Patent Application
20240076266
The present disclosure relates to iodinated compounds, to hydrogels formed from iodinated compounds, and to methods of making and using iodinated compounds and hydrogels, among other aspects. The iodinated compounds of the present disclosure are useful, for example, in forming hydrogels for various biomedical applications.
In vivo crosslinked hydrogels based on (star-poly(ethylene glycol) (star-PEG) polymers functionalized with reactive ester end groups which are reacted with lysine trimer (Lys-Lys-Lys) as a crosslinker to rapidly form crosslinked hydrogels, such as SpaceOAR®, have become clinically significant materials as adjuvants in radiotherapies. See “Augmenix Announces Positive Three-year SpaceOAR® Clinical Trial Results,” Imaging Technology News, Oct. 27, 2016.
Hydrogels in which some of the star-PEG branches have been functionalized with 2,3,5-triiiodobenzamide (TIB) groups replacing part of ester end groups, such SpaceOAR® Vue, have also been developed, which provide enhanced radiocontrast. See “Augmenix Receives FDA Clearance to Market its TraceIT® Tissue Marker,” BusinessWire Jan. 28, 2013. TraceIT® hydrogel remains stable and visible in tissue for three months, long enough for radiotherapy, after which it is absorbed and cleared from the body. Id.
While the above approach is effectual, using the arms of the star polymer to functionalize the hydrogel with iodine means that there are fewer arms available to crosslink. This can be overcome by adding more polymer, but the loading of solids increases, which can adversely impact viscosity. Reducing the molecular weight can cut down on the loading of solids, but this also results in a lower melting point, and problems with processability. An additional effect of the reduced crosslink density per star polymer is that the resulting gel has a slower cure rate, which means the gel is liquid and mobile in vivo for longer time periods, opening up opportunities for unintended side-reactions and material displacement. Moreover, TIB is sparingly water soluble, meaning that there is an upper limit to how much iodine can be added before the solubility of the gel becomes impacted. In the event that the concentration of TIB groups is so high that the star-PEG precipitates out of solution, the TIB groups can physically crosslink the system before it even reacts, requiring greater force to dispense. Finally, star PEG labeled with 2,3,5-triiiodobenzamide end groups often show discoloration from thermal degradation. While this doesn't impact their functionality, this is a cosmetic defect that is preferably avoided.
There is thus a continuing need in the biomedical arts for additional hydrogels, for precursors of such hydrogels, for methods of making such hydrogels and precursors, for methods of using such hydrogels and precursors, and for systems for forming such hydrogels, among other needs.
The present disclosure provides an alternative approach to that described above. Rather than using the arms of the star polymer to functionalize the hydrogel with iodine, in the present disclosure, the crosslinker for the star polymer is functionalized with iodine.
In various aspects, the present disclosure pertains to systems for forming hydrogels that comprise an iodinated polyamino compound and a reactive multi-arm polymer that comprises a plurality of hydrophilic polymer arms having reactive end groups that are reactive with amino groups of the iodinated polyamino compound.
In some embodiments, the iodinated polyamino compound comprises a polyamino moiety that is linked to a carboxy-substituted iodinated moiety by an amide group. In some of these embodiments, the carboxy-substituted iodinated moiety comprises an iodinated group and a carboxylic acid or carboxylate group. In some of these embodiments, the carboxy-substituted iodinated moiety is an iodinated amino acid residue, for instance, an iodinated amino acid residue that comprises an iodinated aromatic group, among others. For example, the iodinated aromatic group may be a monocyclic or multicyclic aromatic moiety that is substituted with one or more iodine groups and one or more hydroxyl groups, among other possibilities.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the polyamino moiety comprises a plurality of —(CH2)x—NH2 groups where x is 0, 1, 2 3, 4, 5 or 6. In some of these embodiments, the plurality of —(CH2)x—NH2 groups may be disposed along a polymeric moiety.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the polyamino moiety comprises a residue of a carboxyl-substituted polyamino compound.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, polyamino moiety comprises two or more amino acid residues selected from residues of lysine, ornithine, and combinations thereof.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer arms of the reactive multi-arm polymer comprise one or more hydrophilic monomers selected from ethylene oxide, N-vinyl pyrrolidone, oxazolines, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or PNIPAAM.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the reactive end groups of the reactive multi-arm polymer are linked to the hydrophilic polymer arms by a hydrolysable ester.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the reactive end groups of the reactive multi-arm polymer are electrophilic groups. In some of these embodiments, the electrophilic groups are selected from imidazole esters, imidazole carboxylates, benzotriazole esters, or imide esters.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the system comprises a first precursor composition that comprises the iodinated polyamino compound and a second precursor composition that comprises the reactive multi-arm polymer.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the system further comprises an accelerant composition.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the first precursor composition is provided in a syringe barrel, the second precursor composition is provided in a vial, and the accelerant composition is provided in a syringe barrel.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the system further comprises a delivery device.
Other aspects of the present disclosure pertain to medical hydrogels that are formed by crosslinking the first and second precursor compositions of the systems set forth in any of the above aspects and embodiments.
Other aspects of the present disclosure pertain to methods of treatment comprising administering a mixture of the first and second precursor compositions of the systems set forth in any of the above aspects and embodiments.
