WO2007102447A1

WO2007102447A1 - Adhesive microcapsule

Info

Publication number: WO2007102447A1
Application number: PCT/JP2007/054131
Authority: WO
Inventors: Yasuaki Ogawa; Hideo Matsugi
Original assignee: Galenisearch, Laboratories
Priority date: 2006-03-09
Filing date: 2007-02-27
Publication date: 2007-09-13
Also published as: JPWO2007102447A1

Abstract

The object is to provide: a microcapsule which contains an antibiotic and is excellent in sustained release properties, biodegradability and adhesion properties; a method for production of the microcapsule; and a stable pasty composition comprising the microcapsule. Disclosed are: an adhesive microcapsule which comprises a particle and an adhesive substance layer coated on the surface of the particle, wherein the particle comprises a biodegradable polymer containing an antibiotic; a method for production of the microcapsule; and a composition comprising the microcapsule.

Description

Description Adhesive Microcapsule Technical Field

The present invention relates to a microphone mouth capsule having a function of adhering to a mucous membrane of a living body and a method for producing the same. The present invention also relates to a paste-like composition in which the microcapsules are dispersed. Background art

When treating a disease locally, it is common to administer a drug to the site of the disease. However, many drugs quickly disappear from the site of administration, and frequent administration is required to obtain efficacy. If self-administration is possible, such as skin diseases, it can be administered frequently using a patch or the like, but such treatment is difficult if self-administration is difficult. In such a case, a microphone capsule that releases the drug gradually over several days in a single administration is preferable. Further, in order to reliably obtain the effectiveness of the drug, it is preferable that the microphone mouth capsule adheres to the administration site and stays there. Furthermore, as a material for the micropower pushell, a biodegradable polymer that decomposes in vivo is preferable.

For this reason, various proposals have been made on microcapsules, focusing on sustained release, adhesion, biodegradability and the like. For example, Non-Patent Document 1 discloses a sustained-release microcapsule using a biodegradable polymer. As a biodegradable microphone mouth capsule containing an antibiotic, Alestin (registered trademark) manufactured by Orapharma Inc.

Patent Document 1 discloses a microsphere mainly composed of a polyanionic substance and a polycationic substance and having excellent adhesion to the gastrointestinal mucosa. In addition, Patent Document 2 discloses an adhesive solid matrix in which a substance that generates a high viscosity with water selected from the group consisting of an acrylic polymer and cellulose ether is dispersed in the vicinity of the surface of the matrix particles. Is disclosed. Furthermore, Non-Patent Document 2 includes Particles using a cross-linked acrylic acid polymer as an adhesive substance are disclosed, and when the adhesive substance is dispersed in the particles, an example of showing good adhesion, and when the adhesive substance is coated on the particle, it adheres. An example of weakness is introduced. In addition, Non-Patent Documents 3 and 4 disclose a method for coating polylactic acid / daricholic acid (PLGA) nanoparticles with an adhesive substance such as chitosan.

(Patent Document 1) Japanese Patent Laid-Open No. 2 0 0 5-10 0 4 8 40

(Patent Document 2) Japanese Patent Laid-Open No. 2 0 0 1-3 5 4 5 5 0

(Non-Patent Document 1) Y. Ogawa, J. Biomaterial Science Polymer Edition, 8: 391-409 (1997)

(Non-Patent Document 2) Y. Akiyama et al, Pharmaceutical Research, Vol. 12,

No. 3, 397-405 (1995)

(Non-Patent Document 3) H. Takeuchi et al, Advanced Drug Delivery Reviews 47: 39-54 (2001)

(Non-Patent Document 4) H. Yamamoto et al, Journal of Control led Release, 102: 373-381 (2005) Disclosure of the Invention

An object of the present invention is to provide a sustained-release microphone mouth capsule containing an antibiotic. Another object of the present invention is to provide a biodegradable microcapsule. A further object of the present invention is to provide a microcapsule having excellent adhesion. In addition, an object of the present invention is to provide a method for producing the microcapsules. Furthermore, the objective of this invention is providing the stable paste-like composition containing this microcapsule. In addition, an object of the present invention is to provide a method for treating a disease using the microcapsule.

