JP2011506644A - Oligo-ethylene glycol based polymer compositions and methods of use - Google Patents

Abstract

The present invention provides biodegradable PEAs, PEURs and PEUs synthesized by solution polycondensation to include α-amino acids and oligo-ethylene ether segments in the polymer backbone. The polymer can be obtained by replacing aliphatic diacids and diols with oligo-ethylene glycol (OEG) during their manufacture. Also provided are compositions in which the bioactive agent is dispersed in the polymer. The composition is biodegraded enzymatically to release incorporated bioactive substances and oligo-ethylene glycol segments, which are completely biodegradable at molecular weights below 400 Da. Because of its relatively rapid enzymatic hydrolysis at the surface, the composition should be used to deliver bioactive agents in a controlled manner within a relatively rapid delivery time, such as about 18-24 hours. Can do.

Description

  The present invention relates generally to drug delivery systems, and in particular to polymer compositions that can deliver a variety of different types of molecules in a controlled and sustained release manner.

For any background information sustained delivery, or is a rapid and smooth release, for example, such as for cancer therapeutics and pain relieving drug delivery, for the purpose of developing a composition that controls the delivery profile of the drug, Efforts using various methods have been made. For example, compositions such as micro / nanospheres, liposomes, albumin conjugates, water-soluble prodrugs, cyclodextrin complexes and hydrogels have been attempted for such purposes, but such compositions are There is a tendency to release large initial bursts, so that sustained delivery over a controlled period of time has not been successful.

  In one approach that was considered, a bioactive agent, including a peptide, was combined with polyethylene glycol (PEG) to increase the half-life of the bioactive agent. The delivery profile of such conjugates generally indicates that the half-life of the circulating drug is proportional to the molecular weight of the PEG molecule used. It has been shown that the biokinetics and biodistribution of PEG also depends on the size of the PEG molecule used.

  Despite these developments in the art, polyethylene glycol and for the administration of various bioactive agents, for example, aimed at achieving a smooth release rate profile with sustained delivery over a controlled period of time. There is a need for new and better compositions and methods for using molecules with similar chemical structures.

SUMMARY OF THE INVENTION The present invention relates to oligo-ethylene glycol-containing (OEG-based) molecules comprising poly (ester amide) (PEA), poly (ester urethane) () containing at least one α-amino acid per repeating unit in the polymer backbone. PEUR) and poly (ester urea) (PEU) polymers based on the assumption that they can be introduced into the polymer backbone. Such oligo-ethylene glycol-containing polymers are referred to herein as poly (ester ether amide) (PEEA), poly (ester ether urethane) (PEEUR) and poly (ester ether urea) (PEEU), which are It can be used to formulate biodegradable polymer compositions for rapid release of one or more dispersed bioactive substances in a consistent and reliable manner. For example, such a composition can be used to release a bioactive agent contained therein with a smooth release rate profile within a period of about 24 hours.

式（I）
式中、
nは約15から約150までの範囲であり；
R¹は、(C₂-C₁₂)アルキレン、(C₂-C₁₂)アルケニレンおよび式（II）

式（II）
のα,ω-ジカルボン酸の残基からなる群より独立に選択され、ここで式（II）中のR⁵は(C₂-C₄)アルキレンおよび(C₂-C₄)アルケニレンからなる群より独立に選択され、R⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR¹は、R⁷が(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンである式（II）のα,ω-ジカルボン酸の残基であり；
個々のn個のモノマーにおけるR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、(C₂-C₂₀)アルキレン、(C₂-C₂₀)アルケニレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）

式（III）
の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせから独立に選択される；
b）構造式（IV）によって記載される化学式を有するPEEAポリマー：

式（IV）
式中、
nは約15から約150までの範囲であり、mは約0.1〜0.9の範囲であり：pは約0.9〜0.1の範囲であり；
R¹は、(C₂-C₁₂)アルキレン、(C₂-C₁₂) アルケニレンおよび式（II）のα,ω-ジカルボン酸の残基からなる群より独立に選択され、ここで式（II）中のR⁵は(C₂-C₄)アルキレンおよび(C₂-C₄)アルケニレンからなる群より独立に選択され、R⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR¹は、R⁷が(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンである式（II）のα,ω-ジカルボン酸の残基であり；
R²は、水素、(C₁-C₁₂)アルキル、(C₆-C₁₀)アリール(C₁-C₆)アルキルまたは保護基からなる群より独立に選択され；
個々のm個のモノマーにおけるR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、(C₂-C₂₀)アルキレン、(C₂-C₂₀)アルケニレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせから独立に選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである；
c）構造式（V）によって記載される化学式を有するポリ(エーテルウレタン)（PEEUR）：

式（V）
式中、nは約15から約150までの範囲であり；
個々のn個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴およびR⁶は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおけるR⁴およびR⁶の少なくとも1つは、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択される；
d）一般構造式（VI）によって記載される化学構造を有するPEEUR：

式（VI）
式中、
nは約15から約150までの範囲であり、mは約0.1〜約0.9の範囲であり、pは約0.9〜約0.1の範囲であり；
R²は、水素、(C₁-C₁₂)アルキル、(C₁-C₆)アルキル(C₆-C₁₀)アリールおよび保護基からなる群より独立に選択され；
個々のm個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴およびR⁶は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおけるR⁴およびR⁶の少なくとも1つは、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである；
e）一般構造式（VII）によって記載される化学式を有するポリ(エーテルウレア)（PEEU）：

式（VII）
式中、
nは約15〜約150であり；
個々のn個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択される；ならびに
f）式VIIIは、構造式（VIII）によって記載される化学式を有するPEEUであり、

式（VIII）
式中、
mは約0.1〜約1.0であり；pは約0.9〜約0.1であり；nは約15〜約150であり；
R²は独立に、水素、(C₁-C₁₂)アルキルまたは(C₆-C₁₀)アリールからなる基であり；
個々のm個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである。 Accordingly, in one embodiment, the present invention provides an OEG-based composition in which a bioactive agent is dispersed in a biodegradable polymer. The polymer contains at least one of the following a) to f).
a) Poly (ester ether amide) (PEEA) having the chemical formula described by Structural Formula (I):

Formula (I)
Where
n ranges from about 15 to about 150;
R ¹ is (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and formula (II)

Formula (II)
Independently selected from the group consisting of residues of α, ω-dicarboxylic acids, wherein R ⁵ in formula (II) is a group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene More independently selected and R ⁷ is independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, provided that at least one R ¹ in each polymer is R ⁷ Is the residue of an α, ω-dicarboxylic acid of formula (II), wherein is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
R ³ in each n monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ independently selected from;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), structural formula (III)

Formula (III)
Independently selected from bicyclic fragments of 1,4: 3,6-dianhydrohexitol, fragments of 1,4-anhydroerythritol, and combinations thereof;
b) PEEA polymer having the chemical formula described by Structural Formula (IV):

Formula (IV)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to 0.9; p ranges from about 0.9 to 0.1;
R ¹ is independently selected from the group consisting of (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and the residue of an α, ω-dicarboxylic acid of formula (II), wherein R ⁵ is independently selected from the group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene, and R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂₎ ) Independently selected from the group consisting of alkylene, provided that at least one R ¹ in each polymer is of the formula (II) wherein R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene A residue of an α, ω-dicarboxylic acid of
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl or protecting groups;
R ³ in each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C Independently selected from the group consisting of ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4: 3,6-dianhydrohexitol bicyclic fragment of structural formula (III), 1,4-anhydroerythritol fragment and combinations thereof independently selected Is; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
c) Poly (ether urethane) having the chemical formula described by structural formula (V) (PEEUR):

Formula (V)
Where n ranges from about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
d) PEEUR having the chemical structure described by the general structural formula (VI):

Formula (VI)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to about 0.9, and p ranges from about 0.9 to about 0.1;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₀ ) aryl and protecting groups;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
e) Poly (ether urea) (PEEU) having the chemical formula described by the general structural formula (VII):

Formula (VII)
Where
n is about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
f) Formula VIII is a PEEU having the chemical formula described by Structural Formula (VIII)

Formula (VIII)
Where
m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 15 to about 150;
R ² is independently a group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl or (C ₆ -C ₁₀ ) aryl;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl.

  In another embodiment, the present invention provides a biodegradable OEG-based polymer having a chemical structure described by formula I, IV, V, VI, VII or VIII above.

In yet another aspect, the present invention provides a biodegradable micelle-forming polymer composition useful for delivery of bioactive agents dispersed therein. The composition comprises
b) Water soluble section
Linked with
a) alternating repeating units of hydrophobic regions comprising at least one biodegradable OEG-based polymer of the present invention having the chemical structure described by structural formula I, IV, V, VI, VII or VIII above ( polymer with repeating alternating units). Water soluble area
i) polyethylene glycol with an Mw of 400 Daltons to about 200 Daltons;
ii) Made of alternating repeating units with at least one ionic or polar amino acid. These alternating repeat units have substantially similar molecular weights, and the molecular weight of the polymer ranges from about 15 kDa to 300 kDa.

  In yet another embodiment, the present invention provides at least one of the OEG-based biodegradable polymers of the present invention having the chemical structure described by Structural Formula I, IV, V, VI, VII or VIII above or those For delivering a bioactive agent to a subject by administering to the subject in vivo an OEG-based polymer composition of the invention comprising at least one bioactive agent dispersed in a blend of Provide a method. The composition can be formulated as a liquid dispersion of polymer particles having at least one bioactive agent dispersed therein. The particles are biodegraded by enzymatic action on their surface, releasing the bioactive substance at a substantially zero order release rate over a period of about 24 hours.

FIG. 6 is a graph showing the effect of enzyme (α-chymotrypsin) concentration on the weight loss rate of the OEG-based PEA of the present invention, AP3EG, at 37 ° C. and pH 7.4. PBS buffer is used as a control. (-■-) = PBS buffer; (-●-) = α-chymotrypsin, 0.05 mg / mL; (-▲-) = α-chymotrypsin, 0.10 mg / mL; (-▼-) = α-chymotrypsin, 0.20 mg / mL. 2 is a graph showing the effect of the diacid structure (monomer 1) incorporated in the PEEA of the present invention on its weight loss at 37 ° C. in PBS or α-chymotrypsin medium (0.1 mg / mL). Solid line = enzyme solution. Dotted line = PBS medium. -■-= monomer 1a (di-p-nitrophenyl adipate with 4 methylene groups);-◯-= monomer 1b (di-p-nitrophenyl sebacate with 8 methylene groups). FIGS. 3A-3C show the in vitro lipase-catalyzed biodegradation in terms of weight loss in mg / cm ² units of the three inventive PEEURs compared to those in pure phosphate buffer medium. It is the graph shown by the comparison with that of PEA 8-L-Leu-6 which does not contain an OEG segment. Figure 3A = EG2-Leu-2; Figure 3B = EG3-Leu-2; Figure 3C = EG4-Leu-2. Curve a) Phosphate buffer medium catalyzed by lipase, pH 7.4, t = 37 ° C .; Curve b) Pure phosphate buffer medium; Curve c) PEA 8-L-Leu in phosphate buffer medium catalyzed by lipase -6 disassembly.

DETAILED DESCRIPTION OF THE INVENTION As long as it forms an OEG with a molecular weight (Mw) from 44 (monoethylene glycol) to 400 Da, but not including 400 Da, it is based on the discovery that it is completely biodegradable. At least one ester bond in the polymer backbone is readily introduced into the diol component (and diacid in the case of PEEA) used for polycondensation of the polymer family of the present invention. Due to the structural properties of the PEEA, PEEUR and PEEU polymers of the present invention, compositions made using such polymers are released with a distributed bioactive agent suitable for achieving various therapeutic goals. It can be adjusted to achieve speed. For example, particles and films made using such polymers have a release rate similar to 24-hour infusion, without a large initial burst of drug release and having a substantially zero order release profile. Can be designed to be biodegradable.

  More particularly, in one embodiment, the present invention relates to biodescriptions herein referred to as poly (ether ester amide) (PEEA), poly (ether ester urethane) (PEEUR) and poly (ether ester urea) (PEEU). Biodegradable polymer compositions comprising at least one bioactive agent distributed in at least one of the family of degradable polymers are provided. The polymer used in the present invention comprises at least one OEG-based backbone segment such that upon biodegradation, an OEG-based backbone segment having a molecular weight (Mw) of 400 Da or less is released. Thus, upon biodegradation, the polymer, including its OEG-based segment, is completely biodegraded without the formation of irritants (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, OEG segments of 400 Da or less are screened out of the circulation by the endoreticular and renal system in mammals, so that any polymer degradation products and any biological activity dispersed in the polymer Substances are excluded from circulation when they undergo enzymatic biodegradation.

  Thus, in one embodiment, the PEEA, PEEUR and PEEU polymers of the present invention comprise at least one diol (or in the case of PEEA) comprising an OEG-based segment having a molecular weight of 400 Da or less during polymer fabrication. It is made by using diacid). When only such diols and diacids are used in the production, the PEEA, PEEUR and PEEU polymers produced are analogs of known PEG-containing polymers, but when subjected to biodegradation, the main degradation products are Α-amino acids such as biological α-amino acids, and OEG segments from 44 to less than 400 Da. Therefore, the polymers of the present invention and compositions based on them have higher molecular weight OEG segments as in the case of polymers that form PEG degradation products (ie, those with Mw of 400 Da or higher). It is readily biodegraded by mammalian subjects without irritation due to degradation of polymers containing.

式（I）
式中、
nは約15から約150までの範囲であり；
R¹は、(C₂-C₁₂)アルキレン、(C₂-C₁₂)アルケニレンおよび式（II）

式（II）
のα,ω-ジカルボン酸の残基からなる群より独立に選択され、ここで式（II）中のR⁵は(C₂-C₄)アルキレンおよび(C₂-C₄)アルケニレンからなる群より独立に選択され、R⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より独立に選択されるが、ただし例外として各ポリマーにおける少なくとも1つのR¹は式（II）のα,ω-ジカルボン酸の残基であり、ここでR⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンであり；
個々のn個のモノマーにおけるR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、(C₂-C₂₀)アルキレン、(C₂-C₂₀)アルケニレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）

式（III）
の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせから独立に選択される；
b）構造式（IV）によって記載される化学式を有するPEEAポリマー：

式（IV）
式中、
nは約15から約150までの範囲であり、mは約0.1〜0.9の範囲であり：pは約0.9〜0.1の範囲であり；
R¹は、(C₂-C₁₂)アルキレン、(C₂-C₁₂)アルケニレンおよび式（II）のα,ω-ジカルボン酸の残基からなる群より独立に選択され、ここで式（II）中のR⁵は(C₂-C₄)アルキレンおよび(C₂-C₄)アルケニレンからなる群より独立に選択され、R⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より独立に選択されるが、ただし例外として各ポリマーにおける少なくとも1つのR¹は式（II）のα,ω-ジカルボン酸の残基であり、ここでR⁷は(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンであり；
R²は、水素、(C₁-C₁₂)アルキル、(C₆-C₁₀)アリール(C₁-C₆)アルキルまたは保護基からなる群より独立に選択され；
個々のm個のモノマーにおけるR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、(C₂-C₂₀)アルキレン、(C₂-C₂₀)アルケニレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせから独立に選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである；
c）構造式（V）によって記載される化学式を有するポリ(エーテルウレタン)（PEEUR）：

式（V）
式中、
nは約15から約150までの範囲であり；
個々のn個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴およびR⁶は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおけるR⁴およびR⁶の少なくとも1つは、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択される；
d）一般構造式（VI）によって記載される化学構造を有するPEEUR：

式（VI）
式中、
nは約15から約150までの範囲であり、mは約0.1〜約0.9の範囲であり、pは約0.9〜約0.1の範囲であり；
R²は、水素、(C₁-C₁₂)アルキル、(C₁-C₆)アルキル(C₆-C₁₀)アリールおよび保護基からなる群より独立に選択され；
個々のm個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴およびR⁶は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおけるR⁴およびR⁶の少なくとも1つは、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである；
e）一般構造式（VII）によって記載される化学式を有するポリ(エーテルウレア)（PEEU）：

式（VII）
式中、
nは約15〜約150であり；
個々のn個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；かつ
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択される；ならびに
f）構造式（VIII）によって記載される化学式を有するPEEU：