In some embodiments, which can be used in conjunction with the above aspects and embodiments, the system further comprises a delivery device. In some of these embodiments, the delivery device comprises a first reservoir that contains the first precursor composition and a second reservoir that contains the second precursor composition, wherein during operation, the first and second precursor compositions are dispensed from the first and second reservoirs, whereupon the first and second precursor compositions interact and crosslink with one another to form the hydrogel. In some of these embodiments, the delivery device comprises a first reservoir that contains the first precursor composition and the second precursor composition and a second reservoir that contains an accelerant composition, wherein during operation, the contents of the first and second reservoirs are dispensed, whereupon the first and second precursor compositions crosslink with one another to form the hydrogel. The first and second reservoirs may comprise syringe barrels, for example.
Other aspects of the present disclosure pertain to medical hydrogels that are formed by crosslinking the first and second precursor compositions of the systems set forth in any of the above aspects and embodiments.
Still other aspects of the present disclosure pertain to methods of making iodinated polyamino compounds, the methods comprising (a) forming a protected carboxyl-substituted polyamino compound by protecting amino groups of the carboxyl-substituted polyamino compound, (b) forming an amide linkage between the carboxyl group of the protected carboxyl-substituted polyamino compound and an amino group of an iodinated amino acid compound, and (c) deprotecting amino groups of the product of step (b).
Potential benefits associated with the present disclosure include one or more of the following: radiocontrast is maintained, complexity and cost of the manufacturing process is reduced, melting point of the solid components of the hydrogel can be maintained above 40° C. (improving storage and handling), homogeneity of the final hydrogel is improved, in vivo persistence is obtained, and cure kinetics are maintained.
The above and other aspects, embodiments, features and benefits of the present disclosure will be readily apparent from the following detailed description.
In some aspects of the present disclosure, a radiopaque crosslinked hydrogel is provided that comprises a crosslinked reaction product of (a) an iodinated polyamino compound and (b) a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound. Unless indicated otherwise, as used herein the prefix “poly” means two or more.
In some aspects of the present disclosure, a system is provided that is configured to dispense an iodinated polyamino compound and a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound under conditions such that the iodinated polyamino compound and the reactive multi-arm polymer crosslink with one another. In certain embodiments, those conditions comprise an environment having a basic pH, for example, a pH ranging from about 9 to about 11, typically ranging from about 9.5 to about 10.5, and beneficially ranging from about 9.8 to about 10.2.
In some aspects of the present disclosure, a system is provided that comprises (a) a first composition that comprises an iodinated polyamino compound and (b) a second composition that comprises a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound. In some embodiments, a third composition in the form of an accelerant composition is provided.
Such a system is advantageous, for example, in that iodine functionality, and thus radiopacity, is provided by the iodinated polyamino compound that acts as a crosslinker for the multi-arm polymer. This allows reactive end groups to be provided on each of the polymer arms, thereby maximizing the crosslinking capacity of the multi-arm polymer, without sacrificing radiopacity.
In various embodiments, the iodinated polyamino compounds of the present disclosure comprise a polyamino moiety that is linked to a carboxy-substituted iodinated moiety. In certain embodiments, the polyamino moiety is linked to the carboxy-substituted iodinated moiety through an amide group. In particular embodiments, detailed below, the iodinated polyamino compounds may comprise peptide oligomers that contain from 2 to 10 lysine and/or ornithine amino acid residues and one or more iodinated amino acid residues.
Carboxy-substituted iodinated moieties of the present disclosure include carboxy-substituted iodinated moieties that comprise an iodinated group and a carboxylic acid or carboxylate group. Carboxylate groups include anionic carboxylate groups, carboxylate amide groups, and carboxylate ester groups.
In some embodiments, the carboxy-substituted iodinated moieties of the present disclosure comprise an iodinated aromatic group (also referred to as an iodo-aromatic group) and a carboxylic acid or carboxylate group. Examples of iodinated aromatic groups include iodine-substituted monocyclic aromatic groups and iodine-substituted multicyclic aromatic groups, such as iodo-phenyl groups and iodo-naphthyl groups. The aromatic groups may be substituted with one two, three, four, five, six or more iodine atoms.
In particular embodiments, the carboxy-substituted iodinated moieties of the present disclosure include at least one hydroxy-iodo-aromatic group and a carboxylic acid or carboxylate group. Examples of hydroxy-iodo-aromatic groups include hydroxy-iodo-phenyl groups and hydroxy-iodo-naphthyl groups. More particular examples of hydroxy-iodo-aromatic groups include hydroxy-iodo-phenyl groups selected from a mono-hydroxy-mono-iodo-phenyl group, a mono-hydroxy-di-iodo-phenyl group, a mono-hydroxy-tri-iodo-phenyl group, a mono-hydroxy-tetra-iodo-phenyl group, a di-hydroxy-mono-iodo-phenyl group, a di-hydroxy-di-iodo-phenyl group, a di-hydroxy-tri-iodo-phenyl group, a tri-hydroxy-mono-iodo-phenyl group, a tri-hydroxy-di-iodo-phenyl group.
In some embodiments, the carboxy-substituted iodinated moieties of the present disclosure comprise iodinated amino acid residues. As used herein, an “amino acid” is an organic compound that contain an amino group (—NH2), a carboxylic acid group (—COOH), and a side group that is specific to each amino acid. Depending on the surrounding pH, the amino group may be positively charged (—NH3+) and/or the carboxylic acid group may be negatively charged (—COO−). An iodinated amino acid is an amino acid in which the side group contains one or more iodine atoms.
