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Substance-containing vesicle, and production method therefor

Foreign code F170009171
File No. AF12-14WO
Posted date Sep 12, 2017
Country China
Application number 201480012267
Gazette No. 105188905
Date of filing Feb 28, 2014
Gazette Date Dec 23, 2015
International application number JP2014055186
International publication number WO2014133172
Date of international filing Feb 28, 2014
Date of international publication Sep 4, 2014
Priority data
  • P2013-041186 (Mar 1, 2013) JP
  • P2013-176068 (Aug 27, 2013) JP
  • 2014JP55186 (Feb 28, 2014) WO
Title Substance-containing vesicle, and production method therefor
Abstract 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 polymer and/or the second polymer are/is crosslinked. As a result, the crosslinked vesicle is made to contain the target substance.
Outline of related art and contending technology Background Art
It is well known, by having the primary structure is precisely controlled amounts of 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 inherent to the nature presents a high molecule, thus investigated as drug delivery systems (DrugDelivery System: DDS) carriers, the use of biomaterial · functional material or the like.
In Patent Document 1 (JP Patent No.8-188541 Publication) are, according to a segment of the population of people to the present invention, there is disclosed: a block copolymer having a non-charged segment and a charged segment is a self-assembled to form an electrostatic bonding type polymeric micelle pharmaceutical carrier.
In Non-Patent Document 1 (SchlaadH. etal ., Macromolecules, 2003, 36(5), 1417-1420) was, discloses: made of poly (1, 2-butadiene) and poly (methyl acrylic cesium) block with a block copolymer composed of polystyrene and poly (1-methyl-4-vinyl pyridine iodide) block copolymer self-assembly to form a block will be referred to as polymersomes of a microcapsule.
In Patent Document 2 (Pamphlet of International Publication No. 2006/118260) are, according to the present invention such as a human portion of the population, there is disclosed: a hydrophilic segment and a cationic segment has a 1st having a non-charged block copolymers (such as PEG-polycation and the like), and the amino acids with uncharged hydrophilic segments and anion sub segment of 2nd block copolymers (such as PEG-polyanion and the like) a self-assembled to form a microcapsule.
In Non-Patent Document 2 (AnrakuY.etal ., J.Am.Chem.Soc., 2010, 132(5), 1631-1636) are, according to the present invention's and the like portion of the population, there is disclosed: a hydrophilic segment and a chargeable segment having uncharged a block copolymer (e.g. PEG-polycation and the like), and the belt and a charged segment is a copolymer of opposite charge (such as a polyanion and the like) a self-assembled to form a microcapsule.
It is generally considered a self-assembled with a polymer obtained by containing void portions with which various kinds of microcapsules, loaded with various substances. (With respect to the overview, see Non-Patent Document 3 (H. Nyinetal. SoftMatter, 2006, 2, 940-949) and Non-Patent Document 4 ("liposomes applied new launch", Kazunari Akiyoshi et al. ed., NTS, 2005)).
As the preparation of a coating material in a gap of microcapsule (hereinafter may be referred to as "substance encapsulated microcapsules" case) method, which stands for: contains the encapsulated substance (hereinafter may be referred to as "encapsulated substance" case) is shaped like a film elements constituting a polymer, or a pre-formed polymer film are mixed together, are self-assembled, the formation of microcapsules is carried out at the same time and to a method of filling a substance in a gap (hereinafter may be referred to as "simultaneous mixing method" in the case of). As a specific example, there may be mentioned an emulsion polymerization method (see Non-Patent Document 5 (F.Szoka, Jretal ., Proc.Natl.Acad.Sci.USA, 4194-4198 197875(9))), lipid organic solution dropping method (see Non-Patent Document 6 (Batzri, S.etal., Biochim. BiophysActa1973, 298, 1015-1019)) and the like.
However, at the same time in the mixing method, there are encapsulated by the self-assembly of the presence of substances affect the formed microcapsules, the microcapsules are formed of blocks, or even if a gap is non-encapsulated microcapsule formation but in the case of substances. In addition, in the case of hazardous organic solvents to be used when forming a film is large, there is also a process becomes complicated, resulting in an organic solvent at the same time there is a problem that an encapsulated material susceptible to damage. 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 and the other steps have to be increased, also having process tends to become complicated. Thus, the present method has poor generality, as a production method of a microcapsule encapsulating of various substances is not practicable.
