Drug-polymer conjugates

Abstract

A polymer-prostaglandin conjugate comprising: a polymer backbone comprising a plurality of groups of formula (I): wherein: T represents a triazole group; q is independently selected at each occurrence and may be present or absent and when present represents a linking group; r is selected from the group consisting of linear or branched hydrocarbons; d is selected from prostaglandin; and L is a group of formula (II) wherein R5 is selected from hydrogen and C1 to C6 alkyl; (R) represents a terminal of a group bonded to the R group; and (D) represents a terminal of a group attached to the group D.

Description

[0001] This application is a divisional application of patent application No. 201880017971.3, filed on March 14, 2018, entitled "Drug-Polymer Conjugate". Technical Field

[0002] This invention relates to polymer-prostaglandin conjugates, monomer-prostaglandin conjugates used in their preparation, and implants containing the polymer-prostaglandin conjugates. Background Technology

[0003] Polymer-drug conjugates containing a drug covalently bound to a polymer are of interest for targeted and controlled delivery of therapeutic agents. In the treatment of many different conditions, site-specific delivery of the drug directly to or near the desired site of action within the subject may be desirable to improve drug efficacy and / or safety. Certain sites within the subject may require complex delivery vehicles to overcome barriers to effective drug delivery. For example, the eye has a limited volume for drug administration and requires drug products with high drug loading to ensure sufficient doses can be delivered while maintaining a minimal product volume. Despite the limited volume, it is desirable to be able to deliver the drug to the site continuously and in a controlled manner over an extended period of time. Administration to the target site typically involves injection of the product. Therefore, it is advantageous and desirable for the product to biodegrade and disappear at the target site after treatment, avoiding the need for removal at the end of treatment. Such removal typically requires surgical intervention.

[0004] Currently, prostaglandins and beta-blockers used to treat glaucoma are formulated as eye drops. When administered carefully to the affected eye, they lower intraocular pressure, which in turn can slow the progression of glaucoma. Prostaglandins and beta-blockers are administered as eye drops alone (i.e., as single agents) or in combination. It is hypothesized that combining prostaglandins with beta-blockers that act through different mechanisms can provide the additional effect of lowering intraocular pressure. For example, some pharmaceutical formulations used to treat glaucoma, such as Xalacom sold by Pfizer, are used in this way. TM eye drops and Ganfort sold by Allergan TM Eye drops containing a combination of prostaglandins and beta-blockers.

[0005] Unfortunately, because glaucoma is an asymptomatic disease, many patients do not use their eye drops diligently, jeopardizing treatment. A recent study by Friedman et al. (Friedman et al., IOVS 2007:48, 5052–5057) showed poor adherence to glaucoma treatment choices, with only 59% of patients having an intraocular pressure-lowering medication at 12 months, and only 10% using the medication continuously. Therefore, patient adherence is a problem in glaucoma treatment.

[0006] Unfortunately, because ophthalmic surgery is more common in the elderly, many patients lack the ability to effectively administer eye drops, jeopardizing treatment. A recent study by An et al. showed that elderly patients have poorer eye drop administration ability, with only 7.4% of patients able to effectively administer their eye drops after cataract surgery (An JA, Kasner O, Samek DA, Levesque V. Evaluation of eye drop administration by inexperienced patient after cataract surgery. J Cataract Refract Surg.. 2014;40:1857-1861). Therefore, eye drop administration ability is a problem in postoperative eye drop therapy.

[0007] Drug delivery systems have been developed to aid in the administration and / or sustained delivery of agents (e.g., drugs) to desired sites of action. One method of delivering drugs to a subject involves using polymers that bind to the drug, allowing it to be delivered to and / or retained at a specific location.

[0008] One form of polymer / drug delivery system utilizes a mixture of polymer and drug, wherein the drug is mixed with a polymer matrix. However, such mixtures typically result in poor control of drug release, often exhibiting a "burst release effect" immediately after administration, and significant changes in the physical properties of the mixture as the drug is released (Sjoquist, B.; Basu, S.; Byding, P.; Bergh, K.; Stjernschantz, J., Metab. Dispos. 1998, 26, 745.). Furthermore, such mixtures have limited dose-loading capacity, leading to very large devices for convenient administration to various sites within the subject.

[0009] Another form of polymer / drug delivery system is based on drug polymerization, incorporating drug molecules as part of the polymer backbone. Such systems are described in US 6,613,807, WO2008 / 128193, WO94 / 04593, and US 7,122,615. However, such polymer systems often provide inefficient drug delivery because drug release depends on the breakdown of the polymer backbone. Furthermore, the breaking of the polymer backbone produces inactive intermediates. Such intermediates can complicate regulatory approval, potentially requiring proof of their safety.

[0010] Another approach to preparing polymer-drug conjugates involves covalently linking drug molecules to a pre-formed polymer backbone. Examples of such conjugates have been reviewed in *Nature Reviews: Drug Discovery*, 2003:2, 347–360. However, this approach can also be problematic. In particular, spatial and thermodynamic constraints can affect the amount of drug that can be covalently linked and also influence the distribution of the drug along the polymer backbone. These factors, in turn, reduce control over drug release. Furthermore, if it is necessary to modulate the properties of the conjugate to improve drug release and / or contribute to patient comfort, particularly in the eye, the use of a pre-formed polymer backbone limits the scope for post-drug modification of the polymer conjugate.