Examples of iodinated amino acid residues include iodinated alpha-amino acid residues, iodinated beta-amino acid residues, iodinated gamma-amino acid residues and iodinated delta-amino acid residues.
Examples of iodinated amino acid residues include amino acid residues that comprise an iodinated aromatic group. As previously noted, examples of iodinated aromatic groups include iodo-phenyl groups and iodo-naphthyl groups. In particular embodiments, the iodinated amino acid residues include amino acid residues that comprise a hydroxy-iodo-aromatic group, such as a hydroxy-iodo-phenyl group or a hydroxy-iodo-naphthyl group. More particular examples of hydroxy-iodo-aromatic groups include hydroxy-iodo-phenyl groups selected from a mono-hydroxy-mono-iodo-phenyl group, a mono-hydroxy-di-iodo-phenyl group, a mono-hydroxy-tri-iodo-phenyl group, a mono-hydroxy-tetra-iodo-phenyl group, a di-hydroxy-mono-iodo-phenyl group, a di-hydroxy-di-iodo-phenyl group, a di-hydroxy-tri-iodo-phenyl group, a tri-hydroxy-mono-iodo-phenyl group, a tri-hydroxy-di-iodo-phenyl group, as previously indicated.
Specific examples of iodinated amino acid residues include residues of the following iodinated amino acids: iodo-phenylalanine,
which comprises a mono-iodo-phenyl group, monoiodotyrosine,
which comprises a mono-iodo-phenyl group, specifically, a mono-hydroxy-mono-iodo-phenyl group, diiodotyrosine,
which comprises a mono-hydroxy-di-iodo-phenyl group, diiodothyronine,
which comprises a di-iodo-phenyl group and a hydroxy-phenyl group, triiodothyronine also known as T3,
which comprises a di-iodo-phenyl group and a mono-hydroxy-mono-iodo-phenyl group, tetraiodothyronine also known as thyroxine or T4,
which comprises a di-iodo-phenyl group and a mono-hydroxy-di-iodo-phenyl group, iodo-phenylalanine, and 6-iodo-L-DOPA, which comprises a di-hydroxy-mono-iodo-phenyl group, among others. Many of these iodinated amino acids are relatively water soluble, and some, including 3,5-diiodotyrosine and L-thyroxine, are well-studied as monomers for bioerodible polymers.
As described further below, the iodinated polyamino compounds of the present disclosure may be formed by amide coupling reaction between a carboxyl-substituted polyamino compound, selected for example, from these described below (after protection of the amino groups) and an iodinated amino acid derivative, for example, a C1-C5-alkyl ester of an iodinated amino acid, preferably a methyl ester of an iodinated amino acid, which effectively acts as a protective group for the carboxylic acid group of the final iodinated polyamino compound. Examples of such iodinated amino acid derivatives include C1-C5-alkyl esters of any of the preceding iodinated amino acids. After coupling, the protective groups on the residue of the carboxyl-substituted polyamino compound are removed and the C1-C5-alkyl ester may be converted into the corresponding carboxylic acid or anionic carboxylate group, thereby providing the final iodinated polyamino compound.
In addition to a carboxy-substituted iodinated moiety, such as one of those described above, the iodinated polyamino compounds of the present disclosure also comprise a polyamino moiety linked to the carboxy-substituted iodinated moiety.
In various embodiments, the iodinated polyamino compounds of the present disclosure comprise a polyamino moiety having a plurality (two, three, four, five, six, seven, eight, nine, ten or more) amino groups. For example, the polyamino moiety may comprises a plurality of (two, three, four, five, six, seven, eight, nine, ten or more) —(CH2)x—NH2 groups where x is 0, 1, 2 3, 4, 5 or 6. In some of these embodiments, the polyamino moiety may comprises a plurality of —(CH2)x—NH2 groups disposed along a polymeric moiety (defined herein as a moiety comprising 2, 3, 4, 5, 6, 7, 8, 9, 10 or more monomer residues). In some embodiments, the polymeric moiety may be selected from a polyamide moiety, such as a peptide moiety, a polyalkylene moiety, or a polysaccharide moiety, among others.
In some embodiments, the polyamino moiety of the iodinated polyamino compounds may correspond to a residue of a carboxyl-substituted polyamino compound (a compound comprising a carboxyl group and a plurality of amino groups). Examples of carboxyl-substituted polyamino compounds include peptides containing from 2 to 10 lysine and/or ornithine amino acid residues, including polylysines (e.g., dilysine, trilysine, tetralysine, pentalysine, etc.) and carboxyl-terminated polyamines such as carboxyl-terminated poly(allyl amine), carboxyl-terminated poly(vinyl amine), or carboxyl-terminated chitosan.