On the other hand, as a principal in the method for use in encapsulating material in the hollow particle, there is the existing material into a void portion of the hollow particles after being encapsulated, which encapsulation, the method of supporting (hereinafter may be referred to as [post-carrying method] case) (see Non-Patent Document 7 (W. Tongetal. J.Phys.Chem.B, 2005, 109, 13159-13165)), such a method is also considered to be applied to the microcapsules.
However, in the case of the rear loading method is applied to the microcapsules, the microcapsules film is sought to travel through the air, will become encapsulated substance into the void portions. For example, it is contemplated that the empty microcapsules swell, the film is relaxed, a film produced from a gap of a substance introduced into the void portions encapsulated after penetration, and to prevent the film is shrunk by a method of encapsulating materials become detached, or in the empty microcapsules formed with a hole, through which the substance is introduced into the void portions are to be encapsulated, sealed off by the hole and prevent a method of encapsulating material is lost, however any one of which is an extremely complex, is very unfavorable for practical use. In addition, taking into account the load is enclosing or encapsulating material, the particle size of microcapsules are available now result, a high possibility that disorder of a structure, so it is not practicable.
In addition, with respect to the liposome lipid bilayer microcapsules and the like, also reports on the lipid bilayer membrane is fitted in the channel proteins and the like (see Non-Patent Document 8(RanquinA, VerseesW, MiereW, SteyaertJ, GelderPV.TherapeuticNanoreactors: CombiningChemistryand BiologyinaNovelTriblockCopolymerDrugDeliverySystem.NanoLett.2005; 5:2220-4)), then the process is still very complicated, and the versatility is extremely low, or not practical.
To address the above technical background of, or the like is quite unexpected insight of the present invention has been proposed: in the presence of a target substance encapsulated by should be empty microcapsules, mixed in an aqueous medium having a membrane and at the same time by the film surrounding the gap formed in the method of empty microcapsules (rather "post-carrying method"), 1st and the 2nd polymer and by a self-assembled, it is possible to easily and efficiently produced in the void (internal aqueous phase) of a target substance is encapsulated in a microcapsule encapsulating material, wherein, having a non-charged hydrophilic block comprises as the film is charged and 1st 1st polymer block of a block copolymer, having a belt and the 1st and the 2nd block on the charge on the charge block has a 2nd polymer of opposite charge, and is applied for a patent (Patent Document 3: pamphlet of International Publication No. 2011/145745).
Prior Art Document
Patent Document
Patent Document 1: JP Patent No.8-188541 Publication
Patent Document 2: pamphlet of International Publication No. 2006/118260
Patent Document 3: pamphlet of International Publication No. 2011/145745
Non-Patent Document
Non-Patent Document: 1 SchlaadH. etal ., Macromolecules, 2003, 36(5), 1417-1420
Non-Patent Document: 2 AnrakuY. etal ., J.Am.Chem.Soc., 2010, 132(5), 1631-1636
Non-Patent Document: 3H. Nyinetal. SoftMatter, 2006, 2, 940-949
Non-Patent Document: 4 "liposomes applied new launch", Kazunari Akiyoshi, Shigeru Tsujii, NTS, Non-Patent Document 2005: 5F. Szoka, Jr.etal., Proc.Natl.Acad.Sci.USA, 4194-4198 197875(9)
Non-Patent Document: 6 Batzri, S.etal., Biochim. BiophysActa1973, 298, 1015 1019-
Non-Patent Document: 7W. Tongetal ., J.Phys.Chem.B, 2005, 109, 13159-13165
Non-Patent Document: 8 RanquinAetal ., NanoLett.2005, 5:2220-4
Scope of claims [claim1]
1. Cross-linked mono-dispersion of microcapsules encapsulating a substance, characterized in,
And the cross-linked film comprising cross-linked film encloses an inner aqueous phase and in the internal aqueous phase into encapsulating the mono-dispersion of microcapsules encapsulating cross-linked material of a target substance,
Wherein the cross-linked film includes 1st charged with uncharged hydrophilic block and as a block copolymer of polymer block 1st, and has a band with the 1st 2nd charged blocks oppositely charged charged blocks of a polymer 2nd, 1st and the 2nd/or polymer and is cross-linked;
At a concentration of a target substance contained in the internal aqueous phase,
1st and the 2nd and/or non-cross linked polymer in the target substance under a non-encapsulated, mono-dispersion of microcapsules encapsulating cross-linked with the substance different empty Non-crosslinked microcapsules single-dispersion, mixing with the substance encapsulated cross-linked microcapsules containing the same concentration of inland waters of the target substance, and the case of a mixture of an aqueous medium,
A substance encapsulation Non-crosslinked microcapsules encapsulating the objective substance hindering the formation of a mono-dispersion of a concentration of.