式（VIII）
式中、
mは約0.1〜約1.0であり；pは約0.9〜約0.1であり；nは約15〜約150であり；
R²は独立に、水素、(C₁-C₁₂)アルキルまたは(C₆-C₁₀)アリールからなる基であり；
個々のm個のモノマー中のR³は、水素、(C₁-C₆)アルキル、(C₂-C₆)アルケニル、(C₂-C₆)アルキニル、(C₆-C₁₀)アリール(C₁-C₆)アルキルおよび-(CH₂)₂SCH₃からなる群より独立に選択され；
R⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレン、CH₂CH(OH)CH₂、CH₂CH(CH₂OH)、構造式（III）の1,4:3,6-ジアンヒドロヘキシトールの二環式断片、1,4-アンヒドロエリトリトールの断片およびそれらの組み合わせからなる群より独立に選択されるが、ただし各ポリマーにおける少なくとも1つのR⁴は、(C₂-C₆)アルキルオキシ(C₂-C₁₂)アルキレンからなる群より選択され；かつ
R⁸は独立に(C₁-C₂₀)アルキルまたは(C₂-C₂₀)アルケニルである。 More particularly, in one embodiment, the present invention is at least dispersed in a biodegradable OEG-based polymer comprising at least one of the following a) to f), or a blend thereof: Compositions comprising one bioactive agent are provided.
a) Poly (ester ether amide) (PEEA) having the chemical formula described by Structural Formula (I):

Formula (I)
Where
n ranges from about 15 to about 150;
R ¹ is (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and formula (II)

Formula (II)
Independently selected from the group consisting of residues of α, ω-dicarboxylic acids, wherein R ⁵ in formula (II) is a group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene More independently selected, R ⁷ is independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, except that at least one R ¹ in each polymer is of the formula A residue of an α, ω-dicarboxylic acid of (II), wherein R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
R ³ in each n monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ independently selected from;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), structural formula (III)

Formula (III)
Independently selected from bicyclic fragments of 1,4: 3,6-dianhydrohexitol, fragments of 1,4-anhydroerythritol, and combinations thereof;
b) PEEA polymer having the chemical formula described by Structural Formula (IV):

Formula (IV)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to 0.9; p ranges from about 0.9 to 0.1;
R ¹ is independently selected from the group consisting of (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and the residue of an α, ω-dicarboxylic acid of formula (II), wherein R ⁵ is independently selected from the group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene, and R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂₎ ) Independently selected from the group consisting of alkylene, with the exception that at least one R ¹ in each polymer is the residue of an α, ω-dicarboxylic acid of formula (II), wherein R ⁷ is (C ₂ -C ₆₎ be alkyloxy (C ₂ -C ₁₂₎ alkylene;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl or protecting groups;
R ³ in each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C Independently selected from the group consisting of ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4: 3,6-dianhydrohexitol bicyclic fragment of structural formula (III), 1,4-anhydroerythritol fragment and combinations thereof independently selected Is; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
c) Poly (ether urethane) having the chemical formula described by structural formula (V) (PEEUR):

Formula (V)
Where
n ranges from about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
d) PEEUR having the chemical structure described by the general structural formula (VI):

Formula (VI)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to about 0.9, and p ranges from about 0.9 to about 0.1;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₀ ) aryl and protecting groups;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
e) Poly (ether urea) (PEEU) having the chemical formula described by the general structural formula (VII):

Formula (VII)
Where
n is about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
f) PEEU having the chemical formula described by Structural Formula (VIII):

Formula (VIII)
Where
m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 15 to about 150;
R ² is independently a group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl or (C ₆ -C ₁₀ ) aryl;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl.

For example, in one embodiment, in a polymer described by structural formula (I) or (IV) or both, R ⁷ in each of the n monomers is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, R ⁴ consists of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and any one (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene Selected from the group. In this embodiment, the polymer is biodegraded to form 15-300 OEGs with Mw from 44 to 400 Da, but not including 400 Da.

In yet another embodiment, in the polymer described by structural formula (V) or (VI) or both, R ⁴ or R ⁶ in each of the n monomers is CH ₂ CH (OH) CH ₂ , CH ₂ Selected from the group consisting of CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene. Or, in the polymers described by structural formula (V) or (VI) or both, R ⁴ and R ⁶ in each of the n monomers are both CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₄ ) alkyloxy (C ₂ -C ₈ ) alkylene. In the latter embodiment, the polymer is believed to biodegrade to form 15-300 OEGs with Mw from 44 to 400 Da, but not including 400 Da.

In yet another embodiment, wherein the polymer in the composition is described by structural formula (VII) or (VIII) or both, R ⁴ in each of the n monomers is CH ₂ CH (OH) CH ₂ , CH Selected from the group consisting of ₂ CH (CH ₂ OH) and (C ₂ -C ₄ ) alkyloxy (C ₂ -C ₈ ) alkylene. In this embodiment, the polymer is biodegraded to form 15-300 OEGs with Mw from 44 to 400 Da, but not including 400 Da.

  As used herein, “alkenyl” refers to a straight or branched chain hydrocarbyl group having one or more carbon-carbon double bonds.

  As used herein, “alkynyl” refers to a straight or branched chain hydrocarbyl group having at least one carbon-carbon triple bond.

  As used herein, “aryl” refers to an aromatic group having in the range of 6 to 14 carbon atoms.

  The PEEA, PEEUR and PEEU polymers used in the compositions of the present invention are: The ratio of “m” to “p” in formulas (IV, VI and VIII) is defined as an irrational number in the description of these polycondensate polymers. Further, since “m” and “p” are each considered to occupy a range in any polycondensate, such a range cannot be defined by a pair of integers. Each polymer chain contains all bis-aminoacyldiol-diester (i) and directional amino acid (eg lysine) monomer residues (ii), in the case of PEEA diacid monomer residues (iii) ), In the case of PEEUR by a diol residue (iii) or in the case of PEEU by a carbonyl (iii), by a rule of being linked to themselves or to each other ( string). That is, only linear combinations i-iii-i, i-iii-ii (or ii-iii-i) and ii-iii-ii are formed. Next, each of these combinations is by a diacid monomer residue (iii) in the case of PEEA, by a diol residue (iii) in the case of PEEUR, or by carbonyl (iii) in the case of PEEU. Linked to themselves or to each other. Thus, each polymer chain is an aggregate but non-random series of monomer residues composed of an integer number of monomers i, ii and iii. However, in general, for polymer chains of any realistic average molecular weight (ie sufficient average length), the ratio of “m” to “p” for monomer residues in formulas (IV, VI and VIII) is a natural number It is not considered to be (rational integer). Furthermore, for all polydisperse copolymer chain condensates, the number of monomers i, ii, and iii averaged over the entire chain (ie, normalized to the average chain length) is considered non-integer. The inevitable result is that these ratios can only have irrational values (ie, any real number that is not a rational number). Irrational numbers, as the term is used herein, are derived from ratios that are not of the form n / j where n and j are integers.

As used herein, the terms “amino acid” and “α-amino acid” mean a compound containing an amino group, a carboxyl group, and a pendant R group such as the R ³ group as defined herein. As used herein, the term “biological α-amino acid” means an amino acid used for synthesis selected from phenylalanine, leucine, glycine, alanine, valine, isoleucine, methionine or mixtures thereof. As used herein, the term “non-directional amino acid” refers to a polymer chain derived from an α-amino acid such that an R group (eg, R ⁸ in formulas VI and VIII) is inserted into the interior of the polymer backbone. It means the chemical moiety inside.

  As used herein, the term “bioactive agent” means a bioactive agent disclosed herein that is dispersed in the polymer of the composition of the invention. As used herein, the term “dispersed” as used in reference to a bioactive agent is a term in which the bioactive agent is mixed, dissolved, or homogenized with the polymer. And / or covalently bonded to the polymer, eg, attached to a functional group in the polymer of the composition or the surface of the polymer particle. Such bioactive substances can include, but are not limited to, small molecule drugs, peptides, proteins, DNA, cDNA, RNA, sugars, lipids and whole cells. The bioactive agent can be administered in a state of polymer particles having various sizes and structures suitable for achieving various therapeutic goals and routes of administration.

  As used herein to describe the OEG-based polymer composition of the present invention, the term “biodegradable” means that the polymer used therein is broken down into products that are harmless in the normal functioning of the body. It means to go. This is because the amino acid used in the production of the polymer of the present invention is a biological L-α-amino acid, and the diol and diacid used in the production of the polymer undergo biodegradation from 44 to 400 Da, but does not include 400 Da This is especially true when forming OEG segments. The polymers in the OEG-based polymer compositions of the present invention contain hydrolyzable esters that provide biodegradability and enzymatically cleavable amide bonds, and typically the chain ends are predominantly amino groups. Optionally, the amino terminus of the polymer may be capped in other ways by acetylation or conjugation with any other acid-containing biocompatible molecule, including but not limited to organic acids, bioinert materials and the present specification. The bioactive substances described in the document can also be included. In one embodiment, the entire polymer composition and any particles made therefrom are substantially biodegradable.

In one option, at least one of the α-amino acids used in the production of the OEG-based polymer of the present invention is a biological α-amino acid. For example, when R ³ is CH ₂ Ph, the biological α-amino acid used in the synthesis is L-phenylalanine. In the option where R ³ is CH ₂ CH (CH ₃ ) ₂ , the polymer comprises a biological α-amino acid, L-leucine. By altering R ³ in the monomers described herein, other biological α-amino acids such as glycine (when R ³ is H), alanine (when R ³ is CH ₃ ), valine (R ³ is CH (CH ₃ ) ₂ ), isoleucine (R ³ is CH (CH ₃ ) CH ₂ CH ₃ ), phenylalanine (R ³ is CH ₂ C ₆ H ₅ ) or methionine (R ³ is (CH ₂ ) ₂ SCH ₃ ) and combinations thereof can also be used. In yet another alternative embodiment, all of the various α-amino acids contained in the polymers used to make in the OEG-based polymer composition of the present invention are all of the biological α-amino acids described herein. It is.

  The polymer composition can be formulated to provide various properties. In one embodiment, the PEEA, PEEUR and PEEU polymer particles of the present invention are in vivo when injected in vivo for local delivery to the surrounding tissue / cell of the bioactive agent dispersed therein. Sizing to agglomerate to form a sustained release polymer depot.

  Accordingly, in yet another embodiment, the present invention provides a method for delivering one or more bioactive agents to a local site within a subject's body. In this embodiment, the method of the invention injects an OEG-based polymer composition of the invention formulated as a polymer particle having at least one bioactive agent dispersed therein at an in vivo site in a subject's body. With that. The injected particles agglomerate to form a polymeric depot of increased size particles, which are thought to slowly release the individual particles, which are biodegraded by the enzymatic action described herein. And is thought to release the dispersed bioactive substance. After biodegradation, each polymer molecule is also expected to release into the circulation 15 to 300 oligo-ethylene glycol (OEG) molecules having a molecular weight of 44 to 400 Da, but not including 400 Da. As described herein, the number of oligo-ethylene glycol (OEG) molecules having a molecular weight of 400 Da or less, released by biodegradation of any particular polymer, depends on the diol used to make the polymer and It is thought to depend on the choice of diacid.

  A dispersion of OEG-based PEEA, PEEUR, or PEEU particles can be injected parenterally, for example, into a body site such as subcutaneous, intramuscular, or organ. Polymer particles of a size that can be passed through a pharmaceutical syringe needle in the range of about 19 to about 27 gauge, such as those having an average diameter in the range of about 1 μm to about 200 μm, can be injected into the body site; They are believed to agglomerate to form large sized particles that form a depot that locally dispenses the dispersed bioactive agent. In other embodiments, the biodegradable polymer particles act as a carrier for the bioactive agent to enter the circulation for systemic targeted and sustained release. It is believed that polymer particles of the present invention having a size in the range of about 10 nm to about 500 nm enter directly into the circulation for such purposes.

  The biodegradable polymer used in the OEG-based polymer composition of the present invention is designed to adjust the rate of biodegradation of the polymer to provide controlled delivery of the bioactive agent over a selected period of time. Can do. For example, typically a thin disk of the composition of the invention will cause a weight loss of about 81% to 56% weight loss within 24 hours (eg, as seen in vivo). Biodegraded by surface erosion in solution.

  The present invention is biodegradable in order to deliver a wide variety of bioactive substances at a rate that can be artificially manipulated by the choice of polymer and particle size in the treatment of a wide variety of diseases and disease symptoms. A delivery approach through polymer particles is used. Although some of the individual components of the polymer compositions and methods described herein have been known, such combinations have heretofore been achieved for the time interval during which the bioactive agent is released. It is unexpected and surprising that it is thought that it allows clinicians to select biodegradable polymers, bioactive substances and particle sizes to control beyond the level of control they have. there were.

Polymers suitable for use in the practice of the present invention, described by structural formulas (I and IV-VIII), are functional groups that allow easy covalent attachment of bioactive substances or coating molecules to the polymer. Have sex. For example, a polymer having a carboxyl group can readily react with an amino moiety, thereby allowing the peptide and the polymer to be covalently linked through the resulting amide group. As described herein, the biodegradable polymer and bioactive agent may include various supplemental functional groups that can be used to covalently link the bioactive agent and the biodegradable polymer. For example, polycondensation of active bis-carbonates (compounds 4a-c in Example 2) with oligo-ethylene glycol (OEG) based di-p-toluenesulfonate (compounds 2a-e in Example 2 below) PEEUR formed by may be useful as a biodegradable analog of PEG for various chemical and biochemical applications.

  Monomers 2a-e can be synthesized by direct condensation of α-amino acids with OEG as the monomer as described in the examples below. Alternatively, various hydrophobic α-amino acids can be used to synthesize monomers 2a-e using peptide chemistry methods well known to those skilled in the art. The latter method allows for the adjustment of the hydrophilic / hydrophobic balance of the biodegradable OEG-based polymer of the present invention. Thus, the properties and biological applications of the polymers and compositions of the present invention can vary widely.

For example, all hetero bonds in the backbone of PEEUR—ether bonds and urethane bonds—are hydrophilic and therefore increase the water solubility of these polymers. By judicious selection of lateral R ³ substituents in the α-amino acids linking the OEG segments, the hydrophilic / hydrophobic balance of the OEG-containing polymers of the present invention is well known in the art and described herein. Can be adjusted using such principles.

  The PEEA, PEEUR and PEEU of the present invention, as well as other polymers obtained via solution active polycondensation, are well known in the art for subsequent chemical / biochemical applications. It contains two end groups that can be used to functionalize using methods such as those described herein. In addition, interaction with mono-ethanolamine allows the terminal active carbonate groups of the polymer to be converted to oxy-ethylurethane groups to increase the hydrophilicity of the polymer.

  Alternatively or additionally, terminal OH groups can be used for subsequent transformations, for example to attach acrylates. In a similar manner, SH-terminated PEEUR can be synthesized by interaction with mercapto-amine. The SH-terminated PEEUR can be attached under mild conditions with a polymer containing an active double bond moiety, eg, a fumaric acid-based unsaturated PEA, as described below, or subsequent conversion. Can also be used for

  The PEEURs of the present invention can also be used for chemical / photochemical grafting to other unsaturated polymers, such as, for example, fumaric acid based unsaturated PEAs to impart hydrophilicity or water solubility to them.

  PEEA, PEEUR and PEEU terminated with unsaturated maleimide rings are of interest for the attachment of polymers used in the compositions of the invention with HS-containing molecules, such as proteins, enzymes, peptides, etc. Can be synthesized in several ways. For example, maleimide-terminated polymers can be synthesized by interaction of terminal amino groups with excess N.N'-alkylene-bis-maleimide, or with active diesters such as N-maleimide-β-alanine. Can do.

  Also, SH-terminated polymers (formed as described above) can be converted to maleimide-terminated PEEA, PEEUR by interaction of terminal amino groups with excess N.N'-alkylene-bis-maleimide. And can also be used to synthesize PEEU.

Terminally active carbonate groups can be converted to maleimide ends according to the following scheme.

  The polymers in the OEG-based polymer composition of the present invention can be produced at the local injection site by allowing the bioactive agent to remain at the injection site for a period of time sufficient for individual endogenous processes to interact with the bioactive agent. It plays an active role in the treatment process, while releasing particles or polymer molecules containing such substances in the course of polymer biodegradation. Fragile bioactive substances are protected by more slowly biodegradable polymers, increasing the half-life and persistence of the bioactive substance.