[0011] Step-growth polymerization is a method already used in the preparation of polymer-drug conjugates. Through step-growth polymerization, polymer-drug conjugates can be prepared by covalently reacting a drug-functionalized monomer having at least two terminal reactive functional groups with a comonomer having complementary terminal functional groups. An example is the reaction of a drug-functionalized dihydroxy monomer with a diisocyanate comonomer to form a drug-polymer conjugate with a polyurethane polymer backbone. However, a problem with step-growth polymerization is that many drug molecules contain multiple functional groups capable of participating in the covalent reactions used to form the polymer. In this case, there is a risk that functional groups on the drug molecule may react with the terminal functional groups of the monomer, resulting in intra-chain incorporation of the drug into the polymer. As a result, the drug becomes part of the polymer backbone structure rather than forming a side group. Prostaglandins are drugs with multiple nucleophilic functional groups, thus the risk of intra-chain incorporation is high.

[0012] It is desired to provide new polymer-drug conjugates that address or improve one or more drawbacks or deficiencies associated with existing materials and / or their manufacturing methods, or at least provide useful alternatives to these materials and their manufacturing methods. Summary of the Invention

[0013] On one hand, the present invention provides a polymer-prostaglandin conjugate comprising:

[0014] Polymer backbone containing multiple groups of formula (I):

[0015]

[0016] in:

[0017] T represents the triazole group;

[0018] Q is chosen independently each time it appears and may or may not be present, and when present it indicates a linking group;

[0019] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0020] D is selected from prostaglandins; and

[0021] L is a group of formula (II).

[0022]

[0023] Where R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0024] (R) indicates the end of a group bonded to the R group; and

[0025] (D) indicates the end of the group attached to group D.

[0026] The polymer-prostaglandin conjugate may include functional groups that promote biodegradation. In one embodiment, group Q provides a biodegradable group, and a preferred embodiment of Formula I for providing a biodegradable backbone has Formula Ia.

[0027]

[0028] in

[0029] R 1 R 1’ R 2 and R 2’ Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1’ R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0030] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0031] q is 0 or 1;

[0032] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0033] D is selected from prostaglandins;

[0034] L is the linking group of formula II.

[0035]

[0036] Where R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0037] (R) indicates the end of a group bonded to the R group; and

[0038] (D) indicates the end of the group attached to group D.

[0039] and

[0040] T stands for triazole group.

[0041] Biodegradation of the polymer backbone can allow the polymer to be cleared from sites of use such as the eye. In some cases, it is desirable for the polymer to remain at the site of use for a period of time to promote the controlled release of prostaglandins into the target tissue prior to polymer backbone degradation and removal of the polymer and drug from the site of use.

[0042] Biodegradability is controlled by the presence of one or more substituents in the main chain, and when R is present in the polymer... 1 R 1’ R 2 R 2’ When at least one of the components is not hydrogen, control over degradation is generally enhanced. For example, R 1 and R 1' At least one of them may not be hydrogen and / or R 2 and R 2' At least one of them may not be hydrogen.

[0043] Prostaglandins can be covalently bound to the linker L at a series of positions on the prostaglandin (including positions 1, 9, 11, or 15). The effectiveness and release of prostaglandins generally favor covalent attachment at the 1-position of the prostaglandin. In this set of embodiments, the drug D in Formulas I and Ia typically has Formula Xb:

[0044]

[0045] in:

[0046] Indicates the junction between prostaglandins and L;

[0047] Indicates a double bond or a single bond;

[0048] Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups;

[0049] R 9 and R 11 It is a hydroxyl group; and

[0050] W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group.

[0051] Polymer-prostaglandin conjugates are typically obtained as copolymers of at least one monomer of formula (IV):

[0052]

[0053] in:

[0054] X can be the same or different each time it appears, and represents a terminal functional group containing alkyne or azide;

[0055] Q is chosen independently each time it appears and may or may not be present, and when present, it indicates a linking group;

[0056] R is selected from the group consisting of: straight-chain or branched hydrocarbons, optionally substituted aryl groups, and optionally substituted heteroaryl groups;

[0057] D stands for prostaglandin;

[0058] L is a group in the following formula:

[0059]

[0060] Where R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0061] (R) indicates the end of a group bonded to the R group; and

[0062] (D) indicates the end of the group attached to group D;

[0063] as well as

[0064] Monomer of formula (V):

[0065] Z-(A) n (V)

[0066] in:

[0067] A may be the same or different each time it appears, and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the terminal functional group is complementary to the terminal functional group X of formula (IV).

[0068] Z is an optional substituted linking group; and

[0069] n is an integer and at least 2, for example, 2 to 8 or 3 to 8.

[0070] In a preferred embodiment, the polymer-prostaglandin conjugate can be obtained as a copolymer, wherein the monomer of formula IV is the monomer of formula IVa.

[0071]

[0072] in

[0073] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0074] q is 0 or 1;

[0075] X is a terminal functional group containing alkyne or azide;

[0076] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0077] D is selected from prostaglandins;

[0078] L is the linking group of formula II.

[0079]

[0080] Where (R) and (D) represent the ends of the linker groups attached to their respective groups, and R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0081] Furthermore, the comonomer of formula V has the properties of formula Va.

[0082] J-(Y–A) n Va

[0083] J represents the connecting functional group.

[0084] n is between 2 and 8;

[0085] Y comprises a subset selected from: polyethers, optionally substituted straight or branched C1 to C1 chains. 10A chain of one or more groups of alkylene, amino ester, amide, carbonate, and carbamate;

[0086] A may be the same or different each time it appears and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the alkyne or azide functional group in the terminal functional group is complementary to the alkyne or azide functional group in the terminal functional group X present on the monomer of formula (IVa).