[claim2]
2. In the mono-dispersion of microcapsules encapsulating cross-linked substance according to claim 1, characterized in, which has a polydispersity index of 0.2 or less.
[claim3]
3. According to claim 1 or 2 mono-dispersion of microcapsules encapsulating material in the cross-linked, characterized in, weight average molecular weight of 10000-40000 of a target substance, contained in the internal aqueous phase of a target substance concentration is more than 5 mg/mL.
[claim4]
4. In the mono-dispersion of microcapsules encapsulating cross-linked substance according to claim 3, characterized in, 1st and a 2nd/or polymer, by cross-linking bonds formed between the cationic groups are selected from, cross-linking bonds formed between anionic groups, cationic groups and cationic groups and the group consisting of cross-linking bonds formed between 1 kind or 2 kinds or more of a cross-linked by cross-linking bonds, a ratio of cross-linked film forming polymer capable of cationic groups and/or anionic groups contained in the total moles of 35% or more to.
[claim5]
5. A substance encapsulation Crosslinked microcapsules, characterized in,
And the cross-linked film comprising cross-linked film encloses an inner aqueous phase and in the internal aqueous phase into the target material and encapsulating the 1st 2nd 1st target substance than a substance having small molecular weight target substance encapsulated Crosslinked microcapsules,
1st target substance, as compared to the 2nd target substance is absent and contained in the aqueous phase is stable within a case;
Wherein the cross-linked film having uncharged hydrophilic block and comprising as 1st charged blocks of a block copolymer polymer 1st, 1st charged blocks and has oppositely charged 2nd band and the charged polymer block has a 2nd, 1st and the 2nd/or crosslinking of a polymer and made into.
[claim6]
6. According to claim 5 of a substance in Crosslinked microcapsules encapsulating, characterized in, 2nd target substance is a crowding agent.
[claim7]
7. A substance encapsulation process for the preparation of microcapsules, characterized in,
A mono-dispersion of microcapsules comprising an empty cross-linking, containing the target substance in the mixture, and a mixture of an aqueous medium, a mono-dispersion of microcapsules encapsulating cross-linking process of clutch means; mono-dispersion of microcapsules containing cross-linked its hollow cross-linked membrane enclosed into an inner aqueous phase and a cross-linked film, and in the internal aqueous phase a target substance is not encapsulated; comprising cross-linked film as having uncharged hydrophilic block and a block copolymer of polymer block charged 1st 1st, having a belt with the 1st and 2nd charged blocks oppositely charged charged blocks of a polymer 2nd, 1st and the 2nd/or polymer and is cross-linked;
In which the substance encapsulated 1st and the 2nd comprising a mono-dispersion of microcapsules containing cross-linked polymer by the 1st and the 2nd/or polymer and is cross-linked by cross-linked film, and the cross-linked film enclosed into an inner aqueous phase, and the target material encapsulating the internal aqueous phase.
[claim8]
8. In the method according to claim 7, characterized in, cross-linked microcapsules with a mono-dispersion empty, mono-dispersion of microcapsules encapsulating cross-linking agents, mono-dispersion of an empty Non-crosslinked microcapsules, and a mono-dispersion not more than 0.2 Non-crosslinked microcapsules encapsulating material has a polydispersity index of that.
[claim9]
9. In accordance with a method described in claim 7 or 8, characterized in, weight average molecular weight of 10000-40000 of a target substance, a mixture containing a target substance in a concentration of more than 5 mg/mL.
[claim10]
10. In the method according to claim 9, characterized in, empty cross-linked microcapsules and microcapsules encapsulating material, 1st and the 2nd polymer/or, by cross-linking bonds are formed between selected from the cationic groups, anionic groups to form crosslinks between, and cationic groups and cationic groups to form crosslinks between 1 or 2 group consisting of more than one cross-linking bonds in a cross-linked, in a proportion of cross-linking bonds formed, cationic groups and/or cross-linked film contains anionic groups to total number of moles of not less than 35%.
[claim11]
11. In accordance with the method according to any one of claim 7-10, characterized in, this method further comprises causing substance encapsulated cross-linked microcapsules with a 1st/2nd with a mono-dispersion and which can be obtained by reacting a polymer or cross-linking agent and a process of reacting is carried out.
