JP6961504B2 - Sustained release device - Google Patents

Description

The present invention relates to a sustained release device.

In recent years, in the treatment of bone infections and the prevention of postoperative infections after surgery to supplement artificial bones (bone filling materials), for example, artificial bones made of porous ceramics are retained by impregnating them with an antibacterial agent. Antibacterial devices to be used have been proposed (see, for example, Non-Patent Document 1).

However, in general, in an artificial bone composed of porous ceramics, the pore diameter of the pores formed in the artificial bone is large, and due to this, the retained antibacterial agent is an artificial bone (antibacterial device). Therefore, it has been difficult to obtain a sustained-release effect of an antibacterial drug for a long period of time because it tends to elute at once to the human body.

Therefore, in Non-Patent Document 2, a space consisting of small holes forming a tubular shape is provided in the artificial bone, the space is filled with an antibacterial agent, and then the space is covered with a lid, so that a large amount of space is contained in the artificial bone. A method of retaining the antibacterial agent by encapsulating it has been proposed, thereby realizing long-term elution of the antibacterial agent from the artificial bone.

However, in this method of Non-Patent Document 2, only the long-term elution of the antibacterial agent is realized by increasing the encapsulation amount of the antibacterial agent, and conversely, in the initial stage of supplementing the artificial bone, An extremely high concentration of the antibacterial agent may be eluted into the human body, resulting in cell necrosis, and further high concentration of the antibacterial agent may be transferred into the blood, resulting in side effects.

It should be noted that such a problem occurs not only with antibacterial agents but also with other drugs such as bone morphogenetic protein (BMP), anti-inflammatory agents, and antithrombotic agents that are retained by artificial bones.

Ken Sugo 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 long-term sustained release effect of a high-concentration drug while suppressing the sustained release of a high-concentration drug in the initial stage after supplementation, and to further suppress side effects due to the transfer of the high-concentration drug into the blood. It is to provide a release device.

Such an object is achieved by the present invention described in the following (1) to ( 6).
(1) a plurality of pores each other have a communicating hole formed in communication, comprising: a porous body which is mainly composed of calcium phosphate-based compound, a drug, a polymer,
The drug is retained in the porous body in the form of a mixture mixed with the polymer .
The drug is a drug having an amino group, which is an antibacterial drug, an antifungal drug, an antiviral drug, a bone morphogenetic protein (BMP), an anti-inflammatory drug, or an antithrombotic drug, and the polymer is phosphorylated. It ’s a pull run,
The mixture is a sustained release device having a viscosity at 25 ° C. of 15.0 mPa · S or more and 5000 mPa · S or less.

(2) It has a communication hole formed by communicating a plurality of pores with each other, and has a porous body composed mainly of a calcium phosphate compound, a drug, and a polymer.
The drug is retained in the porous body in the form of a mixture mixed with the polymer.
The drug is an aminoglycoside antibiotic, and the polymer is phosphorylated pullulan.
The mixture is a sustained release device having a viscosity at 25 ° C. of 15.0 mPa · S or more and 5000 mPa · S or less.
As a result, it is possible to obtain a long-term sustained-release effect of the drug while suppressing the sustained-release of the high-concentration drug in the initial stage after supplementation.

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

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

( 4 ) The sustained release device according to any one of (1) to (3) above, wherein the porous body has a relative porosity of 40% or more and 95% or less.

As a result, while preventing a decrease in the mechanical strength of the porous body, the sustained release of the drug 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.

( 5 ) The sustained release device according to any one of (1) to (4 ) above, wherein the communication hole has an average diameter of 1 μm or more and 200 μm or less.

As a result, the strength required for the porous body can be maintained, and the drug can be smoothly transferred between the pores through the communication holes. Therefore, the drug is gradually transferred from the porous body through the communication holes. The release will be smoother.

(6) In the above mixture, and an amino group in which the drug is provided, the phosphate group of the first functional groups of the polymer comprises a second functional group to form a three-dimensional network obtained by reacting The sustained release device according to any one of (1) to ( 5) above.

Thereby, by reacting the amino group contained in the drug with the phosphoric acid group contained in the polymer, a three-dimensional network composed of the polymer and the drug can be formed in the mixture. Therefore, the drug (drug) that is not involved in the formation of the three-dimensional network is more closely included in the mixture by this three-dimensional network, and as a result, the drug is more firmly retained in the porous body. Therefore, the drug can be sustained-release for a longer period of time while more accurately suppressing the sustained release of the high-concentration drug in the initial stage after supplementation of the sustained-release device.