The present inventor has studied a method for coating an adhesive substance on biodegradable microphone mouth capsule particles. As a result, the present inventors have found that a microcapsule having excellent adhesion can be obtained by kneading the microcapsule particles and the powder of the adhesive substance in a dry manner without using a solvent or the like, thereby completing the present invention. In addition, the present inventor has studied a composition that can easily administer a microphone mouth capsule to a local site. As a result, it was found that glycerin force S is preferable as a dispersion medium for dispersing microcapsules in a paste form, and the present invention has been completed.

Furthermore, the present inventor has found that the encapsulation rate is improved when a divalent metal compound such as zinc oxide is allowed to coexist when the antibiotic is encapsulated in the microcapsule, thereby completing the present invention.

That is, the present invention is an adhesion type microcapsule composed of particles composed of a biodegradable polymer containing an antibiotic and an adhesive substance coated on the surface thereof.

The present invention also relates to a composition comprising particles composed of a biodegradable polymer containing an antibiotic, an adhesive microphone mouth capsule (i) composed of an adhesive substance coated on the surface thereof, and dariserine (ii). is there.

Furthermore, the present invention provides (i) a step of preparing a phase by adding a biodegradable polymer and an antibiotic to a solvent,

(ii) a step of preparing a W phase by adding a dispersant to water;

(ii) Step of mixing O phase with W phase to prepare O / W emulsion,

(iv) a step of evaporating the solvent from the emulsion and then freeze-drying to obtain particles, and

(V) a step of kneading the particles and the adhesive substance,

It is a manufacturing method of the adhesion type micro force process which consists of.

The present invention includes a method for treating a disease comprising administering the microcapsule or the composition.

BEST MODE FOR CARRYING OUT THE INVENTION

(Adhesive microcapsules)

The adhesion type microcapsule of the present invention comprises particles composed of a biodegradable polymer containing an antibiotic and an adhesion substance coated on the surface thereof.

(Biodegradable polymer)

Biodegradable polymers include lactic acid polymer (PLA) and lactic acid / glycolic acid copolymer (PL GA). Of these macromolecules, sustained release of antibiotics PL GA is preferable as the material of the microcapsule. The molar ratio (LZG) of lactic acid (L component) to glycolic acid (G component) in the copolymer is preferably 95 Z 5 to 40/60, more preferably 75/25 to 50 Z50. The weight average molecular weight of PLGA is preferably 3,000 to 25,000, more preferably 3,000 to 15,000, and even more preferably 5,000 to 12,000. The weight average molecular weight can be measured by gel permeation chromatography. Therefore, the biodegradable polymer consists of lactic acid (L component) and glycomonouric acid (G component), and the molar ratio (L / G) of L component to G component is 95 / 5-40 / 60. A copolymer having an average molecular weight of 3,000 to 25,000 is preferred.

(Antibiotics)

Antibiotics should be stable in the presence of water. Tetracycline, chloride, aminoglycoside, pyridonecarboxylic acid, new quinolone, chloromycetin derivatives and the like are preferable. Examples of the tetracycline group include tetracycline hydrochloride, oxytetracycline hydrochloride, demethylchlortetracycline hydrochloride, doxycycline hydrochloride, minomycin hydrochloride, and free bases thereof. Examples of macrolides include erythromycin, azithromycin, clarithromycin, roxithromycin, rokitamicin, josamycin, kiyu samycin, and acetylsviramycin. Aminoglycoside systems include gentamycin sulfate, tobramycin, panymycin, amikacin sulfate, sisomicin sulfate, netilmycin sulfate, micronomycin sulfate, isepamicin sulfate, bekanamycin sulfate, fradiomycin sulfate, lipostamycin sulfate, sulfate Examples include astromycin, spectinomycin hydrochloride, arbekacin sulfate and their free bases. Examples of pyridone carboxylic acids include nalidixic acid, pyromido acid, and pipemetic acid. As new quinolones, lepofloxacin, ciprofloxacin hydrochloride, pazufloxacin mesylate, lomefloxacin hydrochloride, tosufloxacin tosylate, fleloxacin, sparfloxacin, gatifloxacin, pullrifloxacin, moxifloxacin hydrochloride and free of them Strength such as base is listed. As a chloramphenicol derivative, chloram Examples include fenicol, chloramphenicol succinate, and chloramphenicol palmitate.