[claim12]
12. A substance encapsulation process for the preparation of microcapsules, characterized in,
Which comprises the 1st Crosslinked microcapsules containing encapsulated material, mixed in 1st 2nd having small molecular weight than the target substance containing the target substance, and a mixture of an aqueous medium, and form a 2nd substance encapsulated cross-linked microcapsules with a process;
Wherein the 1st substance encapsulated cross-linked microcapsules containing cross-linked film, and the cross-linked film enclosed into an inner aqueous phase, and the target substance encapsulating the 1st internal aqueous phase, cross-linked film having uncharged hydrophilic block and comprising as 1st charged blocks of a block copolymer polymer 1st, 1st charged blocks and has oppositely charged 2nd band and the charged polymer block has a 2nd, 1st and the 2nd/or polymer and the cross-linked;
2nd 1st 2nd substance encapsulated Crosslinked microcapsules which contains a 1st and a 2nd/or and made of polymer and the polymer cross-linked by cross-linked film, and surrounded by the cross-linked film into an inner aqueous phase, 1st and the 2nd target substance is entrapped in the internal aqueous phase.
[claim13]
13. In the method according to claim 12, characterized in, cross-linked substance encapsulated microcapsule is a mono-dispersion 1st, 2nd substance encapsulated cross-linked microcapsules is a mono-dispersion.
[claim14]
14. In the method according to claim 13, characterized in, 2nd target specie concentration is contained in the mixture,
In a 1st and a 2nd/or in the case of non-cross linked polymer, cross-linked substance encapsulated mono-dispersion of microcapsules with the 1st 1st Non-crosslinked microcapsules encapsulating material different from that of a single-dispersion, in a case where mixed in the liquid mixture,
1st and 2nd Non-crosslinked microcapsules encapsulating material encapsulating the blocking target substance concentration formed of a single-dispersion.
[claim15]
15. Method according to any one of claim 12-14, characterized in,
The method further includes placing an empty Crosslinked microcapsules, containing 1st target substance mixed therewith, and a mixture of an aqueous medium, if necessary, 1st and the 2nd/or can be allowed to react with a crosslinking agent reactive polymer and the reaction, the process of forming 1st substance encapsulated cross-linked microcapsules;
Wherein the empty cross-linked microcapsule contains cross-linked film, and the cross-linked film enclosed into an inner aqueous phase, in the 1st and the 2nd internal aqueous phase with a non-encapsulated according to any one of a target substance;
Wherein the 1st and the 2nd polymer containing cross-linked film, 1st and the 2nd/or by cross-linked polymer.
[claim16]
16. In the method according to claim 15, characterized in, resembling a monomolecular dispersion thereof having a cross-linked microcapsule is empty, 1st substance encapsulated mono-dispersion of microcapsule is a cross-linked.
[claim17]
17. In the method according to claim 16, characterized in, 1st at a concentration of a target substance contained in the mixture,
1st/2nd or not cross-linked polymer in the case with, mono-dispersion of microcapsules encapsulating cross-linked with the empty Non-crosslinked microcapsules mixed mono-dispersion different empty encapsulated in the liquid mixture in the case of which,
1st Non-crosslinked microcapsules encapsulating material encapsulating the inhibit target substance concentration formed of a single-dispersion.
[claim18]
18. Method according to any one of claim 12-17, characterized in, 2nd target substance is a crowding agent.
[claim19]
19. An adsorbent material encapsulated microcapsules, characterized in,
As a non-charged hydrophilic block comprising a block comprising a block polymer of 1st and 1st charged polymer, and, has a 1st 2nd charged oppositely charged charged blocks 2nd polymer block formed of a film of a microcapsule, and the microcapsule-encapsulated adsorbent material particles, at least one of 1st and 2nd polymer adsorbed on the adsorbent material particles.
[claim20]
20. Encapsulated adsorbent material in the microcapsule according to claim 19, characterized in, 1st and the 2nd/or polymers are cross linked.
[claim21]
21. In accordance with an adsorbent material encapsulated in the microcapsules claim 19 or 20, characterized in, adsorbent material particles are silica particles.
[claim22]
22. In accordance with claim 19-21 encapsulated adsorbent material in any one microcapsule, characterized in, adsorbent material particles have an average particle diameter of 40 nm -10 μm.
[claim23]
23. Claim 19-22 encapsulated adsorbent material in the microcapsule according to any one, characterized in, on the adsorbent material particles to surface treatment.
[claim24]
24. In accordance with claim 19-23 in any one microcapsule encapsulated adsorbent material, characterized in, adsorbent material particles can adsorb small molecule compounds.