  In addition, the polymers disclosed herein (eg, those having the structural formulas (I and IV-VIII) result in α-amino acids when subjected to enzymatic degradation, while other degradation products contain fatty acids and Either OEG or else diol or diacid that can be metabolized in the manner in which the sugar is metabolized, polymer uptake is safe, studies have shown that the subject metabolizes the polymer degradation products Thus, these polymers and the OEG-based polymer compositions of the present invention can be excreted at the injection site and throughout the body for the subject, except for trauma caused by the injection itself. It is substantially non-inflammatory.

  In PEEA, PEEUR and PEEU polymers useful in the practice of the present invention, multiple different α-amino acids can be used in a single polymer molecule. The polymer may contain at least two different amino acids per repeat unit, and a single polymer molecule may contain multiple different α-amino acids in the polymer molecule, depending on the size of the molecule.

  The polymers described herein can also be used in block copolymers. In yet another embodiment, the polymer can be used as one block in a diblock or triblock copolymer, which can be used, for example, to make micelles, as described below.

  The OEG-based polymer compositions and methods of the present invention are members of a larger family of polyester amide (PEA), polyester urethane (PEUR) and polyester urea (PEU), many of which are unique on the side chain With built-in functional groups, these unique functional groups react with other chemicals to guide the incorporation of other functional groups, further extending the functionality of the polymer. Similarly, OEG-based (ie, PEEA, PEEUR or PEEU) polymers used in the method of the present invention can be used for other chemicals that have a hydrophilic structure to increase the water solubility of the particles without the need for prior modification. It can react immediately with the substance and can react immediately with the bioactive substance and the coating molecule.

  In addition, the OEG-based polymers used in the OEG-based polymer compositions of the present invention show little hydrolytic degradation when tested in saline (PBS) media, such as lipase, chymotrypsin or CT In this enzyme solution, a uniform surface erodible behavior has been observed that results in a substantially zero order release profile as described herein.

  Suitable protecting groups for use in PEEA, PEEUR and PEEU polymers include t-butyl or others known in the art. Suitable 1,4: 3,6-dianhydrohexitols of general formula (III) include those obtained from sugar alcohols such as D-glucitol, D-mannitol or L-iditol. Dianehydrosorbitol is a presently preferred 1,4: 3,6-dianhydrohexitol for use in PEEA, PEEUR and PEEU polymers used in the preparation of the inventive OEG-based polymer compositions of the present invention. Is a bicyclic fragment.

The term “oligo-ethylene glycol (OEG)” as used herein means an oligomer or polymer of ethylene oxide having the chemical structure HO— (CH ₂ —CH ₂ —O) _1-9 —H. The terms “oligo-ethylene glycol containing (OEG containing)” and “oligo-ethylene glycol based (OEG based)” moieties are used herein to release OEG molecules upon enzymatic biodegradation of the polymer. Used to refer to a polymer segment, its OEG may be monodisperse, but more commonly is polydisperse, with a polydispersity index ranging from about 1.05 up to 2.0. The polydisperse OEG molecules described herein are statistically characterized by their weight average molecular weight (Mw) and their number average molecular weight (Mn), the ratio of which is the polydispersity index (Mw / Mn) Called.

The molecular weight and polydispersity herein are determined by gel permeation chromatography (GPC) using polystyrene standards. More specifically, the number average molecular weight and weight average molecular weight (M _n and M _w ) are measured, for example, by a Model 510 gel permeation chromatograph equipped with a high pressure liquid chromatography pump, a Waters 486 UV detector and a Waters 2410 differential refractive index detector. Determined using graphy (Water Associates, Inc., Milford, Mass.). Tetrahydrofuran (THF), N, N-dimethylformamide (DMF) or N, N-dimethylacetamide (DMAc) is used as eluent (1.0 mL / min). Polystyrene or poly (methyl methacrylate) standards with a narrow molecular weight distribution were used for calibration.

Methods for making polymers containing α-amino acids in the general formula are well known in the art. For example, for polymer embodiments of structural formula (I) where R ⁴ is incorporated into an α-amino acid, for polymer synthesis, for example, an α-amino acid with pendant R ³ can be converted to bis- It can be converted to α, ω-diamine. For example, an α-amino acid containing pendant R ³ can be condensed with at least one oligo-ethylene glycol based diol (OEG diol). As a result, an OEG-containing bis-α-aminoacyl diester monomer having a reactive α, ω-amino group is formed. Subsequently, bis-α, ω-diamine enters a polycondensation reaction with a diacid such as adipic acid, sebacic acid or fumaric acid, or with a bis-activated ester or bis-acyl chloride, to form an OEG-containing moiety and ester. The final polymer (PEEA) with ether and amide bonds is obtained. Or, for example, for a polymer of structure (I), instead of a diacid, an activated diacid derivative, such as a bis-para-nitrophenyl diester, can be used as the activated diacid. In addition, bis-di-carbonates such as bis (p-nitrophenyl) oligoether-containing dicarbonates are used as the activated species, and residues of diols containing 2-9 ethylene oxide functionality (ie, containing OEG) It is also possible to obtain a polymer containing a moiety.

  OEG-containing diacid type compounds useful for active polycondensation according to the present invention include α, ω-alkylene dicarboxylic acids of formula (III), which are composed of a short aliphatic non-toxic diacid and OEG as a diol. There is acid.

  These molecules inherently contain at least one ester group that is readily cleavable by biological (enzymatic) and abiotic hydrolysis. The PEEA, PEEUR and PEEU polymer compositions of the present invention have increased hydrophilicity and increased ester groups per unit in the backbone chain compared to previously known PEA, PEUR and PEU polymers. The ester group in some cases confers faster biodegradability than a polymer composed of an aliphatic diol having an alkylene chain and a diacid.

ここで、R⁵＝(CH₂)₂、(CH₂)₃またはCH=CHであり；R⁷＝(-CH₂-CH₂-O-)_kであり、かつk＝1〜9の任意の整数である。
スキーム（I） Examples of the first step of the synthesis include various new OEG-containing diester-diacids (or alkylene-dicarboxylic acids) of structural formula (III), diols, maleic anhydride, succinic anhydride and glutaric anhydride. It can be produced by interaction with a cyclic aliphatic 5-membered or 6-membered anhydride. The general scheme for alkylene-dicarboxylic acid synthesis is shown in Reaction Scheme I below.

Where R ⁵ = (CH ₂ ) ₂ , (CH ₂ ) ₃ or CH = CH; R ⁷ = (— CH ₂ —CH ₂ —O—) _k and k = 1-9 Is an integer.
Scheme (I)

（式IX）
式中、R⁵は、例えば、(CH₂)₂、(CH₂)₃、CH=CHから選択することができ；かつ、R⁷は、k＝1〜9の任意の整数のR⁷＝(-CH₂-CH₂-O-)_kから選択することができる。 As an example of the second step of the synthesis, various active di- (p-nitrophenyl) esters of alkylene-dicarboxylic acids of structural formula IX have been prepared. This reaction is accomplished by the interaction of the diacid formed in the first stage (Formula II) with p-nitrophenol in the presence of various condensing agents.

(Formula IX)
Wherein R ⁵ can be selected from, for example, (CH ₂ ) ₂ , (CH ₂ ) ₃ , CH═CH; and R ⁷ is any integer R ⁷ = k = 1-9. (—CH ₂ —CH ₂ —O—) _k can be selected.

Unsaturated PEEA
(1) Di-p-toluenesulfonate of bis (α-amino acid) diester of unsaturated diol and di-p-nitrophenyl ester of saturated dicarboxylic acid, or (2) Bis (α-amino acid) of saturated diol Di-p-toluenesulfonate of diester and di-nitrophenyl ester of unsaturated dicarboxylic acid, or (3) di-p-toluenesulfonate of bis (α-amino acid) diester of unsaturated diol, and It can be prepared by solution polycondensation of any of the di-nitrophenyl esters of saturated dicarboxylic acids. In the present invention, at least one, and preferably all, of the diols and / or diacids used in the manufacture contain 1 to 8 ether functionalities.

  Salts of p-toluenesulfonic acid are known for use in the synthesis of polymers containing amino acid residues. Aryl sulfonates are used in place of the free base because bis (α-amino acid) diester aryl sulfonates are easily purified by recrystallization and are reactive with amino groups throughout the workup This is because the ammonium tosylate is low. In the polycondensation reaction, the nucleophilic amino group easily appears by the addition of an organic base such as triethylamine, so that a polymer product can be obtained in high yield.

式（X） For polymers of structural formula (I), for example, di-p-nitrophenyl esters of unsaturated dicarboxylic acids are obtained from p-nitrophenyl and unsaturated dicarboxylic acid chlorides, such as triethylamine and p-nitrophenol in acetone. It can be synthesized by dissolving and dropping the unsaturated dicarboxylic acid chloride dropwise with stirring at −78 ° C. and pouring into water to precipitate the product. Suitable acid chlorides include fumaric acid, maleic acid, mesaconic acid, citraconic acid, glutaconic acid, itaconic acid, ethenyl-butanedioic acid and 2-propenyl-butanedioic acid chloride. For polymers of structure (V) and (VI), bis-p-nitrophenyl dicarbonate of saturated or unsaturated diol is used as the activation monomer. A dicarbonate monomer of general formula (X) is used for the polymers of structural formulas (V) and (VI) and each R ¹⁰ is independently one or more of nitro, cyano, halo, trifluoromethyl or tri (C ₆ -C ₁₀ ) aryl optionally substituted with fluoromethoxy; and R ⁶ may be as described above.

Formula (X)

  Di-aryl sulfonates of diesters of α-amino acids and unsaturated diols are mixed with α-amino acids such as p-aryl sulfonic acid monohydrate and saturated or unsaturated diols in toluene to generate water. It can be prepared by heating to reflux temperature to a minimum, followed by cooling. Unsaturated diols free of ether functionality include, for example, 2-butene-1,3-diol and 1,18-octadeca-9-ene-diol.

  Saturated di-p-nitrophenyl esters of dicarboxylic acids and saturated di-p-toluenesulfonates of bis-α-amino acid esters can be prepared as described in US Pat. No. 6,503,538 B1. The synthesis of unsaturated poly (ester amides) (UPEA) useful as biodegradable polymers is known in the art (see, eg, US Pat. Nos. 5,516,881; 6,476,204; 6,503,538). The synthesis of unsaturated PEEA of structural formula (I) is as disclosed above and as described in Example 1 herein.

  For unsaturated compounds having either structural formula (I) or (IV), the following applies: Groups bearing amino-substituted aminoxyl (N-oxide) groups, such as 4-amino TEMPO, can be attached using carbonyldiimidazole or a suitable carbodiimide as a condensing agent. Bioactive agents as described herein can be attached via a double bond functionality. Hydrophilicity can be imparted by bonding with poly (ethylene glycol) diacrylate.

  The biodegradable PEEA, PEEUR and PEEU polymers can contain one to several different α-amino acids per polymer molecule, preferably having a weight average molecular weight in the range of 10,000 to 125,000 g / mol; The polymers and copolymers typically have an intrinsic viscosity at 25 ° C as determined by standard viscometric methods in the range of 0.3 to 3.0, for example in the range of 0.5 to 1.5.

  For unsaturated compounds having the structural formula (VII) for PEEU, the following applies: Groups bearing amino-substituted aminoxyl (N-oxide) groups, such as 4-amino TEMPO, can be attached using carbonyldiimidazole or a suitable carbodiimide as a condensing agent. Other biologically active materials such as those described herein can optionally be attached via the double bond functionality.

スキーム（II）
L-リジンエステルを含み、かつ構造式（VIII）を有するコポリ(エステルウレア)（PEEU）の合成は、類似のスキーム（III）によって行うことができる。

スキーム（III）
トルエン中にあるホスゲン（高毒性）の20％溶液（Fluka Chemie, GMBH, Buchs, Switzerland）を、ジホスゲン（クロロギ酸トリクロロメチル）またはトリホスゲン（ビス(トリクロロメチル)カーボネート）によって置き換えることができる。また、より毒性の低いカルボニルジイミダゾールを、ホスゲン、ジホスゲン、またはトリホスゲンの代わりにビス-求電子性モノマーとして用いることもできる。 For example, the high Mw PEEU of the present invention having the structural formula (VII) can be interfaced by using phosgene as a bis-electrophilic monomer in a chloroform / water system as shown in reaction scheme (II) below. Can be prepared.

Scheme (II)
The synthesis of copoly (ester urea) (PEEU) containing L-lysine ester and having the structural formula (VIII) can be carried out by a similar scheme (III).

Scheme (III)
A 20% solution of phosgene (highly toxic) in toluene (Fluka Chemie, GMBH, Buchs, Switzerland) can be replaced by diphosgene (trichloromethyl chloroformate) or triphosgene (bis (trichloromethyl) carbonate). Also less toxic carbonyldiimidazoles can be used as bis-electrophilic monomers instead of phosgene, diphosgene or triphosgene.

In order to obtain a high Mw PEEU, it is necessary to use a cooled solution of the monomer. For example, add anhydrous sodium carbonate to a suspension of bis (α-amino acid) -α, ω-alkylene diester di-p-toluenesulfonate in 150 mL of water, stir at room temperature for about 30 minutes, Cool to 2-0 ° C. to form the first solution. In parallel, a second solution of phosgene in chloroform is cooled to about 15-10 ° C. The first solution is placed in the reactor for interfacial polycondensation, and the second solution is added immediately and stirred rapidly for about 15 minutes. Subsequently, the chloroform layer can be separated, dried over anhydrous Na ₂ SO ₄ and filtered. The resulting solution can be stored for further use.

  The manufactured PEU polymers are obtained as solutions in chloroform and these solutions are stable during storage. However, certain polymers, such as 1-Phe-4, become insoluble in chloroform after separation. To overcome this problem, PEEU polymer can be separated from chloroform by pouring onto a smooth hydrophobic surface and evaporating the chloroform to dryness. No further purification of the resulting PEEU is necessary. The general procedure for the preparation of PEU is described in published US patent application US2007 / 0128250-A1.

  Polymers useful in the OEG-based polymer compositions of the present invention, such as PEEA, PEEUR and PEEU polymers, are biodegraded on the surface by enzymatic action. For this reason, it has been observed that polymers, such as their particles, administer bioactive substances to a subject at a controlled release rate and their kinetics are close to zero order. Furthermore, because PEEA, PEEUR and PEEU polymers are degraded by enzymes without the generation of harmful byproducts in vivo, the OEG-based polymer compositions of the present invention are substantially non-inflammatory. Even the OEG incorporated inside is of very low Mw, so they are excluded from the body when released from the polymer after biodegradation.

  As used herein, “dispersed” means mixed, dissolved, or dispersed in polymer particles, wherein at least one bioactive agent as disclosed herein is dispersed. Means homogenized, homogenized, and / or covalently bonded (“dispersed”), eg, attached to a functional group in the polymer of the composition or to the surface of the polymer particles.

  Although the bioactive agent can be dispersed in the polymer matrix without chemical bonding to the polymer carrier, the bioactive agent or coating molecule is shared with the biodegradable polymer via a very wide variety of suitable functional groups. It is also envisaged that they can be combined. For example, if the biodegradable polymer is a polyester, the chain end carboxy group can be used to react with a bioactive agent such as hydroxy, amino, thio, or a complementary moiety on the coating molecule. A wide variety of suitable reagents and reaction conditions are disclosed, for example, in March's Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Fifth Edition, (2001); and Comprehensive Organic Transformations, Second Edition, Larock (1999). .

  In other embodiments, the bioactive agent can be linked to the PEEA, PEEUR, or PEEU polymer via an amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl, disulfide bond. Such linkages can be formed from suitably functionalized starting materials using synthetic procedures known in the art.

For example, in one embodiment, the polymer can be linked to the bioactive agent via a polymer end or pendant carboxyl group (eg, COOH). For example, a compound of structure IV, VI and VIII can be reacted with the amino or hydroxyl functional group of a bioactive substance to have a biodegradable substance attached via an amide bond or a carboxylic ester bond, respectively. A polymer can be obtained. In another embodiment, the carboxyl group of the polymer can be benzylated or converted to an acyl halide, acyl anhydride / "mixed" anhydride or active ester. In other embodiments, the free-NH ₂ end of the polymer molecule can be acylated to ensure that the bioactive agent is attached only through the carboxyl group of the polymer rather than to the free end of the polymer.

