example It may be in the shape of a truncated cone, a cylinder, a stick or the like. Also, the main body 10 may be at least a part of an artificial bone head, an artificial joint, an artificial vertebral body, a vertebral cage, or the like.

Next, specific examples of the present invention will be described.
1. Investigation of phosphorylated pullulan as a polymer

Example 1
1-1. Production of porous body <1> First, secondary particles (average particle diameter: 25 μm) of 100 wt% made of granulated primary particles (average particle diameter: 80 nm) of hydroxyapatite (HAP) having a Ca / P ratio of 1.67 A slurry containing parts was prepared. Then, the slurry was put into a homogenizer (“PA92” manufactured by SMT Corporation).

  <2> Next, 3.4 parts by weight of methylcellulose powder was added to an aqueous solution in which 1.4 parts by weight of a surfactant (alkylbenzene sulfonic acid EDT) was added to 27 parts by weight of pure water, and a stirring deaerator (manufactured by Sinky, A paste binder was prepared by dispersing and mixing with “Awatori Nertaro ARE-250”).

<3> Next, by adding the paste-like binder prepared in the step <2> to the slurry prepared in the step <1>, a slurry (mixed slurry) to which the paste-like binder has been added is obtained. The In this case, the temperatures of the slurry and the paste-like binder were 20 ° C. and 35 ° C., respectively.
<4> Next, after the paste-like binder was completely dispersed in the slurry, foaming was performed.

  <5> Next, the obtained bubble-containing slurry was gelled at 83 ° C. Thereafter, the cell-containing slurry was dried by maintaining the obtained gel at 83 ° C., thereby obtaining a green block (pre-sintered block).

<6> Next, the green blocks were each processed into a bottomed cylindrical shape and a truncated cone shape. Thereafter, the green blocks are sintered in the atmosphere at 1050 ° C. for 2 hours, whereby sintered bodies made of hydroxyapatite (HAP) are respectively formed into bottomed cylindrical shapes of 78.5 mm ^2. X Main body 10 having a height of 10 mm (hole: bottom 12.6 mm ² x depth 7 mm), and bottom bottom 13.8 mm ² having a truncated cone shape, top bottom 7.5 mm ² x lid 3 mm in height Obtained as 20. The sintered body was a porous body having communicating holes.

1-2. Preparation of Mixture A mixture of phosphorylated pullulan (30.0 mg) synthesized in advance as a polymer and 5% gentamicin (8.0 mg (titer); manufactured by SIGMA) as an antibacterial agent was added to water for injection (726 mg). The mixture (inclusion) was prepared by mixing. The viscosity of the obtained mixture was 28.1 mPa · s.

1-3. Production of sustained release device 1-2. And the mixture prepared in 1). After filling the hole 15 provided in the main body 10 manufactured in The sustained-release device of Example 1 was manufactured by covering the hole 15 with the cover 20 manufactured in (1).

(Example 2)
1-2. In Example 2, the sustained release device of Example 2 was prepared in the same manner as in Example 1 except that the mixture was prepared by changing the phosphorylated pullulan content to 100.0 mg and the water content for injection to 656 mg. Manufactured. In addition, the viscosity of the obtained mixture was 3156 mPa * S.

(Comparative example 1)
1-2. In Example 1, a sustained-release device of Comparative Example 1 was produced in the same manner as in Example 1 except that the addition of phosphorylated pullulan was omitted and the content of water for injection was changed to 756 mg to prepare a mixture. . The viscosity of the obtained mixture was 10.4 mPa · s.

1-4. Evaluation of Sustained Release Device About each of the sustained release devices of Examples 1 and 2 and Comparative Example 1, each was immersed in 10 mL PBS solution (phosphate buffered saline) for 24 hours, and then the sustained release device was taken out. In addition, while measuring the content of gentamicin (controlled release) in the PBS solution using an HPLC apparatus (“ELITE LaChrom” manufactured by HITACHI), the extracted sustained-release device can be replaced with a new PBS solution. Dipped in The immersion of the sustained release device in PBS solution was repeated for 14 days.
The results are shown in FIG.

