CN102007168A - Oligo-ethylene glycol-based polymer compositions and methods of use - Google Patents
Oligo-ethylene glycol-based polymer compositions and methods of use Download PDFInfo
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- CN102007168A CN102007168A CN2008801262822A CN200880126282A CN102007168A CN 102007168 A CN102007168 A CN 102007168A CN 2008801262822 A CN2008801262822 A CN 2008801262822A CN 200880126282 A CN200880126282 A CN 200880126282A CN 102007168 A CN102007168 A CN 102007168A
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/40—Polyamides containing oxygen in the form of ether groups
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/44—Polyester-amides
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G71/00—Macromolecular compounds obtained by reactions forming a ureide or urethane link, otherwise, than from isocyanate radicals in the main chain of the macromolecule
- C08G71/04—Polyurethanes
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- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
- C08L77/06—Polyamides derived from polyamines and polycarboxylic acids
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
- C08L77/12—Polyester-amides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2230/00—Compositions for preparing biodegradable polymers
Abstract
The invention provides biodegradable PEAs, PEURs and PEUs that are synthesized by solution polycondensation to include a-amino acids and oligo-ethylene ether segments in the polymer backbone. The polymers can be obtained by substituting oligo- ethylene glycol (OEG) for aliphatic di-acid and diols during their fabrication. Also provided are compositions in which bioactive agents are dispersed in the polymers. The compositions biodegrade by enzymatic action to release incorporated bioactive agents and oligo-ethylene glycol segments, which are fully biodegradable at a molecular weight less than 400 Da,. Due to their comparatively rapid surface enzymatic hydrolysis, the compositions can be used to deliver bioactive agents in a controlled manner within a relatively rapid delivery time, such as about 18 to 24 hours.
Description
Invention field
Relate generally to drug delivery system of the present invention, and in particular to the polymer composition that can send various dissimilar molecules with controlled time delivery mode.
Background technology
People have used different methods to attempt the such composition of research and development: the delivery curves of its control medicine, or continue to send or fast but discharge stably, as sending to treatment cancer and lenitive medicine.For example, such composition such as microballoon/nanometer ball, liposome, albumin conjugates (albumin conjugates), water-soluble prodrug, cyclodextrin complexes and hydrogel are attempted being used for this purpose, but follow limited success, reason is that the trend of these compositions is: discharge a large amount of initial burst medicines, and can not continue at controlled time durations to send subsequently.
In a technology that has been studied, biologically active agent---comprises peptide---and combines to increase the transformation period of this biologically active agent with polyoxyethylene glycol (PEG).The delivery curves of this binding substances shows that usually the molecular weight of transformation period of circulation Chinese traditional medicine and employed PEG molecule is proportional.Show that the biodynamics of PEG and bio distribution also depend on employed PEG bulk of molecule.
Though these progress in the capable territory, but be used to give the new of various biologically active agents and better there are demand in composition and method to the molecule that uses polyoxyethylene glycol and similar chemical structure, for example, to reach the steady release rate profile that in controlled time durations, continues to send.
Summary of the invention
The present invention is based on such prerequisite: the molecule that comprises low polyoxyethylene glycol (OEG-yl) can be introduced in the polymer backbone of polyesteramide (PEA), polyester urethane (PEUR) and polyester-urea (PEU) polymkeric substance, and described polymkeric substance comprises at least one a-amino acid in the polymer backbone of every repeating unit.The polymkeric substance that comprises low polyoxyethylene glycol like this is known as polyether ester amides (PEEA), polyether ester carbamate (PEEUR) and polyether ester urea (PEEU) at this paper, and can be used to prepare biodegradable polymer composition, be used for one or more kind dispersive biologically active agents of consistent and reliable mode snap-out release.For example, said composition be used in about 24 hours during in discharge the biologically active agent that wherein comprises with mild release rate profile.
Therefore, in one embodiment, the invention provides the OEG-based composition and use thereof in packaging, wherein biologically active agent is dispersed in the biodegradable polymkeric substance.Described polymkeric substance comprises following a) to f) at least one:
A) have the polyether ester amides (PEEA) of the chemical formula that structural formula (I) describes,
Formula (I)
Wherein the scope of n is from about 15 to about 150;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R in independent n monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment (bicyclic-fragment), 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane;
Formula (II)
Formula (III)
B) have the PEEA polymkeric substance of the chemical formula that structural formula (IV) describes,
Formula (IV)
Wherein the scope of n is from about 15 to about 150, and the scope of m is that the scope of p is from about 0.9 to 0.1 from about 0.1 to 0.9;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or blocking group;
R in independent m monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment (bicyclic-fragment), 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
C) have the poly(ether-urethene) (PEEUR) of the chemical formula that the structure formula V describes,
Formula V
Wherein the scope of n is from about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6In at least one be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
D) have the PEEUR of the chemical structure that general structure (VI) describes,
Formula (VI)
Wherein the scope of n is from about 15 to about 150, and the scope of m is from about 0.1 to about 0.9, and the scope of p is from about 0.9 to about 0.1;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
1-C
6) alkyl (C
6-C
10) aryl and blocking group;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6One of at least be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
E) have the polyethers urea (PEEU) of the chemical formula that general structure (VII) describes,
Formula (VII)
Wherein n is about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
F) formula VIII is the PEEU with chemical formula of structural formula (VIII) description,
Formula (VIII)
Wherein m is about 0.1 to about 1.0, and p is about 0.9 to about 0.1, and n is about 15 to about 150;
R
2Be hydrogen, (C independently
1-C
12) alkyl or (C
6-C
10) aryl;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; Except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl.
In another embodiment, the invention provides biodegradable OEG based polyalcohol with chemical structure of describing with following formula I, IV, V, VI, VII or VIII.
In another embodiment, the invention provides biodegradable one-tenth micellar copolymerization compositions, be used to send the biologically active agent that is dispersed in wherein.Described composition comprises having a) and b) bonded repeats the polymkeric substance of alternate cells, described a) is to comprise at least one hydrophobic part with biodegradable OEG based polyalcohol of the chemical structure that above structural formula I, IV, V, VI, VII or VIII describe of the present invention, described b) be water-soluble portion.Described water-soluble portion is by i) and repetition alternate cells ii) form described i) be to have 400 dalton to the polyoxyethylene glycol of about 200 daltonian Mw, described ii) is at least a ionizable or polare Aminosaeren.Described repetition alternate cells has similar basically molecular weight, and the molecular weight of described polymkeric substance is in the scope of about 15kDa to 300kDa.
In another embodiment still, the invention provides the method that biologically active agent is delivered to described object by giving object in the OEG based polymer compositions body of the present invention, described OEG based polymer compositions of the present invention comprises at least a biologically active agent that is dispersed at least a OEG based, biodegradable polymkeric substance of the present invention or its mixture, and described OEG based, biodegradable polymkeric substance has the chemical structure that above structural formula I, IV, V, VI, VII or VIII describe.Described composition can be configured to polymer beads and the liquid dispersion that is distributed at least a biologically active agent wherein.Described particle is by its surperficial enzyme effect biological degradation, to discharge described biologically active agent with 0 grade release dynamics basically in during about 24 hours.
The accompanying drawing summary
Fig. 1 is presented at 37 ℃ and pH 7.4 times, and enzyme (alpha-chymotrypsin) concentration is to the graphic representation of the weight saving kinetic effect of OEG base PEA-AP3EG of the present invention.The PBS damping fluid in contrast.(■-)=PBS damping fluid; (-●-)=alpha-chymotrypsin of 0.05mg/mL; (-▲-)=alpha-chymotrypsin of 0.10mg/mL;
Alpha-chymotrypsin.
Fig. 2 show to introduce diacid structural (monomer 1) among the PEEA of the present invention to the graphic representation of its influence of the weight saving during at 37 ℃ in PBS or alpha-chymotrypsin medium (0.1mg/mL).Solid line=enzyme solution.Dotted line=PBS medium.-■-=monomer 1a (with hexanodioic acid two p-nitrophenyl esters of 4 methylene radical);-o-=monomer 1b (with sebacic acid two p-nitrophenyl esters of 8 methylene radical).
What Fig. 3 A-C showed is, with regard to three kinds of PEEUR of the present invention with mg/cm
2The weight saving of meter and the weight saving that does not comprise OEG segmental PEA 8-L-Leu-6 Comparatively speaking, the graphic representation of the catalytic biological degradation of external lipase and the comparison of pure phosphoric acid buffer medium.Fig. 3 A=EG2-Leu-2; Fig. 3 B=EG3-Leu-2; Fig. 3 C=EG4-Leu-2.Curve is the catalytic phosphoric acid buffer medium of lipase a), and pH 7.4, t=37 ℃; Curve b) pure phosphoric acid buffer medium; Curve c) degraded of PEA 8-L-Leu-6 in the catalytic phosphoric acid buffer medium of lipase.
Detailed Description Of The Invention
The present invention is based on such discovery: PEA, PEUR and the PEU polymkeric substance---described polymkeric substance contains the backbone segments that has one or more ester bond between amino acid---that comprise a-amino acid are complete biodegradables, as long as described OEG base backbone segments forms molecular weight (Mw) from the OEG of about 44 (monoethylene glycols) in the 400Da scope of (but not comprising 400Da) when biological degradation.At least one ester bond in the described polymer backbone is easy to be introduced in the diol component (next in the situation of PEEA is diacid) that uses in the polycondensation of polymeric families of the present invention.Because the structural performance of PEEA of the present invention, PEEUR and PEEU polymkeric substance, the composition that uses these polymkeric substance to make can be adjusted the rate of release with the biologically active agent that reaches the distribution that is suitable for satisfying various therapeutic goals.For example, use particle that these polymkeric substance make and film can be designed as to be similar to 24 hours infusions and do not have a large amount of initial burst of drug release and have basically biological degradation under 0 grade the situation of release profiles in rate of release.
More specifically, in one embodiment, the invention provides biodegradable polymer composition, it comprises at least a biologically active agent at least a in the biodegradable polymers family that is distributed in, and this biodegradable polymers is known as polyether ester amides (PEEA), polyether ester carbamate (PEEUR) and polyether ester urea (PEEU) in this article.The polymkeric substance that uses in the present composition comprises at least one OEG base backbone segments, so that OEG base backbone segments is released with 400Da or littler molecular weight (Mw) when biological degradation.Therefore, when biological degradation, polymkeric substance---comprises its OEG base segment---and is totally biodegradable, and does not form stimulator (R.Mehvar, J.Pharm Pharmaceut Sci (2000) 3 (1): 125-136; And T.Yamaoka, J.Pharm Sci (1994) Apr, 83 (4): 601-6).In addition, because 400Da or littler OEG segment are avoided circulation by (endoreticular) system of Intranet in the Mammals and the obstruct of kidney system, so polymer degradation products is eliminated from circulation with any biologically active agent that may be dispersed in the polymkeric substance when enzymatic living beings is degraded.
Therefore, in one embodiment, by during making these polymkeric substance, using at least a 400Da or the OEG base segmental glycol (perhaps under the situation at PEEA, being diacid) of small molecular weight more of comprising, prepare PEEA of the present invention, PEEUR and PEEU polymkeric substance.If only use these two pure and mild diacid in the mill, PEEA, the PEEUR and the PEEU polymkeric substance that generate are the analogues of the known PEG of containing polymkeric substance, but main degradation production is an a-amino acid during biological degradation, and as the biology a-amino acid, and 44Da is until the OEG segment less than 400Da.Therefore, be easy to by the mammalian object biological degradation based on above polymkeric substance of the present invention and composition, and the stimulation that does not produce by the OEG segmental polymer unwinds that comprises larger molecular weight, situation such as the polymkeric substance that forms the PEG degradation production (that is, having 400Da or those polymkeric substance of macromolecule more).
More specifically, in one embodiment, the invention provides composition, it comprises at least a biologically active agent that is dispersed in the biodegradable OEG-based polyalcohol, and described OEG-based polyalcohol comprises following a) to f) at least a or mixture:
A) have the polyether ester amides (PEEA) of the chemical formula that structural formula (I) describes,
Formula (I)
Wherein the scope of n is from about 15 to about 150;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R in independent n monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment (bicyclic-fragment), 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane;
Formula (II)
Formula (III)
B) have the PEEA polymkeric substance of the chemical formula that structural formula (IV) describes,
Formula (IV)
Wherein the scope of n is from about 15 to about 150, and the scope of m is that the scope of p is from about 0.9 to 0.1 from about 0.1 to 0.9;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or blocking group;
R in independent m monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment (bicyclic-fragment), 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
C) have the poly(ether-urethene) (PEEUR) of the chemical formula that the structure formula V describes,
Formula V
Wherein the scope of n is from about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6One of at least be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
D) have the PEEUR of the chemical structure that general structure (VI) describes,
Formula (VI)
Wherein the scope of n is from about 15 to about 150, and the scope of m is from about 0.1 to about 0.9, and the scope of p is from about 0.9 to about 0.1;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
1-C
6) alkyl (C
6-C
10) aryl and blocking group;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6One of at least be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
E) have the polyethers urea (PEEU) of the chemical formula that general structure (VII) describes,
Formula (VII)
Wherein n is about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
F) have the PEEU of the chemical formula that structural formula (VIII) describes,
Formula (VIII)
Wherein m is about 0.1 to about 1.0, and p is about 0.9 to about 0.1, and n is about 15 to about 150;
R
2Be hydrogen, (C independently
1-C
12) alkyl or (C
6-C
10) aryl;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; Except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl.
For example, in one embodiment, at structural formula (I) or (IV) or in both polymkeric substance of describing, at every n single intravital R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, and R
4Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and any (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.In this embodiment, polymkeric substance forms 15 to 300 OEG with biological degradation, and these OEG have 44Da until 400Da but do not comprise the Mw of 400Da.
In another embodiment, at the structure formula V or (VI) or in both polymkeric substance of describing, at every n single intravital R
4Or R
6Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.Alternatively, the polymkeric substance in composition is by the structure formula V or (VI) or in both situations about describing, at every n single intravital R
4And R
6All be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
4) alkoxyl group (C
2-C
8) alkylidene group.In the latter's embodiment, polymkeric substance forms 15 to 300 OEG with biological degradation, and these OEG have 44Da until 400Da but do not comprise the Mw of 400Da.
In another embodiment still, wherein the polymkeric substance in the composition structural formula (VII) (VIII) or both describe, at every n single intravital R
4Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
4) alkoxyl group (C
2-C
8) alkylidene group.In this embodiment, polymkeric substance forms 15 to 300 OEG with biological degradation, and these OEG have 44Da until 400Da but do not comprise the Mw of 400Da.
As used herein, " thiazolinyl " refers to have the straight or branched alkyl of one or more carbon-carbon double bond.
As used herein, " alkynyl " refers to have at least one carbon carbon triple-linked straight or branched alkyl.
As used herein, " aryl " refers to have 6 to 14 aryl in the carbon atom scope.
The PEEA that uses in composition of the present invention, PEEUR and PEEU polymkeric substance are polycondensates.Ratio " m " and " p " in the formula (IV, VI and VIII) are defined as irrational number in the description of these condensation polymers.And, because " m " and " p " each occupy scope in any polycondensate, therefore can not be with two such scopes of integers qualification.Each polymer chain all is the monomer residue string that links together according to following rule: all diamino acyl group glycol-diester (i) (ii) are connected with itself with omnidirectional (adirectional) amino acid (for example Methionin) monomer residue; be (iii) to be connected to each other perhaps by the diacid monomer residue to PEEA; to PEEUR is (iii) to be connected to each other by diol residue, is (iii) to be connected to each other by carbonyl to PEEU perhaps.Therefore, only form the linear combination of i-iii-i, i-iii-ii (or ii-iii-i) and ii-iii-ii.And then, every kind of these combinations or be connected with itself, perhaps by the diacid monomer residue (iii) (concerning PEEA) or diol residue (iii) (concerning PEEUR) or carbonyl (iii) (concerning PEEU) be connected to each other.Therefore each polymer chain is the statistical but nonrandom monomer residue string of being made up of integer number number of monomers i, ii and iii.But (that is) polymer chain, enough mean lengths, monomer residue " m " will not be an integer (rational integer) with the ratio of " p " in formula (IV, VI and VIII) to any actual average molecular weight usually.In addition, for the polycondensate of all polydisperse copolymer chains, average monomer i, ii and the number (promptly being normalized to mean chain length) of iii will not be integers on all chains.Thereby conclude that this ratio can only be irrational value (that is, not being any real number of rational number).Term as used herein, irrational number stems from the ratio with n/j form, and wherein n and j are integers.