[0087] In the monomer of formula (IVa), the group R 1 R 1’ R 2 R 2’ Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkylamino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl, and wherein R 1 R 1’ R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups.

[0088] In one set of embodiments, the comonomer of formula Va is of formula Vb.

[0089] J-((OR a ) m -BA) n (Vb)

[0090] in

[0091] A may be the same or different each time it appears and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the alkyne or azide functional group in the terminal functional group is complementary to the alkyne or azide functional group in the terminal functional group X present on the monomer of formula (IVa).

[0092] J represents the connecting functional group.

[0093] R a Selected from ethylene, propylene, butene, and mixtures thereof;

[0094] m ranges from 1 to 300;

[0095] n is between 2 and 8;

[0096] B is a bond, oxygen, or a group of the formula –MOC(O)N(H)M'-, –MOC(O)OM'-, –MC(O)NHM'-, or a group of formula (VIa) or (VIb):

[0097]

[0098] M and M' are independently selected from the following groups: bonds, optional substitutions of C1 to C2. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0099] q is 0 or 1; and

[0100] In the monomers of formulas (IVa), (Va), and (Vb), the group R 1 R 1’ R 2 R 2’ R 3 R 3’ R 4 and R 4’ Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkylamino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl, and wherein R 1 R 1’ R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups; and

[0101] Where R 3 R 3’ R 4 and R 4’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups.

[0102] The presence of one or more of (VIa), (VIb), (VIc), or (VId) introduces additional biodegradation sites, which can be used in R 3 R3' R 4 and R 4' If at least one of them is not hydrogen, it is adjusted.

[0103] When the polymer backbone is branched or forms a network, retention of the polymer at the site of use is further promoted during prostaglandin release. In a preferred set of embodiments, the branched or network polymer backbone can be formed using monomers of formula Va or Vb, where n is 3 or greater, for example 3-8.

[0104] Polymer-prostaglandin conjugates can be polymer network forms containing network segments of formula (XXX):

[0105]

[0106] in

[0107] J represents a connecting functional group, preferably a hydrocarbon or hydrocarbon ether or polyether with optional substitution of C2 to C4 hydrocarbon units;

[0108] R a Each time it appears, it can be ethylidene, propyleneide, or butylidene;

[0109] m ranges from 1 to 300;

[0110] n is 2 to 8, preferably 3 to 8, and especially 3 or 4;

[0111] B is a bond, oxygen, a group of the formula -MOC(O)N(H)M'-, -, –MOC(O)OM'-MC(O)NHM'-, or a group of the formula (VIa), (VIb), (VIc), or (VId):

[0112]

[0113] M and M' are individually chosen from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10 Straight-chain or branched aliphatic), containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, –N(R) groups w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0114] q is 0 or 1; and

[0115] Among them, group R 1 R 1’ R 2 R 2’ R 3 R 3’ R 4 and R 4’ Independently selected from hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkylamino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl, and wherein R 1 R 1’ R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups; and

[0116] Where R 3 R 3’ R 4 and R 4’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups;

[0117] q is 0 or 1;

[0118] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0119] L is the linking group of formula II.

[0120]

[0121] Where R 5 Selected from hydrogen and C1-C6 alkyl groups;

[0122] (R) indicates the end of a group bonded to the R group; and

[0123] (D) indicates the end of the group attached to group D.

[0124] D is selected from prostaglandins; and

[0125] T stands for triazole group.

[0126] In the copolymers of the present invention, biodegradability can be further controlled, wherein R present in the polymer-prostaglandin conjugate 1 R 1' R 2 R 2' R 3 R3' R 4 and R 4' At least one of the components is not hydrogen. Generally, the presence of substituents provides a slower degradation rate than otherwise observed. Without being bound by theory, it is believed that substituents slow down the hydrolysis rate of the backbone, thereby providing a longer period of controlled release at the desired site before polymer biodegradation and clearance.

[0127] Monomer-prostaglandin conjugates of formula (IV) are also provided:

[0128]

[0129] in:

[0130] X can be the same or different each time it appears, and represents a terminal functional group containing alkyne or azide;

[0131] Q is chosen independently each time it appears and may or may not be present, and when present, it indicates a linking group;

[0132] R is selected from the following groups: either straight-chain or branched hydrocarbons with optional substitution;

[0133] D is selected from prostaglandins;

[0134] L is a group in the following formula:

[0135]

[0136] Where R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0137] (R) indicates the end of a group bonded to the R group; and

[0138] (D) indicates the end of the group attached to group D.

[0139] In one respect, the monomer contains functional groups that provide for more efficient biodegradation. Therefore, we provide monomer-prostaglandin conjugates of formula IVa.

[0140]

[0141] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10 Straight-chain or branched aliphatic chains and C1 to C2 chains containing oxygen-containing spacers (-O-). 10 A straight-chain or branched aliphatic ether linkage group;

[0142] q is 0 or 1;

[0143] X is a terminal functional group containing alkyne or azide;

[0144] R is selected from the following groups: either straight-chain or branched hydrocarbons with optional substitution;

[0145] D is selected from prostaglandins;

[0146] L is a group in the following formula:

[0147]

[0148] Where R 5 Selected from hydrogen and C1-C6 alkyl groups;

[0149] (R) indicates the end of a group bonded to the R group; and

[0150] (D) indicates the end of the group attached to group D;

[0151] as well as

[0152] R 1 R 1' R 2 and R 2' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members.