In particular, at least one selected from the group consisting of a tetracycline system, a macrolide system, an aminoglycoside system, and a quinoquinone system is preferable. Tetracycline type is particularly preferable. The content of the antibiotic is preferably 3 to 20 parts by weight, more preferably 5 to 20 parts by weight, and still more preferably 10 to 20 parts by weight with respect to 100 parts by weight of the biodegradable polymer. It is. In the case of administration to the local area of the disease, since a large amount of administration is difficult, a higher content of the antibiotic is preferable because a dose of the entire microphone mouth capsule is smaller. (Adhesive substances)

The adhesion type microcapsule of the present invention has an adhesion substance coated on the surface of particles. This adhesive substance allows the microcapsule to have an adhesive function. Adhesive substances include acrylic acid polymers and chitosan force. Of these, an acrylic acid polymer is preferably used. Of these, a cross-linked acrylic acid polymer is preferred. Cross-linked acrylic acid polymer is the name of general-purpose ropoxyvinyl polymer, and is already used as a pharmaceutical additive. Carbopol and Hibisu Koichi are well known as product names.

The coating amount of the adhesive substance is preferably 0.5 to 10 parts by weight, more preferably 1 to 5 parts by weight with respect to 100 parts by weight of the particles. The average particle size of the particles constituting the adhesive microcapsules of the present invention is preferably 5 to 80 zm, more preferably 10 to 50 m. The average particle size can be measured with a microscope or a counter. The thickness of the adhesive substance layer is preferably 0.1 to 3θΠΐ, more preferably 1 to 10 m.

The attached microphone mouth capsule of the present invention preferably contains a divalent metal compound. Examples of the divalent metal compound include zinc chloride, zinc oxide, zinc acetate, calcium oxide, and calcium chloride. Of these, zinc oxide is particularly preferable. The content of the divalent metal compound is preferably 0 with respect to 100 parts by weight of the biodegradable polymer.

It is 1 to 2 parts by weight, more preferably 0.3 to 1 part by weight.

Manufacturing method of adhesive-type microphone mouth capsule> The manufacturing method of the attachment type microphone mouth capsule of the present invention,

(1) A step of adding a biodegradable polymer and antibiotics to a solvent to prepare an o phase,

(ii) a step of preparing a W phase by adding a dispersant to water;

(ii) Step of mixing O phase with W phase to prepare O / W emulsion,

(V) the step of kneading the particles and the adhesive substance,

Consists of.

(Preparation of O phase)

○ The phase is prepared by adding biodegradable polymers and antibiotics to a solvent and dissolving or dispersing them. Biodegradable polymers and antibiotics are as described in the attached microcapsules section. Examples of the solvent include dichloromethane and black mouth form. The amount of the solvent is preferably 100 to 1,000 parts by weight, more preferably 100 to 500 parts by weight with respect to 100 parts by weight of the biodegradable polymer. Further, it is preferable that a divalent metal compound is further added to the phase. The divalent metal compound is as described in the section of the adhesion type micro force process. When a divalent metal compound is added to the O phase, antibiotics can be encapsulated in the micropower cell with a high encapsulation rate.

(Preparation of W phase)

Phase W is prepared by adding a dispersant to water and dissolving it. Examples of the dispersant include polyvinyl alcohol, polysorbate 80, and the like. The amount of the dispersant is preferably 0.05 to 2 parts by weight, more preferably 0.05 to 1 part by weight with respect to 100 parts by weight of water. In addition, stabilizers, sugars and the like may be added.

(Preparation of O / W emulsion)

0 / W emulsion is prepared by mixing W phase with O phase. The weight ratio (O / W) between the O phase and the W phase is preferably 1/1 to 1 100, more preferably 1 Z 1 to LZ 50.

(Solvent volatilization, lyophilization)

Put the O / W emulsion into the W phase of 10 to 100 times the amount of OZW and slowly Evaporate the solvent in the phase while stirring and dry (dry in water). After collecting the mouth capsule by centrifugal separation and redispersing it in water, it is freeze-dried to obtain particles. Sugar or the like is added to the redispersed water as necessary.