As used herein, term " amino acid " and " a-amino acid " mean and comprise amino, carboxyl and side chain R group R as defined herein
3The compound of group.As used herein, term " biology a-amino acid " means the amino acid (one or more) that uses and is selected from phenylalanine, leucine, glycine, L-Ala, Xie Ansuan, Isoleucine, methionine(Met) or its mixture in synthetic.As used herein, term " omnidirectional (adirectional) amino acid " means the polymkeric substance intrachain chemical part that obtains from a-amino acid, (the R among formula VI and the VIII for example so that the R group
8) be inserted in the polymer backbone.
As used herein, term " biologically active agent " means the biologically active agent in the polymkeric substance that is dispersed in the present composition as disclosed herein.As used herein, term " dispersion " is used to refer to biologically active agent, mean biologically active agent sneaked in the polymkeric substance, dissolve in the polymkeric substance, homogenize with polymkeric substance and/or with the polymkeric substance covalent bonding, for example, be attached to the functional group in the polymkeric substance of composition or the surface of polymer beads.These biologically active agents can include, without being limited to small-molecule drug, peptide, protein, DNA, cDNA, RNA, sugar, lipid and full cell.Biologically active agent administration in the polymer beads with all size and structure can be suitable for satisfying different therapeutic goals and administration path.
As used herein to describe the term " biodegradable " of OEG based polymer compositions of the present invention " mean use therein polymkeric substance and can in the body of normal function, resolve into harmless product.The amino acid that uses in making polymkeric substance of the present invention is that biology L-a-amino acid and the two pure and mild diacid that use in the preparation polymkeric substance form 44Da during in biological degradation until 400Da but when not comprising the OEG segment of 400Da, this is definite especially.Polymkeric substance in the OEG based polymer compositions of the present invention comprises hydrolyzable ester and the enzyme cleavable amido linkage that biodegradable ability is provided, and mainly is to utilize amino to carry out chain termination usually.Randomly, the N-terminal of described polymkeric substance can be acetylation or by combining end-blocking with any other acidiferous biocompatiblity molecules, so that unrestrictedly comprise organic acid, biological non-activity biotechnological formulation and biologically active agent described herein.In one embodiment, whole polymer composition and by any particle that it is made is biodegradable basically.
In an option, at least one a-amino acid that uses in the preparation of OEG based polyalcohol of the present invention is the biology a-amino acid.For example, work as R
3Be CH
2During Ph, the synthetic middle biology a-amino acid that uses is the L-phenylalanine.R therein
3Be CH
2CH (CH
3)
2Option in, described polymkeric substance comprises biology a-amino acid-L-leucine.By changing the intravital R of list described herein
3, also can use other biology a-amino acid, for example, glycine (is worked as R
3When being H), L-Ala (works as R
3Be CH
3The time), Xie Ansuan (works as R
3Be CH (CH
3)
2The time), Isoleucine (works as R
3Be CH (CH
3) CH
2CH
3The time), phenylalanine (works as R
3Be CH
2C
6H
5The time) or methionine(Met) (work as R
3Be (CH
2)
2SCH
3The time) and combination.In another optional embodiment, all various a-amino acids that comprise in the polymkeric substance that uses in preparation OEG based polymer compositions of the present invention all are the biology a-amino acids, as described herein.
Can prepare described polymer composition so that various performances to be provided.In one embodiment, the particulate size of PEEA of the present invention, PEEUR and PEEU polymkeric substance is fit to assemble in vivo formation time control release type polymer depot when injecting in the body, be used for the tissue/cell around wherein the dispersive biologically active agent is delivered locally to.
Therefore, in another embodiment, the invention provides the method that part is sent one or more kind biologically active agents in subject.In this embodiment, the inventive method comprises and is formulated as OEG based polymer compositions polymer beads, that at least a biologically active agent is dispersed in wherein and is injected into position in the intravital body of described object machine of the present invention.Injected particle aggregation forms the particulate polymer depot that size increases, and described gathering will slowly discharge each particle, and this particle can be by the enzymatic action biological degradation, and is as described herein, discharges described dispersive biologically active agent (one or more).After biological degradation, each polymer molecule will be that 44 15 to 300 low polyoxyethylene glycol (OEG) molecules until 400Da (but not comprising 400Da) discharge into the circulation from molecular weight also.As described herein, by any particular polymers biological degradation discharge have 400Da or more the quantity of low polyoxyethylene glycol (OEG) molecule of small molecular weight will depend on the selection of the two pure and mild diacid that use in the preparation to described polymkeric substance.
Described OEG base PEEA, PEEUR or PEEU particulate dispersion can, intramuscularlys for example subcutaneous through parenteral, perhaps are expelled to inner body area for example in the organ.For example, having can be by size range at about 19 polymer beads to the size of about No. 27 cartridge syringe needle tubing, for example the mean diameter scope is at about 1 μ m those between about 200 μ m, can be injected into inner body area, and will assemble the particle that forms the size increase, described particle forms the bank of local allocation dispersive biologically active agent (one or more).In other embodiments, the biodegradable polymers particle enters the carrier of the recycle system as biologically active agent, discharges with general target and time control.Magnitude range can directly enter circulation at about 10nm to the polymer beads of the present invention of about 500nm and be used for this type of purpose.
The biodegradable polymers that is used in the OEG based polymer compositions of the present invention can be designed, and to adjust the biodegradation rate of described polymkeric substance, causes the controlled delivery of biologically active agent in for some time.For example, usually, the thin slice of the present composition will the biological degradation by surface corrosion in enzyme solution (for example, such as what find in vivo), so that experiences the weight saving of about weight saving to 56% of 81% in 24 hours.
The present invention has utilized the delivery technique of biodegradable polymers particle mediation, with in the treatment of numerous diseases and disease symptoms can sending a variety of biologically active agents by the speed that selective polymer and granular size are adjusted.Although some separate constituents in polymer composition described herein and the method are known, but make us unexpected and surprisingly, such combination will guarantee that the practitioner selects biodegradable polymkeric substance, biologically active agent and particle size, surpass the controlled levels reached up to now with the timed interval of controlling during described biologically active agent is released.
The polymkeric substance of describing with structural formula (I and IV-VIII) that is suitable for use in the present invention's practice has permission biologically active agent (one or more) or covers molecule (one or more) and the easy covalently bound functionality of described polymkeric substance.For example, the polymkeric substance that has carboxyl can be easily and amino partial reaction, thereby make peptide be covalently bound to described polymkeric substance by resulting amide group.To describe as this paper, biodegradable polymers and biologically active agent can contain many can be used for biologically active agent is covalently bound to complementary functional groups on the described biodegradable polymers.For example, polycondensation synthetic PEEUR by active two carbonate (the compound 4a-c among the embodiment 2) and basic two tosilate of low polyoxyethylene glycol (OEG) (the compound 2a-e among the following and embodiment 2) can be used for various chemistry and biological chemistry and use as the biodegradable analogue of PEG:
Can come synthon 2a-e by direct condensation a-amino acid and OEG, as the monomer of describing in following examples.Alternatively, the chemistry of peptides method of utilizing those of ordinary skills to know, various hydrophobicity a-amino acids can be used to synthon 2a-e.The method of back will allow to adjust the hydrophilic/hydrophobic balance of the biodegradable OEG based polyalcohol of the present invention.Therefore, the performance of polymkeric substance of the present invention and composition and biological applications can change in wide in range scope.
For example, all heterodesmics (heterolinkages)---ehter bond and urethane bonds---in the PEEUR skeleton are hydrophilic, thereby have strengthened the water-soluble of these polymkeric substance.Side chain R in the a-amino acid that links together by correct selection and OEG segment
3Substituting group utilizes principle well known in the art and as herein described can adjust the hydrophilic/hydrophobic balance that the present invention contains the OEG polymkeric substance.
With other polymer analog that obtains through the active polycondensation of solution, PEEA of the present invention, PEEUR and PEEU comprise two end groups, utilize the described end group of method known in the art and as herein described can be used to functionalized these polymkeric substance, be used for its chemical/biological chemistry subsequently and use.In addition, by with the interaction of monoethanolamine, the terminal active carbonic acid ester group of described polymkeric substance can be changed into oxygen-ethyl carbamic acid ethyl ester group, to strengthen the wetting ability of polymkeric substance.
Still alternatively, terminal OH base can be used to conversion subsequently, for example connects acrylate.In a similar fashion, can be by interacting to synthesize the end capped PEEUR of SH-with mercapto-amine.The end capped PEEUR of SH-can be connected to the polymkeric substance that contains the activity double key part under mild conditions, for example the unsaturated PEA of Yanhusuo acidic group perhaps can be used to conversion subsequently, and is as described below.
PEEUR of the present invention also can be used for carrying out chemistry/photochemistry grafting with other unsaturated polymer, for example carries out chemistry/photochemistry grafting with unsaturated PEA of Yanhusuo acidic group etc., to give its wetting ability or water-soluble.
With the end capped PEEA of undersaturated maleimide ring, PEEUR and PEEU for be connected the polymkeric substance that uses in the present composition with contain the HS molecule for example protein, enzyme, peptide etc. be interesting, and can be synthetic in several modes.For example, can be by terminal amino group and excessive N, N '-alkylidene group-two-maleimide or with active diester for example the interaction of N-maleoyl imido-Beta-alanine synthesize maleimide end-sealed polymkeric substance.
By terminal amino group and excessive N, the interaction of N '-alkylidene group-two-maleimide, the end capped polymkeric substance of SH-(forming as previously discussed) also can be used to synthetic maleimide end-sealed PEEA, PEEUR and PEEU.
Final active carbonic acid ester group can be converted to the maleimide terminal according to following scheme:
By keep biologically active agent to be enough to make individual endogenous process and interactional time of biologically active agent for one section in the injection site; discharge particle or the polymer molecule that contains this type of preparation simultaneously during the biological degradation of polymkeric substance, the polymkeric substance in OEG based polymer compositions of the present invention plays a part positive in the therapeutic process at local injection position.By biological degradation polyalcohol more lentamente, with transformation period and the persistence that increases described biologically active agent (one or more), fragile biologically active agent is protected.
In addition, polymkeric substance disclosed herein (for example, have structural formula (I and IV-VIII) those), behind enzymatic degradation, a-amino acid is provided, other degradation production is OEG simultaneously, perhaps if not, be glycol or diacid, it can carry out metabolism with the approach of lipid acid and sugar metabolism.Picked-up to described polymkeric substance is safe: studies show that object can metabolism and removing polymer degradation products.Therefore, these polymkeric substance and OEG based polymer compositions of the present invention all are non-inflammatory basically in injection site and whole body for object, except injecting any wound that itself causes.
Being used for putting into practice PEEA of the present invention, PEEUR and PEEU polymkeric substance, can utilize a plurality of different a-amino acids in the single polymer molecule.The every repeating unit of described polymkeric substance can comprise at least two kinds of different aminoacids, and single polymer molecule can contain a plurality of different a-amino acids in described polymer molecule, and this depends on described bulk of molecule.
Polymkeric substance as herein described can also be used in the segmented copolymer.In another embodiment, described polymkeric substance is used as a block of diblock or triblock copolymer, and described segmented copolymer for example can be used to prepare micella, and is as described below.
OEG based polymer compositions of the present invention and method are the members in polyesteramide (PEAs), polyester type urethanum (PEURs) and the polyester-urea (PEUs) than big nation, many functional groups that on side chain, have embedding in them, and the functional group of these embeddings can react with other chemical, and cause the adding of extra functional group, with the functionality of the described polymkeric substance of further expansion.Similarly, be easy to have the chemical reaction of hydrophilic-structure with other with in the methods of the invention OEG base (that is, PEEA, PEEUR or PEEU) polymkeric substance, water-soluble to increase, and with biologically active agent with cover molecular reaction, and do not have necessity of modification in advance.
In addition, the OEG based polyalcohol that in OEG based polymer compositions of the present invention, uses, when in salt solution (PBS) medium, detecting, show minimum hydrolytic deterioration, but at enzyme solution for example among lipase, Quimotrase or the CT, observe the surface erosion behavior of homogeneous, it forms zero level release characteristic basically, and is as described herein.
The suitable protecting group that is used in PEEA, PEEUR and the PEEU polymkeric substance comprises the tertiary butyl or other protecting group known in the art.1 of suitable general formula (III), 4:3, the two anhydrous hexitols of 6-comprise those that derive from sugar alcohol, for example D-sorbitol, D-N.F,USP MANNITOL or L-iditol.Two anhydrous Sorbitol Powders are at present preferred 1,4:3, and the two anhydrous hexitol dicyclo parts of 6-are used among PEEA, the PEEUR and PEEU polymkeric substance that uses in the preparation of OEG based polymer compositions of the present invention.
As used herein the meaning of term " low polyoxyethylene glycol (OEG) " has chemical structure HO-(CH
2-CH
2-O)
1-9The oligopolymer of the oxyethane of-H or polymkeric substance.The term of the Shi Yonging part that " comprises low polyoxyethylene glycol (OEG-containing) " and " low polyethylene glycol groups (OEG-based) " partly refer to the polymer segment of release OEG molecule when the polymkeric substance enzymatic living beings is degraded in this article, its OEG can be monodispersed, perhaps more commonly, be polydisperse, wherein the polydispersity index scope about 1.05 until 2.0.Polydispersion OEG molecule described herein characterizes with its weight-average molecular weight (Mw) and its number-average molecular weight (Mn) statistically, and its ratio is known as polydispersity index (Mw/Mn).
The molecular weight of this paper and polymolecularity are by gel permeation chromatography (gel permeationchromatography (GPC)), use polystyrene standards to measure.More specifically, number-average molecular weight and weight-average molecular weight (Mn and Mw) have been measured, for example, use Model 510 gel permeation chromatographs (Water Associates, Inc., Milford, MA), it is equipped with high pressure liquid chromatography pump (high-pressure liquid chromatographic pump), Waters 486UV detector and Waters 2410 differential refractive index detectors.Use tetrahydrofuran (THF) (THF), N, dinethylformamide (DMF) or N,N-dimethylacetamide (DMAc) are as elutriant (1.0mL/min).Polystyrene or polymethylmethacrylate standard substance with narrow molecular weight distributions are used for proofreading and correct.
Preparation contains the polymkeric substance of a-amino acid in general formula method is known in this area.For example, for the embodiment of the polymkeric substance of structural formula (I), wherein R
4Be merged in the a-amino acid, synthetic for polymkeric substance, have side chain R
3A-amino acid can be converted to two-α, ω-diamines by esterification.For example contain side chain R
3A-amino acid can with at least a low polyethylene glycol groups glycol (OEG glycol) condensation.Therefore, have reactive α, the two-alpha-amino group acyl group diester monomer omega-amino-group, that contain OEG is formed.Then, two-α, ω-diamines adds and diacid such as hexanodioic acid, sebacic acid or fumaric acid, and the polycondensation of perhaps two active ester or two-acyl chlorides is to obtain to have the final polymkeric substance (PEEA) that comprises OEG part and ester bond, ehter bond and amido linkage.Alternatively, for example, for the polymkeric substance of structure (I), replace diacid, activatory two acid derivatives for example two-p-nitrophenyl diester can be used as the activatory diacid.In addition, two carbonic ethers that two-two carbonic ethers for example contain two (p-nitrophenyl) oligo-ethers can be used as the activatory material, and to obtain to contain the polymkeric substance of diol residue, described diol residue comprises 2 to 9 ethoxy support functionality (that is, containing the OEG part).Under the situation of PEEUR polymkeric substance, obtain to have the final polymkeric substance that contains OEG part and ester bond, ehter bond and urethane bonds.