Commercially available examples of carboxyl-substituted polyamino compounds also include 16-amino-3-[2-[(4-aminobutyl)(3-aminopropyl)amino]-2-oxoethyl]-12-(3-aminopropyl)-6,9-bis(carboxymethyl)-11-oxo-3,6,9,12-tetraazahexadecanoic acid, L-ornithyl-L-ornithyl-L-ornithine, N2-[1-[N2-[N2-(N-L-valyl-L-alanyl)-L-lysyl]-lysyl]-L-prolyl]-L-Lysine, L-Lysyl-L-tryptophyl-L-lysyl-L-lysine, N2,N5,N5-tris(3-aminopropyl)-L-ornithine, L-lysyl-L-ornithyl-L-lysine, D-lysyl-D-lysyl-D-lysine, glycylglycyl-L-lysylglycylglycyl-L-lysine, N2-[N4-[N-[N-(N-glycylglycyl)glycyl]glycyl]-L-lysyl]-L-lysine, L-Lysyl-L-threonyl-L-lysyl-L-lysine, glycylglycyl-L-lysyl-L-lysylglycyl-L-cysteine, L-lysyl-L-arginyl-L-lysyl-L-lysine, L-arginyl-L-lysyl-L-lysyl-L-lysine, L-leucyl-L-lysyl-L-seryl-L-lysyl-L-lysine, L-alanyl-L-methionylglycyl-L-lysyl-L-lysyl-L-lysine, L-lysyl-L-lysyl-L-lysyl-L-arginyl-L-glutamine, L-seryl-L-isoleucyl-L-lysyl-L-lysyl-Llysyl-L-lysine, N2-(N2-L-ornithyl-L-lysyl)-L-lysine, lysyllysyl-lysine, and L-lysyl-L-lysyl-L-lysyl-L-alanine.
As previously noted, in certain embodiments, the iodinated polyamino compounds of the present disclosure comprise a polyamino moiety linked to a carboxy-substituted iodinated moiety through an amide group. The amide group may be the result of a coupling reaction between an amino group of an iodinated amino acid such as one of those described above and a carboxyl group of a carboxyl-substituted polyamino compound, such as one of those described above. The resulting iodinated polyamino compounds therefore comprise a residue of the carboxyl-substituted polyamino compound and an iodinated amino acid residue. Stated another way, the iodinated polyamino compounds of the present disclosure may be formed by an amidation reaction in which the carboxyl group of a carboxyl-substituted polyamino compound is reacted with the amino group of an iodinated amino acid to form an amide bond between the two residues.
In some aspects, the present disclosure pertains to processes of making iodinated polyamino compounds such as those described above.
In a first process, amino groups of a carboxyl-substituted polyamino compound may be protected with a suitable protective agent. The amino groups are protected for compatibility with other reactants in a subsequent amide coupling reaction (described below). For example, amino groups of a carboxyl-substituted polyamino compound may be protected by reaction with di-tert-butyl dicarbonate. In a particular example, and with reference to
In a second process, an iodinated amino acid derivative, specifically an iodinated amino acid C1-C5-alkyl ester, is coupled with the protected carboxyl-substituted polyamino compound as formed in the first process in an amide coupling reaction (e.g., via a carbodiimide coupling reagent) to form a protected iodinated polyamino compound. In a particular example, and with reference to
In a third process, deprotection and hydrolysis of the product of the second process is performed (e.g., under acidic conditions), to form a final carboxyl-substituted iodinated polyamino compound. For example, as shown in
The process described above can be performed using a variety of carboxyl-substituted polyamino compounds and a variety of iodinated amino acid derivatives. With regard to the latter, when a diiodotyrosine methyl ester is coupled to trilysine as described above, the resulting compound is that shown in
Moreover, more iodinated amino acid groups can be successively added to the chain end, by repeating the first, second and third processes, except that the iodinated polyamino compound formed in the third process is substituted for the trilysine in the first procedure, forming a protected compound, which is then coupled to another an iodinated amino acid C1-C5-alkyl ester along the lines of the second process in an amide coupling reaction, followed by deprotection and hydrolysis along the lines of the third process. The result of performing these additional steps once, where the iodinated amino acid C1-C5-alkyl ester is diiodotyrosine methyl ester, is shown in
If the first, second and third processes are repeated again, with the product of
As noted above, in some aspects of the present disclosure, a radiopaque crosslinked hydrogel is provided that comprises a crosslinked reaction product of (a) an iodinated polyamino compound such as those described above and (b) a reactive multi-arm polymer that comprises a plurality of polymer arms that have reactive end groups that are reactive with the amino groups of the iodinated polyamino compound.
In various embodiments, the crosslinked products of the present disclosure are visible under fluoroscopy. In various embodiments, such crosslinked products have a radiopacity that is greater than 250 Hounsfield units (HU), beneficially anywhere ranging from 250 HU to 500 HU to 750 HU to 1000 HU or more (in other words, ranging between any two of the preceding numerical values). Such crosslinked products may be formed in vivo (e.g., using a delivery device like that described below), or such crosslinked products may be formed ex vivo and subsequently administered to a subject. Such crosslinked products can be used in a wide variety of biomedical applications, including medical devices, implants, and pharmaceutical compositions.
In various embodiments, the reactive end groups of the reactive multi-arm polymer and the amino groups of the iodinated polyamino compound react with one another form a crosslinked product. The reactive multi-arm polymer may be water soluble.
Reactive multi-arm polymers for use herein include those that comprise a plurality of polymer arms (e.g., having two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more arms), wherein two or more polymer arms of the multi-arm polymers comprise one or more reactive end groups. In some embodiments, compositions containing the reactive multi-arm polymers may be provided in which a percentage of the polymer arms comprising one or more reactive end groups may correspond to between 50% and 100% of the total number of polymer arms in the composition (e.g., ranging anywhere from 50% to 70% to 80% to 90% to 95% to 99% to 100% of the total number of polymer arms). Typical average molecular weights for the reactive multi-arm polymers for use herein are of at least 10 kDa, in some cases ranging from 10 kDa to 50 kDa or more. In various embodiments, the reactive multi-arm polymers for use herein have a melting point of 40° C. or greater, preferably 45° C. or greater.