(Kneading)

By kneading the particles and the adhesive substance, a microcapsule having a particle surface coated with the adhesive substance can be obtained. The kneading can be performed using a mechano mill, a pole mill, a high-speed agitation granulator, a rotation / revolution mixer, or the like. The average particle size of the adhesive substance used for kneading is preferably 0, l to 10 zm, more preferably 0.:! To 5 m. Larger particles can be coated more effectively by separating them in advance. A microphone mouth capsule coated with an adhesive substance shows better adhesion than a microcapsule encapsulating an adhesive substance.

It is preferable to knead the particles with poor adherents by using a dry method without using a solvent, etc. ^ When adhering substances are dissolved in water etc. Not suitable for. In addition, when mixed by a method with low shearing force, a microphone mouth capsule with better adhesion can be obtained. As a method of kneading with weak shearing force, there is a method using a rotating and rotating mixer.

The composition of the present invention comprises particles composed of a biodegradable polymer containing an antibiotic, an adherent microcapsule U) composed of an adherent substance covering the surface, and dariserine (i i). Adhesive microcapsules (i) are as described in the previous section. The weight ratio {(i) / (ii)} of microcapsule (i) to glycerin (ii) is preferably lZ5 to l / 0.5, more preferably 1Z2-1 to 1Z1 . When the adhesion type microcapsules are dispersed in glycerin, the adhesion function is not impaired and can be stably dispersed.

The microphone mouth capsule or composition of the present invention can be used in a method for treating a disease. Microcapsules can be administered by a method such as applying or spraying to the affected area. The composition can be administered by applying to the affected area. Diseases include otitis externa, otitis media, otitis media, sinusitis, periodontal disease, periodontitis, peri-crownitis, infectious stomatitis, secondary infection of tooth extraction and oral surgery wounds, vulvitis, intrauterine infection, Examples include cervicitis, chlamydia, fungal infections, keratitis, superficial skin infections, secondary infections such as trauma / burns and surgical wounds, and perianal abscesses. Example

The present invention will be specifically described below with reference to examples. 'The adhesion rate to the mucous membrane was evaluated by the following two methods. .

Evaluation method (1).

Weigh 1 Omg of adherent microcapsules with antibiotics in a plastic weighing pan (5X 5 cm ² ), add rat inverted intestinal tract (length 8 cm) and sprinkle the microcapsules on the inverted intestinal tract. Hold this in a 37 ° C thermostatic bath, add physiological saline, and shake at 37 ° C for 3 hours. Thereafter, the inverted intestinal tract is washed in physiological saline, and antibiotics in the microcapsules adhering to the inverted intestinal tract are extracted and measured.

Evaluation method (2)

Weigh 20 mg of the composition into a 3 mL centrifuge tube, add 10 mL of physiological saline, and shake to make the ointment evenly dispersed. At the same time, add the rat inverted intestinal tract (length: 8 cm) and shake for 1 minute in a 37 ° C water bath (100 rpm). Then, the inverted intestinal tract is washed in physiological saline, and the amount of drug adhering to the inverted intestinal tract is extracted and measured. Example 1

(Preparation of microcapsules)

Random copolymer of lactic acid and glycolic acid (PLGA) with a ratio (molar ratio) of lactic acid (L) to glycolic acid (G) of 50Z50 and a weight average molecular weight of 8,000 (PLGA) 1, 50 Omg Zinc oxide 1 Omg was weighed and dissolved in 2 mL of dichloromethane. Zinc oxide dissolved when left overnight. To this solution, 15 Omg of minocycline hydrochloride (MC), which is a tetracycline antibiotic, was added and stirred to obtain an O phase. On the other hand, 6 mL of an aqueous solution of 1% by weight polyvinyl alcohol (PVA) was prepared and used as W phase. Under stirring, 0 phase was added to W phase to prepare OZW emulsion. Thereafter, dichloromethane was volatilized and then freeze-dried to obtain particles. The average particle size of the obtained particles was 50.

(Formation of coating layer)

Next, 50 Omg of the obtained particles and 5 mg of powdery force l-poxyvinyl polymer (Hibis Koji 104) were lightly kneaded in a mortar to obtain microcapsules (1). The adhesion of the microcapsule (1) was evaluated by the evaluation method (1). The results are shown in Table 1. '

Example 2

A microcapsule (2) was obtained in the same manner as in Example 1 except that 15 mg of Hibisko Co. 104 was used. Table 1 shows the evaluation results of the adhesion of the microcapsules (2).