[claim25]
25. Method for manufacturing a microcapsule encapsulating an adsorbent material, characterized in,
When the film formed on the microcapsule encapsulating the adsorbent material particles; wherein film having uncharged hydrophilic block and comprising as 1st 1st block of a block copolymer charged polymer, and has a 2nd 1st charged blocks of opposite charge to the charged block has a 2nd polymer;
Comprising:
(A) 1st 2nd polymer will be a party of the adsorbent material particles and the mixing, adsorbed on the adsorbent material pellet;
(B) the step (a) 1st or 2nd polymer mixture with mixing continued for another party, the adsorbent material particles by the 1st and the 2nd polymer formed around a film containing the formed microcapsules, the microcapsules encapsulating a step of making an adsorbent material.
[claim26]
26. In the method according to claim 25, characterized in, this method also includes
(C): cross-linking step (b) 1st/2nd polymer microcapsules which are of a and the step of or.
[claim27]
27. In the method according to claim 25 or 26, characterized in, adsorbent material particles are silica particles.
[claim28]
28. In accordance with the method according to any one of claim 25-27, characterized in, adsorbent material particles have an average particle diameter of 40 nm -10 μm.
[claim29]
29. Method according to any one of claim 25-28, characterized in, this method further comprises the step of adsorbent material particles to surface treatment.
[claim30]
30. Method according to any one of claim 25-29, characterized in, small molecule compounds adsorbed on the adsorbent material particles.
[claim31]
31. A substance encapsulation process for the preparation of microcapsules, characterized in,
When the film formed on 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, and has a band with the 1st 2nd charged blocks charged blocks oppositely charged polymer to 2nd;
Comprising:
(A) as compared to the target substance can be water-soluble high precursor is converted into target substance enzyme, encapsulated in the microcapsules containing the 1st and 2nd polymer formed of a film, a process for encapsulating microcapsules prepare enzyme, and,
(B) compared to a precursor thereof, under conditions of low solubility for the target substance, the precursor to the enzyme encapsulated micro capsule penetration, by enzymes, precursors to the target substance is converted, the target material to precipitate, encapsulated in a microcapsule encapsulated into, a process for preparing microcapsules encapsulating material.
[claim32]
32. In the method according to claim 31, characterized in, within the process (b) are, by mixing an aqueous solution of the enzyme encapsulated microcapsules and precursor, the precursor to the enzyme encapsulated micro capsule penetration.
[claim33]
33. In the method according to claim 32, characterized in, within the process (b) prior to, encapsulated microcapsules with a cross-linking enzyme also including 1st and the 2nd/or polymer process.
[claim34]
34. Microcapsule encapsulating a substance, which is prepared by any one of claim 31-33 method.
[claim35]
35. A low-water-soluble substance encapsulated microcapsules, characterized in,
Than the target substance from a highly water soluble 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 1st block of a block copolymer charged polymer, and has a 2nd 1st charged blocks of opposite charge to the charged block has a 2nd polymer.
[claim36]
36. Water-soluble substance encapsulated microcapsules as those described in accordance with claim 34 or 35, characterized in, with respect to the internal water phase in excess of a low water-soluble substance in a water-soluble substance encapsulated at a concentration of low solubility.
[claim37]
37. In accordance with claim 34-36 sparingly water-soluble substance encapsulated in any one microcapsule, characterized in, 1st and the 2nd/or is cross-linked polymer.
[claim38]
38. Claim 1-4 in any one of a composition comprising a mono-dispersion of microcapsules, and the/or, claim 5, a drug delivery system in any one microcapsules 6, 19-22 and 34-37.
[claim39]
39. A method for delivering a drug to methods that involve, characterized in, which comprises,
(A) microcapsules was formed by the membrane, encapsulation of the drug can be encapsulated microcapsules with a drug precursor into an enzyme preparation step, wherein the membrane contains hydrophilic block and having uncharged as 1st 1st block of a block copolymer charged polymer, and has a 2nd 1st charged blocks of opposite charge to the charged block has a 2nd polymer, and,
(B) a particular site in a subject, the precursor to the enzyme encapsulated micro capsule penetration, by enzymes, converting the precursor is a drug, a step of forming a drug.
[claim40]
40. In the method according to claim 39, characterized in, has low water solubility compared to prodrugs thereof, 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.
[claim41]
41. According to the method described in claim 39 or 40, characterized in, step (b) are, also comprise the drug encapsulated into microcapsules deposited and encapsulated within, the microcapsules encapsulating a step of forming a drug.
  • Applicant
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
  • Inventor
  • KATAOKA, Kazunori
  • KISHIMURA, Akihiro
  • ANRAKU, Yasutaka
  • GOTO, Akinori
IPC(International Patent Classification)
Reference ( R and D project ) CREST Establishment of Innovative Manufacturing Technology Based on Nanoscience AREA
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