AU2005201665A1 - Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon - Google Patents
Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon Download PDFInfo
- Publication number
- AU2005201665A1 AU2005201665A1 AU2005201665A AU2005201665A AU2005201665A1 AU 2005201665 A1 AU2005201665 A1 AU 2005201665A1 AU 2005201665 A AU2005201665 A AU 2005201665A AU 2005201665 A AU2005201665 A AU 2005201665A AU 2005201665 A1 AU2005201665 A1 AU 2005201665A1
- Authority
- AU
- Australia
- Prior art keywords
- group
- drug
- carrier
- block copolymer
- chargeable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
Description
AUSTRALIA
Patents Act 1990 COMPLETE
SPECIFICATION
STANDARD
PATENT
Applicant: RESEARCH DEVELOPMENT CORPORATION OF JAPAN Invention Title: Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon The following statement is a full description of this invention, including the best method of performing it known to me/us: ELECTROSTATIC BONDING TYPE MACROMOLECULAR MICELL
DRUG
CARRIER AND DRUG CARRIED
THEREON
FIELD OF THE INVENTION The present invention relates to an electrostatic bonding type macromolecular micell drug carrier and drugs carried thereon. More particularly, the present invention relates to a novel macromolecular micell drug carrier of a chargeable drug such as protein and DNA, which is useful in areas such as a drug delivery system (DDS) which carries a drug to a permissive site in vivo and causes the drug to stably display the functions and effects thereof, drugs to be carried by such a carrier, and a method of carrying a drug on this carrier.
PRIOR ART AND PROBLEMS Macromolecular micell type drugs are attracting the general attention as a useful method for a drug delevery system
(DDS),
for example, and the present inventors have already proposed a macromolecular micell type drug which causes physical adsorption of a hydrophobic drug by a block copolyer comprising a hydrophilic segment and a hydrophobic segment.
The macromolecular micell type drug based on this physical adsorption is attracting the general attention because of a new structure and the possibility of using same in practice.
According to studies carried out by the present inventors, however, it is now clear that there still remain problems to be solved. More specifically, the macro-molecular micell drug based on this physical adsorption, although being very excellent as means to administer a hydrophobic drug, has a structure essentially characterized by physical adsorption of a hydrophobic drug by a block copolymer.
There has therefore been a drawback that the method has been applicable only to drugs having a sufficient hydrophobicity.
Under such circumstances, there is a demand for achievement of novel technical means applicable in a wider range, which permits stable carrying of a drug irrespective of whether the drug is hydrophobic or hydrophilic.
SUMMARY OF THE
INVENTION
The present invention provides an electrostatic bonding type macromolecular micell drug carrier comprising a block.copolymer having a non-chargeable segment and a chargeable segment, which solves the above-mentioned problems.
The present invention also provides embodiments of the above-mentioned carrier, in which the non-chargeable segment is polyethylene glyc the chargeable segment is polyamino polyethylene glycol, the folacid and the block copolymer is shown by any of the following formula and
(II);
R (OCI-H CH,
-R
2 (COCHNH) (COCH, CHNH) -R4 (1) CI1 2
R
3 Ri R, (OC- CH- -Rz (NIICHCO) (NICGCH CO)
-R
4 I
I
CHi Ri Ri (where,
R
1 is a hydrogen atom, a hydrocarbon group or a functional group or a functional group substituted hydrocarbon group; R is NH, CO or R 6 (CHZ)qR7, where
R
6 indicates
OCO,
g r o u p R i s c o (C H Z q 7 ,e 1 0 OCONH, NHCO, NHCOO, NHCONH, CONH or COO, R 7 indicates NH or CO, and q indictes an integerof 1 or more;
R
3 is a carboxyl group, a carboxyl group substituted hydrocarbon group, an amino group substituted hydrocarbon group, a hydrazino group, substituted hydrocarbon group,
(CH
2 )p-NHCNHNH 2 group, where p indicates an integerof 1 or more, a nitrogencontaining heterocyclic group or nitrogen-containing heterocyclic group substituted hydrocarbon group;
R
4 is a hydrogen atom, a hydroxyl grooup or hydrocarbon group having any of CO, NH and O at thebonding terminal thereof; m is a number within a range of from 4 to 2,500; n is a number within a range of from 1 to 300; and x is a number within a range of from 0 to 300, provided that x n).
