Substance-containing vesicle, and production method therefor
|発明の名称 （英語）||Substance-containing vesicle, and production method therefor|
|発明の概要（英語）||Provided is a monodisperse agglomerate of a substance-containing vesicle filled with a substance at a concentration higher than conventionally possible. A mixed solution, in which a target substance is included in an aqueous medium, is mixed with a monodisperse agglomerate of a crosslinked vesicle comprising a prescribed polymer which includes a first polymer, i.e. a block copolymer having uncharged hydrophilic segments and first charged segments, and a second polymer having second charged segments carrying a charge opposite to that of the first charged segments, and in which the first polymerand/or the second polymer are/is crosslinked. As a result, the crosslinked vesicle is made to contain the target substance.|
It is well known, for level-one structure through a carefully controlled high molecular self-assembly, and to obtain microcapsules can be formed. Due to the microcapsules can be diversified molecular design, at the same time with the possibility of new properties in addition to exhibiting high molecule-specific properties, as drug delivery systems were investigated (Drug Delivery System: DDS) carriers, the use of a biomaterial · functional material or the like.
In Patent Document 1 (JP Patent No.8-188541 A) are, according to the present invention such as a human portion of the population, there is disclosed: a block copolymer having a non-charged segment and a charged segment is a self-assembled to form an electrostatic-bound polymeric micelle drug carrier.
In the Non-Patent Document 1(Schlaad H.et al.,Macromolecules,2003,36 (5), 1417-1420), discloses: manufactured by poly (1,2-butadiene) blocks and poly (methyl cesium acrylate) block with a block copolymer composed of polystyrene block and a poly (1-methyl-4-vinyl pyridine iodide) block copolymer self-assembly to form a block will be referred to as polymersomes of the microcapsule.
In Patent Document 2 (Pamphlet of International Publication No. 2006/118260) in which, depending on the portion of the population of people to the present invention, there is disclosed: has a non-charged hydrophilic segment and a cationic segment of the 1st block copolymers (such as PEG-poly cation or the like), and the amino acids with uncharged hydrophilic segments and anion sub-segment of the 2nd block copolymers (such as PEG-polyanion and the like) to form a self-assembly of the microcapsules.
In the Non-Patent Document 2(Anraku Y.et al.,J.Am.Chem.Soc.,2010,132 (5), 1631-1636), according to the present invention or the like is of a portion of the population, there is disclosed: a hydrophilic segment and a chargeable segment having a non-charged block copolymers (such as PEG-poly cation or the like), a copolymer of opposite charge to the charged segment and a band (such as a polyanion and the like) to form a self-assembly of the microcapsules.
It is generally considered a self-assembled polymer obtained by a variety of microcapsules with its air gap portion comprises, loaded with various substances. (With respect to the overview, see Non-Patent Document 3(H.Nyin et al.Soft Matter,2006,2,940-949) and Non-Patent Document 4 ("liposomes applied new launch", Kazunari Akiyoshi et al. ed., NTS, 2005)).
As in the preparation of the microcapsules encapsulating material in a gap (hereinafter may be referred to as "substance encapsulated microcapsules" case) of the method, represented as: which contains the encapsulated substance (hereinafter may be referred to as "encapsulated substance" case) which is the polymer of the membrane component, or a pre-formed polymer film are mixed together, are self-assembled, the microcapsules is carried out while the formation of voids and to enclose a substance in a method (hereinafter may be referred to as "simultaneous mixing method" in the case). As a specific example, there may be mentioned an emulsion polymerization method (see Non-Patent Document 5(F.Szoka,Jr et al.,Proc.Natl.Acad.Sci.USA,1978 75 (9) 4194-4198)), lipid organic solution dropping method (see Non-Patent Document 6(Batzri,S.et al.,Biochim.Biophys Acta 1973,298,1015-1019) ) and the like.
However, at the same time in the mixing method, there are encapsulated by the presence of the substance to affect self-assembly of the formed microcapsules, the microcapsules are formed of blocks, or even if the microcapsule formation but in gap un-encapsulated substance. In addition, in the case of hazardous organic solvents to be used when forming a film is large, there are also becomes complex, an organic solvent at the same time there is a problem that are vulnerable to damage resulting from the encapsulation material. Furthermore, it is difficult to form a uniform particle size, structure of the microcapsules, in order to ensure that such a uniform particle size, structure has to be increased and the other steps, there is also a problem of easily becomes complex processes. Thus, the present method has poor generality, encapsulated microcapsules with various substances to the production method is not practicable.
On the other hand, as the hollow particles mainly in the method used in the coating material, there will be encapsulated substance is introduced into the space of the hollow particles after the prior art, so as to enclose, method of the load (hereinafter may be referred to as [post-carrying method] case) (see Non-Patent Document 7(W.Tong et al.J.Phys.Chem.B,2005,109,13159-13165)), has also been considered such a method is applied to the microcapsules.
However, as the back support method applied to the case of microcapsules, it is sought to traverse the empty microcapsule film, will become encapsulated substance into the void portions. For example, it is envisioned that empty , the film is relaxed, the film from the creation of the gap will be encapsulated substance introduced into the void portions after penetration, the film is shrunk by the encapsulating material and to prevent separation of the method, or a hole is formed in the , through the aperture will become encapsulated substance into the void portions are, blocking the hole and prevent separation of the method or the like is encapsulated material, however any one of which is an extremely complex, for practical use is extremely disadvantageous. In addition, taking into account the load is enclosing or encapsulating material, causing the particle size of microcapsules are available now, a disorder of the structure is a high probability, so it is not practicable.