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

It is an exploded perspective view which shows the porous body provided in 1st Embodiment of the sustained release device of this invention. It is a perspective view which shows the porous body provided in the 2nd Embodiment of the sustained release device of this invention. It is a graph which shows the relationship between the sustained-release amount of gentamicin and time (day) in Examples 1 and 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 the preferred embodiments shown in the accompanying 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 included 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 pores formed by communicating a plurality of pores with each other, a drug, and a polymer, and the drug is a mixture mixed with the polymer. It is characterized in that it is retained in a porous body in a state. By retaining the drug in the porous body in the 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 supplementation site of the sustained release device (bone substitute material). It can and can maintain sustained release of the drug for a long period of time.

[Perforated body 100]
As shown in FIG. 1, the porous body 100 has a main body portion 10 having a hole portion 15 and a lid body 20 for covering the hole portion 15, and the hole portion is formed by the lid body 20. By covering 15 with a lid, an internal space is formed in the porous body 100, and the internal space is filled (stored) in a state where a mixture of the drug and the polymer is formed.

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

The entire shape of the lid 20 has a truncated cone shape, the outer diameter thereof gradually decreases from the upper end to the lower end, and the radius of the upper surface forming a circle is larger than the radius of the lower surface.

As a result, 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, and as a result, the hole 15 is closed. When the body 20 covers the hole, an internal 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 capacity of this internal space varies slightly depending on the filling amount of the drug to be filled by forming the mixture and 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. As a result, the internal space can be filled with a sufficient amount of the drug (mixture) for the sustained release of the drug over a long period of time.

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

The relative porosity of the porous body 100 is preferably 40% or more, more preferably 65% or more. By setting the relative porosity within such a range, the spherical pores are surely communicated with each other to form a communicating hole. As a result, a pore structure in which the communication holes are three-dimensionally communicated is formed. Therefore, the sustained release of the drug filled in the internal space to the outside through the communication hole, that is, the sustained release to the filling site filled with the porous body 100 (bone filling material) is smoothly performed. You will be able to do it. 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 filling material).

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. Further, the standard deviation is preferably 55 μm or less, and more preferably 50 μm or less.

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

In the present specification, the "relative porosity" represents the ratio (%) of the pores in the porous body 100 (main body 10, lid 20), and is, for example, (1-W / D / V). × 100, [In the formula, W is the dry weight, V is the volume, and D is the relational expression of the theoretical density.

Further, in the present specification, the "spherical pores" are spherical pores formed from bubbles, polymer spherical beads, or the like in the porous body 100. The pore diameter can be obtained by acquiring a cross-sectional image of a predetermined portion of the porous body 100 using, for example, a micro CT device or the like, and measuring the pore diameter based on the cross-sectional image. Then, the average pore diameter and standard deviation can be obtained from the measured pore diameters of each spherical pore.

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

Further, 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, irregular shapes having an elliptical shape or a flat shape.

Further, in such a porous body 100, the communication holes are formed by communicating the adjacent spherical pores 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 within such a range, the strength required for the porous body 100 can be maintained. Further, since the drug is smoothly transferred between the spherical pores through the communication holes, the drug is more smoothly released from the porous body 100 through the communication holes.

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

Further, 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. As a result, the effect can be exerted more remarkably.

Examples of the calcium phosphate-based compound include apatites such as hydroxyapatite (HAP), fluorine apatite, and carbonate apatite, dicalcium phosphate, tricalcium phosphate (TCP), tetracalcium phosphate, and octacalcium phosphate. , One or a combination of two or more of these can be used. Further, among these calcium phosphate compounds, those having a Ca / P ratio of 1.0 to 2.0 are preferable, and those having a Ca / P ratio of 1.5 to 2.0 are more preferably used.

Examples of the titanium-based compound include titanium (titanium powder), titanium oxide, titanium carbide, titanium nitride, titanium chloride, barium titanate, and the like, and one or a combination of two or more of these is used. be able to. Further, among these titanium compounds, titanium is preferably used.

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

The polymer is not particularly limited, but is preferably a polysaccharide and a polyether, and one or a combination of two or more of these can be used. Polysaccharides and polyethers are preferably used as polymers because they have excellent biocompatibility.

Examples of the polysaccharide include pullulan, alginic acid, dextrin, dextran, cellulose, chondroitin, hyaluronic acid, maltodextrin, starch (amylose, amylopectin) or derivatives thereof, and one or more of these may be used. Can be used in combination.

Further, examples of the polyether include polyethylene glycol, polypropylene glycol and derivatives thereof, and one or a combination of two or more of these can be used.