In addition, the present invention.provides an electrostatic bonding type macromolecular micell carrier drug in which a drug is carried by the carrier as described above, and a carrying method for the manufacture thereof.
BRIEF DESCRIPTION OF THE
DRAWINGS
Fig. 1 shows a spectral chart of 1H-NMR of PEG-P(Lys).
Fig. 2 shows a graph comparing measuring results of melting for cases with PEG-P(Lys)/DNA, free DNA and (Lys)/DNA.
DETAILED DESCRIPTION OF THE
INVENTION
The present invention as described above was developed as a result of studies carried out by the present inventors to overcome the problems in the conventional physical adsorption type macromolecular micell drug, and realizes a novel electrostatic bonding type macromolecular micell drug carrier essentially different from the physical adsorption type one, drugs carried by means thereof, and a method for carrying the drug.
In the electrostatic bonding type macromolecular micell carrier comprising a non-chargeable segment and a chargeable segment of the present invetnion as described above, various substances are applicable for the both segments within the scope of the present invention.
Applicable non-chargeable segments include, for example, polyalkylene glycol such as polyethylene glycol and plypropylele glycol, polyalkylele oxide, polysaccharide, polyacrylamfide, poly-substituted acrylamide, polymethacrylamide, poly-sub stituted methacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid ester, polymethacrylic acid ester, polyamiflo acid, and derivatives thereof.
Applicable chargeable segments include, for example, a polyamiflo acid having a chargeable side chain, or more specifically, polyaspartic acid, polyglutamic acid, plylysine, polyarginine, polyhistidine, or, polymalic acid, polyacrylic acid, polymethacrylic acid, polyethlele imifle, polyviflylamine, polyacrylamine, polyvinyl imidaZOle, and drivatives thereof.
Substances applicable as a block copolymer of the pr Iesent invention comprising these segments include; Polyethylene glycolipolyaspartic acid block copolymer, polyethylene oxjde-polyglutamic acid block copolymfer, polyethylene glycol-polyarginine block copolymer, polyethylene glycol-polyhistidiine block copolymfer, polyethylene glycolpolyhistidile block copolymer, polyethylene glycol-poly methacrylic acid block copolymfer, polyethylee-polyvinylamine block copolymer, polyethylene glycol-plyarylamine block copolymfer, polyethylene oxjde-polyaspartic acid block copolymer, polyethylene oxije-polyglutamic acid block copolymer, polyethylene oxide-polylysine block copolymer, polyethylene oxjde-polyarylic acid copolymer, polyethylene oxide-polyvinyl imidazole block copolymer polyacrylamide-polyaspartic acid block copolymer, polyacrylamdepolyhitd lc copolymer, polymethacrylamiepolay cdbokcplm erpolmehacylaid-polyvinylamile block copolymer, polyvinylpyrrolidole-polyaspari acid block copolymer, p 0 1 yvinyalcoholpolyarin block copolymer, plyacry]lic acid-ester-Polyhistidine block copolymfer, polyifethacrYuic acidestr-plvnylamile block copolymer, and polymethacrylic acidplYVinlm aol block copolymer.
A representative structure of these block copolymers is one known as AB-type block copolymer.
More specifically, the following paragraph describes an
AB-
type block copolymer comprisin~g a non- .chargeable segment obtained from a polyethylene glycol derivative and polYasParti'c acid as the chargeable segment; C3- (00H2
COH
2 mNFIVCOCI-NH-) T (COCH2 CHINH)
-H
Cl- 2 COOL-
COOL-
This is a polyethylene glycol-poly( a ,6 /3aspartic acid) block copolymer comnprising polyethylene glycol and poly(a /3 -aspatiC~ acid) and is synthesized by copolymferizing /3 -bny--sataeNcroyi anhydride with poly-ethylene glycol which is a unilateral terminal aminogroup(molecular weight: 200 to 250,000) as the initiating agent. T'he molec ular weight of the -benzyl, L-aspartate) portion of this polyethylene glycol -beflzylLaspartate) block copolymer is variable within a range of from about 205 to 62,000. polyethylene glYcOl-Poly( a ,6 /3aspartic acid) block copolymer is available by eliminating benzyl through application of an alkali treatment of this copolymer.