In various embodiments, the polymer arms are hydrophilic polymer arms. Such hydrophilic polymer arms may be composed of any of a variety of synthetic, natural, or hybrid synthetic-natural polymers including, for example, poly(alkylene oxides) such as poly(ethylene oxide) (PEO, also referred to as polyethylene glycol or PEG), poly(propylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(N-vinyl pyrrolidone), polyoxazolines including poly(2-alkyl-2-oxazolines) such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline) and poly(2-propyl-2-oxazoline), poly(vinyl alcohol), poly(allyl alcohol), polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate, or PNIPAAM, polysaccharides, and combinations thereof.
In some embodiments, the polymer arms extend from a core region. In certain of these embodiments, the core region comprises a residue of a polyol that is used to form the polymer arms. Illustrative polyols may be selected, for example, from straight-chained, branched and cyclic aliphatic polyols including straight-chained, branched and cyclic polyhydroxyalkanes, straight-chained, branched and cyclic polyhydroxy ethers, including polyhydroxy polyethers, straight-chained, branched and cyclic polyhydroxyalkyl ethers, including polyhydroxyalkyl polyethers, straight-chained, branched and cyclic sugars and sugar alcohols, such as glycerol, mannitol, sorbitol, inositol, xylitol, quebrachitol, threitol, arabitol, erythritol, adonitol, dulcitol, fucose, ribose, arabinose, xylose, lyxose, rhamnose, galactose, glucose, fructose, sorbose, mannose, pyranose, altrose, talose, tagatose, pyranosides, sucrose, lactose, and maltose, polymers (defined herein as two or more units) of straight-chained, branched and cyclic sugars and sugar alcohols, including oligomers (defined herein as ranging from two to ten units, including dimers, trimers, tetramers, pentamers, hexamers, heptamers, octamers, enneamers and decamers) of straight-chained, branched and cyclic sugars and sugar alcohols, including the preceding sugars and sugar alcohols, starches, amylose, dextrins, cyclodextrins, as well as polyhydroxy crown ethers, and polyhydroxyalkyl crown ethers. Illustrative polyols also include aromatic polyols including 1,1,1-tris(4′-hydroxyphenyl) alkanes, such as 1,1,1-tris(4-hydroxyphenyl)ethane, and 2,6-bis(hydroxyalkyl)cresols, among others.
In certain beneficial embodiments, the core region comprises a residue of a polyol that contains two, three, four, five, six, seven, eight, nine, ten or more hydroxyl groups. In certain beneficial embodiments, the core region comprises a residue of a polyol that is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol, or erythritol, among others.
In certain embodiments, the reactive end groups may be electrophilic groups selected from imidazole esters, imidazole carboxylates, benzotriazole esters, or imide esters, including N-hydroxysuccinimidyl esters. A particularly beneficial reactive end group is an N-hydroxysuccinimidyl ester group. In certain embodiments, the reactive end groups are linked to the polymer arms via hydrolysable ester groups. Hydrolysable ester groups may be selected, for example, from glutarate ester groups, succinate ester groups, carbonate ester groups, or adipate ester groups. In particular embodiments, the polymer arms may be terminated with the following reactive, hydrolysable groups, among others: succinimidyl glutarate groups, succinimidyl succinate groups, succinimidyl carbonate groups, or succinimidyl adipate groups.
Further examples of reactive multi-arm polymers are described, for example, in U.S. Patent Application Nos. 2011/0142936, 2021/0061950, 2021/0061954 and 2021/0061957.
In some aspects of the present disclosure, systems are provided that are configured to deliver an iodinated polyamino compound and a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound under conditions such that the iodinated polyamino compound and the reactive multi-arm polymer crosslink with one another. Such systems can be used to form crosslinked hydrogels, either in vivo or ex vivo.
For example, as shown schematically in
An advantage to this approach is that the iodination is separate from the parent polymer, and the multi-arm polymer can be swapped out with N-hydroxysuccinimidyl-ester-functionalized systems having hydrophilic polymer arms other than polyethylene oxide arms, for example, synthetic, natural, or hybrid synthetic-natural hydrophilic polymer arms such as those described above.
As previously noted, in some aspects of the present disclosure, systems are provided that comprise (a) a first composition that comprises an iodinated polyamino compound (120) and (b) a second composition that comprises a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound (140).
The first composition may be a first fluid composition comprising the iodinated polyamino compound or a first dry composition that comprises the iodinated polyamino compound, to which a suitable fluid such as water for injection, saline, etc. can be added to form a first fluid composition. In addition to the iodinated polyamino compound, the first composition may further comprise additional agents, including those described below.
The second composition may be a second fluid composition comprising the reactive multi-arm polymer or a second dry composition that comprises the reactive multi-arm polymer, to which a suitable fluid such as water for injection, saline, etc. can be added to form a second fluid composition. In addition to the reactive multi-arm polymer, the second composition may further comprise additional agents including as those described below.