The two acid type compounds that contain OEG that are used for active polycondensation according to the present invention are α of formula (III), and ω-alkylene dicarboxylic acids ester constitutes by short aliphatic nontoxic diacid with as the OEG of glycol.
These molecules comprise at least one ester group inherently, and it can be easily by biological (enzyme) and abiotic hydrolysis cutting.PEA, PEUR and PEU polymer phase ratio with previously known, PEEA of the present invention, PEEUR and PEEU polymer composition have the wetting ability of increase and have the ester group quantity of increase in every unit skeletal chain, and the PEA of previously known, PEUR compare by aliphatic diol and have the polymkeric substance that the diacid of alkylidene chain constitutes and have biodegradability faster with the ester group of PEU polymkeric substance in some cases.
As synthetic elaboration of fs,, can prepare the new diester diacid (or alkylidene group-dicarboxylic ester) of the various OEG of containing of structural formula (III) by the interaction of glycol and cyclic aliphatic five or hexa-atomic acid anhydride such as maleic anhydride, succinyl oxide and Pyroglutaric acid.Alkylidene group-dicarboxylic ester synthetic general approach is described among the following reaction scheme I:
R wherein
5=(CH
2)
2, (CH
2)
3Or CH=CH; R
7=(CH
2-CH
2-O-)
k, any integer of k=1-9.
Scheme (I)
Set forth as the synthetic subordinate phase, prepared various active two-(p-nitrophenyl) esters of alkylidene group-dicarboxylic ester of structural formula IX.In the presence of different condensing agents, interact with p-NP by the diacid (formula II) that in the fs, forms and to finish this reaction.
(formula IX)
R wherein
5For example can be from (CH
2)
2, (CH
2)
3, select among the CH=CH; R
7Can be from R
7=(CH
2-CH
2-O-)
kThe middle selection, wherein any integer of k=1-9.
Unsaturated PEEA can prepare by solution polycondensation, the solution polycondensation of two tosilate of two (a-amino acid) diester by (1) unsaturated diol and two p-nitrophenyl esters of saturated dicarboxylic acid, the perhaps solution polycondensation of two tosilate of two (a-amino acid) diester by (2) saturated diols and the dinitrobenzene phenyl ester of unsaturated dicarboxylic acid perhaps passes through the solution polycondensation of the dinitrobenzene phenyl ester of two tosilate of two (a-amino acid) diester of (3) unsaturated diol and unsaturated dicarboxylic acid.In the present invention, at least one that use in the preparation, preferably whole glycol and/or diacid contain 1 to 8 ether functionality.
The salt of known tosic acid is used for the synthetic polymkeric substance that contains amino-acid residue.Arylsulphonate is used for substituting free alkali, and reason is that the arylsulphonate of two (a-amino acid) diester is easy to carry out purifying by recrystallization, and to make amino group in entire operation be the inert ammonium tosylate.In polycondensation, nucleophilic amino appears easily by the adding of organic bases such as triethylamine, therefore obtains polymer product with high yield.
Polymkeric substance for structural formula (1), for example, two p-nitrophenyl esters of unsaturated dicarboxylic acid can be synthetic from p-nitrophenyl and unsaturated chlorination dicarboxylic acid (dicarboxylic acid chloride), for example by triethylamine and p-NP are dissolved in the acetone, follow the unsaturated chlorination dicarboxylic acid of agitation and dropping at-78 ℃, and pour in the water, with precipitated product.Suitable sour muriate (acidchlorides) comprises the muriate of fumaric acid, toxilic acid, methylfumaric acid, citraconic acid, propene dicarboxylic acid, methylene-succinic acid, vinyl-butane bisgallic acid and 2-propenyl-butane bisgallic acid.For structure (V) and polymkeric substance (VI), two p-nitrophenyls, two carbonic ethers saturated or unsaturated diol are used as reactive monomer.Two carbonate monomers of general structure (X) are used to structure formula V and polymkeric substance (VI), wherein, and each R
10Be the optional (C that replaces with one or more nitro, cyano group, halogen, trifluoromethyl or trifluoromethoxy independently
6-C
10) aryl; And R
6Can be described above.
Formula (X)
The diaryl sulfonate of the diester of a-amino acid and unsaturated diol can so prepare: the fusion a-amino acid is for example to aryl sulfonic acid monohydrate and saturated or unsaturated diol in toluene, be heated to reflux temperature, emit up to water and to reach minimum, cooling then.The unsaturated diol that does not comprise ether functionality for example comprises 2-butylene-1, and 3-two is pure and mild 1,18-Linolenic Acid-alkene-glycol.
Saturated two tosilate of saturated two p-nitrophenyl esters of dicarboxylic acid and two (a-amino acid) ester can be by United States Patent (USP) the 6th, 503, preparation described in 538B1 number.As synthesizing of the useful unsaturated polyester of biodegradable polymer (carboxylic acid amide esters) class (UPEA) is knownly (for example to see U.S. Patent number 5,516,881 in this area; 6,476,204; 6,503,538).The synthetic as above disclosed and description in the embodiment 1 of this paper of the unsaturated PEEA of structural formula (I).
In having structural formula (I) or unsaturated compound (IV), below effectively.Utilize phosphinylidyne diimidazole or suitable carbodiimide as condensing agent, can adhere to group, for example the amino TEMPO of 4-with amino amino oxygen (N-oxide compound) base that replaces.Biologically active agent as described herein can be attached by two key functionality.By giving wetting ability in conjunction with polyethyleneglycol diacrylate.
Biodegradable PEEA, PEEUR can comprise one to a plurality of different a-amino acids with the every polymer molecule of PEEU polymkeric substance, and preferably have scope 10,000 to 125, the weight-average molecular weight of 000g/mol; The intrinsic viscosity that these polymkeric substance and multipolymer generally have is determined under 25 ℃, by the normal viscosity method in 0.3 to 3.0 the scope, for example, and in 0.5 to 1.5 scope.
Be used for the unsaturated compound of PEEU having structural formula (VII), below effectively: utilize phosphinylidyne diimidazole or suitable carbodiimide as condensing agent, can adhere to group, for example the amino TEMPO of 4-with amino amino oxygen (N-oxide compound) base that replaces.Other biologically active agent as described herein and analogue can randomly be attached by two key functionality.
For example, the high Mw PEEU that the present invention has structural formula (VII) can utilize phosgene to carry out interfacial preparation as the parents' electronics monomer in the chloroform/water system, shown in reaction scheme (II) below:
Scheme (II)
Contain L-Methionin ester and have structural formula (VIII) the copolyesters urea (copoly (ester ureas), synthetic can being undertaken PEEU) by similar scheme (III):
Scheme (III)
20% phosgene (severe toxicity) toluene solution, (Buchs Switzerland), can use trichloromethylchloroformate (superpalite) or triphosgene (two (trichloromethyl) carbonic ether) to replace for Fluka Chemie, GMBH.The phosphinylidyne diimidazole that toxicity is littler also can be used as parents' electronics monomer, replaces phosgene, trichloromethylchloroformate or triphosgene.
For obtaining high Mw PEEU, it is necessary using the refrigerative monomer solution.For example, to two (the a-amino acid)-α in 150mL water, the suspension of two P-TOLUENE SULFO ACID 99's salt of ω-alkylidene group diester adds anhydrous sodium carbonate, and at room temperature stir about is 30 minutes, and is cooled to about 2-0 ℃, forms first solution.Abreast, second solution of phosgene in chloroform is cooled to about 15-10 ℃.First solution is placed in and carries out interfacial polycondensation in the reactor, and second solution is added rapidly at once and about 15 minutes of vigorous stirring.Then, chloroform layer can be separated, and through anhydrous Na 2SO4 drying, and filters.Resulting solution can be stored, in order to further using.
Prepared PEU polymkeric substance is to obtain with chloroformic solution, and these solution are stable between the shelf lives.Yet some polymkeric substance for example 1-Phe-4 are being insoluble in chloroform after the separation.For overcoming this problem,, can isolate the PEEU polymkeric substance from chloroformic solution by being cast to slick hydrophobic surface and making chloroform evaporated to dry.The PEEU that does not need further purification to obtain.The general method of preparation PEU is described among the U. S. application US2007/0128250-A1 that has announced.
Useful polymkeric substance in OEG based polymer compositions of the present invention is as PEEA, PEEUR and PEEU polymkeric substance, the biological degradation by the enzymatic action on surface.Therefore, polymkeric substance, its particle for example gives object with the speed of sustained release with biologically active agent, and its kinetics is observed and approaches zero level.In addition, because PEEA, PEEUR and PEEU polymkeric substance decompose in vivo through lytic enzyme, and do not produce disadvantageous by product, OEG based polymer compositions of the present invention is non-inflammatory basically.Even the OEG that introduces wherein has so low molecular weight, in case so that they discharge from polymkeric substance after the biological degradation, just can in body, be eliminated.
As used herein, " dispersive (dispersed) " is meant that at least a as disclosed herein biologically active agent is disperseed, mixing, dissolving, homogenizing and/or covalent attachment (" dispersion ") be in polymer beads, for example, be attached to described particulate surface.
Although can being dispersed in the polymeric matrix, biologically active agent need not chemical bond to polymer support, biologically active agent or cover molecule and can be covalently bound on the biodegradable polymers by a variety of suitable functional groups and also be considered.For example, when biodegradable polymers was polyester, the carboxyl end of the chain can be used to biologically active agent or cover complementary portion reaction on the molecule, for example hydroxyl, amino, sulfenyl and analogue.A variety of suitable reactants and reaction conditions are disclosed, for example in March ' s Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, the 5th edition, (2001); With ComprehensiveOrganic Transformations, the 2nd edition, among the Larock (1999).
In other embodiments, biologically active agent can be connected on PEEA as herein described, PEEUR or the PEEU polymkeric substance by amido linkage, ester bond, amino, ketonic bond, thioether bond, sulfinyl, alkylsulfonyl, disulfide linkage.Such key can utilize synthetic method as known in the art to form from suitable functionalized raw material.
For example, in one embodiment, polymkeric substance can be connected with biologically active agent by the end or the side chain carboxyl group (for example COOH) of polymkeric substance.For example, the compound of structure I V, VI and VIII can with the amido functional group of biologically active agent or hydroxy functional group reaction, so that the biodegradable polymers that has respectively the biologically active agent that connects by amido linkage or carboxylic acid ester bond to be provided.In another embodiment, the carboxyl of polymkeric substance can or be converted into carboxylic acid halides, acyl group acid anhydrides/" blended " acid anhydrides or active ester by benzylization.In other embodiments, the freedom of polymer molecule-NH2 end can be by acidylate, with guarantee biologically active agent will be only by polymkeric substance carboxyl in conjunction with and be not joined to the free end of polymkeric substance.
Water-soluble covering molecule (one or more)---polyoxyethylene glycol (PEG) for example; Phosphorylcholine (PC); Glycosaminoglycan comprises heparin; Polysaccharide comprises polysialic acids; Poly-(ionizable or polare Aminosaeren) comprises polyserine, polyglutamic acid, poly aspartic acid, polylysine and poly arginine; Chitosan and alginate, as described herein; And target molecule---for example antibody, antigen and part, after particle produces, also can be coupled on the polymkeric substance of described particle outside, the reactive site that is not occupied by biologically active agent with sealing or with the particle targeted delivery to specific body area, as known in the art.The Mw of the OEG molecule that forms after comprising the individual particle that covers molecule can be about 44 (monoethylene glycols) basically in about 400Da scope any molecular weight of (but not comprising 400Da) can be changed so that be attached to the Mw of a plurality of PEG molecules of described particulate.
Alternatively, biologically active agent or covering molecule can be connected to polymkeric substance by linkers.Really, for improving the surface hydrophobicity of biodegradable polymers, for improving the accessibility of biodegradable polymers to enzyme activation, and for improving the release conditions (release profile) of biodegradable polymers, can utilize joint, so that indirectly biologically active agent is connected to biodegradable polymers.In some embodiments, linker compounds comprises polyoxyethylene glycol, and its Mw that has is about 44 to 400Da, preferably from 200 to 400; Amino acid, for example Serine; Polypeptide with 1 to 100 repeat number; With any other suitable low-molecular weight polymer.Joint is generally separated about 5 dusts to about 200 dusts with biologically active agent and polymkeric substance.
Still in further embodiment, joint is the divalent radical of formula W-A-Q, and wherein A is (C
1-C
24) alkyl, (C
2-C
24) thiazolinyl, (C
2-C
24) alkynyl, (C
3-C
8) cycloalkyl or (C
6-C
10) aryl, and W and Q each independently be-N (R) C (=O)-,-C (=O) N (R)-,-OC (=O)-,-C (=O) O ,-O-,-S-,-S (O) ,-S (O)
2-,-S-S-,-N (R)-,-C (=O)-, wherein each R independently is H or (C
1-C
6) alkyl.
As being used to describe above-mentioned joint, term " alkyl (alkyl) " refers to the straight or branched alkyl, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-hexyl and analogue.
The above-mentioned joint of description as used herein, " thiazolinyl (alkenyl) " refers to the straight or branched alkyl with one or more carbon-to-carbon double bond.
The above-mentioned joint of description as used herein, " alkynyl (alkynyl) " refers to the straight or branched alkyl with at least one carbon-to-carbon triple bond.
The above-mentioned joint of description as used herein, " aryl (aryl) " refers to the aromatic group with 6 to 14 carbon atoms.
In some embodiments, joint can be have about 2 to about 25 amino acid whose polypeptide.The suitable peptide that consider to use comprises poly--L-glycine, poly-L-Lysine, poly--L-L-glutamic acid, poly--the L-aspartic acid, poly-L-histidine, poly--the L-ornithine, poly--the L-Serine, poly--the L-Threonine, poly--L-tyrosine, poly--the L-leucine, poly-L-Lysine-L-phenylalanine, poly--the L-arginine, poly-L-Lysine-L-tyrosine and analogue.
In one embodiment, biologically active agent covalent cross-linking polymkeric substance, promptly biologically active agent is attached to more than a polymer molecule.This covalent cross-linking can carry out under the situation that has or do not have extra polymkeric substance-biologically active agent joint.
The biological activity agent molecule can also be by covalently bound being added in the intramolecularly bridge between two polymer molecules.
Also only stay next reactive group to combine by the potential nucleophile on the protection polypeptide backbone, preparation simple linear polymer polypeptide conjugate with polymkeric substance or polymeric joint structure.Go guard method (for example Boc and Fmoc chemistry) according to peptide well known in the art, go protection.
In an embodiment of the invention, the polypeptide biologically active agent exists with contrapositive (retro-inverso) or the trans peptide of Partial Inverse.
In other embodiments, biologically active agent mixes with the photic crosslinkable form of polymkeric substance in matrix, and after crosslinked, and this material is disperseed (pulverizing) into about 0.1 mean diameter in about 10 mu m ranges.
Joint can at first be connected to polymkeric substance or be connected to biologically active agent or cover molecule.Between synthesis phase, joint can be in not to be protected form or utilizes numerous protecting groups that those of ordinary skills know and be in protected form.Under the situation of protection joint, the not protection end of joint can at first be connected to polymkeric substance or biologically active agent or cover molecule.Then, utilize Pd/H2 hydrogenolysis, gentle acid or basic hydrolysis or any other routine known in the art to go guard method, protecting group can be gone protection.Then, go to protect joint can be connected to biologically active agent or covering molecule, perhaps be connected to polymkeric substance.
Exemplary synthetic (molecule wherein to be connected is an amino oxygen) according to biodegradable polymers of the present invention is described below.