[0153] When R 1 R 1' and R 2 R 2' When at least one of the components is not hydrogen, the rate of biodegradation can be controlled.

[0154] Polymer prostaglandin conjugates are particularly suitable for use in ocular implants, and thus in another embodiment, an ocular implant comprising the above-described polymer-prostaglandin conjugate is provided.

[0155] When R exists in the monomer 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4'When at least one of the components is not hydrogen and / or when a comonomer of formula (Va) is present and n is 3-8 (preferably 3 or 4), the biodegradation of the polymer-prostaglandin conjugate in vivo can be controlled by the presence of substituents. Such biodegradable chemicals introduced into the polymer backbone of formulas (Ia) and (Va) and (Vb) can be used to ensure that the product's lifespan exceeds the treatment cycle controlled by side-group linking chemistry. Conversely, by ensuring that the biodegradation rate is faster than the drug release rate, backbone substitution and the resulting biodegradable chemicals can be used independently of side-group linking chemistry to control the treatment cycle. Such a system ensures no loss of potency near the end of the product's lifespan.

[0156] This invention also allows the product to maintain its integrity and have minimal functional loss during the treatment cycle, but subsequently biodegrades and dissolves as quickly as possible. Such a system can be used to provide a non-linear mass loss relative to time over its service life, with minimal mass loss caused by the polymer backbone during the treatment cycle and rapid mass loss of the polymer backbone after the treatment cycle. Such a mass loss distribution is provided by the crosslinked or hyperbranched polymer structure (where n is 3 or greater) provided by the comonomer (IIIa) together with the biodegradable chemicals introduced into the polymer structure.

[0157] Polymers can be modified into network structures where n is 3-8, providing a non-linear loss of product mass compared to equivalent linear polymer systems. We have found that the potential hydrolysis of biodegradable chemicals (e.g., esters) in a biodegradable backbone such as formula (Ia) is the same, whether contained in a linear polymer or a cross-linked hydrogel. However, in the case of cross-linked polymers, we have found that the cross-linked structure ensures that no significant loss of product mass occurs until a critical proportion of the biodegradable portions within the polymer chain is broken down. Once this critical level is reached, rapid mass loss occurs. Therefore, the mass loss distribution is non-linear, with only very small mass loss until the critical proportion of breaking down occurs, after which rapid mass loss follows. This system allows for the production of products with little or no mass loss during treatment and rapid mass loss after treatment.

[0158] The combination of linking chemistry between the drug and the polymer chain and the biodegradable chemicals incorporated into the polymer chain provides a means to control the drug release rate and the polymer biodegradation rate separately. The therapeutic duration of the product can then be determined by the controlled drug release time or the time taken for polymer biodegradation, whichever is earlier. Modifying the polymer backbone to introduce biodegradable chemicals also typically affects the drug release rate (e.g., by introducing further hydrophilicity into the material). The use of acyloxyalkyl acyl linkers allows for changes in biodegradable chemicals (particularly when such changes are incorporated into the QX of the drug monomer) without a significant alteration to the drug release rate. Attached Figure Description

[0159] Specific embodiments of the present invention are described with reference to the accompanying drawings.

[0160] In the attached diagram:

[0161] Figure 1 The graph includes two curves showing the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugates of Examples 60 and 65 over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C.

[0162] Figure 2 The graph consists of four curves, comparing the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugates of Examples 53 and 66 and the drug-polymer conjugates of Examples 67 and 68 over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C and 55.0°C, respectively.

[0163] Figure 3 includes two graphs (a) and (b) showing the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugates of Examples 56, 53 and 62 over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C, and the % mass loss (b) of the drug-polymer conjugates having different comonomers derived from the same drug monomer.

[0164] Figure 4 The graph, consisting of four curves, shows the cumulative release (μg / 10mg) of latanoprost free acid exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C from the drug-polymer conjugates of Examples 59, 57, 54, and 53 over time. These drug-polymer conjugates share the same segment Q as the drug-polymer conjugates in the examples but have different comonomers (for comparison).

[0165] Figure 5The icon is a four-curve diagram showing the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugates of Examples 63, 64, and 58 over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C, the drug-polymer conjugates having the same drug monomer and different comonomers.

[0166] Figure 6 The graph shows the miosis (mm) in the eyes of dogs treated with the polymer-prostaglandin conjugates of Examples 66 and 63.

[0167] Figure 7 includes two graphs (a) and (b) showing the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugates of Examples 58, 62, 63, and 64 over time (a) and (b) mass loss after exposure to isotonic phosphate buffer (pH 7.4) at 37.0°C and 55.0°C, respectively. Detailed Implementation

[0168] The term "drug" refers to a substance intended for therapeutic use, the application of which (or one or more applications) involves: chemical or physicochemical interaction with the physiological systems of a subject; or action on an infectious agent; or action on a toxin or other toxic substance within the subject's body; or action in vitro on biological materials such as cells.

[0169] As used herein, the term "prodrug" refers to a derivative of a drug moiety, wherein the derivative may have little or no activity of the drug moiety itself, but can be converted into the drug moiety in vivo or in vitro. An example of such derivatization is the acetylation of one or more hydroxyl groups on the drug moiety, such that the prodrug released after in vivo release is deacetylated to produce the drug moiety.