Example 3

A microcapsule (3) was obtained in the same manner as in Example 1 except for using 25 mg of Hibisu Koichi 104. Table 1 shows the evaluation results of the adhesion of the microcapsules (3). '' Comparative example 1

The same operation as in Example 1 was carried out except that Hibisco 104 was not used to obtain a microphone mouth capsule (CE 1). Table 1 shows the evaluation results of the adhesion of the microcapsules (CE 1).

table 1 ·

* Note: Evaluated by evaluation method (1).

As can be seen from Table 1, coating with Hibis® 104 increased adhesion to the rat intestinal intestine. Example 4

The same procedure as in Example 1 was performed, except that MC 10 Omg was used, to obtain a micro cab cell (4). Table 2 shows the evaluation results of the adhesion of the microcapsules (4). Example 5

'OZW emulsion was prepared in the same manner as in Example 1 except that MC 10 Omg was used. Thereafter, dichloromethane was stripped. Thereafter, 30 mg (equivalent to 1.8%) of Hibisco 104 was dissolved in water and freeze-dried to obtain a micro-force (5). Table 2 shows the evaluation results of the adhesion of the microcapsules (5). Comparative Example 2

A microcapsule (CE2) containing hibisco 104 was produced in the same manner as in Example 1 except that 10 Omg MC and 3 Omg hibisco 104 were added to prepare phase O. Table 2 shows the evaluation results of the adhesion of the microcapsules (CE2).

Table 2

* Note: Evaluated by evaluation method (1).

As can be seen from Table 2, after the particles were prepared, dry kneading with a strong l-poxyvinyl polymer powder (Example 4) showed strong adhesion. Also, when the particles were coated with a solution of carboxyvinyl polymer, the particles aggregated. For this reason, it was crushed and used for the evaluation of adhesion.

Examples 6-9

Microcapsules (6) to (9) were obtained in the same manner as in Example 1 except that 50 mg, 100 mg, 200 mg and 30 Omg of minocycline hydrochloride (MC) were added. .

Examples 10-13

Perform the same operation as in Examples 6 to 9 except that no zinc oxide is added. A cell was prepared. The encapsulation efficiency is shown in Table 3.

Table 3

As can be seen from Table 3, when zinc oxide was added, the MC encapsulation rate was high. The MC encapsulation rate (%) was calculated from the measured value by HPLC of the calculated value from the charged amount. Example 1 ''

Particles were prepared in the same manner as in Example 1 except that MC 10 Omg was used. Microcapsules (14) were obtained by kneading 3, 20 Omg particles and 33 mg powder Hibisco 104 using a pole mill. Next, the microcapsule (14) and the same weight of glycerin were kneaded with a spatula to obtain a paste-like composition (1). The adhesiveness of the composition (14) was evaluated by the evaluation method (2). The results are shown in Table 4.

Example 15

A paste-like composition (15) was obtained in the same manner as in Example 14 except that Hibiskoko 104 was used in an amount of 66 mg. The adhesiveness of the composition (15) was evaluated by the evaluation method (2). The results are shown in Table 4.

Example 16

A paste-like composition (16) was obtained in the same manner as in Example 14 except that the amount of Hibisko-ko 104 was changed to 10 Omg. The adhesiveness of the composition (16) was evaluated by the evaluation method (2). The results are shown in Table 4.

Comparative Example 3 A best composition (CE3) was obtained in the same manner as in Example 14 except that Hibisko-co 104 was not used. The adhesion property of the composition (CE3) was evaluated by the evaluation method (2). The results are shown in Table 4.

Table 4

* Note: Evaluated by evaluation method (2).

As is clear from Table 4, the adhesive effect of the paste composition with glycerin was higher than that of the control.

Example 17

5 mg of microcapsules (8) containing MC 20 Omg obtained in Example 8 were dispersed in 0.1 MZL of phosphate buffer (pH = 5, 0) 1 OmL. '3 Hold at 7 ° C and measure elution of MC by rotting bottle method. MC was quantified by HP LC. The results are shown in Table 5.