  Water-soluble coating molecules such as poly (ethylene glycol) (PEG) described herein; phosphorylcholine (PC); glycosaminoglycans including heparin; polysaccharides including polysialic acid; polyserine, polyglutamic acid, polyaspartic acid, Poly (ionic or polar amino acids), including polylysine and polyarginine; chitosan and alginate, etc .; and targeting molecules such as antibodies, antigens and ligands, as are known in the art, bioactive agents It can also be bound to the outside of the particle after production to block the active site not occupied by or to direct delivery of the particle to a specific body part. The Mw of the OEG molecule formed by biodegradation of a single particle, including the coating molecule, is virtually any Mw ranging from about 44 (monoethylene glycol) to 400 Da, but not including 400 Da. As a result, the Mw of the various PEG molecules attached to the particles can vary.

  Alternatively, the bioactive substance or coating molecule can be attached to the polymer via a linker molecule. In fact, to improve the surface hydrophobicity of the biodegradable polymer, to improve the accessibility of the biodegradable polymer to enzymatic activation, and to improve the release profile of the biodegradable polymer A bioactive substance can be indirectly attached to the biodegradable polymer using a linker. In certain embodiments, the linker compound includes a poly (ethylene glycol) having a Mw of about 44 to 400 Da, preferably 200 to 400; an amino acid such as serine; a polypeptide having 1-100 repeats; and any Other suitable low molecular weight polymers are included. The linker typically separates the bioactive material from the polymer from about 5 angstroms to about 200 angstroms.

In yet another embodiment, the linker is a divalent group of formula WAQ, wherein A is (C ₁ -C ₂₄ ) alkyl, (C ₂ -C ₂₄ ) alkenyl, (C ₂ -C ₂₄ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl or (C ₆ -C ₁₀ ) aryl, W and Q are -N (R) C (= O)-, -C (= O) N (R)-, -OC (= O)-, -C (= O) O, -O-, -S-, -S (O), -S (O) _2- , -SS-, -N (R)-,- C (═O) —, where each R is independently H or (C ₁ -C ₆ ) alkyl.

  When used to describe the above linkers, the term “alkyl” includes straight-chain or branched, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like. It refers to a branched chain hydrocarbon group.

  As used herein to describe the above linkers, “alkenyl” refers to a straight or branched chain hydrocarbyl group having one or more carbon-carbon double bonds.

  As used herein to describe the above linkers, “alkynyl” refers to a straight or branched chain hydrocarbyl group having at least one carbon-carbon triple bond.

  As used herein to describe the above linkers, “aryl” refers to an aromatic group having in the range of 6 to 14 carbon atoms.

  In certain embodiments, the linker may be a polypeptide having from about 2 to about 25 amino acids. Suitable peptides envisioned for use include poly-L-glycine, poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L Includes L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-arginine, poly-L-lysine-L-tyrosine, etc. It is.

  In one embodiment, the bioactive agent can covalently crosslink the polymer, i.e., the bioactive agent is associated with a plurality of polymer molecules. This covalent cross-linking can be performed with or without an additional polymer-bioactive agent linker.

  Bioactive agent molecules can also be incorporated into intermolecular crosslinks by covalent attachment between two polymer molecules.

  Linear polymer polypeptide conjugates are made by protecting the potential portion of the nucleophilic group on the polypeptide backbone, leaving only one reactive group attached to the polymer or polymer linker construct. Deprotection is performed according to methods well known in the art for peptide deprotection (eg, Boc and Fmoc chemistry).

  In one embodiment of the invention, the polypeptide bioactive agent is presented as a retro-inverso or partially retro-inverso peptide.

  In other embodiments, the bioactive agent is mixed with a photocrosslinkable type polymer in a matrix, and after crosslinking, the material is dispersed (milled) to an average diameter in the range of about 0.1 to about 10 μm.

The linker can be first attached to the polymer or can be attached to the bioactive agent or coating molecule. During synthesis, the linker may be in an unprotected form or may be in a protected form using various protecting groups well known to those skilled in the art. In the case of a protected linker, the unprotected end of the linker can first be attached to the polymer or bioactive agent or coating molecule. Subsequently, the protecting group can be deprotected using Pd / H ₂ hydrogenolysis, hydrolysis with a weak acid or base, or any other common deprotection method known in the art. Subsequently, the deprotected linker can be attached to the bioactive agent or coating molecule or to the polymer.

  An exemplary synthesis of a biodegradable polymer according to the present invention (the molecule to be attached is aminoxyl) is shown below.

  Polyesters in the presence of groups bearing amino-substituted aminoxyl (N-oxide) groups, such as 4-amino-2,2,6,6-tetramethylpiperidine-1-oxy and N, N′-carbonyldiimidazole Can be substituted with a group bearing an amino-substituted aminoxyl- (N-oxide) group, so that the amino moiety is a carbon of the carbonyl residue of the carboxyl group. To form an amide bond. N, N'-carbonyldiimidazole or a suitable carbodiimide reacts the hydroxyl moiety in the carboxyl group at the chain end of the polyester with an aminoxyl, for example 4-amino-2,2,6,6-tetramethylpiperidine-1-oxy. Convert to the possible intermediate product part. The aminoxyl reactant is typically used in a molar ratio where the reactant: polyester ranges from 1: 1 to 100: 1. The molar ratio of N, N′-carbonyldiimidazole to aminoxyl is preferably about 1: 1.

  One typical reaction is as follows. The polyester is dissolved in the reaction solvent, and the reaction is immediately performed at the temperature used for the dissolution. The reaction solvent may be any that is believed to dissolve the polyester. If the polyester is polyglycolic acid or poly (glycolide-L-lactide) (the monomer molar ratio of glycolic acid to L-lactic acid is greater than 50:50), it is highly purified from 115 ° C to 130 ° C ( Dimethyl sulfoxide (purity greater than 99.9%) or room temperature dimethyl sulfoxide (DMSO) suitably dissolves the polyester. If the polyester is poly-L-lactic acid, poly-DL-lactic acid or poly (glycolide-L-lactide) (the molar ratio of glycolic acid to L-lactic acid is 50:50 or less than 50:50), from room temperature Tetrahydrofuran, dichloromethane (DCM) and chloroform up to 40-50 ° C. suitably dissolve the polyester.

Polymer-bioactive substance binding
In one embodiment, the polymer used to make the inventive OEG-based polymer composition described herein has one or more bioactive agents directly linked to the polymer. The polymer residues can be linked to one or more bioactive agent residues. For example, one residue of the polymer can be directly linked to one residue of the bioactive agent. Each polymer and bioactive material can have one open valence. Alternatively, multiple bioactive agents, multiple bioactive agents, or a mixture of bioactive agents having different therapeutic or symptomatic activity can be linked directly to the polymer. However, because each bioactive residue can be linked to a corresponding polymer residue, the number of residues in one or more bioactive agents is determined by the number of free valences on the polymer residue. Can correspond to a number.

  As used herein, “polymer residue” refers to a group of a polymer having one or more vacant valences. While any synthetically feasible single atom, multiple atoms, or functional groups (e.g., on the polymer backbone or pendant groups) of the polymers of the present invention can be removed to obtain free valences, However, this is conditional on the biological activity being substantially maintained when the group is attached to a residue of the biologically active substance. In addition, any synthetically feasible functional group (eg, carboxyl) can be created on the polymer (eg, on the polymer backbone or pendant group) to obtain a free valence, although this is also the case when the group is biological The condition is that the biological activity is substantially maintained when attached to the residue of the active substance. Based on the desired linkage, one skilled in the art can select suitably functionalized starting materials that can be obtained from the polymers of the present invention using procedures known in the art.

As used herein, a “residue of a compound of structure ( ^* )” is one of formulas (I) and (IV-VIII) as described herein having one or more vacant valences. It refers to a group of a polymer compound. Any synthetically feasible atom, multiple atoms, or functional groups (eg, on the polymer backbone or pendant group) of a compound can be removed to obtain a free valence, but this Is provided that the biological activity is substantially maintained when the group is attached to a residue of the biologically active substance. In addition, any synthetically feasible functional group (eg carboxyl) can be created on a compound of formula (I) and (IV-VIII) (eg on the polymer backbone or pendant group) to obtain a free valence. This is also provided that the biological activity is substantially retained when the group is attached to a residue of the biologically active substance. Based on the desired linkage, one skilled in the art will select a suitably functionalized starting material that can be obtained from compounds of formulas (I) and (IV-VIII) using procedures known in the art. can do.

For example, a residue of a bioactive substance may be converted to an amide (eg, —N (R) C (═O) — or —C (═O) N (R) —), an ester (eg, —OC (═O) — Or -C (= O) O-), ether (eg -O-), amino (eg -N (R)-), ketone (eg -C (= O)-), thioether (eg- The structural formula (S-), sulfinyl (eg -S (O)-), sulfonyl (eg -S (O) _2- ), disulfide (eg -SS-) or direct (eg CC bond) bond It can be linked to the residue of the compound of I) or (IV), wherein each R is independently H or (C ₁ -C ₆ ) alkyl. Such linkages can form suitably functionalized starting materials using synthetic procedures known in the art. Based on the desired linkage, one of ordinary skill in the art will use procedures known in the art to remove from a residue of a compound of structural formula (I) or (IV) and to a given residue of a bioactive or auxiliary substance. A suitably functionalized starting material can be selected which can be obtained from The residue of the bioactive substance or auxiliary substance can be linked to any synthetically feasible position of the residue on the compound of structural formula (I) or (IV). Furthermore, the present invention also provides a compound having a plurality of residues of a bioactive substance or auxiliary bioactive substance directly linked to a compound of structural formula (I) or (IV).

  The number of bioactive substances that can be linked to a polymer molecule typically can depend on the molecular weight of the polymer. For example, for compounds of structural formula (I) where n is from about 5 to about 150, preferably from about 5 to about 70, up to about 150 organisms can be obtained by reacting the bioactive agent with the side groups of the polymer. The molecule of active agent (ie its residue) can be directly linked to the polymer (ie its residue). For unsaturated polymers, the bioactive agent can also be reacted with double bonds in the polymer.

  The PEEA, PEEUR and PEEU polymers described herein absorb water (uptake of 5-25% w / w water on the polymer film) and hydrophilic molecules diffuse easily through it Make it possible. This feature makes these polymers suitable for use as an over coating on the particles to control the release rate. Moisture absorption also improves the biocompatibility of polymers and polymer compositions based on such polymers. In addition, due to the hydrophilic nature of PEEA, PEEUR and PEEU polymers, the particles become sticky and agglomerated when delivered in vivo, especially at in vivo temperatures. Thus, polymer particles spontaneously form polymer depots when injected subcutaneously or intramuscularly for local delivery, such as by hypodermic needle or needleless injection. Particles with an average diameter in the range of about 1 micrometer to about 100 micrometers, which are sized not to circulate efficiently in the body, are suitable for forming such polymer depots in vivo. Alternatively, for oral administration, the gastrointestinal tract can tolerate much larger particles, for example, microparticles having an average diameter from about 1 micrometer to about 1000 micrometers.

  Particles suitable for use in the OEG-based polymer compositions of the present invention can be prepared using immiscible solvent techniques. In general, these methods require the preparation of two immiscible liquid emulsions. A single emulsion method can be used to make polymer particles that incorporate at least one hydrophobic bioactive agent. In the single emulsion method, the bioactive substance to be incorporated into the particles is first mixed with the polymer in a solvent and then emulsified in an aqueous solution with a surface stabilizer such as a surfactant. In this way, polymer particles containing the hydrophobic bioactive substance conjugate are formed and suspended in the aqueous solution, and the hydrophobic conjugate in the particles therein is stable without significant elution in the aqueous solution. However, such molecules are thought to elute in body tissues such as muscle tissue.

  Most biologics, including polypeptides, proteins, DNA, cells, etc., are hydrophilic when using this terminology herein. The double emulsion method can be used to make polymer particles containing an internal aqueous phase and a hydrophilic bioactive material dispersed therein. In the double emulsion method, a hydrophilic bioactive substance dissolved in an aqueous phase or water is first emulsified in a polymer lipophilic solution to form a primary emulsion, and then the primary emulsion is added to water and emulsified again. By forming a secondary emulsion, particles are formed having a continuous polymer phase and an aqueous bioactive material in a dispersed phase. In any emulsification method, a surfactant and an additive can be used to prevent aggregation of particles. Chloroform or DCM immiscible in water is used as the solvent for PEA and PEUR polymers, but at a later point in the preparation, the solvent is removed using methods known in the art.

  However, these two emulsion methods have limitations for certain biologically active substances with low water solubility. In this context, “low water solubility” is less hydrophobic than a truly lipophilic drug such as Taxol, but less hydrophilic than a truly water soluble drug such as many biologics. Means active agent. These types of intermediate compounds are too hydrophilic for high loading and stable matrixing into single emulsion particles, but are highly hydrophobic for high loading and stability within double emulsions. Pass. In such cases, a triple emulsion process coats the polymer layer with particles of poorly water-soluble polymer and drug. In this way, the resulting drug loading is relatively low (approximately 10% w / w), but provides structural stability and controlled drug release rate.

  In the triple emulsion process, the bioactive substance is mixed into a polymer solution and the mixture is emulsified in an aqueous solution with a surfactant or lipid, such as di- (hexadecanoyl) phosphatidylcholine (DHPC; a short-chain derivative of a natural lipid). Thus, the first emulsion is prepared. In this way, particles containing the active substance are formed and suspended in water to form a first emulsion. The second emulsion is formed by adding the first emulsion to the polymer solution and emulsifying the mixed solution, and as a result, water droplets containing polymer / drug particles therein are formed in the polymer solution. Water and surfactants or lipids cause the particles to separate and dissolve the particles in the polymer solution. Subsequently, the second emulsion is added to the surfactant or lipid aqueous solution, and the mixture is emulsified to form the final particles in water to form a third emulsion. The resulting particle structure has one or more particles of polymer and bioactive material in the center, surrounded by water and a surface stabilizer such as surfactant or lipid, which is pure It is thought that it is covered with a polymer shell. Surface stabilizers and water are believed to prevent the solvent in the polymer coating from contacting and dissolving the particles inside the coating.

  In order to increase the filling of the bioactive substance by the triple emulsion method, the active substance with low water solubility is coated with a surface stabilizer in the first emulsion without polymer coating and without dissolving the bioactive substance in water can do. In this first emulsion, the water, surface stabilizer and active substance have comparable volumes, or each have a volume ratio in the range of (1-3) :( 0.2 to about 2): 1. In this case, water is used not to dissolve the active substance but to protect the bioactive substance with the help of surface stabilizers. Subsequently, double and triple emulsions are prepared as described above. This method provides drug loading up to 50%.

  Alternatively or additionally, in the single, double or triple emulsion method described above, the bioactive agent can be combined with the polymer molecules described herein prior to using the polymer to make the particles. it can. Additionally or alternatively, the bioactive agent can be combined with the polymer outside of the particles described herein after production of the particles.

  Many emulsification techniques are believed to be successful in making the above emulsions. However, the presently preferred method of making the emulsion is by using a solvent that is immiscible with water. For example, in a single emulsion method, the emulsification procedure involves dissolving the polymer with a solvent, mixing with the molecules of the bioactive agent, adding to water, and subsequently stirring with a mixer and / or sonicator. It consists of stages. The size of the particles can be controlled by controlling the agitation rate and / or the concentration of polymer, bioactive agent and surface stabilizer. The thickness of the coating can be controlled by adjusting the ratio of the second emulsion to the third emulsion.

  Suitable emulsion stabilizers include nonionic surfactants such as mannide monooleate, dextran 70,000, polyoxyethylene ether, polyglycol ether, all of which are commercially available, for example, Sigma Easily available from Chemical Co., St. Louis, Mo. The surfactant is considered to be present at a concentration of about 0.3% to about 10%, preferably from about 0.5% to about 8%, more preferably from about 1% to about 5%.