[0170] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are safe and effective for use in pharmaceutical preparations. Pharmaceutically acceptable salts include salts containing acidic groups present in the compounds of this invention. Suitable salts may include sodium, potassium, ammonium, calcium, diethylamine, and piperazine salts, etc. Pharmaceutically acceptable salts are described in StahlPH, Wermuth CG, 2002. Handbook of pharmaceutical salts: Properties, selection and use. Weinheim / Zurich: Wiley-VCH / VHCA.

[0171] It is expected that the term "prostaglandin" as used herein includes, but is not limited to, natural prostaglandins and prostaglandin analogues. Prostaglandins are typically present as the acid residue portion of an ester formed at the linker (D) end in polymeric prostaglandin conjugates and monomeric prostaglandin adjuvants.

[0172] The term "ACOA" refers to the [(alkoxycarbonyl)oxy]alkyl alcohol moiety of the ester, which is the linking group of the acid moiety of the ester provided by the drug (D). ACOA links the drug to the polymer backbone moiety R and has the formula (II).

[0173]

[0174] Polymers having a drug covalently attached thereto are sometimes referred to in the art as “polymer-drug conjugates”. In some cases, it may be convenient to refer to the polymer-drug conjugates of the present invention as “drug-polymer conjugates”, “pharmaceutical-polymer conjugates”, “drug-polymer conjugates”, “polymer conjugates”, “polymer prodrugs”, or simply “conjugates”.

[0175] Hydrogels are macromolecular polymer gels composed of a network of cross-linked polymer chains. Hydrogels are hydrophilic monomers synthesized through chain growth polymerization or stepwise growth polymerization together with functional cross-linking agents that promote network formation.

[0176] In one aspect, the present invention relates to polymer-pharmaceutical conjugates comprising a polymer backbone and a plurality of releasable drugs covalently bonded to and side-attached to the polymer backbone. According to this aspect, the polymer backbone comprises a plurality of triazole groups.

[0177] The triazole group present in the polymer backbone of the polymer-drug conjugate as a product of azide / alkynyl coupling is a 1,2,3-triazole group.

[0178] The 1,2,3-triazole group can be prepared by reacting a comonomer having a suitable complementary terminal functional group comprising an alkyne and / or an azide functional group under linking reaction conditions. As used in the context of this invention, the terms "complementary terminal functional group" and "complementary terminal functional group" refer to a terminal chemical group capable of reacting with another chemical group to form a covalent intermolecular bond therebetween.

[0179] A suitable linking reaction for the formation of 1,2,3-triazoles is the Huisgen 1,3-dipolar cycloaddition (thermal) of azides and alkynes, yielding a mixture of 1,4- and 1,5-regioisomers of 1,2,3-triazoles. Linking reactions suitable for forming triazole groups can also be metal-catalyzed. For example, the copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) variant of the Huisgen cycloaddition of azides and terminal alkynes forms 1,2,3-triazoles. The use of a copper catalyst in the Huisgen cycloaddition reaction leads to the formation of 1,4-substituted 1,2,3-triazoles from azides and terminal alkynes, while the use of a ruthenium catalyst allows for the use of either terminal or internal alkynes, resulting in the formation of substituted 1,5-regioisomers. The use of a silver catalyst also yields 1,4-substituted 1,2,3-triazoles. Other metals that can be used include, but are not limited to, Ni, Pt, Pd, Rh, and Ir; the regiochemistry of 1,2,3-triazoles obtained by using these metal catalysts is hardly well-defined. WHBinder and R. Sachsenhofer describe some exemplary linking functional groups in Macromol Rapid Commun, 2007, 28, 15-54, the contents of which are incorporated herein by reference.

[0180] Polymer-prostaglandin conjugates of formula (I) are typically obtained as copolymers of at least one monomer of formula (IV):

[0181]

[0182] in:

[0183] X can be the same or different each time it appears, and represents a terminal functional group containing alkyne or azide;

[0184] Q is chosen independently each time it appears and may or may not be present, and when present, it indicates a linking group;

[0185] R is selected from the following groups: either straight-chain or branched hydrocarbons with optional substitution;

[0186] D is selected from prostaglandins;

[0187] L is a group in the following formula:

[0188]

[0189] Where R 5 Selected from hydrogen and C1 to C6 alkyl groups;

[0190] (R) indicates the end of a group bonded to the R group; and

[0191] (D) indicates the end of the group attached to group D;

[0192] And the monomer of formula (V):

[0193] Z-(A) n (V)

[0194] in:

[0195] A may be the same or different each time it appears, and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the terminal functional group is complementary to the terminal functional group X of formula (IV).

[0196] Z is an optional substituted linking group; and

[0197] n is an integer and at least 2, for example, 2 to 8 or 3 to 8.

[0198] Group Q may be absent and, in some embodiments, may be selected from the group consisting of:

[0199]

[0200] in

[0201] (R) represents the end of the group connected to group R, and the opposite end is connected to T in formula (I), (Ia) and (XXX) and X in formula (IV), (IVa) and (IVb).

[0202] t and v are each independently 0 or 1, and at least one of t and v is 1 (preferably one of t and v is 1 and the other is 0);

[0203] R 1 R 1' R 2 and R 2' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0204] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10 Straight-chain or branched aliphatic), containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groupsw ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0205] q is 0 or 1; and

[0206] s is 0-10, preferably 0-6; and preferred examples of Q include the following:

[0207]

[0208] In another set of embodiments, Q is present in the monomer of formula (IV) (and the resulting segment of formula I), and each QX is independently selected from the following groups:

[0209]

[0210] Where s is 0 to 10, preferably 0 to 6.