Polyester can with the 4-amino-2 for example of the group with amino amino oxygen (N-oxide compound) base that replaces, 2,6,6-tetramethyl piperidine-1-oxygen, at N, there is reaction down in N '-phosphinylidyne diimidazole, so that with the hydroxylic moiety in the carboxyl that contains on the basic group instead of polyesters chain end of the amino amino oxygen (N-oxide compound) that replaces, make and the carbon covalent attachment of amino part and the carbonyl residue of described carboxyl to form amido linkage.N, N '-phosphinylidyne diimidazole or suitable carbodiimide are converted into the intermediate product part with the hydroxylic moiety in the carboxyl on the polyester chain end, and itself and amino oxygen be 4-amino-2,2,6 for example, 6-tetramethyl piperidine-1-oxygen reaction.Generally, use the amino oxygen reactant with the reactant and the polyester mol ratio of 1: 1 to 100: 1 scope.N, the mol ratio of N '-phosphinylidyne diimidazole and amino oxygen is preferably about 1: 1.
Type reaction is as follows.Polyester is dissolved in the reaction solvent, and easily reacts under the dissolved temperature being used for.Reaction solvent can be that polyester will be dissolved in any solvent wherein.When polyester was polyglycolic acid (polyglycolic acid) or poly-(glycollide-L-rac-Lactide) (having the oxyacetic acid 50: 50 or more and the monomer mole ratio of L-lactic acid), highly refined (99.9+% purity) methyl-sulphoxide at room temperature was suitable for dissolved polyester at 115 ℃ to 130 ℃ times or DMSO.When polyester be poly--during L-lactic acid, when poly-DL-lactic acid or poly-(glycollide-L-rac-Lactide) (had 50: 50 or less than 50: 50 the oxyacetic acid and the monomer mole ratio of L-lactic acid), tetrahydrofuran (THF), methylene dichloride (DCM) and chloroform ℃ are suitable for dissolved polyester in room temperature to 40～50.
Polymkeric substance-biologically active agent key
In one embodiment, the polymkeric substance that is used to make OEG based polymer compositions of the present invention as described herein has the biologically active agent that one or more is directly connected to polymkeric substance.The residue of polymkeric substance can be connected with the residue of this one or more biologically active agent.For example, polymkeric substance residue can directly connect a residue of biologically active agent.Each can have an open valency (open valence) polymkeric substance and biologically active agent.Alternatively, more than one biologically active agent, a plurality of biologically active agent or the mixture that has different therapeutic activities or alleviate the biologically active agent of activity (palliative activity) can directly be connected with polymkeric substance.Yet because the residue of each biologically active agent can be connected with the corresponding residue of polymkeric substance, therefore the number of the residue of described one or more biologically active agent can be corresponding to the valent number of the opening on the polymer residue.
As used herein, " residue of polymkeric substance (residue of a polymer) " refers to the group with one or more open valent polymkeric substance.Any synthetic feasible atom, a plurality of atom or the functional group (for example on polymer backbone or side group) of polymkeric substance of the present invention can be removed, so that open valency to be provided, condition is that biological activity is retained substantially when group is connected to the residue of biologically active agent.In addition, any synthetic feasible functional group's (for example carboxyl) can form at (for example on polymer backbone or side group) on the polymkeric substance, and so that open valency to be provided, condition is that biological activity is retained substantially when group is connected to the residue of biologically active agent.Based on required key, those of ordinary skills can select suitably functionalized raw material, and this raw material can be obtained by polymkeric substance of the present invention with methods known in the art.
As used herein, " residue of the compound of structural formula (*) (residue of a compoundof structural formula (*)) " refers to has one or more the open valent polymkeric substance formula (I) as described herein and (IV-VIII) group of compound.Any synthetic feasible atom, a plurality of atom or the functional group (for example on polymer backbone or side group) of this compound can be removed, so that open valency to be provided, condition is that biological activity is retained substantially when group is connected to the residue of biologically active agent.In addition, any synthetic feasible functional group's (for example carboxyl) can be in formula (I) and (IV-VIII) (for example on polymer backbone or side group) formation on the compound, so that open valency to be provided, condition is that biological activity is retained substantially when group is connected to the residue of biologically active agent.Based on required key, those of ordinary skills can select suitably functionalized raw material, this raw material can with methods known in the art by formula (I) and (IV-VIII) compound obtain.
For example, the residue of biologically active agent can pass through amido linkage (for example-N (R) C (=O)-or-C (O) N (R)-), ester bond (for example-OC (=O)-or-C (=O) O-), ehter bond (for example-O-), amino key (for example-N (R)-), ketonic bond (for example-C (=O)-), thioether bond (for example-S-), sulfinyl key (for example-S (O)-), sulphonyl key (for example-S (O)
2-), disulfide linkage (for example-S-S-) or directly (for example C-C key) key and with structural formula (I) or (IV) residue of compound be connected, wherein each R independently is H or (C
1-C
6) alkyl.Utilize synthetic method known in the art, such key can form from suitably functionalized raw material.Based on the key of expectation, those of ordinary skills can select suitably functionalized raw material, utilize methods known in the art, and this raw material can derive from the residue of structural formula (I) or compound (IV) and the given residue of biologically active agent or adjuvant.The residue of biologically active agent or adjuvant can be connected to structural formula (I) or (IV) any synthetic feasible position on the residue of compound.In addition, the present invention also provides the compound of the residue with an above biologically active agent or adjuvant biologically active agent, and described biologically active agent or adjuvant biologically active agent directly are connected with structural formula (I) or compound (IV).
The number of the biologically active agent that can be connected with polymer molecule generally can depend on the molecular weight of polymkeric substance.For example, for the compound of structural formula (I), wherein n is about 5 to about 150, preferred about 5 to about 70, by making the reaction of pendant group of biologically active agent and polymkeric substance, can reach about 150 biological activity agent molecule (being its residue) can directly be connected with polymkeric substance (being its residue).In unsaturated polymer, biologically active agent can also react with the two keys in the polymkeric substance.
PEEA described herein, PEEUR and PEEU polymkeric substance absorb water (on polymeric film, 5% to 25%w/w water absorbs), make hydrophilic molecules diffuse through them easily.This characteristic makes these polymkeric substance be suitable for use as the tectum on the particle, with sustained release speed.Water absorbs and also to strengthen polymkeric substance and based on the biocompatibility of the polymer composition of this base polymer.In addition, because the water-wet behavior of PEEA, PEEUR and PEEU polymkeric substance, when being sent in vivo, become viscosity and assembling of particle is especially in vivo under the temperature.Therefore, when subcutaneous or intramuscularly during with local delivery, for example by hypodermic needle injection or Needleless injection (needle-less injection), polymer beads forms polymer depot naturally.The mean diameter scope be about 1 micron to about 100 microns particle---its size can not effectively circulate in vivo---is suitable for forming in vivo this type of polymer depot.Alternatively, for oral administration, gi tract (GI tract) can be stood much bigger particle, for example about 1 micron particulate to about 1000 microns mean diameters.
The particle that is suitable for OEG based polymer compositions of the present invention can utilize immiscible solvent technology (immiscible solvent technique) to be prepared.Generally speaking, these methods require the milk sap of two kinds of immiscible liquids of preparation.Substance emulsion process (single emulsion method) can be used to prepare the polymer beads that has added at least a hydrophobic biologically active agent.In the substance emulsion process, be impregnated in the particle biologically active agent at first in solvent with mixed with polymers, then in the aqueous solution with for example tensio-active agent emulsification of surface stabilizer.In this way, polymer beads with hydrophobic biologically active agent conjugate is formed and is suspended in the aqueous solution, hydrophobic conjugate in particle described in this aqueous solution will be stable, there is not obvious elution water inlet solution, but this quasi-molecule will be advanced body tissue by elution, for example muscle tissue.
Term biotechnological formulation used herein comprises that polypeptide, protein, DNA, cell and analogue great majority are hydrophilic.Dual emulsion process can be used for preparing and has inner water and hydrophilic biologically active agent and be dispersed in wherein polymer beads.In dual emulsion process, water or be dissolved in the water hydrophilic biologically active agent at first in polymkeric substance lipophilic solution emulsification to form elementary emulsion, this elementary emulsion is placed in the water then, with emulsification once more, form second emulsion, the particle that wherein has successive polymer phase and the moisture biologically active agent (one or more) in disperse phase is formed.Tensio-active agent and additive can be used in twice emulsification, to prevent particle aggregation.The solvent that is used as PEA and PEUR polymkeric substance with the chloroform or the DCM of water immiscibility, but in preparation, use methods known in the art to remove this solvent afterwards.
Yet, having the biologically active agent of low water solubility for some, these two kinds of emulsion processes have limitation.In this context, " low water solubility (low water solubility) " refer to hydrophobicity than real lipophilic drugs for example low the but wetting ability of Taxol than the low biologically active agent of for example many biotechnological formulations of real water soluble drug.The intermediate compound of these types is for high load and firm ground materialization enter in single emulsified particle, and wetting ability is too high; But for for high load in two emulsions and stability, hydrophobicity is too high.Under these circumstances, by triple emulsion processes, polymer layer is covered by by polymkeric substance and has on the particle that drugs of low aqueous solubility makes.This method provide low relatively medicine carrying capacity (～10%w/w), but provide structural stability and controlled drug release rate.
In triple emulsion processes; by biologically active agent is mixed in the polymers soln; then in the aqueous solution with tensio-active agent or lipid two (palmitoyl) phosphatidylcholine (DHPC, the short chain derivative of neutral grease) this mixture of emulsification for example, prepare first emulsion.By this way, the particle that contains promoting agent is formed and is suspended in the water, to form first emulsion.By first emulsion being put into polymers soln and this mixture of emulsification, be formed in the polymers soln so that wherein contain polymer particulate water droplet, second emulsion is formed.Water and tensio-active agent or lipid will separate particle and this particle of dissolving in polymers soln.Then, by second emulsion being put into water and this mixture of emulsification that contains tensio-active agent or lipid, be formed on the final particle in the water, the 3rd emulsion is formed.The resulting granules structure will have one or more particle, and these particles are formed by polymkeric substance and the biologically active agent at the center, its by water and surface stabilizer for example tensio-active agent or lipid surround, and be coated with the straight polymer shell.Surface stabilizer and water will prevent that the solvent in the polymer coating layer (coating) from contacting with particle in this coating and dissolve them.
For increase the capacity value of biologically active agent by triple emulsion processes, the promoting agent with low water solubility can need not polymer coating layer (coating) and need not the described biologically active agent of dissolving in water with surface stabilizer bag quilt in first emulsion.In this first emulsion, the scope that water, surface stabilizer and promoting agent have similar volume or volume ratio respectively is (1 to 3): (0.2 to about 2): 1.In this case, water is used, and is not for the lytic activity agent, but in order under the help of surface stabilizer, to protect biologically active agent.Then, double emulsion and triple emulsion are produced as mentioned above.This method can provide and can reach 50% medicine capacity value.
Alternatively or additionally, in above-mentioned substance, dual or triple emulsion process, before using the polymer manufacture particle, biologically active agent can be coupled to polymer molecule as described herein.Still alternatively, biologically active agent can be coupled to after particle produces on the polymkeric substance on the described particle outside, and is as described herein.
Many emulsifying technologies will work in the preparation above-mentioned emulsion.Yet the preferred emulsions preparation method utilizes immiscible solvent in water at present.For example, in the substance emulsion process, emulsifying step is made up of following: with described dissolution with solvents polymkeric substance, mix with biological activity agent molecule (one or more), put into water, stir with mixing tank and/or ultrasonator then.By the concentration of control stirring velocity and/or polymkeric substance, biologically active agent (one or more) and surface stabilizer, can control granular size.By regulating the ratio of second emulsion and the 3rd emulsion, bag can Be Controlled by layer thickness.
Suitable emulsion stabilizer can comprise nonionic surface active agent, for example monooleate mannide ester (mannide monooleate), macrodex, 000, Soxylat A 25-7, polyglycol ether and surfactant-like, all these is easily from for example Sigma ChemicalCo., St.Louis, Mo. is commercially available.Described tensio-active agent will exist with about 0.3% to about 10% concentration, and preferred about 0.5% to about 8%, and more preferably from about 1% to about 5%.
Described at least a biologically active agent can be controlled by layer thickness, granular size, structure and bag tegillum density by regulating bag from the rate of release of the present composition.Described bag tegillum density can be coupled to bag by adjusting and be regulated by last biologically active agent capacity value.For example, when described bag was not contained biologically active agent, polymer coating was the density maximum, and the biologically active agent elution of granule interior is the slowest by described bag quilt.In comparison, when biologically active agent be loaded into (promptly mix with it or " matrixization (matrixed) ") or be coupled to alternatively described bag by in polymkeric substance the time, in case described biologically active agent is broken away from polymkeric substance and gone out by elution, then this bag is begun to become porous by the outside surface from described bag quilt.Therefore, can be at the biologically active agent at particle center with the speed wash-out that increases.The biologically active agent capacity value is high more in the bag quilt, and bag tegillum density is low more, and elution speed is high more.Biologically active agent capacity value in described bag quilt can be below or above the biologically active agent capacity value of the granule interior of externally wrapping under the tegillum.Biologically active agent (one or more) can also mix by the particle with different rates of release that will prepare as mentioned above and be controlled from the particulate rate of release.
The detailed description for preparing the method for double emulsion polymkeric substance and triple emulsion polymkeric substance can find in following document: Pierre Autant etc., United States Patent (USP) 6,022,562; Iosif DanielRosea etc., Microparticle formation and its mechanism in single and doubleemulsion solvent evaporation, Journal of Controlled Release (2004) 99:271-280; L.Mu and A Feng, A novel controlled release formulation forthe anticancer drug paclitaxel (Taxol): PLGA nanoparticles containingvitamin E (TPGS, J.Control.Release (2003) 86:33-48; Somatosincontaining biodegradable microspheres prepared by a modified solventevaporation method based on W/O/W-multiple emulsions, Int.J.Pharm. (1995) 126:129-138; And F.Gabor etc., Ketoprofenpoly (d, l-lactic-co-glycolic acid) microspheres:influence ofmanufacturing parameters and type of polymer on the releasecharacteristics, J.Microencapsul.16 (1) (1999) 1-12, each piece of writing is incorporated this paper into its integral body.
In sending the another embodiment of water-soluble biological promoting agent, described particle can be prepared to mean diameter for the nano particle of about 20nm to about 200nm, for delivery to the recycle system.By the substance emulsion process, utilize to be dispersed in wherein, promptly be mixed in the emulsion or be coupled to the promoting agent of polymkeric substance, as described herein, can prepare described nano particle.Described nano particle can also be provided with the micelle composition that contains polymkeric substance as herein described, and described polymkeric substance biological example promoting agent is coupled to PEA and the PEUR on it.Alternatively or the biologically active agent on being coupled to polymkeric substance, because described micelle formation in water, the water-soluble biological promoting agent can not be loaded in the described micella under having the situation of solvent simultaneously yet.
More specifically, biodegradable micella is formed by the hydrophobic polymer chains that is coupled to the water-soluble polymers chain.Yet described micellar external portion mainly partly is made up of the water soluble ionization part or the polarity of described polymkeric substance, and the hydrophobic part of described polymkeric substance mainly is assigned to described micellar inside and polymer molecule is kept together.
The biodegradable hydrophobic part that is used to prepare the micellar polymkeric substance is made by PEA, PEEUR or PEEU polymkeric substance, as described herein.For strong-hydrophobicity PEEA, PEEUR or PEEU polymkeric substance, composition for example 1,4:3,6-two anhydrous-two-L-leucine ester of D-sorbyl alcohol, or rigidity aromatic diacid, as α, ω-two (4-carboxyl phenoxy group)-(C
1-C
8) alkane, can be included in the polymer repeat unit.In comparison, the water-soluble portion of polymkeric substance comprises i) have at least 200 and be less than polyoxyethylene glycol and the b of 200 Mw) at least a ionizable or amino acid whose repetition alternate cells of polar, wherein said repetition alternate cells has similar basically molecular weight, and the Mw of wherein said polymkeric substance is in about 10kD arrives the scope of about 300kD.That described repetition alternate cells can have is similar basically, at the molecular weight of about 300D to about 700D scope.In the embodiment of the molecular weight of polymkeric substance more than 10kD, at least one amino acid unit is to be selected from Serine, L-glutamic acid, aspartic acid, Methionin and arginic ionizable or polar amino acid therein.In one embodiment, the amino acid whose unit of ionizable comprises at least one ionizable poly-(amino acid) for example block of glutaminate or aspartate, and this unit can be included in the described polymkeric substance.Micelle composition of the present invention can further comprise the pharmaceutically acceptable water-bearing media with certain pH value, and under this pH value, at least a portion ionizable amino acid in the polymkeric substance water-soluble portion is ionized.