In addition, the lipid bilayer of the liposome or the like with respect to the microcapsule membrane, also reports on lipid bilayer method or the like is fitted in the channel proteins (see Non-Patent Document 8(Ranquin A,Versees W,Miere W,Steyaert J,GelderPV.Therapeutic Nanoreactors: Combining Chemistry and Biology in a NovelTriblock Copolymer Drug Delivery System.Nano Lett.2005; 5:2220-4)), however the procedure still is extremely complex, and the versatility is extremely low, or not practical.
Against the above background technology, the present invention or the like is proposed quite unexpected findings: the presence of a target substance encapsulated in the it through, mixed in an aqueous medium having both film and the method of the gap formed in a membrane enclosed (rather "post-carrying method"), and the 1st and the 2nd through self-assembly of the polymer, it is possible to easily and efficiently produced in the void (internal aqueous phase) are encapsulated in the microcapsule encapsulating material of the target substance, wherein, having an uncharged hydrophilic block comprises as the film is charged and 1st 1st polymer block of a block copolymer, and has a band and the 1st 2nd of opposite charge on the charge on the charge block of the block polymer 2nd, and is applied for a patent (Patent Document 3: pamphlet of International Publication No. 2011/145745).
Prior Art Document
Patent Document 1: JP Patent No.8-188541 A
Patent Document 2: pamphlet of International Publication No. 2006/118260
Patent Document 3: pamphlet of International Publication No. 2011/145745
Non-Patent Document: 1Schlaad H.et al.,Macromolecules,2003,36 (5), 1417-1420
Non-Patent Document: 2Anraku Y.et al.,J.Am.Chem.Soc.,2010,132 (5), 1631-1636
Non-Patent Document: 3H.Nyin et al.Soft Matter,2006,2,940-949
Non-patent Document: "development of a new Liposome Application" 4, Kazunari Akiyoshi, Shigeru Tsujii, NTS, Non-Patent Document 2005: 5F.Szoka,Jr.et al.,Proc.Natl.Acad.Sci.USA,1978 75 (9) 4194-4198
Non-Patent Document: 6Batzri,S.et al.,Biochim.Biophys Acta 1973,298,1015-1019
Non-Patent Document: 7W.Tong et al.,J.Phys.Chem.B,2005,109,13159-13165
Non-Patent Document: 8Ranquin A et al.,Nano Lett.2005,5:2220-4
1. Microcapsule encapsulating method for producing a substance, characterized in,
In the film formation of the microcapsule encapsulating the target substance, wherein the film contains as having uncharged hydrophilic block and a block copolymer of polymer block charged 1st 1st, 1st and has a band with opposite charge of the charged blocks of the 2nd charging block polymer 2nd;
(A) as compared to the target substance can be water-soluble high precursor is converted into target substance enzyme, encapsulated in the microcapsule which is film-forming polymer containing 1st and 2nd, prepare enzymes encapsulated microcapsule technology, and,
(B) compared to the precursor, under conditions of low solubility for the target substance, micro encapsulated enzyme precursor to permeate the bladder, through enzymes, precursors to the target substance is converted, the target material to precipitate, encapsulated in a microcapsule encapsulated into, microcapsule encapsulated substance preparation processes,
Wherein, in the processing (b) before, further comprising cross-linked enzyme encapsulated 1st and a 2nd/or microcapsules of the polymer processes,
The target substance is a low water-soluble substance, a low water-soluble substance in excess of the solubility of the substance relative to the inner aqueous phase at a concentration of low water solubility is encapsulated.
2. In the method according to claim 1, characterized in, to the processes (b) are, through an aqueous solution of the enzyme encapsulated microcapsules and precursor, the precursor to the enzyme encapsulated micro capsule penetration.
3. One substance encapsulated microcapsules, which is prepared through the method of claim 1 or 2.
4. A low-water-soluble substance encapsulated microcapsules, characterized in,
Than the low water-soluble substance from water-soluble high precursor is transformed to obtain a low-water-soluble substance linked to an enzyme of low precursor is transformed into water-soluble substance encapsulated in the microcapsules for formed from film,
Wherein the membrane contains hydrophilic block and having uncharged as 1st charged blocks of the block copolymer of the 1st polymer, and has a 1st 2nd charged with opposite charges charged blocks of the block polymer of the 2nd, 1st and a 2nd/or cross-linked polymer;
A low water-soluble substance relative to the inner aqueous phase in excess of the low solubility of the encapsulated at a concentration of water-soluble substance.
5. One microcapsule in the drug delivery system of claim 3 or 4.
6. A method for delivering a drug to objects of the method, characterized in, which comprises,
(A) microcapsules was formed by the membrane, encapsulation can be encapsulated microcapsules of the drug of the drug precursor into the step of preparing the enzyme, wherein the film contains as having uncharged hydrophilic block and a block copolymer of polymer block charged 1st 1st, 1st charged blocks and has a tape and the 2nd 2nd polymer of opposite charge of the charged blocks, and,
(B) at a specific position of objects, the precursor to the enzyme encapsulated micro capsule penetration, through enzymes, converting the precursor is a drug, a step of forming a drug.
7. In the method according to claim 6, characterized in, has low water solubility compared to prodrug, step (b) are, compared to the precursor exhibits a relatively low solubility of the drug under conditions, precursors to the enzyme encapsulated micro capsule penetration.
8. According to the method described in claim 6 or 7, characterized in, step (b) are, further comprising the encapsulated into microcapsules and encapsulated within a drug precipitation, a step of forming microcapsule encapsulated drug.
|参考情報 （研究プロジェクト等）||CREST Establishment of Innovative Manufacturing Technology Based on Nanoscience AREA|
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