Polyethylene glycol-POlysine block copolymer, shown by the following formula, having a cationic segment as the block copolymer: CH3 (OCH,-CH n (COCHNH)
-H
I
(CH-
2
NI-L
NH2 is synthesized through polymerization of a -carbobenzoxy-Llysine anhydride with unilateral terminal primary aminogroup polyethylene glycol (molecular weight: 200 to 250,000) as the initiating agent. Polyethylene glycol-polylysine block copolymer is available by subjecting the resultant polyethylene glycol-olly(e -carbobenzoxy-L-lysine) block copolymer to a deprotecting reaction by the use of methane sulfonic acid.
acidIn the present invention, while there is no particular limitation in the kind of drugs capable of being electrostatically carried in a macromolecular micell comprising a block copolmer as described above, applicable ones include macromolecular drugs such as peptide hormone, protein,
DNA,
RNA, and oligonucleotide and low molecular weight drugs having a chargeable functional group in molecules such as Adriamycin and Daranomycin.
When causing the macromolecular micell to carry any of these drugs, it is the basic practice to mix the block copolymer and drugs, it is th e on clurdn the drug or a solution theref. Various operations including dialysis, stirring, dilution, concentration, ultrasonication, temperature control, PH control and addition of an organic solvent may appropriately be adapted.
When including lyoszyme, an antimicrobial enzyme, in the polyethylene glycol-poly(a cn be artic acid) block copolymer shown above, lysozyme can be carried by mixing an aqueous solution of the copolymer with an aqueous solution of lysozyme under appropriate conditions including mixing ratio, ionic strength and pH.
Furthermore, when causing the polyethylene glycolpolylysine block copolymer described above to carry DNA, it is possible to conducted.DNA to be carried by mixing an aqueous solution of the copolymer with an aqueous DNA solution under conditions including appropriate mixing ratio, ionic strength and pH.
As described above, according to the electrostatic bonding type macromolecular micell drug carrier and the carried drug using same of the present invention, a stable macromolecular mice llstructure is available and chargeable substances such as protein and DNA can be efficiently incorporated into the internal nucleus therof. It is thus decomposed in vivo into the body in a stable state.
The present invention is now described further in detail by means of examples. It is needless to mention that the present invention is not limited to these examples.
Examle 1 E oly-L-lysine (degree of polymerization: 20,0.43 mg) was dissolved into distilled water (1.0ml), and a polyethylene glycol-polyaspartic acid block copolymer (PEG-P(Asp): molecular weight of PEG: 5,000, 23 aspartic acid residues per a chain of the block copolymer, 1.0 mg) was dissolved into distilled water (1.0 ml). Thereafter, these aqueous solutions were mixed. A weight average particle size of 41.3 nm and a number average particle size of 36.0 nm of the resultant mixture were measured by the method of dynamic light scattering. A zeta-potential of 0.643 and 0.569 mV for the entire surface of the mixture was measured by the method of trophoretic light scattering.
Example 2 2 Polyaspartic acid (degree of polymerization: 20, 0.32 mg) was dissolved into distilled water.(1.0 ml), and polyethylene glycol-poly-L-lysine block copolymer PEG-P(Lys); molecular (weight of PEG: 5,000, 20 L-lysine residues per chain of block copolymer, 1.0 mg) was dissolved into distilled water (1.0 ml). Thereafter, these aqueous solutions were mixed. A weight average particle size of 28.2 nm and a number average particle size of 42.8 nm of the resultant mixture were measured by the method of the dynamic light scattering.
Example 3 Chicken albumen lysozyme (1.0 mg) was dissolved into distilled water (1.0 ml), and PEG-P(Asp) (3.0 mg) was dissolved into distilled water (3.0 ml). Thereafter, these solutions were mixed. A weight average particle size of 24.9 nm and a number average particle size of 23.1 nm of the resultant mixture were measured by the method of the dynamic light scattering.
Examp ing insulin (1.42 mg) was dissolved into a 0.0005N hydrochloric acid (1.5 ml), and PEG-P(Lys) having a particle size of 0.58 mg was dissolved into distilled water (1.0 ml). Thereafter, these solutions were mixed. A weight average particle size of 24.5 nm, and a number average particle size of 22.4 nm of the mixed solution were measured by the methodof dynamic light scattering.