The molecular weight of the water-soluble portion of described polymkeric substance is high more, and the micellar porosity is big more, and be loaded into micellar water-soluble biological promoting agent and/or big biologically active agent such as proteinic amount big more.In one embodiment, therefore, the molecular weight of the complete water-soluble portion of polymkeric substance at about 5kD to the scope of about 100kD.
In case form, micella can be used for storing and transportation by freeze-drying, and reconstruct in above-mentioned water-bearing media.Yet some biologically active agent of not recommending lyophilize to contain will to be frozen the drying process sex change is some proteinic micella for example.
Alive part in the micella partly is separated from each other in water, and produces the space that absorbs water soluble preparation biological example promoting agent (one or more).Ionization chain with same type electric charge is with mutually exclusive and generation more space.Ionized polymkeric substance also attracts biologically active agent, for matrix provides stability.In addition, the water-soluble outside of described micellar prevents that micella is adhered on the protein in the body fluid after the ionization position is occupied by the therapeutic biologically active agent.The micella of the type has very high porosity, can reach 95% of micelle volume, allows high load water-soluble biological preparation, for example polypeptide, DNA and other biologically active agent.Micellar granular size scope is extremely about 200nm of about 20nm, for the circulation in the blood, is preferably about 20nm to about 100nm.
By for example dynamic light scattering, use the spectrometer that helium-neon laser for example is housed, can measure granular size.Generally speaking, granular size is at room temperature measured, and comprises the repeatedly analysis (for example 5-10 time) to the consideration sample, to produce the mean value of particle diameter.(scanning electron microscopy SEM), also determines granular size easily to use scanning electronic microscope.In order to do like this, dried particles is coated with into the thickness of about 100 dusts, detects with scanning electronic microscope then with gold/palladium mixture sputter.Alternatively, polymkeric substance---particle form or non-particulate form---can be by directly covalently bound to biologically active agent, rather than do not having under the situation that chemistry connects to wherein mixing biologically active agent (" load (loading) "), its use know in this area and as hereinafter any of described several method carry out.The biological activity agent content is generally such amount, it is with respect to polymkeric substance, show as about 0.1% biologically active agent, about 1% biologically active agent more preferably, even more preferably about 2% biologically active agent to about 20% (w/w) to about 25% (w/w) to about 40% (w/w).The percentage composition of biologically active agent will depend on desired amount and the situation of being treated, as discussing in more detail below.
The medicine family that is used to be dispensed into biodegradable polymers composition of the present invention and also comprises antiproliferative agents, rapamycin and any analogue thereof or derivative, taxol or its any taxanes (taxene) analogue or derivative, everolimus (everolimus), sirolimus, tacrolimus or its any not department name from the biologically active agent of its release, and Statins, as Simvastatin, atorvastatin, fluvastatin, Pravastatin, lovastatin, superstatin; Geldanamycin, for example 17AAG (17-allyl amino-17-demethoxylation geldanamycin); Ebormycine D (Epothilone D) and other ebormycine class, other polyketone class inhibitor, Cilostazole and the analogue of 17-dimethylamino ethylamino-17-demethoxylation-geldanamycin and heat shock protein 90 (Hsp90).
Consider to be dispersed in that additional biologically active agent in the used polymkeric substance comprises such preparation in the OEG based polymer compositions of the present invention, when discharging in the auto-polymerization composition granule in its biodegradation process or flowing out, promote for example nitric oxide production endogenous generation of the natural Wound healing agent of therapeutic, the natural Wound healing agent of such therapeutic is by the endogenous generation of endotheliocyte.Alternatively, the biologically active agent that discharges in the autohemagglutination compound between degradative phase can directly work in promoting the natural wound healing process that is caused by endotheliocyte.These biologically active agents can be any such preparations, its supply, transfer or release nitrogen protoxide improve nitric oxide production endogenous levels, stimulate nitric oxide production endogenous synthetic, perhaps, perhaps suppress the propagation of smooth muscle cell as the substrate of nitricoxide synthase.Such formulation example is as comprising amino oxygen class (aminoxyls), furazan class (furoxans), nitrosothiols, nitrate and anthocyanin; Nucleosides, such as adenosine, and Nucleotide, as adenosine diphosphate (ADP) (ADP) and adenosine triphosphate (ATP); Neurotransmitter/neuromodulator is such as vagusstoff and serotonin (thrombotonin/5-HT); Histamine and catecholamine are such as suprarenin and norepinephrine; Lipid molecule is such as sphingosine-1-phosphate ester and Ultrapole L; Amino acid is such as arginine and Methionin; Peptide such as bradykinin, P material and calcitonin-gene-related peptide (calcium gene-related peptide, CGRP), and protein, such as Regular Insulin, vascular endothelial growth factor (VEGF) and zymoplasm.
Multiple biologically active agent, bag can be by for example covalently bound surfaces to polymer beads by the part of molecule and biologically active agent.Biologically active agent, for example targeting antibodies, polypeptide (for example antigen) and medicine and analogue can be by covalent coupling to the surfaces of described polymer beads.In addition, the part that adheres to as antibody or polypeptide or Yelkin TTS (PC), bag by molecule for example polyoxyethylene glycol (PEG) also can be surperficial link coupled, described means of adhering to as the attachment area on the described particle surface of sealing arrive non-target organism molecule and the surface in the patient to prevent particle adhesion.
For example, known small protein matter motif (small proteinaceous motif), for example proteic B structural domain of bacterium A and the proteic function equivalence of G district, thus by the Fc district in conjunction with and the capture antibody molecule.This type of protein motif can be attached to the surface of polymkeric substance, particularly described polymer beads.This quasi-molecule will be taken on for example part of binding antibody, as the target part, perhaps will take on capture antibody with the part of catching precursor cell or the part of catching cell from patient's blood flow.Therefore, the antibody type of utilizing A albumen or G protein function district can be connected to polymer coating is those antibody that contain the Fc district.Capture antibody again can be near polymer surfaces in conjunction with and catch precursor cell, progenitor cell for example, and described precursor cell---it preferably is immersed in the growth medium in the polymkeric substance---secrete the various factors and with other cell interaction of object.In addition, be dispersed in the described polymer beads one or more plant biologically active agents for example bradykinin can activate described precursor cell.
In addition, be used for the attached precursors cell or from the blood capturing endothelial ancestral cell of object (progenitor endothelial cells, biologically active agent PECs) they are the monoclonal antibodies at known progenitor cell surface marker.For example, (complementary determinants CDs) comprises CD31, CD34, CD102, CD105, CD106, CD109, CDw130, CD141, CD142, CD143, CD144, CDw145, CD146, CD147 and CD166 by the complementary determiner of report decoration endothelial cell surface.These cell surface markers can have the specificity of variation, and are not characterized fully under many circumstances at the degrees of specificity in specific cells/growth type/stage.In addition, these cell sign molecules had formed antibody already at them, with especially with the cell of identical pedigree on CDs overlapping (with regard to antibody recognition): described cell is monocyte under the endotheliocyte situation.Circulation endothelium progenitor cell is along growing path some approach from (marrow) monocyte to mature endothelial cell.CDs106,142 and 144 is had some specific mature endothelial cells by the report mark.Present known CD34 is special to endothelial progenitor cells, therefore is preferably capturing endothelial ancestral cell from the blood at the implanted position of polymer beads at present, and described implantation is for the local delivery active ingredient.The example of this antibody-like comprises single-chain antibody, chimeric antibody, monoclonal antibody, polyclonal antibody, antibody fragment, Fab fragment, IgA, IgG, IgM, IgD, IgE and humanized antibody.
Following additional biologically active agent and small-molecule drug will be effective especially for the dispersion in polymer beads composition of the present invention, no matter the time control that is suitable for being formed for the local delivery biologically active agent of the size of described composition discharges the biodegradable polymers bank, perhaps be suitable for entering systemic circulation, as described herein.Be dispersed in biologically active agent in the used polymer beads of the present composition and methods of treatment will according to they in therapeutic goal disease or its symptom suitable treatment or to alleviate effect selected.
In one embodiment, suitable biologically active agent is not limited but comprises various types of compounds, and described compound promotes when existing with the time control delivery mode or helps wound healing.This type of biologically active agent comprises the wound healing cell---comprise some precursor cells, it can be protected by the biodegradable polymers particle in the present composition and sends.This type of wound healing cell comprises for example pericyte and endotheliocyte, and the inflammation healing cell.For such cell being raised the position of body interpolymer bank, be used in the part that polymer beads in the present composition and the methods of treatment can comprise this type of cell, for example antibody and littler molecule ligand, it specifically in conjunction with " cell adhesion molecule (cellular adhesion molecules) " (CAMs).The exemplary part of wound healing cell comprises the part of those specificitys in conjunction with intercellular adhesion molecule (ICAMs), for example ICAM-I (CD54 antigen); ICAM-2 (CD102 antigen); ICAM-3 (CD50 antigen); ICAM-4 (CD242 antigen); And ICAM-5; Vascular cell adhesion molecule (VCAMs), for example VCAM-I (CD106 antigen); Nerve cell adhesion molecule (NCAMs), for example NCAM-1 (CD56 antigen); Or NCAM-2; PECAM PECAMs, for example PECAM-1 (CD31 antigen); White corpuscle-endothelial cell adhesion molecule (ELAMs), for example LECAM-1; Or LECAM-2 (CD62E antigen) and analogue.
On the other hand, suitable biologically active agent comprises extracellular matrix protein matter, and it is the macromole that can be dispersed in the polymer beads that uses in the present composition, for example by covalently or non-covalently combination.The example of useful extracellular matrix protein matter for example comprises the glycosaminoglycan (proteoglycan (proteoglycans)) that is connected with protein usually and fibrous protein (collagen protein for example; Elastin; Fibronectin and ln).Also can utilize the biosimulation thing (bio-mimics) of exoprotein.Still biocompatible glycoprotein, for example alginate and chitin derivatives that these are normally inhuman.For the wound healing peptide of the specific fragment of this type of extracellular matrix protein matter and/or their biosimulation thing also can be used as biologically active agent.
Protein growth factor is the additional bioactive agents kind, and it is fit to be dispersed in the polymer beads that uses in the present composition as herein described and the methods of treatment.This type of biologically active agent is effective in promoting wound healing and other morbid state known in the art.For example, Thr6 PDGF BB-BB (PDGF-BB), tumor necrosis factor-alpha (TNF-α), Urogastron (EGF), keratinocyte growth factor (KGF), thymosin B4; With various angiogenesis factors, such as vascular endothelial growth factor (VEGFs), fibroblast growth factor (FGFs), tumour necrosis factor-β (TNF-β) and insulin-like growth factor-i (IGF-I).In these protein growth factors much is that commerce can get, and perhaps can use the technology known in this area and recombinant production.
---described carrier contains the gene of the various biomolecules of encoding---can be dispersed in the polymer beads, be used for the time control release delivery alternatively, to comprise the expression system of carrier, particularly adenovirus carrier.The method and the carrier that prepare this type of expression system are known in the art.For example, the albumen somatomedin can be dispersed in the polymer beads of the present invention, be used for by selecting size to be suitable for to form the particle of polymer depot and described somatomedin is administered to the expectation body area, so that local delivery is perhaps used described somatomedin by selecting to enter round-robin granular size general.These somatomedins are VEGF, PDGF, FGF, NGF and evolution and function associated biomolecule preparation and vasculogenesis enzyme zymoplasm for example for example, also can be as the biologically active agent among the present invention.
Organic or inorganic compound " small-molecule drug " is the additional bioactive agents kind, and it is fit to be dispersed in the polymer beads used in the present composition as herein described and the methods of treatment.Such medicine comprises for example biocide and anti-inflammatory agent, and some accelerator for concrescence, for example, and such as the synthetic inhibitor of vitamin A and lipid peroxidation.
A lot of microbiotic also can be dispersed in the present composition in the employed polymer beads, so that by prevention or control infection and the normal healing process that promotes indirectly.Suitable microbiotic comprises many types, such as aminoglycosidic antibiotics or quinolones (quinolones) or beta-lactam, such as cynnematin (cefalosporines), as Ciprofloxacin, gentamicin, tobramycin, erythromycin, vancomycin, Oxazacillin, Cloxacillin Sodium, methicillin, lincomycin, Ampicillin Trihydrate and Totazina.Suitable microbiotic is described in the literature.
Suitable antimicrobial agents in order comprises for example Adriamycin PFS/
(Pharmacia andUpjohn),
(Bristol-Myers Squibb Oncology/Immunology),
(Bedford),
(Merck), Dauno
(NeXstar),
(Sequus), Doxorubicin
(Astra),
PFS (Pharmacia and Upjohn),
(Bayer),
(Bristol-Myers Squibb Oncology/Immunology),
(SuperGen),
(Immunex) and
(Bristol-Myers SquibbOncology/Immunology).In one embodiment, peptide can be a glycopeptide." glycopeptide (glycopeptide) " refers to oligopeptides (for example seven peptides (heptapeptide)) microbiotic, is characterized as the optional many cyclic peptide nuclears that replace with glycosyl group, for example vancomycin.
Be included in the glycopeptide in this classification biocide example can shown by Raymond C.Rao and Louise W.Crandall " Glycopeptides Classification; Occurrence; and Discovery; " (" Bioactive agents and the PharmaceuticalSciences " Volume 63, edit by Ramakrishnan Nagarajan, by MarcalDekker, Inc. publishes) in find.The other example of glycopeptide is disclosed in United States Patent (USP) the 4th, 639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; With 5,843, in No. 889; At EP 0802199; EP 0801075; EP 0667353; WO97/28812; WO 97/38702; WO 98/52589; Among the WO 98/52592; And at J.Amer.Chem.Soc, 1996,118,13107-13108; J.Amer.Chem.Soc, 1997,119,12041-12047; And J.Amer.Chem.Soc., 1994,116, among the 4573-4590.Representative glycopeptide comprises that those are accredited as A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, unwrapping wire trip rhzomorph, actinoidin, ardacin, Ah 's mycin, penicillin far away, Balhimyein, Chloroorientiein, Chloropolysporin, Decaplanin, N-demethyl vancomycin, Eremomycin, Galacardin, Helvecardin, her peptimycin, triumphant vigorous sporangiocyst rhzomorph, LL-AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, few daughter bacteria element, Spontycine, the Rui Situo mycin, Synmonicin, trip wall rhzomorph, UK-68597, UD-69542, UK-72051, the glycopeptide of vancomycin and analogue.Term " glycopeptide (glycopeptide) " or " glycopeptide antibiotic (glycopeptide antibiotic) " are also intended to comprise the general category of top disclosed glycopeptide as used herein, sugar moieties is non-existent on this glycopeptide, i.e. the aglycone series of glycopeptide.For example the disaccharides of removing on the vancomycin by mild hydrolysis that is connected in phenol has produced the vancomycin aglycone.Being included in equally in term " glycopeptide antibiotic " scope is the synthesis of derivatives of the general category of top disclosed glycopeptide, comprises alkylation and acyl derivative.In addition, in the scope of this term be according to the similar mode of Vancosamine (vancosamine), further added the glycopeptide, particularly aminoglycoside of other saccharide residue.