In some embodiments, the iodinated polyamino compound (120) is initially combined with the reactive multi-arm polymer (410) at an acidic pH at which crosslinking between the reactive groups of the reactive multi-arm polymer (410) and the amino groups of the iodinated polyamino compound (120) is suppressed. Then, when crosslinking is desired, a pH of the mixture of the iodinated polyamino compound (120) and the reactive multi-arm polymer (410) is changed from an acidic pH to a basic pH, leading to crosslinking between same.
In particular embodiments, the system comprises (a) a first precursor composition that comprises an iodinated polyamino compound as described hereinabove, (b) a second precursor composition that comprises a reactive multi-arm polymer as described hereinabove, and (c) a third composition, specifically, an accelerant composition, that contains an accelerant that is configured to accelerate crosslinking reaction between the iodinated polyamino compound and the reactive multi-arm polymer.
The first precursor composition may be a first fluid composition comprising the iodinated polyamino compound that is buffered to an acidic pH or a first dry composition that comprises the iodinated polyamino compound and acidic buffering composition, to which a suitable fluid such as water for injection, saline, etc. can be added to form a first fluid composition comprising the iodinated polyamino compound that is buffered to an acidic pH. In some embodiments, for example, the acidic buffering composition may comprise monobasic sodium phosphate, among other possibilities. The first fluid composition comprising the iodinated polyamino compound may have a pH ranging, for example, from about 3 to about 5, typically ranging from about 3.5 to about 4.5, and more typically ranging from about 3.8 to about 4.2. In addition to the iodinated polyamino compound, the first precursor composition may further comprise additional agents, such as therapeutic agents and/or further imaging agents (beyond the iodine groups that are present in the iodinated polyamino compound).
The second precursor composition may be a second fluid composition comprising the reactive multi-arm polymer or a second dry composition that comprises the reactive multi-arm polymer from which a fluid composition is formed, for example, by the addition of a suitable fluid such as water for injection, saline, or the first fluid composition comprising the iodinated polyamino compound that is buffered to an acidic pH. In addition to the reactive multi-arm polymer, the second precursor composition may further comprise additional agents, such as therapeutic agents and/or further imaging agents (beyond the iodine groups that are present in the iodinated polyamino compound).
In a particularly beneficial embodiment, the first precursor composition is a first fluid composition comprising the iodinated polyamino compound that is buffered to an acidic pH and the second precursor composition comprises a dry composition that comprises the reactive multi-arm polymer. The first precursor composition may then be mixed with the second precursor composition to provide a prepared fluid composition that is buffered to an acidic pH and comprises the iodinated polyamino compound and the reactive multi-arm polymer. In a particular example, a syringe may be provided that contains a first fluid composition comprising the iodinated polyamino compound that is buffered to an acidic pH, and a vial may be provided that comprises a dry composition (e.g., a powder) that comprises the reactive multi-arm polymer. The syringe may then be used to inject the first fluid composition into the vial containing the reactive multi-arm polymer to form a prepared fluid composition that contains the iodinated polyamino compound and the reactive multi-arm polymer, which can be withdrawn back into the syringe for administration.
The accelerant composition may be a fluid accelerant composition that is buffered to a basic pH or a dry composition that comprise a basic buffering composition to which a suitable fluid such as water for injection, saline, etc. can be added to form a fluid accelerant composition that is buffered to a basic pH. For example, the basic buffering composition may comprise sodium borate and dibasic sodium phosphate, among other possibilities. The fluid accelerant composition may have, for example, a pH ranging from about 9 to about 11, typically ranging from about 9.5 to about 10.5, and more typically ranging from about 9.8 to about 10.2. In addition to the above, the fluid accelerant composition may further comprise additional agents, such as therapeutic agents and/or further imaging agents (beyond the iodine groups that are present in the iodinated polyamino compound).
Examples of further imaging agents include (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g. green, blue, cyan fluorescent proteins), (b) contrast agents for use in conjunction with magnetic resonance imaging (MRI), including contrast agents that contain elements that form paramagnetic ions, such as Gd(III), Mn(II), Fe(III) and compounds (including chelates) containing the same, such as gadolinium ion chelated with diethylenetriaminepentaacetic acid, (c) contrast agents for use in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in an increase in the reflected ultrasonic energy) or organic and inorganic echolucent particles (i.e., particles that result in a decrease in the reflected ultrasonic energy), (d) radiocontrast agents, such as those based on the clinically important isotope 99mTc, as well as other gamma emitters such as 123I, 125I, 131I, 111In, 57Co, 153Sm, 133Xe, 51Cr, 81mKr, 201Tl, 67Ga, and 75Se, among others, (e) positron emitters, such as 18F, 11C, 13N, 15O, and 68Ga, among others, may be employed to yield functionalized radiotracer coatings, and (f) contrast agents for use in connection with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coatings of the present disclosure, allowing for deep tissue imaging and device marking, for instance, NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, for instance, partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulating nanoparticles, and semiconductor quantum dots, among others. NIR-sensitive dyes include cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives and borondipyrromethane (BODIPY) analogs, among others.
A prepared fluid composition that is buffered to an acidic pH and comprises the iodinated polyamino compound and the reactive multi-arm polymer as described above, and a fluid accelerant composition that is buffered to basic pH as described above, may be combined form crosslinked hydrogels, either in vivo or ex vivo.
In various embodiments, a system is provided that include one or more delivery devices for delivering first and second compositions to a subject.