  The release rate of the at least one bioactive agent from the composition of the present invention can be controlled by adjusting the coating thickness, particle size, structure, and coating density. The density of the coating can be adjusted by adjusting the loading of the bioactive material associated with the coating. For example, if the coating does not contain a bioactive agent, the polymer coating is the most dense and the bioactive agent elutes most slowly through the coating from the inside of the particle. In contrast, when the bioactive agent is loaded into the polymer in the coating (ie, mixed or “matrixed”), or alternatively bound to the polymer in the coating, the bioactive agent is removed from the polymer. The coating becomes porous when it begins to elute from the outer surface of the coating. As a result, the bioactive substance at the center of the particle can be eluted at an increased rate. The higher the packing in the coating, the lower the density of the coating layer and the higher the dissolution rate. The bioactive agent loading in the coating may be lower or higher than that in the interior of the particles below the outer coating. The release rate of the bioactive substance from the particles can also be controlled by mixing particles with different release rates prepared as described above.

  A detailed description of how to make double and triple emulsion polymers can be found in Pierre Autant et al, US Pat. No. 6,022,562; Iosif Daniel Rosca et al., Microparticle formation and its mechanism in single and double emulsion solvent evaporation, Journal of Controlled Release. (2004) 99: 271-280; L. Mu and A Feng, A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS, J. Control. Release (2003) 86: 33-48 ; Somatosin containing biodegradable microspheres prepared by a modified solvent evaporation method based on W / O / W-multiple emulsions, Int. J. Pharm. 126 (1995) 129-138, and F. Gabor et al., Ketoprofenpoly (d, l -lactic-co-glycolic acid) microspheres: influence of manufacturing parameters and type of polymer on the release characteristics, J. Microencapsul. (1999) 16 (1): 1-12, each of which is hereby incorporated in its entirety. Incorporated into the book.

  In yet another embodiment for delivery of a water soluble bioactive agent, the particles can be made as nanoparticles having an average diameter of about 20 nm to about 200 nm for delivery to the circulation. Nanoparticles can be made by a single emulsion method, as described above, in which the active substance is dispersed internally, ie mixed in an emulsion or bound to a polymer. Nanoparticles can also be provided as micelles comprising a PEA or PEUR polymer as described herein with a bioactive agent bound thereto. As an alternative or in addition to the bioactive substance bound to the polymer, the micelles are formed in water, so that the water-soluble bioactive substance can also be loaded into the micelles simultaneously without a solvent.

  More specifically, biodegradable micelles are formed of hydrophobic polymer chains that are joined with water-soluble ionized polymer chains. The outer part of the micelle consists mainly of a water-soluble ionized or polar area of the polymer, while the hydrophobic area of the polymer is mainly distributed inside the micelle and anchors the polymer molecules.

The biodegradable hydrophobic areas of the polymers used to make micelles are made of PEEA, PEEUR or PEEU polymers as described herein. For highly hydrophobic PEEA, PEEUR or PEEU polymers, di-L-leucine ester of 1,4: 3,6-dianhydro-D-sorbitol or α, ω-bis (4-carboxyphenoxy) (C ₁ -C ₈ ) Components such as rigid aromatic diacids such as alkanes may be included in the polymer repeat unit. In contrast, the water-soluble area of the polymer is
i) a polyethylene glycol having an Mw of at least 200 and less;
b) comprising alternating repeating units with at least one ionic or polar amino acid, wherein the alternating repeating units have substantially the same molecular weight and the polymer Mw is in the range of about 10 kD to 300 kD is there. The alternating repeating units can have substantially similar molecular weights ranging from about 300 Da to about 700 Da. In one embodiment where the molecular weight of the polymer is greater than 10 kDa, the at least one amino acid unit is an ionic or polar amino acid selected from serine, glutamic acid, aspartic acid, lysine and arginine. In one embodiment, the unit of ionic amino acid comprises at least one block of ionic poly (amino acid) such as glutamic acid or aspartic acid, which can be included in the polymer. The micelle composition of the present invention may further comprise a pharmaceutically acceptable aqueous medium having a pH value at which at least a portion of the ionic amino acids in the water soluble region of the polymer is ionized.

  The higher the molecular weight of the water-soluble segment of the polymer, the greater the micelle porosity, and the more micelles are loaded with water-soluble and / or large bioactive substances such as proteins. Thus, in one embodiment, the molecular weight of the fully water soluble section of the polymer is in the range of about 5 kDa to about 100 kDa.

  Once formed, the micelles can be lyophilized for storage and transport and reconstituted in the aqueous medium described above. However, it is not recommended to freeze-dry micelles containing certain biologically active substances, such as certain proteins, that would be denatured by the lyophilization process.

  The charged parts inside the micelles are partially separated from each other in the water, creating a space for the absorption of water-soluble agents such as bioactive substances. Ionized chains with the same type of charge are thought to repel each other and create more space. The ionized polymer also attracts bioactive substances and provides stability to the matrix. In addition, the water-soluble exterior of the micelle prevents adhesion between the micelle and the protein in the body fluid after the ionization site has been captured by the therapeutic bioactive substance. This type of micelle is very porous, reaching up to 95% of the micelle volume, allowing a high degree of filling of water-soluble biologics such as polypeptides, DNA and other bioactive substances. Micellar particle size ranges from about 20 nm to about 200 nm, preferably about 20 nm to about 100 nm for circulation in blood.

  The size of the particles can be determined, for example, by dynamic light scattering using a spectrometer incorporating a helium-neon laser. In general, the size of the particles is determined at room temperature and involves multiple (eg, 5-10) analyzes of the sample to determine the average diameter of the particles. Also, the size of the particles is determined immediately using a scanning electron microscope (SEM). To do so, dry particles are sputter coated with a gold / palladium mixture to a thickness of approximately 100 Angstroms and subsequently inspected using a scanning electron microscope. Alternatively, the polymer in particle or other form is incorporated into the polymer without chemical attachment (“filling”) using any of several methods well known in the art and described below. Instead, it can also be attached directly to the biologically active substance by a covalent bond. The content of the bioactive substance is generally about 0.1% to about 40% (w / w) bioactive substance, more preferably about 1% to about 25% (w / w) bioactive substance relative to the polymer, Even more preferred is an amount corresponding to about 2% to about 20% (w / w) of bioactive material. The percentage of bioactive agent will depend on the desired dose and the condition being treated, as discussed in more detail below.

  Bioactive materials for dispersion into and release from the biodegradable polymer composition of the present invention include anti-proliferants, rapamycin and analogs or derivatives thereof, paclitaxel or taxanes thereof. Any of the analogs or derivatives, everolimus, sirolimus, tacrolimus, or any of the drug families named as ~ limus, and statin drugs such as simvastatin, atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin, 17AAG (17 Geldanamycins such as -allylamino-17-demethoxygeldanamycin); epothilone D and other epothilones, 17-dimethylaminoethylamino-17-demethoxy-geldanamycin, and heat shock protein 90 (Hsp90 ), Shi Other polyketide inhibitors such as rostazole are also included.

  Other bioactive substances envisaged for dispersion in the polymers used in the OEG-based polymer compositions of the present invention are produced endogenously by endothelial cells when released or eluted from the polymer particles during degradation. Agents that promote endogenous production of therapeutic natural wound healing substances such as nitric oxide are included. Alternatively, bioactive substances released from the polymer during degradation may have direct activity in promoting the natural wound healing process by endothelial cells. These biologically active substances donate, transport or release nitric oxide, increase endogenous nitric oxide levels, stimulate endogenous synthesis of nitric oxide, or serve as substrates for nitric oxide synthase. Or any agent that inhibits smooth muscle cell proliferation. Such agents include, for example, aminoxyls, furoxans, nitrosothiols, nitrates and anthocyanins; nucleosides such as adenosine, and adenosine diphosphate (ADP) and adenosine triphosphate (ATP). ); Nucleotides such as acetylcholine and 5-hydroxytryptamine (serotonin / 5-HT); neurotransmitters / neuromodulators such as histamine; and catecholamines such as adrenaline and noradrenaline; Lipid molecules; amino acids such as arginine and lysine; peptides such as bradykinin, substance P and calcium gene-related peptide (CGRP), and tags such as insulin, vascular endothelial growth factor (VEGF) and thrombin It includes Park quality.

  Various bioactive substances, coating molecules and ligands of bioactive substances can be attached to the surface of the polymer particles, for example by covalent bonds. Biologically active substances such as targeting antibodies, polypeptides (eg, antigens) and drugs can be covalently attached to the surface of the polymer particles. In addition, coating molecules, such as polyethylene glycol (PEG) as a ligand for the attachment of antibodies or polypeptides, or attachment sites on the surface of particles to prevent the particles from sticking to non-target biomolecules and surfaces in the patient's body Phosphatidylcholine (PC) or the like as a means for blocking can also be bound to the surface.

  For example, small proteinaceous motifs such as the B domain of bacterial protein A and functionally equivalent regions of protein G are known to bind to antibody molecules through the Fc region and thereby capture the antibody molecule. Such proteinaceous motifs can be attached to the polymer, in particular to the surface of the polymer particle. Such molecules are, for example, as ligands for attaching antibodies for use as targeting ligands, or to capture antibodies to retain progenitor cells, or to capture cells from the patient's bloodstream It is thought to act as a ligand for For this reason, the types of antibodies that can be attached to the polymer coating using the protein A or protein G functional region are those that contain an Fc region. The capture antibody then appears to bind and retain progenitor cells such as progenitor cells in the vicinity of the polymer surface, during which the progenitor cells, preferably immersed in the growth medium inside the polymer, have various factors. Secretes and interacts with other cells of interest. In addition, one or more bioactive substances dispersed in the polymer particles, such as bradykinin, may activate progenitor cells.

  In addition, biologically active substances for attaching to progenitor cells from the blood of a subject or for capturing endothelial progenitor cells (PEC) include monoclonal antibodies against known progenitor cell surface markers. For example, complementarity determinants (CD) reported to modify the surface of endothelial cells include CD31, CD34, CD102, CD105, CD106, CD109, CDw130, CD141, CD142, CD143, CD144, CDw145, CD146, CD147 And CD166. These cell surface markers may be of various specificities, and the degree of specificity for a particular cell / development type / stage is often not well characterized. In addition, these cell marker molecules for which antibodies are produced are thought to overlap (with respect to antibody recognition) with CDs on cells of the same lineage, in particular in the case of endothelial cells, on monocytes. Blood progenitor endothelial progenitor cells are in the process along the developmental pathway from (bone marrow) monocytes to mature endothelial cells. CDs 106, 142 and 144 have been reported to mark mature endothelial cells with some specificity. CD34 is currently known to be specific for endothelial progenitor cells, so at present, endothelial progenitor cells from the blood are sited at the site where polymer particles are implanted for local delivery of active agents. Preferred to capture. Examples of such antibodies include single chain antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, antibody fragments, Fab fragments, IgA, IgG, IgM, IgD, IgE and humanized antibodies, and active fragments thereof. .

  The following additional bioactive agents and small molecule drugs are sized to form a sustained release biodegradable polymer depot for local delivery of the bioactive agent as described herein. Regardless of whether it is sized to enter the systemic circulation or not, it is believed to be particularly effective for dispersion in the polymer particle composition of the present invention. The bioactive substances dispersed in the polymer particles used in the therapeutic polymer composition of the present invention and the method of treatment are in terms of their suitable therapeutic or palliative effects in the treatment of the disease of interest or its symptoms. It is considered to be selected.

  In one embodiment, suitable bioactive agents include, but are not limited to, various classes of compounds that promote or contribute to wound healing when provided in a sustained release manner. Such bioactive agents include wound healing cells including certain progenitor cells, which can be protected and delivered by biodegradable polymer particles in the compositions of the present invention. Such wound healing cells include, for example, pericytes and endothelial cells, and inflammatory healing cells. In order to mobilize such cells in vivo to the site of the polymer depot, the polymer particles used in the compositions and therapeutic methods of the present invention are antibodies and small molecules that specifically bind to “cell adhesion molecules” (CAM). A ligand for such a cell, such as a ligand, can be included. Exemplary ligands for wound healing cells include cells such as ICAM-1 (CD54 antigen); ICAM-2 (CD102 antigen); ICAM-3 (CD50 antigen); ICAM-4 (CD242 antigen); and ICAM-5 Internal adhesion molecule (ICAM); Vascular cell adhesion molecule (VCAM) such as VCAM-1 (CD106 antigen); NCAM-1 (CD56 antigen); or Neural cell adhesion molecule (NCAM) such as NCAM-2; PECAM-1 ( Those that specifically bind to the platelet endothelial cell adhesion molecule PECAM such as CD31 antigen); LECAM-1; or leukocyte endothelial cell adhesion molecule (ELAM) such as LECAM-2 (CD62E antigen).

  In another aspect, suitable biologically active agents include extracellular matrices that are macromolecules that can be dispersed in polymer particles used in the compositions of the invention attached, for example, covalently or non-covalently. Contains protein. Examples of useful extracellular matrix proteins include, for example, glycosaminoglycans (proteoglycans) that are normally linked to proteins, and fibrillar proteins (eg, collagen; elastin; fibronectin and laminin). Bio-mimics of extracellular proteins can also be used. These are usually non-human but biocompatible glycoproteins such as alginate and chitin derivatives. Wound healing peptides that are specific fragments of such extracellular matrix proteins and / or their biomimetics can also be used as bioactive agents.

  Proteinaceous growth factors are a further category of bioactive agents suitable for dispersion in the polymer particles used in the compositions and therapeutic methods of the invention described herein. Such bioactive agents are effective in promoting wound healing and other disease states, as is known in the art. For example, platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF), keratinocyte growth factor (KGF), thymosin B4; and vascular endothelial growth factor (VEGF) Various angiogenic factors such as fibroblast growth factor (FGF), tumor necrosis factor-β (TNF-β) and insulin-like growth factor-1 (IGF-1). Many of these proteinaceous growth factors are commercially available or can be produced recombinantly using techniques well known in the art.

  Alternatively, expression systems comprising vectors incorporating genes encoding various biomolecules, particularly adenoviral vectors, can be dispersed in polymer particles for sustained release delivery. Methods for preparing such expression systems and vectors are well known in the art. For example, for the administration of growth factors to a desired body part for local delivery by selection of particles sized to form a polymer depot or systemically by selection of particles of a size expected to enter the circulation. In addition, proteinaceous growth factors can be dispersed in the polymer particles of the present invention. Growth factors such as VEGF, PDGF, FGF, NGF, and evolutionary and functionally related biologics, and angiogenic enzymes such as thrombin, can also be used as the bioactive substances of the present invention.

  “Small molecule drugs” that are organic or inorganic compounds are a further category of bioactive agents suitable for dispersion in the polymer particles used in the compositions and treatment methods of the invention described herein. It is. Such drugs include, for example, antibacterial and anti-inflammatory drugs, as well as certain healing promoters such as vitamin A and lipid peroxidation inhibitors.

  Various antibiotics can be dispersed in the polymer particles used in the compositions of the present invention in order to indirectly promote the natural healing process by preventing or inhibiting infection. Suitable antibiotics include aminoglycosides, or quinolones, or β-lactams such as cephalosporin, such as ciprofloxacin, gentamicin, tobramycin, erythromycin, vancomycin, oxacillin, Cloxacillin, methicillin, lincomycin, ampicillin and colistin are included. Suitable antibiotics are described in the literature.

  Suitable antibacterials include, for example, Adriamycin PFS / RDF® (Pharmacia and Upjohn), Blenoxane® (Bristol-Myers Squibb Oncology / Immunology), Cerubidine (Registered) Trademark) (Bedford), Cosmegen (registered trademark) (Merck), DaunoXome (registered trademark) (NeXstar), Doxil (registered trademark) (Sequus), Doxorubicin Hydrochloride (registered) (Trademark) (Astra), Idamycin (registered trademark) PFS (Pharmacia and Upjohn), Mithracin (registered trademark) (Bayer), Mitamycin (registered trademark) (Bristol-Myers Squibb Oncology / Immunology) Nipen (R) (SuperGen), Novantrone (R) (Immunex) and Rubex (R) (Bristo l-Myers Squibb Oncology / Immunology). In one embodiment, the peptide can be a glycopeptide. “Glycopeptide” refers to an oligopeptide (eg, heptapeptide) antibiotic that is characterized by a polycyclic peptide core that may be substituted with a sugar group, such as vancomycin.