Term " lipid glycopeptide (lipidated glycopeptide) " refers specifically to those and has been synthesized to be modified to and contains the substituent glycopeptide antibiotic of lipid.As used herein, term " lipid substituting group (lipid substituent) " refers to and contains 5 or more a plurality of carbon atom, is preferably any substituting group of 10 to 40 carbon atoms.The lipid substituting group can be chosen wantonly and contain 1 to 6 heteroatoms that is selected from halogen, oxygen, nitrogen, sulphur and phosphorus.The lipid glycopeptide antibiotic is known in this area.For example referring to U.S. Patent number 5,840,684,5,843,889,5,916,873,5,919,756,5,952,310,5,977,062,5,977,063, EP 667,353, WO 98/52589, WO 99/56760, WO 00/04044, WO 00/39156, its disclosure is incorporated into this paper as a reference by complete.
The anti-inflammatory biologically active agent also can be used for being dispersed in the present composition and the method in the employed polymer beads.Depend on body part to be treated and disease, this type of anti-inflammatory biologically active agent for example comprises, analgesic agent (for example, NSAIDS and salicylic acid salt), steroid, antirheumatic, gastrointestinal drug, gout preparation, hormone (glucocorticosteroid), nasal preparation, ophthalmic preparation, otic preparation (for example, the combination of microbiotic and steroid), medicine for respiratory system and skin and mucosal drug.Referring to Physician ' s Desk Reference, 2001 editions.Particularly, anti-inflammatory agent can comprise dexamethasone, its by chemical name be (11 θ, 16I)-9-fluoro-11,17,21-trihydroxy--16-methyl pregnant steroid-1,4-diene-3,20-diketone.Alternatively, the anti-inflammatory biologically active agent can be maybe to comprise sirolimus (rapamycin), and it is from the isolating triolefin macrolide antibiotic of streptomyces hygroscopicus (Streptomyces hygroscopicus).
The polypeptide biologically active agent that is included in the present composition and the method also can comprise " peptide mimics (peptide mimetics) ".This type of peptide analogs that is called as " peptide mimics (peptidemimetics) " or " simulating peptide (peptidomimetics) " in this article generally is used to pharmaceutical industry, it has the character (Fauchere that is similar to template peptide (template peptide), J. (1986) Adv.Bioactive Agent Res., 15:29; Veber and Freidinger (1985) TINS, p.392; With (1987) J.Med.Chem. such as Evans, 30:1229), and develop by computerize molecular model method usually.Generally speaking, be similar to typical polypeptide (paradigm polypeptide) (polypeptide that promptly has biochemical property or pharmacologically active) on the simulating peptide structure, be selected from the peptide bond that following key option replaces by methods known in the art but have one or more:--CH
2NH--,--CH
2S--, CH
2-CH
2--,--CH=CH--(cis and trans),--COCH
2--,--CH (OH) CH
2--and--CH
2SO--, described method is further described in following reference: Spatola, A.F. exists, and " " middle B.Weinstein edits for Chemistryand Biochemistry of Amino Acids; Peptides, and Proteins, Marcel Dekker, New York, p.267 (1983); Spatola, A.F., Vega Data (March nineteen eighty-three), Vol.1, Issue 3, " Peptide Backbone Modifications " (summary); Morley, J.S., Trends.Pharm.Sci., (1980) pp.463-468 (summary); Hudson, D. etc., Int.J.Pept.Prot.Res., (1979) 14:177-185 (--CH
2NH--, CH
2CH
2--); Spatola, A.F. etc., Life Sci., (1986) 38:1243-1249 (CH
2-S-); Harm, M.M., J.Chem.Soc.Perkin TransI (1982) 307-314 (--CH=CH-, cis and trans); Almquist, R.G. etc., J.Med.Chem., (1980) 23:2533 (COCH
2-); Jennings-Whie, C. etc., Tetrahedron Lett., (1982) 23:2533 (COCH
2-); Szelke, M. etc., European Appln., EP 45665 (1982) CA:97:39405 (1982) (CH (OH) CH
2-); Holladay, M.W. etc., Tetrahedron Lett., (1983)
24: 4401-4404 (C (OH) CH
2-); And Hruby, V.J., Life Sci., (1982) 31:189-199 (CH
2-S-).The simulation of this type of peptide can have the significant advantage that is better than the natural polypeptides embodiment, for example comprises: more economical production, bigger chemical stability, enhanced pharmacological properties (transformation period, absorb, tire, effect etc.), the specificity (for example biological activity of wide spectrum) that changes, antigenicity and other advantage that reduces.
In addition, the amino acid whose replacement of one or more in peptide (for example, replacing L-Methionin with D-Methionin) can be used to produce the peptide of more stable peptide and anti-endogenous peptase.Alternatively, be covalently bound to the synthetic polypeptide of biodegradable polymers, can also be called trans peptide (inverso peptides) by the preparation of D-amino acid.When peptide during with the assembling of the reverse direction of native sequence polypeptide, it is called as contrary formula peptide (retro peptide).Generally speaking, the polypeptide from the preparation of D-amino acid is very stable for enzymically hydrolyse.Situation (US patent 6,261, the 569B1 and the reference wherein of the preservation biologic activity of many relevant contrapositives or the trans polypeptide of Partial Inverse have been reported; B.Fromme etc., Endocrinology (2003) 144:3262-3269).
It is apparent that the invention of this theme can be used for preparing composition to be applied to prevention or to treat a variety of diseases or its symptom.
After the preparation of the polymer beads that is mounted with biologically active agent, composition can be by freeze-drying, and this exsiccant composition can be suspended in before using in the suitable medium.
At least a promoting agent of any suitable and significant quantity can be in time discharges (comprise the polymer depot that forms in vivo those) from described polymer beads, and will depend on for example concrete polymkeric substance, grain type usually or if present, polymkeric substance/biologically active agent connects.Usually, can reach about 100% polymer beads can discharge from polymer depot, and described polymer depot is suitable for avoiding the round-robin particle to form by size in vivo.Particularly, can reach that it is about 90%, can reach 75%, can reach and 50%, maybe can reach it and 25% can from polymer depot, discharge.Usually influence is the property quality and quantity of polymkeric substance/biologically active agent, the type of polymkeric substance/biologically active agent key and other Substance Properties and the amount that exists said preparation from the factor of the speed of polymkeric substance release.
In case OEG based polymer compositions of the present invention as above is produced, then composition is prepared, be used for that subsequently intrapulmonary delivery send, stomach and intestine are sent, subcutaneous delivery, intramuscular send, enter central nervous system is sent, intraperitoneal is sent or organ in send.Described composition will comprise that usually one or more kinds are suitable for " the pharmaceutically acceptable vehicle or the carrier " of per os, mucous membrane or subcutaneous delivery, as water, salt solution, glycerol, polyoxyethylene glycol, hyaluronic acid, ethanol etc.In addition, for example wetting agent or emulsifying agent, pH buffer substance, food flavouring and similar substance can exist in examples of such carriers auxiliary substance.For example, vehicle such as washing composition, can be served various purposes: as the properties-correcting agent of emulsion stabilizer, interfacial tension or increase less deliquescent medicine and enter particulate load.The example of the vehicle that is adapted at using in the present composition comprise polyvinyl alcohol (PVA),
80, Pluronic F-68, sodium lauryl sulphate (SDS),
-35 and N-dodecyl-β-D-maltoside, octyl group-β-D-glycopyranoside,
CA-630, N-capryloyl-N-methylglucosamine, N-nonanoyl-N-methylglucosamine, N-decanoyl-N-methylglucosamine,
P-40 substituent, Saponin, hexadecyl methyl brometo de amonio, CHAPS,
BB and 3-(dodecyl dimethyl ammonia) propane sulfonic acid inner salt (SB3-12), it all is obtained commercially.
Nose will neither cause stimulating nasal mucosa significantly not disturb the carrier of fibre function again interior will comprising usually with lung's preparation.Thinner for example water, aqueous salt or other known substance can be used with the invention of this theme.Preparation can also contain sanitas in this lung, such as but not limited to butylene-chlorohydrin and Benzalkonii Chloridum.Tensio-active agent can exist, to strengthen the absorption of nasal mucosa.
For rectum and urethral suppositories, the carrier that uses in the present composition can comprise traditional tackiness agent and carrier, for example theobroma oil (theobroma oil) or other triglyceride level, esterification, hydrogenation and/or the vegetables oil of fractionation modification, glycerinated gelatin, poly-alkaline ethylene glycol (polyalkalineglycols), the mixture of different molecular weight polyethylene glycol and the fatty acid ester of polyoxyethylene glycol.
Send for vagina, preparation of the present invention can be impregnated in vaginal suppository matrix (pessarybases) or comprise vaginal suppository matrix, for example comprise those of polyethylene triglyceride mixture, or be suspended in oil for example in Semen Maydis oil or the sesame oil, randomly contain colloidal silica.Referring to, Richardson etc. for example., Int.J.Pharm. (1995) 115:9-15.
For the further discussion of the appropriate carrier that is used for the particular delivery pattern, referring to for example Remington:The Science and Practice of Pharmacy, Mack PublishingCompany, Easton, Pa., 19th edition, 1995.Those of ordinary skills can easily be identified for the suitable carrier of particular bioactive agent/polymer beads composition, granular size and mode of administration.
Except treating the mankind, OEG based polymer compositions of the present invention also is intended to be used for for example veterinary treatment of pet (as cat, dog, rabbit and ferret), agricultural animal (as pig, horse, donkey, milk cow and beef cattle) and horse racing of multiple mammals patient.
Can choose the biologically active agent of being paid close attention to (one or more) that contains " significant quantity " wantonly with composition in the methods of the invention, it is dispersed in OEG base PE PEEA of the present invention, PEEUR or the PEEU polymkeric substance.That is to say that a certain amount of biologically active agent can be included in the composition, it will cause object to produce enough therapeutic or the reaction of alleviating property, to prevent, to reduce or eliminate symptom.According to the object of being treated, by the mode of administration of ability, desired therapeutic degree, the severity of the symptom for the treatment of, selected concrete promoting agent and the composition of the age of treatment target and general situation, object-immunity system or the like factor, required accurate amount will change.Suitable effective amount can easily be determined by those of ordinary skills.Therefore, " significant quantity " will fall into by in the confirmable wide relatively scope of routine test.For example, for the purposes of the present invention, effective dose usually every dose of about 1 μ g to about 100mg by the scope of active agent delivery in, for example from about 5 μ g to about 1mg, or about 10 μ g arrive about 500 μ g.
In case preparation is finished, adopt standard technique, OEG based polymer compositions of the present invention is by per os, use through mucous membrane or through subcutaneous or intramuscularly or similar fashion.About the mucosal delivery technology, comprise in the nose, lung, vagina and rectum technology, referring to, Remington:TheScience and Practice of Pharmacy for example, the same, and about the intranasal administration technology, referring to European publication the 517th, No. 565 and Illum etc., J.Controlled Rel (1994) 29:133-141.
Dosage treatment can be the OEG based polymer compositions of the present invention of single dose, perhaps multiple doses scheme, as known in the art.The also near small part of described dosage is determined by the demand of object, and is depended on doctor's judgement.And, if disease prevention expects that described polymer composition was applied usually before the disease symptoms of protopathy demonstration or concern.If treatment is expected, for example reduce symptom or recurrence, described polymer composition is applied after protopathy shows usually.
Described preparation can carry out the body build-in test in many exploitations are used for studying the animal model of per os, subcutaneous or mucosal delivery.For example, conscious sheep model is the art-recognized model of the nasal delivery there of test substances.Referring to for example Longenecker etc., J.Pharm.Sci. (1987) 76:351-355 and Illum etc., J.Controlled Rel. (1994) 29:133-141.Usually, the polymer composition with powder, lyophilized form is blown in the nasal cavity.Use standard technique as known in the art, can measure the promoting agent in the blood sample.
In order to set forth the present invention, a series of PEEA are synthesized.At first, two p-nitrophenyl ester NA, NS and the NF of three kinds of dissimilar dicarboxylic acid are synthesized as monomer, so that the dicarboxylic ester fragment of PEEA to be provided.NA and NS have saturated methylene radical structure, and NF has the two keys (referring to scheme IV) of undersaturated C=C in the methylene radical structure.
As the monomer of the amino acid segment that PEEA is provided, two tosilate of three kinds of dissimilar two-L-phenylalanine diester have been synthesized, described in the embodiment of this paper.All three kinds of salt all comprise the residue of glycol oligomer, and ehter bond is (plan V) in segment.
La: hexanodioic acid two p-nitrophenyl esters (NA), x=4
1b: sebacic acid two p-nitrophenyl esters (NS), x=8
1c: fumaric acid two p-nitrophenyl esters (NF)
Scheme (IV)
2a:k=2, R
3=CH
2C
6H
5: two tosilate (P2EG) of L-phenylalanine glycol ether diester;
2b:k=3, R
3=CH
2C
6H
5: two tosilate (P3EG) of L-phenylalanine triglycol diester;
2c:k=4, R
3=CH
2C
6H
5: two tosilate (P4EG) of L-phenylalanine Tetraglycol 99 diester;
2d:k=1, R
3=CH
2CH (CH
3)
2: two tosilate (L1EG) of L-leucine (list) ethylene glycol diester;
2e:k=1, R
3=CH
3: the tosilate (A1EG) of L-L-Ala (list) ethylene glycol diester;
Scheme (V)
The chemical structure of two tosic acid salt monomer 2a-c is referred to herein as P2EG, P3EC and P4EG, all by ultimate analysis, FTIR and
1The HNMR spectrum reaches
13CNMR composes and confirms.The FTIR spectrum has shown 1741cm
-1Place's primary amine salt and ester carbonyl group-CO-and 1127cm
-1Place-CH
2-O-CH
2-the existence of characteristic signal.
The illustrative example of OEG of the present invention base PEEA synthetic is that the solution polycondensation by the various combination of monomer 1 (1a, 1b or 1c) and monomer 2 (2a, 2b or 2c) carries out, shown in following scheme (VI).
When x=4, AP2EG (k=2); AP3EG (k=3); AP4EG (k=4);
When x=8, SP2EG (k=2); SP3EG (k=3); SP4EG (k=4).
Wherein, FP2EG (k=2); FP3EG (k=3); FP4EG (k=4)
Scheme (VI)
The chemical structure of these PEEA polymkeric substance detects by FTIR and NMR spectrographic and confirms.The FTIR spectrum of all fumaroyl PEEA has confirmed unsaturated-C=C-key (983cm-1) and ester carbonyl group (1740cm
-1), ether group (1115cm
-1), amide group (1640 and 1530cm
-1) existence.NMR spectrum based on three kinds of typical PEEA of triglycol is in full accord with the expection chemical structure of the PEEA polymkeric substance shown in the plan V I.
The solution polycondensation of the combination by monomer 1a-c and 2a-c has synthesized nine kinds of dissimilar PEEA, lists table 1 in.
Table 1
The polyether ester amine of formula I
A)Performance
aSynthesis condition: c=0.90mol/L.t=70 ℃, THF is as solvent.
bIn DMSO, measure C=0.25g/dL down for 25 ℃.
C can't obtain the molecular weight data of fumaric acid-based PEEA owing to insoluble in THF.
The A-hexanodioic acid,, F-fumaric acid and S-sebacic acid; P=L-Phe; K is 2,3,4 in scheme 6.
In hexanodioic acid and sebacic acid base PEEA, AP3EG and SP3EG obtain the highest Mn, Mw and reduced viscosity η
Red
Synthetic PEEA has than the corresponding saturated or unsaturated lower T of PEA that contains the aliphatic diol residue
g(Katsasava, J Polym Sci Pol Chem (1999) 37 (4) such as R.: 391-407and Guo et al, supra).In fact, in each PEEA series, the increase of ehter bond quantity causes T
gCorresponding reduction, and in saturated PEEA series than in unsaturated PEEA, show more obvious.Therefore, the low T of PEEA
gOwing to the existence of ehter bond, this makes chain flexibility increase, and promotes the segmental of chain to move.