In some embodiments, the system may include a delivery device that comprises a first reservoir that contains a first composition that comprises an iodinated polyamino compound as described above and a second reservoir that contains a second composition that comprises a reactive multi-arm polymer that comprises a plurality of reactive end groups that are reactive with the amino groups of the iodinated polyamino compound as described above. In some embodiments, the system may include a delivery device that comprises a first reservoir that contains first composition that comprises the iodinated polyamino compound and the reactive multi-arm polymer and is buffered to an acidic pH, such as the prepared fluid composition previously described, and a second reservoir that contains second composition, such as the fluid accelerant composition described above. In either case, during operation, the first composition and second composition are dispensed from the first and second reservoirs and combined, whereupon the iodinated polyamino compound and the reactive multi-arm polymer and crosslink with one another to form a hydrogel.
Regardless of the first and second compositions selected, in particular embodiments, the system may include a delivery device that comprises a double-barrel syringe, which includes first barrel having a first barrel outlet, which first barrel contains the first composition, a first plunger that is movable in the first barrel, a second barrel having a second barrel outlet, which second barrel contains the second composition, and a second plunger that is movable in the second barrel.
In some embodiments, the device may further comprise a mixing section having a first mixing section inlet in fluid communication with the first barrel outlet, a second mixing section inlet in fluid communication with the second barrel outlet, and a mixing section outlet. In some embodiments, the device may further comprise a cannula or catheter tube that is configured to receive first and second fluid compositions from the first and second barrels. For example, a cannula or catheter tube may be configured to form a fluid connection with an outlet of a mixing section by attaching the cannula or catheter tube to an outlet of the mixing section, for example, via a suitable fluid connector such as a luer connector.
As another example, the catheter may be a multi-lumen catheter that comprises a first lumen and a second lumen, a proximal end of the first lumen configured to form a fluid connection with the first barrel outlet and a proximal end of the second lumen configured to form a fluid connection with the second barrel outlet. In some embodiments, the multi-lumen catheter may comprise a mixing section having a first mixing section inlet in fluid communication with a distal end of the first lumen, a second mixing section inlet in fluid communication with a distal end of the second lumen, and a mixing section outlet.
During operation, when the first and second plungers are depressed, the first and second fluid compositions are dispensed from the first and second barrels, whereupon the first and second fluid compositions interact and ultimately crosslink to form a hydrogel, which is administered onto or into tissue of a subject. For example, the first and second fluid compositions may pass from the first and second barrels, into the mixing section via first and second mixing section inlets, whereupon the first and second fluid compositions are mixed to form an admixture, which admixture exits the mixing section via the mixing section outlet. In some embodiments, a cannula or catheter tube is attached to the mixing section outlet, allowing the admixture to be administered to a subject after passing through the cannula or catheter tube.
As another example, the first fluid composition may pass from the first barrel outlet into a first lumen of a multi-lumen catheter and the second fluid composition may pass from the second barrel outlet into a second lumen of the multi-lumen catheter. In some embodiments the first and second fluid compositions may pass from the first and second lumen into a mixing section at a distal end of the multi-lumen catheter via first and second mixing section inlets, respectively, whereupon the first and second fluid compositions are mixed in the mixing section to form an admixture, which admixture exits the mixing section via the mixing section outlet.
Regardless of the type of device that is used to mix the first and second fluid compositions or how the first and second fluid compositions are mixed, immediately after an admixture of the first and second fluid compositions is formed, the admixture is initially in a fluid state and can be administered to a subject (e.g., a mammal, particularly, a human) by a variety of techniques. Alternatively, the first and second fluid compositions may be administered to a subject independently and a fluid admixture of the first and second fluid compositions formed in or on the subject. In either approach, a fluid admixture of the first and second fluid compositions is formed and used for various medical procedures.
For example, the first and second fluid compositions or a fluid admixture thereof can be injected to provide spacing between tissues, the first and second fluid compositions or a fluid admixture thereof can be injected (e.g., in the form of blebs) to provide fiducial markers, the first and second fluid compositions or a fluid admixture thereof can be injected for tissue augmentation or regeneration, the first and second fluid compositions or a fluid admixture thereof can be injected as a filler or replacement for soft tissue, the first and second fluid compositions or a fluid admixture thereof can be injected to provide mechanical support for compromised tissue, the first and second fluid compositions or a fluid admixture thereof be injected as a scaffold, and/or the first and second fluid compositions or a fluid admixture thereof can be injected as a carrier of therapeutic agents in the treatment of diseases and cancers and the repair and regeneration of tissue, among other uses.
After administration of the compositions of the present disclosure (either separately as first and second fluid compositions that mix in vivo or as a fluid admixture of the first and second fluid compositions) a crosslinked hydrogel is ultimately formed at the administration location.
After administration, the compositions of the present disclosure can be imaged using a suitable imaging technique. Typically, the imaging techniques is an x-ray-based imaging technique, such as computerized tomography or X-ray fluoroscopy.
As seen from the above, the compositions of the present disclosure may be used in a variety of medical procedures, including the following, among others: a procedure to implant a fiducial marker comprising a crosslinked product of the first and second fluid compositions, a procedure to implant a tissue regeneration scaffold comprising a crosslinked product of the first and second fluid compositions, a procedure to implant a tissue support comprising a crosslinked product of the first and second fluid compositions, a procedure to implant a tissue bulking agent comprising a crosslinked product of the first and second fluid compositions, a procedure to implant a therapeutic-agent-containing depot comprising a crosslinked product of the first and second fluid compositions, a tissue augmentation procedure comprising implanting a crosslinked product of the first and second fluid compositions, a procedure to introduce a crosslinked product of the first and second fluid compositions between a first tissue and a second tissue to space the first tissue from the second tissue.