Example 5 Ex polyethylene glycol-polylysine block copolymer was synthesized inaccordance with the following formula:
HN-C
CHItOClH2CH2-)-NH I C -C Ii )4 NIJCOOCIn2 (CIH2)4 NHCOOCH2 Acid treatment C H NHCO-I -H C OCHtCmj NI1 -(-COCI-'HN -1 H H2)4 NH2 polyethylene glycol-polylysine block copolymer Fig. 1 shows 1H-NMR spectra for a case with a PEG molecular weight of 4,300 and 20 L-lysine residues.
This PEG-P(Lys) block copolymer (PEG molecular weight; 4,300, average degree of polymerization of polylysine chain; was dissolved into 1.0 ml of 0.1 M PBS (pH: 7.4) solution of Salmon Testes DNA in an amount of 50 ug/ml, and into ml of 0.1 M PBS 0.6 M NaCl 2mM Na 2 EDTA (pH: 7.4) so that the number of lysine residues of PEG-P(Lys) relative to DNA phosphte group became 0.25, 0.50, 1.0, 2.0, 4.0, 10 and times as large, respecively. These solutions were mixed and then held at the room temperature for three hours. No precipitation was observed in any of these samples. For a complex using polylysine homopolymer, on the other hand, precipitation took place in samples with ratios of lysine residues: DNA phosphate group of 1.0 and 2.0. Subse quently, a 20 1 fraction was taken from each sample and uently, a 20 10.g% agarose gel. As a subjected to electrophoresis using 09% agarose gel As a result, the amount of DNA migrating along with the increase dded to DNA decrease.: in the amount of PEG-P(Lys) added to DNA decreased, and DNA migration was almost inhibited at an amount of addition (r of PEG-P(Lys) with wich the charge became equivalent to that of DNA. It was consequently confirmed that a quantitatively stable poly ion complex was formed by the PEG-P(Lys) block copolymer and
DNA.
When using a plylysine homopolymer (molecular weight: 1,000 to 4,000) having a degree of polymerization almost equal to that of the PEG-P(Lys) block copolymer, inhibition of DNA migration by addition of polylysine homopolymer was not observed and a stable complex was unavailable.
Example 6 A pEG-P(Lys) block copolymer was dissolved into 1.0 ml of 1mM PBS (pH: 7.4) solution of Salmon Testes DNA in an aomount of 50 P g/ml, and into 1.0ml of ImM PBS (pH: 7.4) so that the number of lysine residues of PEG-P(Lys) relative to DNA phosphate group became 0.10, 0.20, 0.50and 1.0 times as large, respectively. A complex was formed by mising these solutions. After holding the complex at 4C for a night, the thermal melting curve of each sample was measured by adding methanol in an amount of 50 vol.% by the use of an ultraviolet absorban of 260 nm.
As a result, while the control DNA showed a first milting stage at about 45C the complex of DNA and PEG-P(Llys) showd two stage of melting at about 45 C and about The increase in absorbance at about 45'C gradually decreased according as the amount of added PEG-P(Lys) was increased, whereas the increment of absorbance at about 65 C in that place. In the sample in which PEG-P(Lys) was added up to times to DNA, the increase in absorbance at about diappears, and only the increase in absorbance at about was observed, suggesting that the structure of DNA was completely stabilized. This confirmed that DNA and
PEG-
P(Lys) stoichiometrically form a complex.
Fig. 2 shows a case where the number of lysine residues of PEG-P(Lys) is equal to 0.50 times relative to DNA phosphote group, and cases with free DNA and P(Lys)/DNA.
Remarkable differences are observed also in Fig. 2.
Example 7 Poly-L-lysine (degree of polymerization: 20)(40 mg) was dissolved into 4 ml of the phosphate buffer solution, and polyethylene glycol-polyasparatic acid block copolymer(PEG P(Asp);molecular weight of PEG: 5000, 20 aspharatic acid residues per a chain of the block copolymer, 2, 32mg) was dissolved into .3 ml of the phosphate buffer solution.