  Examples of glycopeptides included in this category of antibacterial agents are `` Glycopeptides Classification, Occurrence, and Discovery '' by Raymond C. Rao and Louise W. Crandall, Bioactive agents and the Pharmaceutical Sciences Volume 63, Ramakrishnan Nagarajan, Marcal Dekker, Inc. Publishing). Additional examples of glycopeptides include U.S. Pat. Nos. 4,639,433, 4,643,987, 4,497,802, 4,698,327, 5,591,714, 5,840,684 and 5,843,889; EP 0 802 199, EP 0 801 075, EP 0 667 353, WO 97/28812, WO 97/38702, WO 98/52589, WO 98/52592; and J. Amer. Chem. Soc. (1996) 118: 13107-13108; J. Amer. Chem. Soc. (1997) 119: 12041-12047 and J. Amer. Chem. Soc. (1994) 116: 4573-4590. Representative glycopeptides include A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, actaplanin, actinoidin, aldacine, avopalsin, azleomycin, balhimyein, chloro Orientiene (Chloroorientiein), chloropolisporin, decouplerine, N-demethylvancomycin, elmomycin, galacardin, hervecardin, ispeptin, kibdelin, LL-AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM47766, MM47766 MM55266, MM55270, MM56597, MM56598, OA-7653, olenchin, parvodisine, ristocetin, ristomycin, symmonisin, teicoplanin, UK-68597, UD-69542, UK-72051, vancomycin and the like are included. Also, as used herein, the term “glycopeptide” or “glycopeptide antibiotic” refers to the general class of glycopeptides disclosed above in which no sugar moiety is present, ie, the aglycone series of glycopeptides. Shall also be included. For example, if the disaccharide moiety added to the phenol on vancomycin is removed by mild hydrolysis, vancomycin aglycone is obtained. Also included within the scope of the term “glycopeptide antibiotics” are synthetic derivatives of the general class of glycopeptides disclosed above, including alkylated and acylated derivatives. In addition, glycopeptides with additional addition of other sugar residues, particularly aminoglycosides, in a manner similar to vancosamine are within the scope of this term.

  The term “lipidated glycopeptide” specifically refers to a glycopeptide antibiotic that has been synthetically modified to include a lipid substituent. As used herein, the term “lipid substituent” refers to any substituent containing 5 or more carbon atoms, preferably 10 to 40 carbon atoms. The lipid substituent may comprise 1 to 6 heteroatoms selected from halo, oxygen, nitrogen, sulfur and phosphorus. Lipidated glycopeptide antibiotics are well known in the art. For example, U.S. Pat. WO 00/04044, WO 00/39156, the disclosures of which are incorporated herein by reference in their entirety.

16I)-9-フルオロ-11,17,21-トリヒドロキシ-16-メチルプレグナ-1,4-ジエン-3,20-ジオンと呼ばれる。または、抗炎症性の生物活性物質は、シロリムス（ラパマイシン）であることができるか、またはこれを含むことができ、これはストレプトミセス-ハイグロスコピクス（Streptomyces hygroscopicus）から単離されたトリエンマクロライド系抗生物質である。 Anti-inflammatory bioactive agents are also useful for dispersion in the polymer particles used in the compositions and methods of the present invention. Depending on the body part and disease to be treated, such anti-inflammatory bioactive substances include, for example, analgesics (eg, NSAIDS and salicylic acid), steroids, anti-rheumatic drugs, gastrointestinal drugs, gout formulations, Included are hormones (glucocorticoids), nasal formulations, ophthalmic formulations, otic formulations (eg, antibiotic and steroid combinations), respiratory drugs, and skin and mucosal drugs. See Physician's Desk Reference, 2001 Edition. Specifically, the anti-inflammatory drug can include dexamethasone, which is chemically

16I) -9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione. Alternatively, the anti-inflammatory bioactive substance can be or can include sirolimus (rapamycin), which is a triene macrolide isolated from Streptomyces hygroscopicus Antibiotics.

Polypeptide biologically active substances included in the compositions and methods of the invention can also include “peptide mimetics”. Such peptide analogs, referred to herein as “peptidomimetics” or “peptidomimetics”, are widely used in the pharmaceutical industry and have properties similar to those of template peptides (Fauchere, J. (1986) Adv. Bioactive agent Res., 15:29; Veber and Freidinger (1985) TINS, p. 392; and Evans et al. (1987) J. Med. Chem., 30: 1229), usually Developed using computerized molecular modeling. In general, peptidomimetics are structurally similar to paradigm polypeptides (ie, polypeptides having biochemical properties or pharmacological activity), but are known in the art and further described in the following references: by the method _{are, - CH 2 NH -, -} CH 2 S -, CH 2 -CH 2 -, - CH = CH - ( cis and trans), - COCH ₂ -, - Having one or more peptide bonds optionally substituted by a bond selected from the group consisting of CH (OH) CH ₂ -and --CH ₂ SO--: Spatola, AF in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, AF, Vega Data (March 1983), 1 (3), “Peptide Backbone Modifications” (Review) Morley, JS, Trends. Pharm. Sci., (1980) pp. 463-468 (review); Hudson, D. et al., Int. J. Pept. Prot. Res., (1979) 14: 177 -185 (--CH ₂ NH--, CH ₂ CH _2- ); Spatola, AF et al., Life Sci. , (1986) 38: 1243-1249 (--CH ₂ --S--); Harm, MM, J. Chem. Soc. Perkin Trans I (1982) 307-314 (--CH = CH--, cis and Almquist, RG et al., J. Med. Chem., (1980) 23: 2533 (--COCH _2- ); Jennings-Whie, C. et al., Tetrahedron Lett., (1982) 23 : 2533 (--COCH _2- ); Szelke, M. et al., European Appln., EP 45665 (1982) CA: 97: 39405 (1982) (--CH (OH) CH _2- ); Holladay , MW et al., Tetrahedron Lett., (1983) 24: 4401-4404 (--C (OH) CH _2- ); and Hruby, VJ, Life Sci., (1982) 31: 189-199 (- -CH ₂ -S--). Such peptidomimetics may have significant advantages over the native polypeptide embodiments, including, for example: more economical production, higher chemical stability, improved pharmacological properties ( Half-life, absorption, potency, efficacy, etc.), altered specificity (eg, broad biological activity), reduced antigenicity, etc.

  In addition, substitution of one or more amino acids within the peptide (eg, D-lysine instead of L-lysine) can be used to create more stable peptides and peptides that are resistant to endogenous peptidases. it can. Alternatively, synthetic polypeptides covalently linked to biodegradable polymers can be prepared from D-amino acids, which are referred to as inverso peptides. If the peptide is assembled in the opposite direction of the native peptide sequence, it is called a retropeptide. In general, polypeptides prepared from D-amino acids are very stable to enzymatic hydrolysis. In many cases, conservation of biological activity has been reported for retro-inverso or partially retro-inverso polypeptides (US Pat. No. 6,261,569 B1 and references therein; B. Fromme et al, Endocrinology (2003). 144: 3262-3269).

  It will be readily apparent that the present invention can be used to prepare compositions for use in the prevention or treatment of a wide variety of diseases or their symptoms.

  Following preparation of the polymer particles filled with the bioactive agent, the composition can be lyophilized and the dried composition suspended in a suitable medium prior to administration.

  Any suitable and effective amount of at least one active agent can be released from polymer particles (including those in polymer depots formed in vivo) over time, typically, for example, It is believed that it depends on the particular polymer, particle type, or polymer / bioactive agent binding, if present. Typically, up to about 100% of the polymer particles can be released from a polymer depot formed in vivo by particles sized to avoid circulation. Specifically, up to about 90%, up to 75%, up to 50%, or up to 25% can be released from the polymer depot. Factors that typically affect the rate of release from the polymer include the nature and amount of the polymer / bioactive agent, the type of polymer / bioactive agent binding, and the nature and amount of other materials present in the formulation. is there.

  Once the OEG-based polymer composition of the present invention is made as described above, the composition is formulated for subsequent pulmonary, gastrointestinal, subcutaneous, intramuscular, central nervous system, intraperitoneal or intraorgan delivery. To do. The composition generally comprises one or more “pharmaceutically acceptable excipients or vehicles” suitable for oral, mucosal or subcutaneous delivery, such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol. Conceivable. In addition, auxiliary substances such as wetting or emulsifying agents, pH buffering substances, flavoring agents and the like may be present in such vehicles. For example, additives such as surfactants may serve a variety of purposes: as emulsion stabilizers, as interfacial tension modifiers, or to increase the loading of poorly soluble drugs into particles. There is. Examples of suitable additives for use in the compositions of the present invention include polyvinyl alcohol (PVA), TWEEN® 80, Pluronic F-68, sodium dodecyl sulfate (SDS), Brij® ) -35 and N-dodecyl-β-D-maltoside, octyl-β-D-glucopyranoside, IGEPAL® CA-630, N-octanoyl-N-methylglucamine, N-nonanoyl-N-methylglucamine Camin, N-decanoyl-N-methylglucamine, Nonidet® P-40 replacement, saponin, hexadecylmethylammonium bromide, CHAPS, EMPIGEN® BB and 3- (dodecyldimethylammonio) ) Propanesulfonate internal salt (SB3-12), all of which are commercially available.

  Intranasal and pulmonary formulations will usually include vehicles that do not cause irritation to the nasal mucosa and do not significantly interfere with ciliary function. Diluents such as water, saline or other known materials can be used with the present invention. Intrapulmonary formulations may include preservatives including but not limited to chlorobutanol and benzalkonium chloride. A surfactant may be present to promote absorption by the nasal mucosa.

  For rectal and urethral suppositories, the vehicle used in the composition of the invention is cocoa butter (cocoa butter) or other triglycerides, vegetable oils modified by esterification, hydrogenation and / or fractionation, glycerin Conventional binders and carriers may be included such as treated gelatin, polyalkali glycols, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

  For vaginal delivery, the formulations of the invention can be incorporated into pessary bases such as those containing a mixture of polyethylene triglycerides, or suspended in oils such as corn oil or sesame oil, optionally containing colloidal silica. Can be made. See, for example, Richardson et al., Int. J. Pharm. (1995) 115: 9-15.

  See, for example, Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th edition, 1995, for further discussion on suitable vehicles for use for a particular mode of delivery. One skilled in the art can readily determine the vehicle to use for a particular bioactive agent / polymer particle combination, particle size and mode of administration.

  In addition to human treatment, the OEG-based polymer compositions of the present invention can be used in pets (eg, cats, dogs, rabbits and ferrets), livestock (eg, pigs, horses, mules, dairy cows and beef cattle), and racehorses. Also contemplated for use in veterinary treatment of various affected mammals.

  The composition used in the present invention may optionally include an “effective amount” of the bioactive substance of interest dispersed in the OEG-based PE PEEA, PEEUR or PEEU polymer of the present invention. That is, an amount of a bioactive agent that is believed to produce a sufficient therapeutic or palliative response in a subject to prevent, reduce or eliminate symptoms can be included in the composition. The exact amount required is, among other factors, the subject being treated; the age and general condition of the subject being treated; the ability of the subject's immune system, the degree of treatment desired; the severity of the condition being treated Degree; it will vary depending on the particular bioactive agent selected and the mode of administration of the composition. An appropriate effective amount can be readily determined by one of skill in the art. Thus, the “effective amount” is considered to fall within a relatively wide range that can be determined through routine testing. For example, in the context of the present invention, an effective amount typically ranges from about 1 μg to about 100 mg, for example, from about 5 μg to about 1 mg, or from about 10 μg to about 500 μg of bioactive agent delivered per dose. It is thought that.

  Once formulated, the OEG-based polymer composition of the invention is administered orally, transmucosally, such as by subcutaneous or intramuscular injection, using standard techniques. See, for example, Remington: The Science and Practice of Pharmacy, supra, Easton, Pa., 19th edition, 1995 for transmucosal delivery techniques, including intranasal, intrapulmonary, intravaginal, and rectal techniques, and See European Patent Publication No. 517,565 and Illum et al., J. Controlled Rel. (1994) 29: 133-141 for methods of intranasal administration.

  Dosage treatment may be a single dose or a multiple dose schedule of the OEG-based polymer composition of the invention, as is known in the art. The dosage regimen will be determined, at least in part, by the subject's needs and will depend on the judgment of the clinician. Further, where disease prevention is desired, the polymer composition is generally administered prior to the onset of symptoms of the primary disease or the symptoms of the disease of interest. If treatment is desired, such as, for example, alleviation of symptoms or recurrence, the polymer composition is generally administered after the onset of symptoms of the primary disease.

  These formulations can be tested in vivo in many animal models developed for oral, subcutaneous or transmucosal delivery testing. For example, a conscious sheep model is an art-recognized model for testing intranasal delivery of substances. See, for example, Longenecker et al, J. Pharm. Sci. (1987) 76: 351-355, and Illum et al., J. Controlled Rel. (1994) 29: 133-141. The polymer composition, generally in powdered and lyophilized form, is blown into the nasal cavity. A blood sample can be assayed for the active agent using standard techniques known in the art.

  To illustrate the present invention, a series of PEEAs were synthesized. First, NA, NS and NF, which are three different di-p-nitrophenyl esters of dicarboxylic acid, were synthesized as monomers for obtaining PEEA carboxylate segment. NA and NS have a saturated methylene structure, while NF has an unsaturated C = C double bond within the methylene structure (see Scheme IV).

  As monomers for obtaining the PEEA amino acid segment, three different di-p-toluenesulfonates of bis-L-phenylalanine diester were synthesized as described in the examples herein. All three salts contained oligomeric residues of ethylene glycol with ether linkages in the segment (Scheme V).

1a：アジピン酸ジ-p-ニトロフェニル（NA）、x＝4
1b：セバシン酸ジ-p-ニトロフェニル（NS）、x＝8
1c：フマル酸ジ-p-ニトロフェニル（NF）
スキーム（IV）

2a：k＝2、R³＝CH₂C₆H₅：L-フェニルアラニンジエチレングリコールジエステルのジ-p-トルエンスルホン酸塩（P2EG）
2b：k＝3、R³＝CH₂C₆H₅：L-フェニルアラニントリエチレングリコールジエステルのジ-p-トルエンスルホン酸塩（P3EG）
2c：k＝4、R³＝CH₂C₆H₅：L-フェニルアラニンテトラエチレングリコールジエステルのジ-p-トルエンスルホン酸塩（P4EG）
2d：k＝1、R³＝CH₂CH(CH₃)₂：L-ロイシン(モノ)エチレングリコールジエステルのジ-p-トルエンスルホン酸塩（L1EG）
2e：k＝1、R³＝CH₃：L-アラニン(モノ)エチレングリコールジエステルのp-トルエンスルホン酸塩（A1EG）
スキーム（V）

1a: Di-p-nitrophenyl adipate (NA), x = 4
1b: Di-p-nitrophenyl sebacate (NS), x = 8
1c: Di-p-nitrophenyl fumarate (NF)
Scheme (IV)

2a: k = 2, R ³ = CH ₂ C ₆ H ₅ : di-p-toluenesulfonate (P2EG) of L-phenylalanine diethylene glycol diester
2b: k = 3, R ³ = CH ₂ C ₆ H ₅ : Di-p-toluenesulfonate (P3EG) of L-phenylalanine triethylene glycol diester
2c: k = 4, R ³ = CH ₂ C ₆ H ₅ : Di-p-toluenesulfonate (P4EG) of L-phenylalanine tetraethylene glycol diester
2d: k = 1, R ³ = CH ₂ CH (CH ₃ ) ₂ : di-p-toluenesulfonate (L1EG) of L-leucine (mono) ethylene glycol diester
2e: k = 1, R ³ = CH ₃ : p-toluenesulfonate (A1EG) of L-alanine (mono) ethylene glycol diester
Scheme (V)

The chemical structures of di-p-toluenesulfonate monomers 2a-c, designated herein as P2EG, P3EC and P4EG, were all confirmed by elemental analysis, FTIR spectra and ¹ H- and ¹³ C-NMR spectra. The FTIR spectrum showed the presence of both the primary amine salt, ester carbonyl -CO-, in 1741 cm ^-1 and the characteristic signal of -CH ₂ -O-CH ₂ -in the 1127 cm ^-1 region.

x＝4の場合、AP2EG（k＝2）；AP3EG（k＝3）；AP4EG（k＝4）；
x＝8の場合、SP2EG（k＝2）；SP3EG（k＝3）；SP4EG（k＝4）。

ここで、FP2EG（k＝2）；FP3EG（k＝3）；FP4EG（k＝4）。
スキーム（VI） Illustrative OEG-based PEEA synthesis of the present invention involves solutions of various combinations of monomer 1 (1a, 1b or 1c) and monomer 2 (2a, 2b or 2c) as shown in Scheme (VI) below. Performed by polycondensation.