The first and second fluid compositions, fluid admixtures of the first and second fluid compositions, or the crosslinked products of the first and second fluid compositions may be injected in conjunction with a variety of medical procedures including the following: injection between the prostate or vagina and the rectum for spacing in radiation therapy for rectal cancer, injection between the rectum and the prostate for spacing in radiation therapy for prostate cancer, subcutaneous injection for palliative treatment of prostate cancer, transurethral or submucosal injection for female stress urinary incontinence, intra-vesical injection for urinary incontinence, uterine cavity injection for Asherman's syndrome, submucosal injection for anal incontinence, percutaneous injection for heart failure, intra-myocardial injection for heart failure and dilated cardiomyopathy, trans-endocardial injection for myocardial infarction, intra-articular injection for osteoarthritis, spinal injection for spinal fusion, and spine, oral-maxillofacial and orthopedic trauma surgeries, spinal injection for posterolateral lumbar spinal fusion, intra-discal injection for degenerative disc disease, injection between pancreas and duodenum for imaging of pancreatic adenocarcinoma, resection bed injection for imaging of oropharyngeal cancer, injection around circumference of tumor bed for imaging of bladder carcinoma, submucosal injection for gastroenterological tumor and polyps, visceral pleura injection for lung biopsy, kidney injection for type 2 diabetes and chronic kidney disease, renal cortex injection for chronic kidney disease from congenital anomalies of kidney and urinary tract, intravitreal injection for neovascular age-related macular degeneration, intra-tympanic injection for sensorineural hearing loss, dermis injection for correction of wrinkles, creases and folds, signs of facial fat loss, volume loss, shallow to deep contour deficiencies, correction of depressed cutaneous scars, perioral rhytids, lip augmentation, facial lipoatrophy, stimulation of natural collagen production.
As previously indicated, crosslinked hydrogel compositions in accordance with the present disclosure include lubricious compositions for medical applications, compositions for therapeutic agent release (e.g., by including one or more therapeutic agents in a matrix of the crosslinked hydrogel), and implants (which may be formed ex vivo or in vivo) (e.g., compositions for use as tissue markers, compositions that act as spacers to reduce side effects of off-target radiation therapy, cosmetic compositions, etc.).
Trilysine (H-Lys-Lys-Lys-OH) Acetate (1 eq) was suspended in a mixture of DMF:H2O (1:1). Triethylamine (4.1 eq) was slowly added and the mixture was stirred for 10 minutes at room temperature, resulting in a clear solution. Di-tert-butyl dicarbonate (4.2 eq) was added to the solution that was stirred for overnight. Then, the reaction solution was diluted in dichloromethane (DCM) and the solution was acidified to pH=4-5 with 1N HCl (aq). The aqueous layer was saturated with NaCl and extracted with DCM twice. The combined organic layers were washed with water twice, washed with brine twice and, dried over anhydrous sodium sulfate (Na2SO4). Then, after filtration of the solution, the solvent was removed, and vacuum dried without further purification to obtain white color product (yield: 80%).
Diiodotyrosine methyl ester hydrochloride (1 eq) was dissolved in DMF and neutralized by adding quantitative amount of triethylamine (1 eq) and the mixture was stirred for an hour before using directly with further purification.
To a solution of Boc-trilysine (Boc-TL) from Example 1 (1 eq) in DMF, EDC-HCl (1 eq), and catalytic amount of n-hydroxyl succinimide (NHS) were consecutively added at room temperature, and the mixture was stirred for 15 min. Then, the diiodotyrosine methyl ester (1 eq), prepared in-situ in DMF, was directly transferred in the reaction solution and was stirred at room temperature for overnight. After that, the solvent was removed, and the obtained residue was re-dissolved in DCM and extracted with water to remove ammonium salt and urea salt. Subsequently, the organic layer was washed with water three times to remove DMF residue, and dried over anhydrous Na2SO4. Finally, after filtration of the solution, the solvent was removed, and vacuum dried to obtain pale-yellow color product (Yield: 80%).
Boc-trilysine-diiodotyrosine methyl ester (Boc-TL-DIT-OMe) from Example 2 was dissolved in a mixture of DCM. Trifluoroacetic acid (TFA) with equal amount as the solvent was added and the solution was stirred at room temperature overnight. Then, the reaction mixture was evaporated in vacuo and evaporated several times after adding DCM to remove residual TFA and give the product in quantitative yield.
The iodinated trilysine of EXAMPLE 3 is dissolved in acidic buffer solution (pH value between 3.8-4.2) then further mixed with reactive star PEG, for example, a star PEG having a polyol residue core region and 8 hydrophilic polyethylene oxide arms having reactive succinimidyl glutarate end groups, as a prepared fluid composition in one syringe. Another buffer solution is prepared having controlled pH value around 9.8-10.4 as a fluid accelerant composition in another syringe. Subsequently, a hydrogel is formed by combining the prepared fluid composition and the fluid accelerant composition to form crosslinked hydrogel simultaneously.
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 63/398,756 filed on Aug. 17, 2022, the disclosure of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63398756 | Aug 2022 | US |