Thereafter, these aqueous solutions were mixed.
weight average particle size of 44.7 nm and a number average particle size of 41.3nm of the resultant mixture were measured by the method of dynamic light scattering.
Example 8 dis- Ploly-L-lysine (degree of polymerization:20) was dissolved into 4 ml of the phosphate buffer solution, and
PEG-
P(Asp)(molecular weight of PEG:50 0 0 80 asparatic acid residues per a chain of the block copolymer 4.5mg) was dissolved into 4.5 ml of the phosphate buffer solution.
Therefore, these aqueous solution were mixed. A weight average particle size of 43.6 nm and a number average particle size of 41.8 nm of the resultant mixture are measured by the method of dynamic light scattering.
ExamPle 9 polyethylene glycol-poly-L-lysine block copolymer(PEG- PLys:.(molecular weight of PEG:50 0 20 lysine residues per a chain of the block copolymer, 5mg) was dissolved into Iml of the phosphate buffer solution, and polyethylene glycol- ,polyasparatic acid block copolymer(PEG-P(Asp): molecular weight of PEG: 5000, 20 asparatic acid residues per a chain of the block copolymer, 5mg, was dissolved into 1 ml of the phosphate buffer solution.
Thereafter, these aqueous solutions were mixed.
A
weight average particle size of 30.8 nm and a number average particle size of 28.8 nm of the resultant mixture were measured by the method of dynamic light scattering' According to the present invention, as described above in detail, there are provided a carrier capable of stably carrying a drug under the effect of a macro molecular micell structure, and a drug carried by this carrier. It is possible to stably incorporate chargeable substances such as protein and DNA which tend to be easily decomposed in vivo.
Claims (7)
- 2. The carrier as claimed in Claim 1, wherein said non- chargeable segment is polyethylene glycol.
- 3. The carrier as claimed in Claim 1, wherein said charge- able segment is polyamino acid.
- 4. The carrier as claimed in Claim 1, wherein said block copolymer comprises one shown by the following formulae (I) and (II); and (OCH, CH, -R (COCHNH) (COCH, CHNH) (1) I (I CH, Ri, R, (OCH, CH, (NHCHCO) (NHCHCH, CO) -R4 (I) I I CHi RlR R (where, R is a hydrogen atom, a hydrocarbon group or a function- al group or a functional group sustituted hydrocarbon group; R 2 is NH, CO or R 6 (CH 2 )qR7, where R 6 indicated OCO, 'OCONH, NHCO, NHCOO, NHCONH, CONH or COO, R 7 indcates N or C, and q indicates an integer of 1 or more: R 3 is a carboxyl group, a carboxyl groupsubstituted hydrocarbon group, an amino group substituted hydrogen group, a hydrazino group substituted hydrocarbon group, (CH)p-NHCNHNHZ group, where p indicates an integer of 1 or more, a nitrogen-containing heterocyclic group or a nitrogen-containing heterocyclic group substituted hydrocarbon group; R 4 is a hydrogen atom, a hydroxyl group or a hydrocarbon group hvaing any of CO, NH and O at the bonding terminal thereof; m is a number within a range of from 4 to 2,500; n is a number within a range of rom 1 to 300; and x is a number within a range of from 0 to 300, provided that x n). The carrier as claimed in Claim 4, wherein R 3 is a group expressed by -COOH, -CH 2 COOH, -(CH 2 3 NH 2 -(CH 2 2 NHCNHNH2, or a heterocyclic group shown by the fol- lowing formula; N <0
- 6. An electrostatic bonding type macromolecular micell carrier drug wherein a chargeable drug is carried by a carrier of any of Claims 1 to 5 having an opposite charge.
- 7. A method of carrying a chargeable drug on an electrostatic bonding type macromolecular micell carrier, which comprises the steps of mixing a chargeable drug with any of carriers of Claims 1 to 5 having an opposite charge, and causing said chargeable drug to be carried by electrostatic bonding within a macromolecu- lar micell.
- 8. A drug carrier substantially as herein described with reference to any one of the Examples.