At pH is the Biodegradation Kinetics of having studied two representative triglycol base PEEA polymkeric substance of the present invention (AP3EG and SP3EG) in 7.4 PBS damping fluid and the alpha-chymotrypsin buffered soln under 37 ℃.In alpha-chymotrypsin solution, two kinds of polymkeric substance all show than weight saving faster in the PBS damping fluid, and the biological degradation level of these PEEA polymkeric substance in enzyme solution depends on the concentration of chemical structure and enzyme.In the polymkeric substance of being tested, AP3EG is to enzymatic living beings degraded the most responsive (Fig. 2).
In addition, no matter how use different alpha-chymotrypsin concentration in biological degradation research, the weight saving kinetics of exemplary OEG base PEEA is in close proximity to zero level, and this is owing to surface erosion.
For setting forth the synthetic of PEEUR of the present invention, following monomer---the activity two p-nitrophenyl carbonic ethers that contain the ether block of all lengths---is synthesized, described in this paper embodiment 2.Independent ether glycol, glycol ether, triglycol, Tetraglycol 99 be obtained commercially and be applicable to this task.According to general approach (VII) composite reactive two p-nitrophenyl carbonic ethers.
Wherein, 4a:k=2; 4b:k=3; 4c:k=4.
Scheme (VII)
The monomeric chemical structure ultimate analysis that obtains,
1H NMR confirms, and identifies with the fusing point of report.Carry out illustrative embodiment synthetic of OEG of the present invention base PEEUR by being similar to above-mentioned PEEA synthetic solution polycondensation method, as shown in following scheme (VIII).
Scheme (VIII)
By GPC (weight average molecular weight range of synthetic PEEUR is 31 for DMF, PMMA) assessment, 400-51, in the 000g/mol, glass transition temperature range is in 12-39 ℃.On L1EG base PEEUR, carry out the catalytic biological degradation of lipase.The results are shown among Fig. 3 A-C, wherein the PEEUR of data presentation acquisition does not carry out chemical hydrolysis in phosphate buffered saline buffer.By contrast, the catalytic biodegradable speed of lipase is high and do not rely on the R of formula V-VI
6The middle segmental length of OEG.
The following examples intended as illustrative explanation the present invention, and unrestricted the present invention.
Embodiment 1
In the present embodiment, preparation and the test of a series of saturated and undersaturated OEG base PEA (PEEA) have been described, to illustrate the character of the present composition.
A. material preparation
Under the situation that nothing is further purified, use L-phenylalanine (L-Phe), tosic acid monohydrate (TosOH.H
2O), sebacoyl chloride, adipyl chloride, fumaryl chloride, glycol ether, triglycol and Tetraglycol 99 (Alfa Aesar, Ward Hill, MA) and p-NP (J.T.Baker, Phillipsburg, NJ).By (Fisher Scientific, Fairlawn NJ), distill then with hydrolith backflow dry triethylamine.Through the dry N of hydrolith, dinethylformamide (DMF) (Aldrich Chemical, Milwaukee, WI) also distillation.Other solvent such as toluene, trifluoroethanol (TFE), tetrahydrofuran (THF) (THF), ethyl acetate, acetone, acetonitrile, N, N-N,N-DIMETHYLACETAMIDE (DMA) and methyl-sulphoxide (DMSO) purchase in VWR Scientific (West Chester, PA) and carry out purifying with standard method before use.
B. monomer and polymkeric substance is synthetic
It is synthetic to be used for formula (I) and PEEA (IV) to prepare following monomer: two p-nitrophenyl esters (1a-c) of dicarboxylic acid and two tosilate (2a-c) of two-L-phenylalanine-glycol ester;
By making the reaction of corresponding acyl chlorides and p-NP, carry out two p-nitrophenyl esters (compound 1a-c) synthetic of dicarboxylic acid, (US 6 as previously mentioned, 503,538B1, and Guo, K. etc., J.Polym Sci Pol Chem (2005) 43 (7): 1463-1477).In brief, at room temperature prepare triethylamine (0.0603mol) and the solution of p-NP (0.0603mol) in 100mL acetone, and this solution is remained on-78 ℃ with dry ice and acetone.(0.03mol 3.2mL) is added dropwise in the above-mentioned frozen soln, stirs 2 hours at-78 ℃, at room temperature continues to stir then to spend the night with the fumaryl chloride in the 40mL acetone then.Afterwards, mixture is introduced in the 800mL distilled water with precipitated product, fumaric acid two p-nitrophenyl esters (1c), and it is filtered, and thoroughly cleans with distilled water, and is dry under 50 ℃ of vacuum, at last from the acetonitrile recrystallization purifying.
By revising method of (1999, the same) middle descriptions such as Katsarava, two tosilate (compound 2a-c) of preparation two-L-phenylalanine ester are shown in preceding scheme (V).
Typically, the L-Phe in 300mL toluene (0.176mol), tosic acid monohydrate (0.176mol) and ethylene glycol (0.08mol) are placed in and are equipped with Dean and Stark apparatus, CaCl
2In the flask of drying tube and magnetic stirrer.This reaction mixture is heated (about 140 ℃) to refluxing, up to the water that produces 6.1mL (0.34mol), then, and cool to room temperature, except that desolvating, dry in a vacuum this mixture overnight is passed through recrystallization purifying at last by rotary evaporation.Compound 2a (P2EG) recrystallization in water, compound 2b and 2c are from the 2-propanol crystal.
Be presented through the synthetic example that contains OEG polymer AP 2EG of solution polycondensation: 10mmol triethylamine (1.42mL) is added dropwise in the mixture of monomer 1a (4.0mmol) in the dry DMA of 3mL and 2a (4.0mmol), and this solution is heated to 60 ℃, follows stirring to dissolve fully until monomer.This reaction flask was maintained at below 70 ℃ 48 hours, need not to stir.The viscous soln that obtains (according to the monomeric type of using, its color is light yellow to dark-brown) is divided into two groups, with different solvent depositions.With the undersaturated PEEA reaction mixture of acetone diluted (FP2EG9, FP3EG and FP4EG) with precipitated product.Use acetone cleaning cleaning polyalcohol twice then, filter, under vacuum dry 48 hours at last.
Be settled out saturated PEEA in cold ethyl acetate, filtration product also is further purified 48 hours by the circulation ethyl acetate in the Soxhlet device, and drying is 48 hours under vacuum.
Polymer dissolution.Except FP2EC, nearly all PEEA is dissolved in DMSO, DMF and fumaric acid, but water insoluble, methyl alcohol and ethyl acetate.Saturated PEEA also is dissolved in trifluoroethanol, THF and chloroform.But three kinds of undersaturated PEEA only are slightly soluble in those conventional organic solvents.Therefore, with PEA polymer phase ratio derived from aliphatic diol, OEG base PEEA, particularly undersaturated PEEA demonstrates tangible change aspect solvability.For example, SP3EC and SP4EG, the two all is dissolved in acetone, and SPB (1,4-butyleneglycol-Ji PEA) and SPH (1,6-hexylene glycol-Ji PEA) they are insoluble.
C. be used for determining monomer and the chemical structure of polymkeric substance and the testing method of performance.
Determine chemical structure with Fourier transform infrared spectroscopy (FTIR) and NMR spectrum.Characterize for FTIR, sample is ground into powder and with 1: the ratio of 10w/w is mixed with KBr.(this spectrograph has Omnic software, is used for data and obtains and analyze for Madison, WI) the FTIR spectroscopic data of FTIR spectrograph acquisition sample to use Perkin-Elmer Nicolet Magana 560 then.By Varian Unity NOVA-400400MHz spectrograph (Palo Alto, CA)---its for
1H and
13C NMR respectively 400 and 100MHz under operate, the record sample NMR spectrum.Deuterate methyl-sulphoxide (DMSO-d
6, Cambridge Isotope laboratories) and be used as solvent.(Atlantic Microlab, Norcross GA) carry out the ultimate analysis of institute's synthetic polymer to use PE 2400CHN elemental analyser.
(TAInstruments, New Castle characterize on DE) thermal properties of synthetic monomer and polymkeric substance at differential scanning calorimeter DSC 2920.Under the nitrogen gas stream speed of 10 ℃/minute scanning speeds and 25mL/min, measure from 0 ℃ to 300 ℃.TA UniversalAnalysis
TMSoftware is used to the dsc data analysis, as measuring second-order transition temperature.The fusion heat absorption begins the place and is measured as fusing point.
(Model 510 for gel permeation chromatograph by being equipped with high pressure liquid chromatography pump, Waters 486UV detector and Waters2410 differential refractive index detector, WatersAssociates Inc.Milford, USA), measure number average and weight-average molecular weight and the molecular weight distribution (MWD) of synthetic PEEA.Tetrahydrofuran (THF) (THF) is used as elutriant (1.0mL/min).With polystyrene standards calibration post with narrow molecular weight distributions.Reduced viscosity (the η of synthetic polymer
Red) under 25 ℃, under the concentration of 0.25g/dL, in DMSO solution, by the Cannon-Ubbelhode viscometer determining.
For the research of biodegradability, in 10% (wt/v) chloroformic solution, cast on the Teflon Petri dish PEEA film and make solvent at room temperature fully the evaporation.Further dry this film spends the night under the room temperature in a vacuum, and it is the roundel of 12.5mm that last punching press (punch) becomes diameter.
Comprising the pure PBS damping fluid of dry PEEA film disk and 10mL or at the PBS damping fluid (pH=7.4 of different concns (0,0.05,0.1 or 0.2mg/mL), 0.1M) in the bottle of alpha-chymotrypsin solution in, carry out the external biological degraded test of OEG base PEEA.Two kinds of representative OEG base PEEA polymkeric substance (AP3EG and SP3EG) are used to this biological degradation research.At 37 ℃ of incubation samples, follow constant back and forth to shake (100rpm) then.At predetermined interval, from medium, remove the PEEA film, wash gently with distilled water, surface water is removed with filter paper and is weighed.Based on following equation, estimate biodegradable degree from the weight saving of PEEA membrane sample:
W wherein
0Be the original weight of doing the PEEA membrane sample before immersing, W
tBe the weight that the PEEA membrane sample is done in incubation t hour (enzyme is arranged or do not have enzyme) back.The weight saving mean value of three samples of record.
The molecular weight of PEEA polymkeric substance changes is also monitored by GPC.
The surface hydrophilicity of PEEA film is measured in remaining on the conditioning room of 65% relative humidity and 21 ℃ by using MASS Contact Angle Analyzer.Distilled water is used as sprawls liquid, and measures the contact angle at five surf zone places of selecting at random of each PEEA film.Test two PEEA films of each sample type.
The structure of monomer 2 determines that the chemical structure of two tosic acid salt monomer 2a-e all determines by FTIR and NMR spectroscopic analysis.In FTIR spectrum, main absorption band is as ester group (1736-1750cm
-1) and ether group (about 1127cm
-1), be instructed to.Between 2500 to 3300cm
-1Between wide absorption be attributable to primary amine salt and the aliphatic hydrocrbon structure that exists in the ester salt.2a-e's
1The HNMR data also demonstrate-CH
2-O-CH
2-characteristic signal.
The FTIR spectrum of the fumaroyl PEEA of affirmation of polymer architecture shows ester group (～1740cm
-1), ether group (～1115cm
-1), amide group (～1640cm
-1With～1530cm
-1) and unsaturated-C=C-key (～983cm-1) characteristic absorption band.Greatly about 2900cm
-1The wide absorption at place is attributable to the aliphatic hydrocrbon structure that exists in the polymkeric substance.PEEA's
1H-NMR spectrum (400MHz, DMSO-d
6) demonstrate-the NH-key ether CH in (8.90 or 8.24ppm), two ester units
2-O-CH
2Key (about 3.50ppm) and in acid unit-proton signal of HC=CH-key (6.83ppm).Data from ultimate analysis are also consistent with the component result calculated.
The Biodegradation Kinetics of the representational OEG base PEEA polymkeric substance of two kinds of biological degradation results of study (AP3EG and SP3EG) is studied in the buffered soln of the PBS of 37 ℃ of pH 7.4 that containing alpha-chymotrypsin.Data from this biological degradation research show, compared in pure PBS damping fluid, two kinds of polymkeric substance all demonstrate faster and more obvious weight saving in alpha-chymotrypsin solution, and the degree of the biodegradability of these PEEA polymkeric substance in enzyme solution depends on the concentration of chemical structure and enzyme simultaneously.Biological degradation data presentation AP3EG is to enzymatic living beings degraded very responsive (Fig. 1).
Even in the alpha-chymotrypsin solution of 0.05mg/mL concentration, AP3EG is biological degradation easily also, loses 13% molecular weight in initial 8 hours, loses 31% molecular weight after one day.The biological degradation curve display enzymic hydrolysis speed of AP3EG increases with the increase of alpha-chymotrypsin concentration.And no matter alpha-chymotrypsin concentration difference, weight saving kinetics is in close proximity to zero level.Also observe the AP3EG film and can keep its constant surf zone can reach 80% weight saving well, polymer samples thins down simultaneously.The result shows that PEEA polymeric film of the present invention has experienced uniform surface erosion in the enzymic hydrolysis process, this is the result with the common body biological degradation type opposite of aliphatic polyester.
The diacid monomer 1a-b of different lengths is shown in Fig. 2 to the influence of biodegradability among the OEG base PEEA of the present invention.Wherein generalized data show, (derived from monomer 1a: hexanodioic acid two p-nitrophenyl esters with 4 methylene radical) trend of experience alpha-chymotrypsin catalytic hydrolysis is lower than SP3EG (derived from monomer 1b: sebacic acid two p-nitrophenyl esters with 8 methylene radical) to AP3EG.In 0.10mg/mL alpha-chymotrypsin solution, SP3EG also demonstrates the Biodegradation Kinetics near zero level, and even than the biological degradation of AP3EG biodegradation rate faster, the weight saving of 81% couple 56% in 24 hours.This result can be owing to more hydrophobic PEEA, and as SP3EG, it has bigger avidity to alpha-chymotrypsin, therefore has higher speed of enzyme hydrolysis than AP3EG.
Compare PEA saturated derived from linear aliphatic and similar structures undersaturated glycol, these OEG bases PEEA also demonstrates much higher alpha-chymotrypsin catalysis biological degradation rate.For example, in 24 hours, the weight saving of SP3EG is 81.3%, and the weight saving of SPBU (from 2-butylene-1, the 4-glycol) is 13.8%, and SPB (derived from 1, the 4-butyleneglycol) has only 6.4%.Therefore, compare and have aliphatic backbone segments that (that is the PEA of) analog structure, derived from aliphatic diol introduces ehter bond in the OEG base PEEA skeleton and to have strengthened the enzymatic living beings degraded.
Table 2
Weight saving, molecular weight and the contact angle of incubation PEEA polymkeric substance after 18 hours before incubation and in different media
aPrimary sample in contrast
Also with the PEEA polymeric film in the gpc measurement incubation medium to study its biological degradation (table 2).Although demonstrating AP3EG (34.9%) and SP3EG (64.8%) sample, weight saving in 0.1mg/mL alpha-chymotrypsin solution, had tangible biological degradation in 18 hours, but the GPC data presentation goes out very little change aspect molecular weight or molecular weight distribution, and proportional result appears at lower (0.05mg/mL, in the alpha-chymotrypsin concentration of alpha-chymotrypsin concentration less weight saving), higher (0.20mg/mL, more weight saving) and the PBS damping fluid (almost not having weight saving).
In this embodiment, the preparation of a series of saturated OEG base PEUR (PEEUR) and test are described to set forth the character of the present composition.Be the crucial monomer of synthesis hydrophilic PEEUR, acquisition contains the activity two p-nitrophenyl carbonic ethers of the ether block of all lengths.Activity two p-nitrophenyl carbonic ethers according to general scheme VII Synthetic 2 EG, 3EG and 4EG.