As is apparent from Table 5, MC was gradually released from the microphone mouth capsule over a long period of time.

Example 18

The same procedure as in Example 1 was performed using 15 Omg of the free base instead of MC to obtain microcapsules (18). The average particle diameter of the obtained particles was 80 m.

Example 19 '

Perform the same operation as in Example 18 except that zinc oxide was not added. Cell (1 9) was obtained. The average particle diameter of the obtained particles was 80 m.

Example 2 0

The same procedure as in Example 1 was performed using clarithromycin (C M) 20 O mg, which is a macrolide antibiotic, instead of M C to obtain microcapsules (2 0). The average particle diameter of the obtained particles was 50 m.

Examples 2 1 to 2 4

A microcapsule was prepared in the same manner as in Example 20, except that no zinc oxide was added. Table 6 shows the encapsulation efficiency.

Table.6

As can be seen from Table 6, when zinc oxide was added, the CM encapsulation rate was high. The CM containment rate (%) was calculated from the measured value by HPLC for the calculated value from the charged amount. . The invention's effect

The microcapsules of the present invention have excellent sustained release properties, 'biodegradability, and adhesion properties. The composition of the present invention is excellent in stability. Further, according to the composition of the present invention, microcapsules can be easily administered to a local site. According to the method for producing a microcapsule of the present invention, a microcapsule having excellent adhesion can be easily produced. In addition, according to the production method, antibiotics can be efficiently encapsulated in the micropower cell. In addition, since the microphone mouth capsule of the present inventor is excellent in adhesion to the affected part and releases the drug over a long period of time, an excellent therapeutic effect can be obtained. Industrial applicability

The microphone mouth capsule of the present invention is effective for local diseases where sustained release of antibiotics is effective. Can be used for therapeutic drugs.

Claims

1. Adhesive-type microphone mouth capsule made of biodegradable polymer-containing antibiotics and adhesive substance coated on the surface.

2. The biodegradable polymer is composed of lactic acid (L component) and glycolic acid (G component), and the molar ratio of L component to G component (L 2 ί6 blue ZG) is 9 5 Ζ 5 to 4 0 Ζ 6 2. The microcapsule according to claim 1, which is a co-polymer having a weight average molecular weight of 3, 00 to 25, 00 and 0. spear

3. The microphone mouth capsule according to claim 1, wherein the adhesive substance is composed of a strong ruboxy vinyl polymer.

4. The microcapsule according to claim 1, wherein the coating amount of the adhesive substance is 0.5 to 10 parts by weight with respect to 100 parts by weight of the particles.

5. The microcapsule according to claim 1, wherein the antibiotic is at least one selected from the group consisting of a tetracycline series, a macrolide series, an amino dividend system, and a new quinone series.

6. The microphone mouth capsule according to claim 1, wherein the content of the antibiotic is 3 to 20 parts by weight with respect to 100 parts by weight of the biodegradable polymer.

7. The microcapsule according to claim 1, comprising 0.1 to 2 parts by weight of the bivalent metal compound with respect to 100 parts by weight of the biodegradable polymer.

8 · Particles composed of biodegradable polymers containing antibiotics, and adherent-type microcapsules (i) and glycerin (i A composition comprising i).

9. The composition according to claim 8, wherein the weight ratio {(i) / (i i)} of microcapsule (i) to glycerin (i .i) is lZ5 to l / 0.5.

10. (i) The process of preparing the O phase by adding biodegradable polymers and antibiotics to the solvent,

(i i) a step of preparing a W phase by adding a dispersant to water;

(i i i) A step of preparing a ZW emulsion by mixing the O phase with the W phase,

(i v) a step of evaporating the solvent from the emulsion and then freeze-drying to obtain particles, and

(V) a step of kneading the particles and the adhesive substance,

A method for producing an adhesion-type microcapsule comprising:

11. The production method according to claim 10, wherein the kneading of the particles and the adhesive substance is carried out by a dry method.

12. The method according to claim 10, wherein a divalent metal compound is further added to the O phase.

13. A method for treating a disease comprising administering the microcapsule according to claim 1.

14. A method for treating a disease comprising administering the composition according to claim 8,