[0211] In one set of embodiments, the drug-polymer conjugate comprises polymer segments of formula Ia.

[0212]

[0213] in

[0214] R 1 R 1' R 2 and R 2' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0215] R present in polymers 1 R 1' R 2 and R 2' At least one of them is not hydrogen;

[0216] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10 Straight-chain or branched aliphatic), containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0217] q is 0 or 1;

[0218] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0219] L is a linking group; and

[0220] D is selected from prostaglandins; and

[0221] T stands for triazole group.

[0222] In some embodiments of the comonomer of formula Vb, group B is a bond, oxygen, group of formula –MOC(O)N(H)M', or group of formula (VI):

[0223]

[0224] in

[0225] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10 Straight-chain or branched aliphatic), containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0226] q is 0 or 1;

[0227] in

[0228] Group R 3 R 3’ R 4 and R 4’ Independently selected from the group consisting of: hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 alkoxy-C1 to C6 alkyl, wherein R 3 R 3’ and R 4 R 4’One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members.

[0229] In some implementations, group R 3 R 3' R 4 and R 4' At least one of them is not hydrogen.

[0230] In a preferred embodiment, formula (VIa) has formula (VIa-1) or (VIa-2).

[0231]

[0232] In this embodiment, the resulting polymer contains the substituent R. 1 R 1' R 2 R 2' R 3 R 3' (And in the case of equation (IVa), R is included) 4 and R 4' ), at least one of which is not hydrogen. In some implementations, R 1 R 1' R 2 R 2' At least one of them is not hydrogen; in other embodiments, R 3 R 3' R 4 and R 4' At least one of them is not hydrogen; in some embodiments, the group R 1 R 1' R 2 R 2' At least one of them is not hydrogen, and R 3 R 3' R 4 and R 4' At least one of them is not hydrogen.

[0233] In some embodiments, the polymer backbone of the polymer-drug conjugate contains at least one triazole group selected from the group consisting of: formulas (VIIa) and (VIIb)

[0234]

[0235] The main chain may contain multiple triazole groups, such as (VIIa), (VIIb) and combinations thereof.

[0236] Other comonomers used to prepare the polymer-drug conjugates of the present invention contain terminal functional groups containing alkynes and / or azides. Those skilled in the art will understand that, under suitable reaction conditions, the alkyne and azide functional groups can covalently react to form triazole groups. Linked reaction conditions are described, for example, in Chem. Rev. 2008, 108, 2952, Angew. Chem. Int. Ed. 2001, 40, 2004, Angew. Chem. Int. Ed. Engl. 2002, Jul 15, 41(14): 2596-9, Aldrichimica Acta 2010, 43(1): 15, and Accounts of Chemical Research 44(9): 666–676.

[0237] In one aspect of the invention, the drug conjugated to the polymer backbone of the drug-polymer conjugate and in the monomer is selected from the group consisting of prostaglandins, β-blockers, and combinations of two or more thereof. In some embodiments, it is useful to use two or more drugs from these drug classes for a specific treatment or to optimize treatment. Combinations of drugs from the prostaglandin and β-blocker classes are examples of combination therapies that can be provided by conjugating two or more drugs to the same polymer backbone.

[0238] In the monomer-drug conjugate of formula (Ia), each substituent X represents a group containing a terminal functional group, which comprises an alkyne or azide functional group. The terminal functional group X may be the same or different each time it appears. When the terminal functional group (X) is the same, the monomer is typically a diazid or diynyl monomer.

[0239] Those skilled in the art will understand that the terms "acetylene" and "azide" represent the following structures:

[0240] Alkyne: -C≡CH

[0241] Azide:

[0242] In one embodiment, the drug is conjugated to the polymer backbone via an ACOA bond formed between the drug D and the linker L. For example, in one embodiment, the drug is covalently bonded to the linker via a carboxylic acid ester. The ester may comprise an acid moiety –C(O)- derived from the acid functional group of the drug and an alcohol moiety provided by the linker, or the acid moiety of the ACOA may be derived from the linker and the alcohol moiety provided by the drug.

[0243] The prostaglandins described in this article consist of an α-chain, an ω-chain, and a 5-membered ring, and are numbered according to the C20 prostaglandin acid grouping as follows:

[0244]

[0245] On one hand, the present invention relates to a drug-polymer conjugate comprising a polymer backbone and a PGF2α prostaglandin conjugated to the polymer backbone.

[0246] The prostaglandin delivered by the polymer-drug conjugate of the present invention comprises at least one functional group selected from the group consisting of: a carboxylic acid group at position 1, a hydroxyl group at position 9, a hydroxyl group at position 11, and a hydroxyl group at position 15.

[0247] The carboxylic acid group at position 1 and the hydroxyl groups at positions 9, 11, and 15 of prostaglandins can serve as reactive functional groups for the conjugation of prostaglandin drugs to polymers. When the drug is conjugated to the polymer backbone, the prostaglandin is conjugated to the polymer backbone via groups selected at positions 1, 9, 11, or 15. Therefore, the drug moiety linked to the polymer (denoted as D in the formula described herein) is an acid residue (in the case of conjugation at position 1) or an alcohol residue (in the case of conjugation at positions 9, 11, or 15) of the ACOA linking group that conjugates the prostaglandin to the polymer backbone. Thus, the moiety represented by D can be a releasable prostaglandin.