  As apparent from FIG. 3, in the sustained release devices of Examples 1 and 2, gentamicin is included by phosphorylated pullulan in the mixture, thereby compensating for the loading as compared with the sustained release device of Comparative Example 1. The results showed that gentamicin was sustainedly released over a long period (14 days) while suppressing the sustained release of a high concentration of gentamicin in the initial stage (one day later).

2. Examination when polyethylene glycol is used as the polymer 2-1. Production of sustained release devices

(Example 3)
1-2. In Example 1, in place of phosphorylated pullulan, polyethylene glycol (500 mg) was used, and the content of water for injection was changed to 256 mg to prepare a mixture. As a porous body 100, a bottom surface having a bottomed cylindrical shape of 176.6 mm ² × height 12 mm: a main body portion 10 of the (hole bottom 38.5 mm ² × depth 8 mm), and the bottom surface 40.7 mm ² × on the bottom 28.3 mm ² × lid 20 in height 3mm to form a frustoconical A sustained-release device of Example 3 was produced in the same manner as in Example 1 except that those having the above were used. In addition, the viscosity of the obtained mixture was 575 mPa * S.

(Comparative example 2)
1-2. Except that the addition of polyethylene glycol was omitted, the content (potency) of gentamicin drug substance powder was changed to 80.2 mg, the water content for injection was changed to 0 mg, and the drug substance powder was directly filled in the hole 15 Produced the sustained-release device of Comparative Example 2 in the same manner as in Example 3.

(Comparative example 3)
1-2. In Example 1, a sustained-release device of Comparative Example 3 was produced in the same manner as in Example 3 except that the addition of polyethylene glycol was omitted and the content of water for injection was changed to 756 mg to prepare a mixture. The viscosity of the obtained mixture was 10.4 mPa · s.

2-2. Evaluation of Sustained Release Device The sustained release devices of Example 3 and Comparative Examples 2 and 3 were immersed in 10 mL PBS solution (phosphate buffered saline) for 24 hours, respectively, and then the sustained release device was taken out, and thereafter In addition, while measuring the content of gentamicin (controlled release) in the PBS solution using an HPLC apparatus (“ELITE LaChrom” manufactured by HITACHI), the extracted sustained-release device can be replaced with a new PBS solution. Dipped in This sustained-release device was immersed in PBS solution repeatedly for 21 days.

  The result is shown in FIG. The vertical axis in the graph of FIG. 4 represents the content of gentamycin in the PBS solution converted (divided) by the volume of the PBS solution and the filling amount of gentamycin in the sustained release device.

  As is apparent from FIG. 4, in the sustained-release device of Example 3, the gentamicin is included in the mixture by polyethylene glycol, so that after supplementation, as compared with the sustained-release device of Comparative Examples 2 and 3. The results showed that gentamicin was gradually released over a long period (21 days) while suppressing the sustained release of a high concentration of gentamicin in the early stage (after 1 day).

10 body portion 15 hole portion 20 lid body 100 porous body

Claims (10)

A porous body having a communication hole formed by communicating a plurality of pores, a drug, and a polymer,
The sustained-release device, wherein the drug is held in the porous body in a mixed state with the polymer.   The sustained release device according to claim 1, wherein the porous body comprises an inner space, and the drug is filled in the inner space in the state of the mixture.   The sustained-release device according to claim 1 or 2, wherein the porous body has a relative porosity of 40% or more and 95% or less.   The sustained-release device according to any one of claims 1 to 3, wherein the communication hole has an average diameter of 1 µm to 200 µm.   The sustained-release device according to any one of claims 1 to 4, wherein the porous body includes a calcium phosphate compound as a main material.   The sustained release device according to any one of claims 1 to 5, wherein the polymer contains at least one of polysaccharides and polyethers. The drug has a first functional group, and the polymer has a second functional group reactive with the first functional group;
The sustained-release device according to any one of claims 1 to 6, wherein a three-dimensional network obtained by reacting the first functional group and the second functional group is formed in the mixture. .   The controlled release device according to claim 7, wherein the drug is an antibacterial agent.   The sustained release device according to claim 8, wherein the antibacterial drug is an aminoglycoside antibiotic and the polymer is phosphorylated pullulan.   The sustained-release device according to any one of claims 1 to 9, wherein the mixture has a viscosity at 25 ° C of 15.0 mPa · S or more and 5000 mPa · S or less.

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