Usually, drip the p-nitrophenyl chloroformate ester of 0.02mol in the 0.01mol ether glycol solution of cold (10 ℃), the temperature of reaction that raises then is until room temperature and stirred 1 hour.This reaction soln that refluxes is then discharged fully until HCl, solution is evaporated until drying, to obtain solid product, its following being further purified: 1. at toluene/normal hexane (3: recrystallization glycol ether-two p-nitrophenyl carbonic ether (4a among the plan V II) in mixture 1v/v).Yield 73%, m.p.110-112 ℃ (reference, 108-110 ℃, R.Katsarava etc., Vysokomolek.Soed. (Russia) (1987), 29A:2069); 2. (3: 1v/v) the mixture recrystallization is based on the activated carbon acid esters of 3EG and 4EG (4b and 4c the plan V II) from methylene dichloride/ether.Yield: 4b 60%, 4c 54%, m.p.:4b, 59-61 ℃; 4c 48-50 ℃.
Wetting ability counterpart (counter-partner)---based on two tosilate (the compound 2d-e of the diamines of the shortest glycol (ethylene glycol), plan V) and low hydrophobic a-amino acid---L-L-Ala and L-leucine, the preparation of establishing criteria plan V, as described herein.The following recrystallization of product: 2e (A1EG)-from acetone (50/1v/v) mixture, mp=223-225 ℃, and 2d (L1EG)-from acetone (50/1v/v) mixture, mp=235-237 ℃.
According to plan V III, in the presence of the triethylamine as acid acceptor, concentration c=1.2mol/L, 16 hours by a definite date, in DMA, carries out the polycondensation of monomer 2d-e and 4a-c by t=80 ℃ under standard conditions.
The molecular weight of synthetic polymkeric substance (PEEUR) is 31,400 to 51, and in the 000g/mol scope, polymolecularity is in the 1.3-1.5 scope.Polymkeric substance has the second-order transition temperature (Tg) in 12 ℃ to 39 ℃ scopes.
All PEEUR are dissolved in DMF, chloroform and THF.The leucine based polyalcohol also is dissolved in ethanol.
The catalytic external biological Study on degradation of lipase
In pH is 7.4 0.2N phosphate buffered saline buffer, t=37 ℃, use lipase as enzyme, carry out the external biological degraded of PEEUR.The PEEUR highly-hydrophilic, and this polymeric film can not keep shape (observing strong contraction) in buffered soln.Therefore, be the research biological degradation,, make Teflon chassis (backing discs) overlie polymer of d=4cm, remove then and dry polymer by the Teflon dish is sunk in the PEEUR chloroformic solution.Constantly repeat this process until examine and seize the weight of about 400-500mg.The Teflon chassis that covers PEEUR then is dried to constant weight and is used for the external biological Study on degradation.In this process, only 2d (L1EG)-Ji PEEUR is retained on the chassis.More hydrophilic 2e Ala-2 base-PEEUR flows out on the chassis from buffering solution, so can not be by weight saving postgraduate thing degradability.
The catalytic biological degradation result of study of the lipase of 2d (L1EG)-Ji PEEUR is summarized among Fig. 3 A-C, and wherein data presentation does not have the biological degradation of obvious degree in the pure phosphoric acid damping fluid.But the catalytic biodegradation rate of the lipase of these PEEUR is sizable and is in close proximity to based on L-leucine, hexanodioic acid and 1 the catalytic biodegradation rate of the lipase of the PEA of the formula I of 6-hexylene glycol.This studies show that the segmental length of EG (EG2, EG3 or EG4) does not influence the biodegradation rate of the PEEUR that is tested basically.
All publications, patent and patent document are merged in this paper as a reference, just as being incorporated herein by reference separately.
The present invention is with reference to various concrete and preferred embodiment described with technology.Yet, should be appreciated that and can make many variations and change, and still within the spirit and scope of the present invention.Therefore, the present invention is only limited by claims.
Claims (25)
1. composition comprises at least a biologically active agent that is dispersed in the biodegradable polymkeric substance, and described polymkeric substance comprises following a) to f) at least one:
A) have the polyether ester amides (PEEA) of the chemical formula that structural formula (I) describes,
Formula (I)
Wherein the scope of n is from about 15 to about 150;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R in independent n monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane;
Formula (II)
Formula (III)
B) have the PEEA polymkeric substance of the chemical formula that structural formula (IV) describes:
Formula (IV)
Wherein the scope of n is from about 15 to about 150, and the scope of m is that the scope of p is from about 0.9 to 0.1 from about 0.1 to 0.9;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or blocking group;
R in independent m monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
C) have the poly(ether-urethene) (PEEUR) of the chemical formula that the structure formula V describes,
Formula V
Wherein the scope of n is from about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6One of at least be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
D) have the PEEUR of the chemical structure that general structure (VI) describes,
Formula (VI)
Wherein the scope of n is from about 15 to about 150, and the scope of m is from about 0.1 to about 0.9, and the scope of p is from about 0.9 to about 0.1;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
1-C
6) alkyl (C
6-C
10) aryl and blocking group;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except the R in each polymkeric substance
4And R
6One of at least be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
E) have the polyethers urea (PEEU) of the chemical formula that general structure (VII) describes,
Formula (VII)
Wherein n is about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
F) have the PEEU of the chemical formula that structural formula (VIII) describes,
Formula (VIII)
Wherein m is about 0.1 to about 1.0, and p is about 0.9 to about 0.1, and n is about 15 to about 150;
R
2Be hydrogen, (C independently
1-C
12) alkyl or (C
6-C
10) aryl;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; Except at least one R in each polymkeric substance
4Be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl.
2. composition according to claim 1, wherein said polymkeric substance is described with structural formula (I) or (IV), and in every n monomer, described R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
3. composition according to claim 1, wherein said polymkeric substance is described with structural formula (I) with (IV), and in every n monomer, described R
4Be independently selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, and described R
7Be (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
4. composition according to claim 1, wherein said polymkeric substance is described with the structure formula V or (VI), and in every n monomer, R
4Or R
6Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
5. composition according to claim 1, wherein said polymkeric substance is described with the structure formula V with (VI), and in every n monomer, R
4And R
6Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
4) alkoxyl group (C
2-C
8) alkylidene group.
6. composition according to claim 1, wherein said polymkeric substance is described with structural formula (VII) or (VIII), and in every n monomer, the R in every n monomer
4Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
7. composition according to claim 1, wherein to discharge from 15 to 300 molecular weight when biological degradation be 44Da to 400Da to each polymer molecule but do not comprise low polyoxyethylene glycol (OEG) molecule of 400Da.
8. composition according to claim 1, wherein said R
3Be selected from CH
2CH (CH
3)
2, CH
2C
6H
5And CH
3
9. composition according to claim 1, wherein said composition is used for form administration with the liquid dispersion of described polymer beads by preparation.
10. composition according to claim 9, wherein the particle of every polymer molecule comprises about 5 to about 150 biological activity agent molecules.
11. the polymkeric substance of the chemical formula that has structural formula (I), (IV), (V), (VI), (VII) or (VIII) describe:
A) its Chinese style (I) is:
Formula (I)
Wherein the scope of n is from about 15 to about 150;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R in independent n monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane;
Formula (II)
Formula (III)
B) formula (IV) is:
Formula (IV)
Wherein the scope of n is from about 15 to about 150, and the scope of m is that the scope of p is from about 0.9 to 0.1 from about 0.1 to 0.9;
R wherein
1Be independently selected from (C
2-C
12) alkylidene group, (C
2-C
12) residue of alpha, omega-dicarboxylic acid ester of alkenylene and formula (II), the R in its Chinese style (II)
5Be independently selected from (C
2-C
4) alkylidene group and (C
2-C
4) alkenylene, R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, except at least one R in each polymkeric substance
1Be the residue of the alpha, omega-dicarboxylic acid ester of formula (II), wherein R
7Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or blocking group;
R in independent m monomer
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, (C
2-C
20) alkylidene group, (C
2-C
20) alkenylene, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
C) formula V is:
Formula V
Wherein the scope of n is from about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except R
4And R
6In at least one be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2And CH
2CH (CH
2OH);
D) formula (VI) is:
Formula (VI)
Wherein the scope of n is from about 15 to about 150, and the scope of m is from about 0.1 to about 0.9, and the scope of p is from about 0.9 to about 0.1;
R
2Be independently selected from hydrogen, (C
1-C
12) alkyl, (C
1-C
6) alkyl (C
6-C
10) aryl and blocking group;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4And R
6Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH), structural formula (III) 1,4:3, the dicyclo fragment, 1 of the two anhydrous hexitols of 6-, the fragment and the combination thereof of 4-dehydration tetrahydroxybutane are except R
4And R
6In at least one be selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2And CH
2CH (CH
2OH); With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl;
E) formula (VII) is:
Formula (VII)
Wherein n is about 15 to about 150;
At independent n single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3With
R
4Be independently selected from (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group, CH
2CH (OH) CH
2, CH
2CH (CH
2OH); With
F) formula (VIII) is:
Formula (VIII)
Wherein m is about 0.1 to about 1.0, and p is about 0.9 to about 0.1, and n is about 15 to about 150;
R
2Be hydrogen, (C independently
1-C
12) alkyl or (C
6-C
10) aryl;
At independent m single intravital R
3Be independently selected from hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl (C
1-C
6) alkyl and-(CH
2)
2SCH
3
R
4Be independently selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group; With
R
8Be (C independently
1-C
20) alkyl or (C
2-C
20) thiazolinyl.
12. it is according to claim 11 with structural formula (I) or the composition of (IV) describing, wherein R
7Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
13. it is according to claim 11 with structural formula (I) with the composition of (IV) describing, wherein R
7Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
4) alkoxyl group (C
2-C
8) alkylidene group.
14. it is according to claim 11 with structure formula V and the composition of (VI) describing, wherein R
4And R
6Be independently selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
15. it is according to claim 11 with structural formula (VII) or the composition of (VIII) describing, wherein R
4Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
4) alkoxyl group (C
2-C
12) alkylidene group.
16. it is according to claim 11 with structural formula (VII) with the composition of (VIII) describing, wherein R
4Be selected from CH
2CH (OH) CH
2, CH
2CH (CH
2OH) and (C
2-C
6) alkoxyl group (C
2-C
12) alkylidene group.
17. composition according to claim 11, wherein R
3Be CH
2CH (CH
3)
2Or CH
3
18. composition according to claim 11, wherein R
3Be selected from hydrogen, CH
2CH (CH
3)
2, CH
3, CH (CH
3)
2, CH (CH
3), CH
2CH
3And CH
2C
6H
5
19. composition according to claim 11, wherein said composition are configured to mean diameter at the particle of about 10 nanometers to about 1000 micrometer ranges.
20. be used for sending to object the method for biologically active agent, it comprises:
In subject, give the described composition of claim 1 and
Form from 15 to 300 weight-average molecular weight of every polymer molecule (Mw) in vivo for 44Da at least and less than low polyoxyethylene glycol (OEG) molecule of 400Da, send described biologically active agent with controlled delivery speed to object simultaneously.
21. method according to claim 20, the biological degradation of wherein said composition by the surface enzyme effect.
22. the described method of claim 20 further is included in the liquid dispersion that administration is formulated as described composition polymeric film or polymer beads before.
23. method according to claim 22, wherein said administration comprise described composition grain is injected into the intravital part of described object.
24. the described method of claim 20 further is included in before the administration described composition is mixed with and has mean size at the polymer beads of about 1 μ m to the about 500nm scope.
25. composition, it comprises at least a biologically active agent that is dispersed in in the micellar copolymerization thing, and described one-tenth micellar copolymerization thing comprises following repetition alternate cells:
A) hydrophobic part, it comprises the described polymkeric substance of at least a claim 11, described part link to each other with water-soluble portion and
B) water-soluble portion of Yi Xia repetition alternate cells:
I) Mw be at least 200Da and less than the polyoxyethylene glycol of 400Da and
Ii) at least a ionizable or polare Aminosaeren,
Wherein said repetition alternate cells has similar basically molecular weight, and the Mw scope of described polymkeric substance is at the extremely about 300kDa of about 15kDa.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99294007P | 2007-12-06 | 2007-12-06 | |
| US60/992,940 | 2007-12-06 | ||
| PCT/US2008/085583 WO2009073814A2 (en) | 2007-12-06 | 2008-12-04 | Oligo-ethylene glycol-based polymer compositions and methods of use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102007168A true CN102007168A (en) | 2011-04-06 |
Family
ID=40718502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008801262822A Pending CN102007168A (en) | 2007-12-06 | 2008-12-04 | Oligo-ethylene glycol-based polymer compositions and methods of use |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2227223A4 (en) |
| JP (1) | JP2011506644A (en) |
| CN (1) | CN102007168A (en) |
| CA (1) | CA2714156A1 (en) |
| WO (1) | WO2009073814A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002152A (en) * | 2010-10-27 | 2011-04-06 | 中国科学院长春应用化学研究所 | Aliphatic dicarboxylic acid-1,2-propanediol polyester and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2323671A4 (en) * | 2008-08-13 | 2012-09-26 | Medivas Llc | Aabb-poly(depsipeptide) biodegradable polymers and methods of use |
| CN112011267B (en) * | 2020-09-07 | 2021-12-28 | 江苏瑞复达高温新材料股份有限公司 | Heat-preservation and heat-insulation coating and preparation method thereof |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060177416A1 (en) * | 2003-10-14 | 2006-08-10 | Medivas, Llc | Polymer particle delivery compositions and methods of use |
| US7304122B2 (en) * | 2001-08-30 | 2007-12-04 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
| US6503538B1 (en) * | 2000-08-30 | 2003-01-07 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
| US20060013855A1 (en) * | 2004-04-05 | 2006-01-19 | Medivas, Llc | Bioactive stents for type II diabetics and methods for use thereof |
| WO2006132950A2 (en) * | 2005-06-03 | 2006-12-14 | Medivas, Llc | Therapeutic polymers and methods of use |
| JP5178520B2 (en) * | 2005-09-22 | 2013-04-10 | メディバス エルエルシー | Solid polymer delivery compositions and methods of use thereof |
| EP1926780B1 (en) * | 2005-09-22 | 2013-08-14 | Medivas, LLC | Bis-( -amino)-diol-diester-containing poly(ester amide) and poly(ester urethane) compositions and methods of use |
| US20070106035A1 (en) * | 2005-10-26 | 2007-05-10 | Medivas, Llc | Aromatic di-acid-containing poly (ester amide) polymers and methods of use |
| JP2009513783A (en) * | 2005-10-26 | 2009-04-02 | メディバス エルエルシー | Aromatic dibasic acid-containing poly (ester amide) polymers and methods of use |
| JP2009518289A (en) * | 2005-11-21 | 2009-05-07 | メディバス エルエルシー | Polymer particles for delivery of macromolecules and methods of use |
| US8658210B2 (en) * | 2006-04-17 | 2014-02-25 | Advanced Cardiovascular Systems, Inc. | Polyesteramide platform for site specific drug delivery |
| CA2649672C (en) * | 2006-05-02 | 2015-07-07 | Medivas, Llc | Delivery of ophthalmologic agents to the exterior or interior of the eye |
-
2008
- 2008-12-04 JP JP2010537081A patent/JP2011506644A/en active Pending
- 2008-12-04 CN CN2008801262822A patent/CN102007168A/en active Pending
- 2008-12-04 WO PCT/US2008/085583 patent/WO2009073814A2/en active Application Filing
- 2008-12-04 CA CA2714156A patent/CA2714156A1/en not_active Abandoned
- 2008-12-04 EP EP08856254.1A patent/EP2227223A4/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002152A (en) * | 2010-10-27 | 2011-04-06 | 中国科学院长春应用化学研究所 | Aliphatic dicarboxylic acid-1,2-propanediol polyester and preparation method thereof |
| CN102002152B (en) * | 2010-10-27 | 2013-06-12 | 中国科学院长春应用化学研究所 | Aliphatic dicarboxylic acid-1,2-propanediol polyester and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2714156A1 (en) | 2009-06-11 |
| JP2011506644A (en) | 2011-03-03 |
| EP2227223A2 (en) | 2010-09-15 |
| WO2009073814A3 (en) | 2009-12-17 |
| EP2227223A4 (en) | 2013-11-27 |
| WO2009073814A2 (en) | 2009-06-11 |
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Application publication date: 20110406 |