[0248] Prostaglandins are conjugated to the polymer backbone via a [alkoxycarbonyl)oxy]alkyl (ACOA) ester linker of formula II. The [alkoxycarbonyl)oxy]alkyl ester linker has been found to be hydrolyzed unstable in a biological environment and can help ensure adequate drug release from the polymer conjugate to achieve therapeutic levels in the vicinity of the polymer conjugate material.

[0249] When a prostaglandin is attached to the polymer backbone via an ACOA ester linker of formula II, the ACOA ester linker can link the drug at positions selected from the group consisting of: positions 1, 9, 11, and 15 of the drug.

[0250] Typically, the ACOA linking group of Formula II can link the drug at the 1-position of prostaglandin, thereby forming a link with prostaglandin. The ACOA link is in the form of an ester. Esters are generally described in terms of the acid and alcohol residues they are derived from their theory. In the case of ACOA, prostaglandin provides the acid residue of the ester, and the R group provides the alcohol residue of the ester.

[0251] As used herein, the term "acid residue" refers to the portion of the ACOA linker group derived from the carboxylic acid functional group of the drug after it has been conjugated to the polymer backbone. Acid residues typically have the structure -C(O)-. In the case of prostaglandins, the carboxylic acid group is located at position 1.

[0252] As used herein, the term "alcohol residue" refers to the portion of the ACOA linker group derived from the hydroxyl functional group of the drug after it has been conjugated to the polymer backbone. Alcohol residues typically have the structure -O-. In the case of prostaglandins, the hydroxyl group may be selected from those located at positions 9, 11, or 15.

[0253] Typically, group D is a prostaglandin of formula Xb.

[0254]

[0255] in:

[0256] This indicates the junction point between the prostaglandin and the linker group L;

[0257] Indicates a double bond or a single bond;

[0258] Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups;

[0259] W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group.

[0260] It should be understood that prostaglandins contain chiral centers, preferably of formula X(e).

[0261]

[0262] In a preferred embodiment, at least 80 mol% (more preferably at least 90 mol%) of prostaglandin is present in the drug-polymer conjugate as an optical isomer.

[0263] Examples of drug monomer conjugates of formula II, where the drug is a prostaglandin in the form of an acid residue, include monomers of formula (IIb):

[0264]

[0265] in:

[0266] R is a straight-chain or branched aliphatic chain;

[0267] Group R 1 R 1' R 2 and R 2' Independently selected from hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkoxy-(C1 to C6 alkyl), and wherein R 1 R 1’ R 2 and R 2’One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0268] Where R 1 R 1’ R 2 and R 2’ At least one of them is preferably not hydrogen;

[0269] q is 0 or 1;

[0270] s is 0 to 10, preferably 0 to 6;

[0271] R 5 The alkyl group is selected from hydrogen and C1 to C6 alkyl groups, preferably from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0272] in:

[0273] Indicates a double bond or a single bond;

[0274] Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups;

[0275] W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group.

[0276] Specific examples of drug-polymer conjugates include conjugates of formula (Ia).

[0277]

[0278] The substituents are as defined above, except that D is selected from specific prostaglandins in the form of acid residues shown in Table 1.

[0279] Specific drug monomers have formula (IVa):

[0280]

[0281] The substituents are as defined above, except that D is selected from specific prostaglandins in the form of acid residues shown in Table 1.

[0282] Table 1

[0283]

[0284] In this embodiment, the linker L provides the alcohol moiety of the ester formed with the acid residues of prostaglandin.

[0285]

[0286] Where R 5 It is selected from hydrogen and C1 to C6 alkyl groups, preferably from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, more preferably selected independently from hydrogen and methyl.

[0287] In the most preferred embodiment, the drug-polymer comprises segments of formula (Ib) or mixtures thereof:

[0288]

[0289] In another set of embodiments, a drug monomer and a copolymer formed therefrom are provided, wherein the drug monomer has (IVc):

[0290]

[0291] In one aspect, the present invention provides a drug-polymer conjugate comprising a polymer backbone and a plurality of drugs covalently bound to and side-attached to the polymer backbone, wherein the polymer backbone comprises a plurality of biodegradable groups of formula (IX):

[0292]

[0293] in:

[0294] t and v are each independently 0 or 1, and at least one of t and v is 1 (preferably one of t and v is 1 and the other is 0); R 1 R 1' R 2 and R 2' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0295] Preferably, R 1 R 1' R 2 and R 2' At least one of them is preferably not hydrogen;

[0296] q is 0 or 1; and

[0297] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, group -O- (C1 to C1) 10Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0298] and

[0299] T stands for triazole group.

[0300] In a preferred embodiment, the polymer-prostaglandin conjugate comprises a polymer backbone and a plurality of prostaglandin groups covalently bonded to side groups of the polymer backbone via linking groups of formula (II). The polymer backbone comprises a plurality of biodegradable groups of formula (IX):

[0301]

[0302] in:

[0303] t and v are each independently 0 or 1, and at least one of t and v is 1 (preferably one of t and v is 1 and the other is 0);

[0304] R 1 R 1' R 2 and R 2' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0305] Preferably, R 1 R 1' R 2 and R 2' At least one of them is not hydrogen;

[0306] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w)-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0307] q is 0 or 1; and

[0308] T stands for triazole group.

[0309] Compounds of formula (IX) include various variants and can be in the form of any one or a combination of two or more of formulas (IXa), (IXb), (IXc), and (IXd) in the polymer backbone:

[0310]

[0311]

[0312] Wherein group R 1 R 1' R 2 R 2' M and T are as defined in this paper with respect to Equation I.