When x = 4, AP2EG (k = 2); AP3EG (k = 3); AP4EG (k = 4);
When x = 8, SP2EG (k = 2); SP3EG (k = 3); SP4EG (k = 4).

Here, FP2EG (k = 2); FP3EG (k = 3); FP4EG (k = 4).
Scheme (VI)

The chemical structure of these PEEA polymers was confirmed by FTIR and NMR spectra. The FTIR spectra of the PEEA all Fumarirubesu, unsaturated -C = C-bond (983cm ^-1), and esters carbonyl (1740 cm ^-1), an ether group 1115cm ^-1), amide groups (1640 and 1530 cm ^-1) Existence was confirmed. The NMR spectra of three typical PEEAs based on tri-ethylene glycol were in complete agreement with the expected chemical structure of the PEEA polymer shown in Scheme VI.

  Nine different PEEAs were synthesized by solution polycondensation of combinations of monomers 1a-c and 2a-c and are listed in Table 1.

^a 合成条件：c＝0.90mol／L。t＝70℃、溶媒としてTHF。
^b DMSO中、25℃で測定、C＝0.25g／dL。
^c フマル酸ベースのPEEAに関する分子量データはTHF中に不溶性であるため得られず。
A-アジピン酸、F-フマル酸およびS-セバシン酸；P＝L-Phe；スキーム6においてK＝2,3,4。 (Table 1) Properties of poly (ether ester amide) ^a) of formula I

^a Synthesis condition: c = 0.90 mol / L. t = 70 ° C., THF as solvent.
^b Measured in DMSO at 25 ° C, C = 0.25 g / dL.
The molecular weight data relating ^c fumaric acid-based PEEA can not be obtained because it is insoluble in THF.
A-Adipic acid, F-Fumaric acid and S-Sebacic acid; P = L-Phe;

Of the adipic acid and sebacic acid based PEEAs, AP3EG and SP3EG achieved the highest M _n , M _w , and low viscosity η _red .

The synthesized PEEA had a lower T _g than the corresponding saturated or unsaturated PEA containing residues of aliphatic diols (Katsasava, R. et al. J Polym Sci Pol Chem (1999) 37 (4): 391 -407 and Guo et al, supra). In fact, in each PEEA series, increase in the number of ether bonds is invited lowering T _g of corresponding thereto, which appeared to be more pronounced with saturated PEEA series than in unsaturated PEEA. Therefore, a decrease in T _g of the PEEA promote chain segment motion causes increased flexibility of the chain, was attributed to the presence of ether bonds.

  The biodegradation kinetics of two representative inventive triethylene glycol-based PEEA polymers (AP3EG and SP3EG) were studied at 37 ° C. in PBS buffer at pH 7.4 and α-chymotrypsin buffer. Both polymers exhibited a much faster weight loss in α-chymotrypsin solution than in PBS buffer, and the level of biodegradation of these PEEA polymers in enzyme solution was dependent on both chemical structure and enzyme concentration . Of the polymers tested, AP3EG was most sensitive to enzymatic biodegradation (Figure 2).

  Furthermore, regardless of the difference in α-chymotrypsin concentration used in the biodegradation test, the weight loss kinetics of an exemplary OEG-based PEEA was very close to the zero order due to surface erosion.

ここで、4a：k＝2；4b：k＝3；4c：k＝4。
スキーム（VII） To illustrate the synthesis of PEEUR of the present invention, the following monomers—active bis-p-nitrophenyl carbonates containing various lengths of ether blocks— were synthesized as described in Example 2 herein. did. Individual ether diols, di-ethylene glycol, tri-ethylene glycol, tetra-ethylene glycol are commercially available and suitable for this task. Active bis-p-nitrophenyl carbonate was synthesized according to general scheme (VII).

Here, 4a: k = 2; 4b: k = 3; 4c: k = 4.
Scheme (VII)

スキーム（VIII） The chemical structure of the resulting monomer was confirmed by elemental analysis, ¹ H NMR, and identified by the reported melting point. An exemplary OEG-based PEEUR synthesis of the present invention was performed by a solution polycondensation method similar to the PEEA synthesis described above, as shown in Scheme (VIII) below.

Scheme (VIII)

The weight average molecular weight of the synthesized PEEUR was in the range of 31,400-51,000 g / mol as evaluated by GPC (DMF, PMMA), and the glass transition temperature was in the range of 12-39 ° C. Lipase-catalyzed biodegradation was performed on L1EG-based PEEUR. The results are illustrated in FIGS. 3A-C and the data indicate that the resulting PEEUR was not subjected to chemical hydrolysis in phosphate buffer. In contrast, the rate of biodegradation under lipase catalysis was high and did not depend on the length of the OEG fragment in R ⁶ of formulas V-VI.

  The following examples are intended to illustrate but not limit the present invention.

Example 1
This example describes the preparation and testing of a series of saturated and unsaturated OEG-based PEAs (PEEA) to illustrate the properties of the compositions of the present invention.

A. Material preparation
L-phenylalanine (L-Phe), p-toluenesulfonic acid monohydrate (TosOH.H ₂ O), sebacoyl chloride, adipoyl chloride, fumaryl chloride, diethylene glycol, tri-ethylene glycol and tetra-ethylene glycol (Alfa Aesar, Ward Hill, MA) and p-nitrophenol (JT Baker, Phillipsburg, NJ) were used without further purification. Triethylamine (Fisher Scientific, Fairlawn, NJ) was dried by refluxing with calcium hydride followed by distillation. N, N-dimethylformamide (DMF) (Aldrich Chemical, Milwaukee, Wis.) Was dried over calcium hydride and distilled. Other solvents such as toluene, trifluoroethanol (TFE), tetrahydrofuran (THF), ethyl acetate, acetone, acetonitrile, N, N-dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO) are available from VWR Scientific (West Chester, PA ) And purified by standard methods before use.

B. Monomers and Polymer Synthesis The following monomers were prepared for PEEA synthesis of formulas (I) and (IV): di-p-nitrophenyl ester of dicarboxylic acid (1a-c), and bis-L-phenylalanine- Di-p-toluenesulfonate of glycol-ester (2a-c).

  Synthesis of di-p-nitrophenyl esters of dicarboxylic acids (compounds 1a-c) was performed by reacting the corresponding acyl chloride with p-nitrophenol as previously described (US Pat. No. 6,503,538 B1). And Guo, K., et al. J. Polym Sci Pol Chem (2005) 43 (7): 1463-1477). Briefly, a solution of triethylamine (0.0603 mol) and p-nitrophenol (0.0603 mol) in 100 mL acetone was prepared at room temperature and the solution was kept at -78 ° C. with dry ice and acetone. Subsequently, fumaryl chloride (0.03 mol, 3.2 mL) in 40 mL acetone was added dropwise to the above cooled solution with stirring at −78 ° C. over 2 h, followed by continued stirring at room temperature overnight. The mixture is then poured into 800 mL of distilled water to precipitate the product di-p-nitrophenyl fumarate (1c), which is filtered, washed thoroughly with distilled water and subjected to reduced pressure. Dried at 50 ° C. and finally purified by recrystallization from acetonitrile.

  The di-p-toluenesulfonate salt of bis-L-phenylalanine ester (compounds 2a-c) was described in Katsarava at all, 1999, supra, as shown in scheme (V) above. Prepared by changing the procedure.

Typically, L-Phe (0.176 mol), p-toluenesulfonic acid monohydrate (0.176 mol) and glycol (0.08 mol) in 300 mL toluene are added to a Dean-Stark apparatus, CaCl ₂ drying tube and magnetic Placed in a flask equipped with a stirrer. The reaction mixture was heated (about 140 ° C.) and refluxed until 6.1 mL (0.34 mol) of water was formed, followed by cooling to room temperature, removing the solvent by rotary evaporation, and the mixture under reduced pressure overnight. Dried and finally purified by recrystallization. Compound 2a (P2EG) was recrystallized in water and compounds 2b and 2c were crystallized from 2-propanol.

Solution polycondensation of monomers 1 and 2:
PEEA was prepared by solution polycondensation of 2a-c and one of di-p-nitrophenyl esters (1a-c) according to scheme (VI). The composition and names of the polymers are shown in Scheme VI and Table 3 (PEEA starting from F such as FP3EG was unsaturated based on the fumaryl moiety).

  An example of OEG-containing polymer AP2EG synthesis via solution polycondensation is presented. To a mixture of monomers 1a, 4.0 mmol and 2a, 4.0 mmol in 3 mL dry DMA, 10 mmol (1.42 mL) triethylamine was added dropwise and the solution was heated to 60 ° C. with stirring until the monomer was completely dissolved. The reaction vial was then kept below 70 ° C. for 48 hours without stirring. The resulting viscous solution (light yellow to dark brown color depending on the type of monomer used) was divided into two groups and precipitated with different solvents. Unsaturated PEEA reaction mixture (FP2EG9, FP3EG and FP4EG) was diluted with acetone to precipitate the product. The polymer was subsequently washed twice with acetone, filtered and finally dried under reduced pressure for 48 hours.

  Saturated PEEA was precipitated in cold ethyl acetate and the product was filtered and further purified by circulating ethyl acetate in a Soxhlet apparatus for 48 hours and dried under reduced pressure for 48 hours.

Polymer solubility
Almost all PEEA except FP2EC was soluble in DMSO, DMF and formic acid, but not in water, methanol and ethyl acetate. Saturated PEEA was also soluble in trifluoroethanol, THF and chloroform. However, the three unsaturated PEEAs were only very slightly soluble in their normal organic solvent. Thus, compared to PEA polymers obtained from aliphatic diols, OEG-based PEEA, especially unsaturated PEEA, showed a significant improvement in solubility. For example, SP3EC and SP4EG were both dissolved in acetone, while SPB (1,4-butanediol-based PEA) and SPH (1,6-hexanediol-based PEA) were insoluble.

C. Test methods used to confirm the chemical structure and properties of monomers and polymers The chemical structure was confirmed by Fourier transform infrared (FTIR) and NMR spectra. For FTIR characterization, the samples were crushed into powder and mixed with KBr at a ratio of 1:10 w / w. Subsequently, FTIR spectra of the samples were obtained using a Perkin-Elmer Nicolet Magana 560 (Madison, Wis.) FTIR spectrometer with Omni software for data collection and analysis. Sample NMR spectra were recorded on a Varian Unity NOVA-400 400 MHz spectrometer (Palo Alto, CA) operating at 400 and 100 MHz for ¹ H and ¹³ C NMR, respectively. Deuterated dimethyl sulfoxide (DMSO-d ₆ , Cambridge Isotope laboratories) was used as a solvent. Elemental analysis of the synthesized polymer was performed using a PE 2400 CHN elemental analyzer (Atlantic Microlab, Norcross, GA).

  The thermal properties of the synthesized monomers and polymers were characterized by a differential scanning calorimeter DSC 2920 (TA Instruments, New Castle, DE). The measurement was performed from 0 ° C. to 300 ° C. at a scanning speed of 10 ° C./min and a nitrogen gas flow rate of 25 mL / min. TA Universal Analysis ™ software was used for thermal data analysis such as determination of glass transition temperature. The melting point was determined at the beginning of the melting endotherm.

The number average and weight average molecular weight and molecular weight distribution (MWD) of the synthesized PEEA were determined by gel permeation chromatography (Model 510) equipped with a high pressure liquid chromatography pump, a Waters 486 UV detector and a Waters 2410 differential refractive index detector. , Waters Associates Inc. Milford, USA). Tetrahydrofuran (THF) was used as eluent (1.0 mL / min). The column was calibrated using polystyrene standards with a narrow molecular weight distribution. The reduced viscosity (η _red ) of the synthesized polymer was determined in a DMSO solution at a concentration of 0.25 g / dL and 25 ° C. using a Cannon-Ubbelhode viscometer.

  For the biodegradability test, the PEEA film was poured from a 10% (wt / v) chloroform solution into a Teflon (registered trademark) Petri dish to completely evaporate the solvent at room temperature. The film was further dried overnight at room temperature under reduced pressure and finally punched out as a small disk with a diameter of 12.5 mm.

式中、W_oは浸漬前の乾燥PEEAフィルム試料の元の重量であり、W_tは、t時間にわたるインキュベーション（酵素の存在下または非存在下）後の乾燥PEEAフィルム試料の重量である。3つの標本の重量減少平均を記録した。 In vitro biodegradability testing of OEG-based PEEA has been performed with small concentrations of dry PEEA film and various concentrations (0, 0.05) in 10 mL of pure PBS buffer, or PBS buffer (pH = 7.4, 0.1 M). , 0.1 or 0.2 mg / mL) in α-chymotrypsin solution. Two representative OEG-based PEEA polymers (AP3EG and SP3EG) were used in this biodegradability test. Subsequently, the samples were incubated at 37 ° C. under constant reciprocal shaking (100 rpm). At predetermined intervals, the PEEA film was removed from the incubation medium, gently washed with distilled water, and surface water was blotted with a filter paper and weighed. The degree of biodegradation was estimated from the weight loss of the PEEA film sample based on the following formula.

Where W _o is the original weight of the dry PEEA film sample before soaking and W _t is the weight of the dry PEEA film sample after incubation (in the presence or absence of enzyme) for t time. The average weight loss of three specimens was recorded.

  The molecular weight change of PEEA polymer was also monitored by GPC.

  The surface hydrophilicity of the PEEA film was determined by using a MASS contact angle analyzer in a conditioning room maintained at 65% relative humidity and 21 ° C. Distilled water was used as a coating solution, and contact angles were measured at five randomly selected surface regions of each PEEA film. Two PEEA films of each sample type were tested.

Confirmation of the structure of monomer 2 The chemical structures of di-p-toluenesulfonate monomers 2a-e were all confirmed by analysis of FTIR and NMR spectra. Major absorption bands such as ester groups (1736-1750 cm ⁻¹ ) and ether groups (about 1127 cm ⁻¹ ) were found in the FTIR spectrum. The broad absorption between 2500-3300 cm ⁻¹ was attributed to both the primary amine salt and the aliphatic hydrocarbon structure present in the ester salt. The ¹ H NMR data of 2a to e also showed a characteristic signal of —CH ₂ —O—CH ₂ —.

FTIR spectra of the PEEA for confirmation Fumarirubesu structure of the polymer, an ester group (approximately 1740 cm ^-1), ether group (approximately 1115cm ^-1), amide groups (approximately 1640 cm ^-1 and near 1530 cm ^-1) and unsaturated -C = It exhibited a characteristic absorption band of C-bond (approximately 983 cm ^-1 ). The broad absorption around 2900 cm ⁻¹ was attributed to the aliphatic hydrocarbon structure present in the polymer. ¹ H-NMR spectrum of PEEA (400 MHz, DMSO-d 6) has, -NH- bond proton signal (8.90 or 8.24ppm), ether CH ₂ -O-CH ₂ bond in the diester units (about 3.50 ppm) and The —HC═CH— bond (6.83 ppm) in the acid unit was shown. Data from elemental analysis was also consistent with that calculated for the composition.

Results of biodegradability test
The biodegradation kinetics of two representative OEG-based PEEA polymers (AP3EG and SP3EG) were tested at 37 ° C. in a PBS buffer solution at pH 7.4 containing α-chymotrypsin. The data from this biodegradability test indicate that both polymers exhibit a much faster and more significant weight loss in α-chymotrypsin solution than in pure PBS buffer, and that these polymers in enzyme solution It was shown that the degree of biodegradability of PEEA polymer depends on both chemical structure and enzyme concentration. This biodegradation data showed that AP3EG is very sensitive to enzymatic biodegradation (Figure 1).

  Even in 0.05 mg / mL α-chymotrypsin solution, AP3EG was readily biodegraded, with a 13% decrease in molecular weight in the first 8 hours and a 31% decrease in molecular weight after 1 day. The biodegradation profile of AP3EG showed that the rate of enzymatic hydrolysis increased with increasing α-chymotrypsin concentration. Furthermore, regardless of the difference in α-chymotrypsin concentration, the weight loss kinetics were very close to zero order. The AP3EG film also maintained its constant surface area very well up to a weight loss of up to 80%, during which time the polymer sample gradually became thinner. This result indicates that the PEEA polymer film of the present invention was subject to uniform surface erosion during enzymatic hydrolysis, which is a type of bulk biodegradation common to aliphatic polyesters. Contrasting results.