- 9. A method of carrying a chargeable drug on an electrostatic bonding type macromolecular micell carrier, substantially as herein described with reference to any one of the Examples. Dated this 2 0 t h day of April 2005 RESEARCH DEVELOPMENT CORPORATION OF JAPAN By their Patent Attorneys GRIFFITH HACK
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2005201665A AU2005201665B2 (en) | 1995-01-10 | 2005-04-20 | Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7-2210 | 1995-01-10 | ||
AU10134/00A AU1013400A (en) | 1995-01-10 | 2000-01-07 | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon |
AU45742/02A AU4574202A (en) | 1995-01-10 | 2002-05-31 | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon |
AU2005201665A AU2005201665B2 (en) | 1995-01-10 | 2005-04-20 | Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU45742/02A Division AU4574202A (en) | 1995-01-10 | 2002-05-31 | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2005201665A1 true AU2005201665A1 (en) | 2005-05-12 |
AU2005201665B2 AU2005201665B2 (en) | 2009-02-05 |
Family
ID=25614091
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU45742/02A Abandoned AU4574202A (en) | 1995-01-10 | 2002-05-31 | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon |
AU2005201665A Expired AU2005201665B2 (en) | 1995-01-10 | 2005-04-20 | Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU45742/02A Abandoned AU4574202A (en) | 1995-01-10 | 2002-05-31 | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon |
Country Status (1)
Country | Link |
---|---|
AU (2) | AU4574202A (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2517760B2 (en) * | 1989-05-11 | 1996-07-24 | 新技術事業団 | Water-soluble polymerized pharmaceutical preparation |
CA2087125A1 (en) * | 1992-01-23 | 1993-07-24 | Mridula Nair | Chemically fixed micelles |
KR940003548U (en) * | 1992-08-14 | 1994-02-21 | 김형술 | Laundry dryer |
-
2002
- 2002-05-31 AU AU45742/02A patent/AU4574202A/en not_active Abandoned
-
2005
- 2005-04-20 AU AU2005201665A patent/AU2005201665B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
AU2005201665B2 (en) | 2009-02-05 |
AU4574202A (en) | 2002-07-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0721776B1 (en) | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon | |
Putnam et al. | Polyhistidine–PEG: DNA nanocomposites for gene delivery | |
JP4535229B2 (en) | Polyethylene glycol-polycation block copolymer | |
AU668967B2 (en) | Physical trapping type polymeric micelle drug preparation | |
AU739969B2 (en) | Cationic polymer/lipid nucleic acid delivery vehicles | |
US20180015036A1 (en) | Substance-encapsulating vesicle and process for producing the same | |
WO2001037879A1 (en) | Polyion complex micelles of core/shell structure | |
WO2004087931A1 (en) | Conjugate for gene transfer comprising oligonucleotide and hydrophilic polymer, polyelectrolyte complex micelles formed from the conjugate, and methods for preparation thereof | |
EP2042184A1 (en) | Physiologically active polypeptide, polymer micelle having protein enclosed therein, and process for production of the polymer micelle | |
US20120064346A1 (en) | Fine particles of crystalline polyol, and method of preparing same | |
US9795563B2 (en) | Particulate pharmaceutical composition | |
AU2005201665B2 (en) | Electrostatic Bonding Type Macromolecular Micelle Drug Carrier and Drug Carried Thereon | |
AU1013400A (en) | Electrostatic bonding type macromolecular micelle drug carrier and drug carried thereon | |
Dung et al. | Preparation and biophysical characterization of pluronic F127-dendrimer conjugate as a delivery agent of antisense oligonucleotides | |
Manna et al. | Alginic acid-based pH and thermo responsive reversible switched polymeric micelle via RAFT polymerization | |
Panambur et al. | POLY (N-ISOPROPYLACRYLAMIDE)-BASED STIMULI-RESPONSIVE MATERIALS | |
AU2015264793A1 (en) | Particulate medicinal composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PC1 | Assignment before grant (sect. 113) |
Owner name: TOUDAI TLO, LTD. Free format text: FORMER APPLICANT(S): RESEARCH DEVELOPMENT CORPORATION OF JAPAN |
|
FGA | Letters patent sealed or granted (standard patent) | ||
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired | ||
NBA | Allowances - extensions of time- section 223(1) |
Free format text: THE TIME IN WHICH TO PAY A RENEWAL FEE HAS BEEN EXTENDED TO 10 SEP 2010 |
|
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |