GB2402677A - Biodegradable polymer - Google Patents

Biodegradable polymer Download PDF

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Publication number
GB2402677A
GB2402677A GB0310335A GB0310335A GB2402677A GB 2402677 A GB2402677 A GB 2402677A GB 0310335 A GB0310335 A GB 0310335A GB 0310335 A GB0310335 A GB 0310335A GB 2402677 A GB2402677 A GB 2402677A
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polymer
alkyl
integer
boc
linker
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GB0310335D0 (en
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Jonathan Clark
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SIRUS PHARMACEUTICALS Ltd
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SIRUS PHARMACEUTICALS Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/42—Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/40—Polyamides containing oxygen in the form of ether groups

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Polymers & Plastics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Polyethers (AREA)

Abstract

A biodegradable polymer having units of the formulae <EMI ID=1.1 HE=20 WI=157 LX=322 LY=457 TI=CF> <PC>wherein B is selected from oxygen, sulphur, alkyl, alkyl ether, alkyl thioether, hydroxyl alkyl and alkyl aryl; ```s is 0 or an integer of 100; ```m is 0 or an integer of up to 1000; ```q is 0 or an integer of up to 1000; ```n is 0 or an integer of 1 to 100; and ```A is a functional group. Functional group A is linked via a linker, a drug, protein, peptide or saccharide molecule or a molecule providing the polymer with a degree of water-solubility that is higher or lower than that of the polymer. The polymer can be used for the delivery of therapeutic agents.

Description

BIODEGRADABLE POLYMER
Field of the Invention
This invention relates to a biodegradable polymer.
Summary of Invention
According to the invention, a novel biodegradable, biocompatible polymer is suitable for the delivery of therapeutic agents. The drug compounds can be covalently bound to the polymer or trapped within the polymer matrix. The polymer can additionally be targeted to specific tissues by the addition of targeting agents to the polymer.
The novel polymer has units of the formulae -B':,:NO]?/\N AJAR
A
wherein B is selected from oxygen, sulphur, alkyl, alkyl ether, alkyl thioether, hydroxyl alkyl and alkyl aryl; s is 0 or an integer of 100; m is 0 or an integer of up to 1000; q is 0 or an integer of up to 1000; n is 0 or an integer of 1 to 100; and A is a functional group that provides a point of attachment for further components, typically selected from carboxyl, amino, amido, thio and hydroxyl substituents. The further components include drug, linker to which drug is added, peptde, linker to which peptide is added, protein, linker to which protein is added, saccharine, linker to which saccharide is added, and groups that modify the physical properties of the polymer, such as water solubility.
The polymer example can contain a range of different (A) substitutents
Description of Preferred Embodiments
As used herein, the term "alkyl" means a straight or branched chain alkyl group of up to 8 carbon atoms. Examples are methyl and ethyl. "Alkyl ether", i.e alkoxy may be interpreted accordingly. "Alkyl thiother", i.e alkylthio, may also be interpreted accordingly.
"Aryl" means any aromatic group, including heteroaromatic groups, monocyclic or bcyclic, having up to 12 carbon atoms. Examples are thienyl, phenyl and naphthyl.
A polymer of the invention may be prepared by methods that are generally known. A typical example includes the polymerization of a diacid and a diamine.
The all-acid shown is polymerised with a all-amine containing substituents. A typical example of a all-amine would be Iysine. The allacid will typically have a range of values for m, the exact range mixture effecting the physical properties of the polymer produced. 0 0
HOJI f COW OH
O O
The all-amine components which can be used in this polymerization are indicated below, wherein \OH FOR H2N, I.N/R2 H2NjJ]n H2NjJ]n H2N In n is typically O or an integer of up to 10, and R. R1 and R2 are typically selected from hydrogen, alkyl, aryl, alkyl ether, amino acid, peptide, linker and therapeutic agent.
In one embodiment, specific building blocks can be chosen with a view to determining properties of the polymer. Typical building blocks used to modulate the physical properties of the final polymer are shown below, where n is 0 or an integer of up to 10. The components are mixed with activated d'-acid in a ratio of (1:1) (all-acid: total all-amine) content. Suitable di-amines include diaminopropionic acid, ornithine and Iysine derivatives. They can be connected to saccharide derivatives such as glucamine or alternatively to polyethylene glycols to modulated water solubility. They can also be used as free carboxylic acids.
\N'OH H2N X'O: O H2NjJ]n OH OH H2NJ in \OH H2N jJ]n wherein X can be oxygen, sulphur or nitrogen (NH), R3 is typicaly as defined above for other R groups, and p is O or an integer of up to 10.
Additionally, tn-functional groups such as tri-amines can be added to increase cross-linking. This has significant effect on polymer properties which would be understood by those skilled in the art of polymer chemistry. Solubility and molecular weight in particular are altered. The degree of cross-linking also has an impact on biodegradability which would also be understood by someone skilled in the art of polymer therapeutics and delivery systems. o
H2NN6NH2 H2N: in Alternatively or in addition, selected building blocks can add components.
For example, therapeutic components can be added to the all-amine components, preferably priorto the polymerization step, but not necessarily. The therapeutic component may be connected directly to the all-amine unit or through a linker to aid the release of the therapeutic agent or to modulate the physical or biological properties of the material.
In the examples below: H2N X' LIZ H2NX' 'Drug H2,N/\ H2N]n H2N]n H2N]n n is O or an integer of up to 10, X and Y make up the linker and Z is a therapeutic agent.
Suitable linkers can be amino acids, peptide, or a chain such as 6-aminohexanoic acid, 5-aminopentanoic acid, 4-amnobutanoic acid, 3-aminopropanoic acid, or a combination of these components.
The third example above shows a free thiol, which when incorporated within a polymer allows the attachment of biological agents which may be therapeutic or may serve the function of targeting the polymer to a particular tissue, cellular compartment or biological process.
Biological agents can also be attached to the polymer through other functional groups which can be incorporated into the polymemn a similar way to the thiol, through the dia-mine component. These include amine, carboxylic and hydroxyl groups.
Alternatively the therapeutic agent can be entrapped in the soluble polymer matrix during polymerization or diffused into the soluble polymer matrix after synthesis. The polymer used this way Is primarily to aid the dissolution of the drug into aqueous media.
Polymers of the present invention may be used in conjugates of the type described in British Patent Applications Nos.0218827.4,0218828.2, 0218829. 0, 0218830.8 and 0306445 8. A typical synthesis is shown in the chart, below.
The following Example illustrates the invention.
Example
Preparation of poly(ethylene glycol)-bis succinamic acid Diaminopolyethylene glycol (Mw = 1500,119 9), succinct anhydride (24.0 9, 237.6 mmol, 3.0 eq) and DMAP (1.0 9, 8.20 mmol, 0.1 eq) were dissolved in DCM (300 mL). The solution was then heated to reflux and left at reflux for 48 hours. The precipitate that formed was then filtered off and the filtrate concentrated to give a white solid, the crude diacid product. Purification via precipitation and reverse phase chromatography yielded the PEG diacid compound.
Preparation of N-hydroxysuccinimide activated his (succinamic acid) poly(ethylene glycol).
The his (succinamic acid) poly(ethylene glycol) (1.3 9), DIC (362 _L, 3 eq), DMAP (1 mg, 0.01 eq) and N-hydroxysuccinimide (266 mg, 3.0 eq) were dissolved in dry DCM (10 mL) and stirred overnight. The reaction was then concentrated down and acetonitrile added. The solution was filtered, concentrated and precipitated to yield his (succinamic Nhydroxysuccinimide ester) poly(ethylene glycol).
Preparation of Boc-lysine(Boc)-linker 5-Aminovaleric acid monohydrochloride (693 mg, 4 5 mmol, 1.0 eq) was dissolved in water (15 mL) and MeCN (10 mL). Sodium carbonate (478 mg, 4.5 mmol, 1.0 eq) was added as a solution in water (5 mL), followed by Boc-Lys(Boc)OSu (2.0 9,4.5 mmol,1.0 eq) as a solution In MeCN (20 mL). The reaction was then left to stir overnight. The reaction mixture was concentrated and water added before being extracted with ethyl acetate (3 x 50 mL). The combined organic layers were then washed with 0 01 N HCI (2 x 50 mL), brine, dried over MgSO4 and concentrated. Punfcation by normal phase chromatography yielded the product (1.6 9, 80%).
Boc-lysine (Boc)-linker coupling to 3-hydroxy lidocaine Boc-Lys(Boc)linker (1.63 g, 3 66 mmol) was dissolved in dry DCM (16 mL). To this was added DIC (573 _L, 3.66 mmol, 1.0 eq) and DMAP (58 mg, 0.48 mmol, 0.13 eq). The now cloudy solution was left to stir for 15 minutes.
3-hydroxylidocaine lidocaine (1.01 9, 4.03 mmol, 1.1 eq) was added as a solution in DCM. This was then left to stir overnight. The solvent was evaporated, the residue dissolved in ethyl acetate and washed with water. The organic layer was then washed with a weak base solution, dried and evaporated to dryness. Purification via reverse phase chromatography yielded the product (pale yellow solid,1.85 9, 75%).
Deprotection of BocLys(Boc) linker-3-hydroxy-lidocaine ester The BocLys(Boc)-linker-3-hydroxy-lidocaine (0.20 9, 0.29 mmol) was dissolved in TFA:water (95:5,10 mL) and stirred at room temperature for 30 min. The solvents were evaporated, the residue taken up in water (15 mL) and freeze dried to give the deprotected material.
Polymerisation of Lys-linker-3-hydroxy-lidocaine esterwith bis (succinamic N-hydroxysuccinimide ester) poly(ethylene glycol) The Lyslinker-3-hydroxy-lidocaine ester (0.12 9, 0.15 mmol) and his (succinamic acid N-hydroxysuccinimide ester) poly(ethylene glycol) (0.28 9,0.15 mmol) were dissolved in DMF (400 L) and treated with NMM (64 L, 0. 58 mmol). The oil was left to stand overnight, then precipitated from ether. The resulting polymer was dried on high vac line for 30 min. Preparation of Boc-lys(Boc)-CONH-butyl-NH Boc N-Boc-1,4-diaminobutane monohydrochloride (430 mg, 2.25 mmol, 1.0 eq) was dissolved in water (15 mL) and MeCN (10 mL). Sodium carbonate (120 mg,1.12 mmol, 0.5 eq) was added as a solution in water (5 mL), followed by Boc-Lys(Boc)OSu (1.0 9,2.25 mmol,1.0 eq) as a solution in MeCN (20 mL).
The reaction was then left to stir overnight. The reaction mixture was concentrated and water added before being extracted with DCM (3 x 50 mL).
The combined organic layers were then washed with 0.01N HCI (2 x 50 mL), brine, dried over MgSO4 and concentrated. Purification by normal phase chromatography yielded the product (white foam, 1.0 g, 86%).
Deprotection of Boc-Lys(Boc)-butyl-NHBoc Method as for deprotection of BOC-Lys(BOC)linker-3-hydroxy-lidocaine ester Polvmer synthesis HN t- GINO aim 0 - r,H NF16 - JN] o - N i: BccN N O O C O O 608u BocN N OH tNO, BocN In BocN: a BocN In 9 KNIN-O ' + NMM H,N In drug Polyrnor

Claims (3)

1. A polymer having units of the formulae ÀI'BtJlN't-oN/B-loo\ À N wherein B is selected from oxygen, sulphur, alkyl, alkyl ether, alkyl thioether, hydroxyl alkyl and alkyl aryl; s is O or an integer of 100; m is O or an integer of up to 1000; q is O or an integer of up to 1000, n is O or an integer of 1 to 100; and A Is a functional group.
2. A polymer according to claim 1, wherein A is selected from carboxyl carboxyl, amino, amido, two and hydroxyl substituents.
3. A conjugate of a polymer according to claim 1 or claim 2 and, linked via the group A, optionally via a linker, a drug, protein, peptde or saccharide molecule, or a molecule providing the conjugate with a degree of water-solublity that Is higher or lower than that of the polymer.
GB0310335A 2003-05-06 2003-05-06 Biodegradable polymer Withdrawn GB2402677A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8742079B2 (en) 2007-08-20 2014-06-03 Protalix Ltd. Saccharide-containing protein conjugates and uses thereof
US9194011B2 (en) 2009-11-17 2015-11-24 Protalix Ltd. Stabilized alpha-galactosidase and uses thereof
US9732333B2 (en) 2011-01-20 2017-08-15 Protalix Ltd. Nucleic acid construct for expression of alpha-galactosidase in plants and plant cells

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064486A2 (en) * 1999-04-28 2000-11-02 Vectramed, Inc. Enzymatically activated polymeric drug conjugates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000064486A2 (en) * 1999-04-28 2000-11-02 Vectramed, Inc. Enzymatically activated polymeric drug conjugates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Polymeric Materials Science & Engineering, Vol. 66, 1992, Ertel S. I. et. al., "Copolymers of amino acids and poly(ethylene glycol): A new family of functionalized drug-carriers", pages 486-487. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8742079B2 (en) 2007-08-20 2014-06-03 Protalix Ltd. Saccharide-containing protein conjugates and uses thereof
US9194011B2 (en) 2009-11-17 2015-11-24 Protalix Ltd. Stabilized alpha-galactosidase and uses thereof
US9708595B2 (en) 2009-11-17 2017-07-18 Protalix Ltd. Stabilized alpha-galactosidase and uses thereof
US10280414B2 (en) 2009-11-17 2019-05-07 Protalix Ltd. Stabilized α-galactosidase and uses thereof
US10870842B2 (en) 2009-11-17 2020-12-22 Protalix Ltd. Stabilized alpha-galactosidase and uses thereof
US9732333B2 (en) 2011-01-20 2017-08-15 Protalix Ltd. Nucleic acid construct for expression of alpha-galactosidase in plants and plant cells

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