  FIG. 2 shows the effect of different lengths of diacid monomers 1a-b in the OEG-based PEEA of the present invention on biodegradability. The data summarized therein show that AP3EG (monomer 1a: obtained from di-p-nitrophenyl adipate with 4 methylene groups) is subject to hydrolysis under α-chymotrypsin catalysis as SP3EG (monomer 1b: obtained from di-p-nitrophenyl sebacate having 8 methylene groups). In a 0.10 mg / mL α-chymotrypsin solution, SP3EG also exhibits near-zero order biodegradation kinetics, with a faster biodegradation rate than that of AP3EG, with a weight loss within 24 hours of 56% versus 81% Even showed. This result may be due to the more hydrophobic PEEA, such as SP3EG, having a greater affinity for α-chymotrypsin and thus a higher rate of enzymatic hydrolysis than AP3EG.

  These OEG-based PEEAs have also been shown to have a much higher α-chymotrypsin-catalyzed biodegradation rate than PEA with a similar structure derived from linear aliphatic saturated and unsaturated diols. It was done. For example, within 24 hours, the weight loss of SP3EG was 81.3%, while the weight loss of SPBU (derived from 2-butene-1,4-diol) was 13.8%, compared with SPB (from 1,4-butanediol) Obtained) was only 6.4%. Thus, incorporation of ether linkages into the backbone of OEG-based PEEA enhances enzymatic biodegradation compared to PEA with an aliphatic backbone segment (ie derived from an aliphatic diol) and similar structure .

^a 対照としての元の試料。 Table 2 Weight loss, molecular weight and contact angle of PEEA polymer before and after 18 hours incubation in various media

^a Original sample as ^a control.

  PEEA polymer films in the incubation medium were also measured by GPC to check for their biodegradation (Table 2). Weight loss showed significant biodegradation of AP3EG (34.9%) and SP3EG (64.8%) samples in 0.1 mg / mL α-chymotrypsin solution within 18 hours, but GPC data showed molecular weight and molecular weight None of the distributions showed almost slight changes, low α-chymotrypsin (0.05 mg / mL, less weight loss), high α-chymotrypsin (0.20 mg / mL, more weight loss) and PBS buffer ( There was almost no weight loss).

Example 2
This example describes the preparation and testing of a series of saturated OEG-based PEUR (PEEUR) to illustrate the properties of the composition of the present invention. Active bis-p-nitrophenyl carbonate containing ether blocks of various lengths was obtained for the synthesis of the key monomer for hydrophilic PEEUR. Active bis-p-nitrophenyl carbonates of 2EG, 3EG and 4EG were synthesized according to general scheme VII.

In general, to a cooled (-10 ° C) solution of 0.01 mol ether-diol, 0.02 mol p-nitrophenyl chloroformate was added stepwise followed by raising the reaction temperature to ambient temperature. And stirred for 1 hour. The reaction solution was subsequently refluxed until the liberation of HCl was complete, and the solution was evaporated to dryness to give a solid product that was further purified as follows.
1． Diethylene glycol-bis-p-nitrophenyl carbonate (4a in Scheme VII) was recrystallized in a mixture of toluene / n-hexane (3: 1 v / v). Yield 73%, mp 110-112 ° C (ref. 108-110 ° C, R. Katsarava, et al., Vysokomolek. Soed. (Russia) (1987), 29A: 2069).
2.3 Activated carbonates based on 3EG and 4EG (4b and 4c in Scheme VII) were recrystallized in a dichloromethane / diethyl ether (3: 1 v / v) mixture. Yield: 4b 60%, 4c 54%, mp: 4b, 59-61 ° C; 4c 48-50 ° C.

Hydrophilic counter-partner, the shortest diol (ethylene glycol) and the less hydrophobic α-amino acids-di-p-toluenesulfonate of diamines based on L-alanine and L-leucine ( Compounds 2d-e, Scheme V) were prepared according to standard Scheme V as described herein. The product was recrystallized as follows.
From a mixture of 2e (A1EG) -acetone / ethanol (50/1 v / v), mp = 223-225 ° C .; and
From a 2d (L1EG) -acetone / water (50/1 v / v) mixture, mp = 235-237 ° C.

  The polycondensation of monomers 2d-e and 4a-c is carried out in DMA according to scheme VIII in the presence of triethylamine as acid acceptor, concentration c = 1.2 mol / L, t = 80 ° C., duration 16 hours. Performed under standard conditions.

  The synthesized polymer (PEEUR) had a molecular weight in the range of 31,400-51,000 g / mol and a polydispersity in the range of 1.3-1.5. The glass transition temperature (Tg) of the polymer was in the range of 12-39 ° C.

  All of these PEEURs were soluble in DMF, chloroform and THF. Leucine-based polymers were also soluble in ethanol.

In vitro biodegradability test under lipase catalyst
In vitro biodegradation of PEEUR was carried out at t = 37 ° C. in 0.2 N phosphate buffer, pH 7.4 using lipase as an enzyme. PEEUR was highly hydrophilic and the polymer film could not keep its shape in the buffer (strong shrinkage was observed). For this reason, in order to study biodegradation, a Teflon (registered trademark) support disk made of d = 4 cm was prepared by immersing a Teflon (registered trademark) disk in a PEEUR chloroform solution and then removing the polymer and drying it. (Backing disc) was covered with polymer. This procedure was repeated until the weight of the disc reached approximately 400-500 mg. Subsequently, a Teflon (registered trademark) support disk covered with PEEUR was dried to a constant weight and used in an in vitro biodegradability test. Only 2d (L1EG) based PEEUR remained on the support during this procedure. The much more hydrophilic 2e Ala-2 based PEEUR flowed from the support into the buffer and could not be considered for biodegradation due to weight loss.

  The results of the lipase-catalyzed biodegradability test for 2d (L1EG) -based PEEUR are summarized in Figures 3A-C, and the data in it are recognizable in pure phosphate buffer. This indicates that was not seen. However, the lipase-catalyzed biodegradation rate of these PEEURs is quite high, very close to the lipase-catalyzed biodegradation rate of PEA of formula I based on L-leucine, adipic acid and 1,6-hexanediol. It was. This test showed that the length of the EG fragment (EG2, EG3 or EG4) had no substantial effect on the biodegradation rate of the PEEUR tested.

  All publications, patents and patent literature are incorporated herein by reference in the same manner as if individually incorporated by reference.

  The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims (25)

A composition comprising at least one bioactive agent dispersed in a biodegradable polymer comprising at least one of the following a) to f):
a) Poly (ester ether amide) (PEEA) having the chemical formula described by Structural Formula (I):

Formula (I)
Where
n ranges from about 15 to about 150;
R ¹ is (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and formula (II)

Formula (II)
Independently selected from the group consisting of residues of α, ω-dicarboxylic acids, wherein R ⁵ in formula (II) is a group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene More independently selected and R ⁷ is independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, provided that at least one R ¹ in each polymer is R ⁷ Is the residue of an α, ω-dicarboxylic acid of formula (II), wherein is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
R ³ in each n monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ independently selected from;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), structural formula (III)

Formula (III)
Independently selected from bicyclic fragments of 1,4: 3,6-dianhydrohexitol, fragments of 1,4-anhydroerythritol, and combinations thereof;
b) PEEA polymer having the chemical formula described by Structural Formula (IV):

Formula (IV)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to 0.9; p ranges from about 0.9 to 0.1;
R ¹ is independently selected from the group consisting of (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and the residue of an α, ω-dicarboxylic acid of formula (II), wherein R ⁵ is independently selected from the group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene, and R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂₎ ) Independently selected from the group consisting of alkylene, provided that at least one R ¹ in each polymer is of formula (II) wherein R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene A residue of an α, ω-dicarboxylic acid of
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl or protecting groups;
R ³ in each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C Independently selected from the group consisting of ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4: 3,6-dianhydrohexitol bicyclic fragment of structural formula (III), 1,4-anhydroerythritol fragment and combinations thereof independently selected Is; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
c) Poly (ether urethane) having the chemical formula described by structural formula (V) (PEEUR):

Formula (V)
Where
n ranges from about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
d) PEEUR having the chemical structure described by the general structural formula (VI):

Formula (VI)
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to about 0.9, and p ranges from about 0.9 to about 0.1;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₀ ) aryl and protecting groups;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of R ⁴ and R in each polymer. ^At least one of ⁶ is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
e) Poly (ether urea) (PEEU) having the chemical formula described by the general structural formula (VII):

Formula (VII)
Where
n is about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
f) PEEU having the chemical formula described by Structural Formula (VIII):

Formula (VIII)
Where
m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 15 to about 150;
R ² is independently a group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl or (C ₆ -C ₁₀ ) aryl;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4 of structural formula (III): Independently selected from the group consisting of a bicyclic fragment of 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, provided that at least one R ⁴ in each polymer is Selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl. The polymer is described by structural formula (I) or (IV), and
In each of the n monomers, R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene,
The composition of claim 1. The polymer is described by structural formulas (I) and (IV), and
In each of the n monomers, R ⁴ is selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene. Independently selected and
R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene,
The composition of claim 1. The polymer is described by structural formula (V) or (VI), and
In each of the n monomers, R ⁴ or R ⁶ is from CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene. Selected from the group consisting of
The composition of claim 1. The polymer is described by structural formulas (V) and (VI), and
In each of the n monomers, R ⁴ and R ⁶ are from CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₄ ) alkyloxy (C ₂ -C ₈ ) alkylene. Selected from the group consisting of
The composition of claim 1. The polymer is described by structural formula (VII) or (VIII), and
In each of the n monomers, R ⁴ in each of the n monomers is CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) Selected from the group consisting of alkylene,
The composition of claim 1.   The composition of claim 1, wherein each polymer molecule releases 15 to 300 oligo-ethylene glycol (OEG) molecules having a molecular weight of 44 to 400 Da but not including 400 Da upon biodegradation. R ³ _{is, CH 2 CH (CH 3)} 2, CH 2 C 6 H is selected from ₅ the group consisting of CH _3, The composition of claim 1.   2. The composition of claim 1, wherein the composition is formulated for administration in the form of a liquid dispersion of polymer particles.   10. The composition of claim 9, wherein the particles comprise from about 5 to about 150 bioactive agent molecules per polymer molecule. A polymer having the chemical formula described by structural formula (I), (IV), (V), (VI), (VII) or (VIII):
a) Formula (I) is

Formula (I)
And
Where
n ranges from about 15 to about 150;
R ¹ is (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and formula (II)

Formula (II)
Independently selected from the group consisting of residues of α, ω-dicarboxylic acids, wherein R ⁵ in formula (II) is a group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene More independently selected and R ⁷ is independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, provided that at least one R ¹ in each polymer is R ⁷ Is a residue of an α, ω-dicarboxylic acid of formula (II) independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
R ³ in each n monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ independently selected from;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), structural formula (III)

Formula (III)
Independently selected from a bicyclic fragment of 1,4: 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof;
b) Formula (IV) is

Formula (IV)
And
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to 0.9; p ranges from about 0.9 to 0.1;
R ¹ is independently selected from the group consisting of (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₁₂ ) alkenylene and the residue of an α, ω-dicarboxylic acid of formula (II), wherein R ⁵ is independently selected from the group consisting of (C ₂ -C ₄ ) alkylene and (C ₂ -C ₄ ) alkenylene, and R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂₎ ) Independently selected from the group consisting of alkylene, provided that at least one R ¹ in each polymer is independently selected from the group wherein R ⁷ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene. A residue of an α, ω-dicarboxylic acid of the formula (II) selected;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₆ -C ₁₀ ) aryl (C ₁ -C ₆ ) alkyl or protecting groups;
R ³ in each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl (C Independently selected from the group consisting of ₁ -C ₆ ) alkyl and-(CH ₂ ) ₂ SCH ₃ ;
R ⁴ is (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, (C ₂ -C ₂₀ ) alkylene, (C ₂ -C ₂₀ ) alkenylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1,4: 3,6-dianhydrohexitol bicyclic fragment of structural formula (III), 1,4-anhydroerythritol fragment and combinations thereof Independently selected; and
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
c) Equation (V) is

Formula (V)
And
Where
n ranges from about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ and CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of at least R ⁴ and R ⁶ One is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ and CH ₂ CH (CH ₂ OH);
d) Equation (VI) is

Formula (VI)
And
Where
n ranges from about 15 to about 150, m ranges from about 0.1 to about 0.9; p ranges from about 0.9 to about 0.1;
R ² is independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₁ -C ₆ ) alkyl (C ₆ -C ₁₀ ) aryl and protecting groups;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ and R ⁶ are (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH), 1 of structural formula (III) , 4: 3,6-dianhydrohexitol, a fragment of 1,4-anhydroerythritol, and combinations thereof, independently selected from the group consisting of at least R ⁴ and R ⁶ One is selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ and CH ₂ CH (CH ₂ OH);
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl;
e) Formula (VII) is

Formula (VII)
And
Where
n is about 15 to about 150;
R ^{3 in} each n monomers is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is independently selected from the group consisting of (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene, CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH); and
f) Formula (VIII) is

Formula (VIII)
And
Where
m is about 0.1 to about 1.0; p is about 0.9 to about 0.1; n is about 15 to about 150;
R ² is independently a group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl or (C ₆ -C ₁₀ ) aryl;
R ^{3 in} each m monomer is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₆ -C ₁₀ ) aryl ( Independently selected from the group consisting of C ₁ -C ₆ ) alkyl and — (CH ₂ ) ₂ SCH ₃ ;
R ⁴ is independently selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene;
R ⁸ is independently (C ₁ -C ₂₀ ) alkyl or (C ₂ -C ₂₀ ) alkenyl. Wherein R ⁷ is selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene ( 12. A composition according to claim 11 described by I) or (IV). Wherein R ⁷ is selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₄ ) alkyloxy (C ₂ -C ₈ ) alkylene ( 12. A composition according to claim 11 described by I) and (IV). R ⁴ and R ⁶ are independently selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene. 12. A composition according to claim 11 described by structural formulas (V) and (VI). Wherein R ⁴ is selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₄ ) alkyloxy (C ₂ -C ₁₂ ) alkylene ( 12. A composition according to claim 11 described by VII) or (VIII). Wherein R ⁴ is selected from the group consisting of CH ₂ CH (OH) CH ₂ , CH ₂ CH (CH ₂ OH) and (C ₂ -C ₆ ) alkyloxy (C ₂ -C ₁₂ ) alkylene ( 12. A composition according to claim 11 described by VII) and (VIII). R ³ is, CH ₂ CH (CH ₃₎ is ₂ or CH _3, The composition of claim 11. R ³ is selected from the group consisting of hydrogen, CH ₂ CH (CH ₃ ) ₂ , CH ₃ , CH (CH ₃ ) ₂ , CH (CH ₃ ), CH ₂ CH ₃ and CH ₂ C ₆ H ₅ ) 12. A composition according to claim 11.   12. The composition of claim 11, wherein the composition is formulated as particles having an average diameter ranging from about 10 nanometers to about 1000 micrometers. A method for delivering a bioactive substance to a subject comprising:
Administering the composition of claim 1 to a subject in vivo, and delivering a bioactive agent to the subject at a controlled delivery rate, wherein the weight average molecular weight (Mw) is at least 15 to 300 per polymer molecule Forming a oligo-ethylene glycol (OEG) molecule that is 44 Da but less than 400 Da in vivo.   21. The method of claim 20, wherein the composition is biodegraded by surface enzyme action.   21. The method of claim 20, further comprising formulating the composition as a liquid dispersion of polymer films or polymer particles prior to the administering step.   23. The method of claim 22, wherein the administration comprises injecting particles of the composition into a local site within the subject's body.   21. The method of claim 20, further comprising formulating the composition into polymer particles having an average size of about 1 [mu] m to about 500 nm prior to said administration. A composition comprising at least one bioactive agent dispersed in a micelle-forming polymer,
a) a hydrophobic zone comprising at least one polymer according to claim 11 and connected to a water-soluble zone;
b) i) a polyethylene glycol having an Mw of at least 200 Da and less than 400 Da, and
ii) comprising alternating repeating units with water-soluble zones that are alternating repeating units of at least one ionic or polar amino acid,
The alternating repeating units have substantially the same molecular weight and the Mw of the polymer is in the range of about 15 kDa to 300 kDa,
Composition.

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