Further, as the derivative of the polysaccharide or the polyether, when the drug described later has a first functional group, a second functional group having reactivity with the first functional group may be introduced. preferable. As a result, the first functional group and the second functional group react in the mixture to form a three-dimensional network composed of a polymer (polysaccharide or polyether) and a drug. The effects obtained by forming the network will be described in detail later in the description of the drug.

Further, the weight average molecular weight of the polymer varies depending on the type of polymer and is not particularly limited, but is preferably 10,000 or more and 3,000,000 or less, and is preferably 500,000 or more and 2 More preferably, it is less than, million. As a result, it is possible to impart a viscosity in a more appropriate range to the mixture of the polymer and the drug, so that the effect obtained by filling the mixture in the internal space of the porous body 100 is more remarkable. Can be demonstrated. The range of viscosity of the mixture will be described later.

As for the filling amount of the polymer in the mixture, when the filling amount of the polymer is A [mg] and the filling amount of the drug in the mixture is B [mg], the A / B is more than 1.0 and 100. It is preferably 0 or less, and more preferably 3.0 or more and 30.0 or less. This allows the viscosity of the mixture to be set in an appropriate range to ensure that the drug is 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 viscous substance is imparted in the state of this mixture. Therefore, sustained release at a high concentration is suppressed in the initial stage after supplementation of the sustained release device (bone substitute material), and the sustained release device is released from the sustained release device in an appropriate concentration range for a long period of time. By shifting from a sustained release device to a living body, it exerts a pharmacological action.

The drug may have a pharmacological action and is not particularly limited, but for example, an antibacterial drug, an antifungal drug, an antiviral drug, a bone morphogenetic protein (BMP), an antiinflammatory drug, and an anti. Examples thereof include thrombotic agents, and one or a combination of two or more of these can be used, and among them, an antibacterial agent is preferable. By using an antibacterial agent as a drug, it is possible to obtain a long-term sustained release effect of the antibacterial agent while suppressing the sustained release of a high concentration antibacterial agent in the initial stage after supplementation of the sustained release device. Therefore, it is possible to accurately suppress or prevent cell necrosis at the site supplemented with the sustained release device, and to accurately suppress or prevent the growth of bacteria at such site for a long period of time. It is possible to obtain remarkable effects such as suppressing side effects due to blood transfer of antibacterial agents at a concentration.

Antibacterial agents include, for example, penicillin antibiotics such as sawacillin and passetocin, cephem antibiotics such as keflex, kefural and cefzone, macrolide antibiotics such as claris and claricid, and tetracycline such as minomycin and redamycin. Antibiotics, phosphomycin antibiotics such as phosmicin, aminoglycoside antibiotics such as canamycin and gentamicin, new quinolone antibacterial agents such as clavite, taribid and ozex, glycopeptide antibiotics such as vancomycin and teicoplanin. Can be mentioned.

The filling amount of such an antibacterial agent filled in the internal space of the porous body 100 is preferably 0.1 mg or more and 50 mg or less, and more preferably 0.1 mg or more and 30 mg or less as a titer. .. This allows the antibacterial agent to be sustained release from the sustained release device over a long period of time.

Examples of antifungal agents include polyene antifungal agents such as tricomycin and nystatin, imidazole antifungal agents such as econazole and myconazole, triazole antifungal agents such as fluconazole and itraconazole, and butenafin. Examples thereof include allylamine-based antifungal agents and flucytosine (5-FC) -based antifungal agents such as flucytosine.

Antiviral agents include, for example, nucleic acid synthesis-inhibiting antiviral agents such as acyclovir, ganciclovir, and ramibdin, intracellular entry-suppressing antiviral agents such as zanamivir and oseltamivir, and host infection-enhancing antiviral agents such as interferon. Examples include viral drugs.

The bone morphogenetic protein (BMP) may be any bone morphogenetic protein (BMP) that has an activity of promoting bone formation by inducing the differentiation of undifferentiated mesenchymal cells into osteoblasts, and is, for example, BMP-1 and BMP. -2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-12 (above, homodimer), or heterodimers or modifications of these BMPs. The body (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) and the like. Can be mentioned.

Anti-inflammatory agents include, for example, salicylic acid analgesics such as aspirin, anthranil analgesics such as mephenamic acid, indol acetic analgesics such as indomethacin and acemetacin, phenylacetate analgesics such as diclofenac, Non-steroidal anti-inflammatory analgesics as cyclooxygenase (COX) inhibitors, including propion analgesics such as ibuprofen, loxoprofen, naproxene, anti-cytogenic analgesics such as anti-TNF-α antibody, anti-IL-6 antibody, cytokine-binding protein And the like, including anti-cytogenase drugs.

Antithrombotic agents include, for example, heparin sodium, heparin such as heparin calcium, warfarin such as warfarin potassium, antithrombotic agents such as argatroban, urokinase, thisokinase, arteprase, thrombolytic agents such as nateplase, ticlopidine hydrochloride, etc. Examples thereof include thrombolytic agents such as cilostazole and ethyl icosapentate.

Moreover, it is preferable that the drug has a first functional group. When the drug has a first functional group, the first functional group is selected by selecting a polymer (a derivative of a polysaccharide or a polyether) into which a second functional group reactive with the first functional group is introduced. The group and the second functional group can be reacted to form a three-dimensional network composed of the polymer and the drug in the mixture. Therefore, in the mixture, the drug that is not involved in the formation of the three-dimensional network forms the inclusion contained by the three-dimensional network, and as a result, the drug is more firmly retained in the porous body 100. The effect obtained by mixing the polymer and the drug in the mixture can be remarkably exhibited. That is, the drug can be sustained-release for a longer period of time while more accurately suppressing the sustained release of the high-concentration drug in the initial stage after supplementation 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 within such a range, the effect obtained by mixing the polymer and the drug in the mixture can be more remarkablely exhibited.

Examples of the first functional group contained in the drug include a hydroxyl group, a carboxy group, an amino group and the like. On the other hand, when the first functional group is a hydroxyl group, the second functional group is, for example, an alkoxy group. When the first functional group is a carboxy group, the second functional group includes, for example, a vinyl group (carbon-carbon double bond), an acetylene group (carbon-carbon triple bond), and an amino group. And the like, and when the first functional group is an amino group, examples of the second functional group include a phosphate group, a sulfate group, a vinyl group (carbon-carbon double bond), a carboxy group and the like. Be done.

Among these, a combination in which the first functional group is an amino group and the second functional group is a phosphoric acid group is preferable. In the case of the combination of the first functional group and the second functional group, the first functional group and the second functional group can be reacted with excellent reactivity, so that the three-dimensional network can be further formed in the mixture. It can be reliably formed into an inclusion state. Specific examples of the combination drug and polymer (derivative of polysaccharide) in which the first functional group is an amino group and the second functional group is a phosphoric acid group include gentamicin as an aminoglycoside antibiotic. Examples include a combination with phosphorylated pullulan.

<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 included 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 mainly on the differences from the sustained release device of the first embodiment, and the same 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 included in the sustained release device is different.

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

In the main body 10, the spherical pores (communication holes) provided in the porous body are filled by impregnating the mixture, and the supplemented portion is directly filled with the sustained release device from the mixture in the communication holes. In addition, the drug is released slowly.

The sustained release device of the second embodiment also has the same effect as that of the first embodiment.

The sustained release device of the present invention has been described above based on the illustrated embodiment, but the present invention is not limited thereto.

For example, in the sustained release device of the present invention, each configuration can be replaced with any configuration capable of exerting similar functions, or any configuration can be added.

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

Further, in the sustained release device of the above embodiment, the case where the shape of the main body 10 has a bottomed cylindrical shape or a cubic shape has been described, but the present invention is not limited to such a shape, and the main body 10 is, for example, spherical. It may have a shape such as a truncated cone shape, a columnar shape, or a stick shape. Further, the main body portion 10 may form at least a part of an artificial bone head, an artificial joint, an artificial vertebral body, a vertebral body cage, or the like.

Next, specific examples of the present invention will be described.
1. 1. Examination when phosphorylated pullulan is used as a polymer

(Example 1)
1-1. Production of Porous <1> First, 100 weights of secondary particles (average particle size: 25 μm) composed of granulated particles of primary particles (average particle size: 80 nm) of hydroxyapatite (HAP) having a Ca / P ratio of 1.67. A slurry containing a part was prepared. Then, the slurry was put into a homogenizer (manufactured by SMT Co., Ltd., "PA92").

<2> Next, 3.4 parts by weight of methylcellulose powder was added to an aqueous solution prepared by adding 1.4 parts by weight of a surfactant (alkylbenzenesulphonic acid EDT) to 27 parts by weight of pure water, and a stirring defoamer (manufactured by Shinky). A paste-like binder was prepared by dispersing and mixing with "Awatori Rentaro 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 is added is obtained. rice field. At this time, the temperatures of the slurry and the paste-like binder were set to 20 ° C. and 35 ° C., respectively.
<4> Next, the paste-like binder was completely dispersed in the slurry and then foamed.

<5> Next, the obtained bubble-containing slurry was gelled at 83 ° C. Then, the obtained gel was held at 83 ° C. to dry the cell-containing slurry, whereby a green block (pre-sintering block) was obtained.

<6> Next, the green blocks were processed into a bottomed cylindrical shape and a truncated cone shape, respectively. Then, by sintering the green block in the air at 1050 ° C. for 2 hours, the sintered bodies composed of hydroxyapatite (HAP) were each formed into a bottomed cylindrical shape with a bottom surface of 78.5 mm ^2. × Height 10 mm (hole: bottom surface 12.6 ^{mm 2} × depth 7 mm) main body 10 and cone-shaped lower bottom surface 13.8 mm ² × upper bottom surface 7.5 mm ² × height 3 mm lid Obtained as 20. The sintered body was a porous body having communication holes.

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

1-3. Manufacture of Sustained Release Device 1-2. The mixture prepared in the above 1-1. After filling the hole 15 provided in the main body 10 manufactured in the above 1-1. The sustained release device of Example 1 was manufactured by covering the hole 15 with the lid body 20 manufactured in 1.

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

(Comparative Example 1)
1-2. The sustained release device of Comparative Example 1 was produced in the same manner as in Example 1 above, 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 For each of the sustained release devices of Examples 1, 2 and Comparative Example 1, the sustained release device was taken out after being immersed in 10 mL PBS solution (phosphate buffered saline) for 24 hours, and then taken out. , The content (sustained release amount) of gentamycin released slowly in the PBS solution was measured using an HPLC device (HITACHI, "ELITE LaChrom"), and the sustained release device taken out was used as a new PBS solution. Soaked in. Immersion of this sustained release device in PBS solution was repeated for 14 days.
The result is shown in FIG.

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

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

(Example 3)
1-2. In, instead of the phosphorylated pullulan, using polyethylene glycol (500 mg), by changing the content of the water for injection to 256mg mixture was prepared, as the porous body 100, the bottom surface 176.6mm ² × of a bottomed cylindrical shape 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 The sustained-release device of Example 3 was produced in the same manner as in Example 1 except that the device having The viscosity of the obtained mixture was 575 mPa · S.

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

(Comparative Example 3)
1-2. The sustained release device of Comparative Example 3 was produced in the same manner as in Example 3 above, 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 For each of the sustained release devices of Example 3 and Comparative Examples 2 and 3, the sustained release device was taken out after being immersed in 10 mL PBS solution (phosphate buffered saline) for 24 hours, and then taken out. , The content (sustained release amount) of gentamycin released slowly in the PBS solution was measured using an HPLC device (HITACHI, "ELITE LaChrom"), and the sustained release device taken out was used as a new PBS solution. Soaked in. Immersion of this sustained release device in PBS solution was repeated for 21 days.

The result is shown in FIG. In the graph of FIG. 4, the vertical axis shows the value obtained by converting (dividing) the content of gentamicin in the PBS solution by the volume of the PBS solution and the filling amount of gentamicin in the sustained release device.

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

10 Body part 15 Hole part 20 Lid body 100 Porous body

Claims (6)

Have a plurality of communication holes pores each other are formed in communication, comprising: a porous body which is mainly composed of calcium phosphate-based compound, a drug, a polymer,
The drug is retained in the porous body in the form of a mixture mixed with the polymer .
The drug is a drug having an amino group, which is an antibacterial drug, an antifungal drug, an antiviral drug, a bone morphogenetic protein (BMP), an anti-inflammatory drug, or an antithrombotic drug, and the polymer is phosphorylated. It ’s a pull run,
The mixture is a sustained release device having a viscosity at 25 ° C. of 15.0 mPa · S or more and 5000 mPa · S or less. It has a communication hole formed by communicating a plurality of pores with each other, and includes a porous body composed mainly of a calcium phosphate compound, a drug, and a polymer.
The drug is retained in the porous body in the form of a mixture mixed with the polymer.
The drug is an aminoglycoside antibiotic, and the polymer is phosphorylated pullulan.
The mixture is a sustained release device having a viscosity at 25 ° C. of 15.0 mPa · S or more and 5000 mPa · S or less. The sustained release device according to claim 1 or 2 , wherein the porous body has an internal space, and the internal space is filled with the drug in the state of the mixture. The sustained release device according to any one of claims 1 to 3, 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 4 , wherein the communication hole has an average diameter of 1 μm or more and 200 μm or less. The invention according to any one of claims 1 to 5 , wherein a three-dimensional network obtained by reacting an amino group contained in the drug with a phosphoric acid group contained in the polymer in the mixture is formed. Sustained release device.

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