[0313] This invention typically uses esters to conjugate prostaglandin drugs to a polymer backbone. We have found that the ACOA linker group is hydrolytically unstable in a biological environment and is less affected by the backbone groups. This allows for enhanced backbone biodegradation by including ester groups as in formulas (I), (Ia), and (XXX) and monomers of formulas (IVa) and (IVa), and by using R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' One or more sites in the polymer conjugate may use non-hydrogen substituents to further control biodegradation. Biodegradable portions may be present in the polymer backbone of the polymer conjugate in some embodiments of the invention. Ester, anhydride, and carbonate biodegradable portions can further help ensure sufficient drug release from the polymer conjugate to achieve therapeutic levels in the vicinity of the polymer conjugate material and efficient removal of the polymer from the site of application through biodegradation of the backbone. The biodegradation of the backbone can be controlled to allow complete delivery of the prostaglandin payload from the polymer backbone, or it can degrade rapidly enough to provide drug removal from the site of application before complete release of the drug from the linker of Formula II.

[0314] The breakdown of cleavable covalent bonds can be promoted by hydrolysis (i.e., hydrolytic cleavage) and can occur in the presence of water and an acid or base. In some embodiments, cleavage can occur in the presence of one or more hydrolases or other catalysts or at least endogenous biological compounds that contribute to the cleavage process. For example, ACOA linkages can be hydrolyzed to produce prostaglandin 1-carboxylic acid, aldehydes, and alcohols. Ester biodegradation moieties can be hydrolyzed to produce carboxylic acids and alcohols.

[0315] At least the drug can be released from the conjugate itself. However, as further described below, the polymer backbone can also be biodegraded in vivo or in vitro, causing the polymer backbone to break down into lower molecular weight fragments, with the drug remaining attached to such fragments via L. In this case, the drug can still be released or cleaved from L, which may or may not associate with the polymer conjugate itself.

[0316] In some embodiments, the monomers of formula (V) having complementary terminal functional groups can be homofunctional. That is, each comonomer can contain one type of terminal functional group. The terminal functional groups of the comonomers will be complementary and capable of reacting with each other to form triazole groups. For example, one comonomer of formula (V) can contain terminal functional groups containing alkyne functional groups, while another comonomer of formula (V) contains terminal functional groups containing azide functional groups. These comonomers will be able to copolymerize under suitable conditions to form polymer conjugates having triazole groups in the polymer backbone.

[0317] Examples of complementary monomers of formula (IV), (IVa), and (IVb) capable of copolymerizing with monomers of formula (V), (Va), and (Vb) to form polymer-prostaglandin conjugates include monomers of formula (IV), (IVa), and (IVb) in which each group X is an alkynylene and monomers of formula (IV), (IVa), and (IVb) in which each group X is an azide.

[0318] The monomers of formulas (IV) and (V) can react with each other, for example, in a 1:1 molar ratio.

[0319] The comonomer used for reaction with drug-monomer conjugates has formula (V)

[0320] Z-(A) n (V)

[0321] in:

[0322] A may be the same or different each time it appears, and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the terminal functional group is complementary to the terminal functional group X of formula (IV).

[0323] Z is an optional substituted linking group; and

[0324] n is an integer and at least 2.

[0325] In one set of embodiments, the comonomer of formula (V) has the characteristics of formula (Va).

[0326] J-(Y–A) n Va

[0327] J represents the connecting functional group.

[0328] n is between 2 and 8;

[0329] Y is a chain comprising one or more groups selected from the group consisting of: polyethers, optionally substituted straight or branched C1 to C2 groups. 10 Alkylene, amino, alkylamino, ether (-O-), ester, amide, carbonate, and carbamate. In this embodiment, Y-containing formula (OR) is preferred. a ) m The polyether, wherein R a Independently ethylene, propylene, and butylene, m is 1-300 (preferably 2-300), and the polyether has one or more groups selected from the group consisting of: optionally substituted straight-chain or branched C1-C 10 Alkylene, amino, ether, ester, amide, carbonate and carbamate.

[0330] Comonomers can have formula V, and can have formula Vb.

[0331] J-((OR a ) m -BA) n (Vb)

[0332] in

[0333] A may be the same or different each time it appears, and represents a group containing a terminal functional group, which contains an alkyne or azide functional group, wherein the alkyne or azide functional group in the terminal functional group is complementary to the alkyne or azide functional group in the terminal functional group X present on the monomer of formula (IVa).

[0334] J represents the connecting functional group.

[0335] R a Selected from ethylene, propylene, butene, and mixtures thereof;

[0336] m ranges from 1 to 300;

[0337] n is between 2 and 8;

[0338] B is a bond, oxygen, a group of the formula –MOC(O)N(H)M'-, –MOC(O)OM'-, –MC(O)NHM'-, selected from groups of formulas (VIa), (VIb), (VIc), and (VId):

[0339]

[0340] or

[0341] in

[0342] M and M' are independently selected from the following groups: bonds, optional substitutions of C1 to C2. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0343] q is 0 or 1; and

[0344] In the monomers of formulas (Va), (Vb), (Vc), and (Vc), the group R 3 R 3' R 4 and R 4' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkylamino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl, and wherein R 1 R 1' One of them, where R 3 R 3' R 4 R 4' One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups.

[0345] In one set of embodiments, the comonomer of formula (V) has formula (Vb):

[0346] J-((OR a ) m -BA) n(Vb)

[0347] R a Each time it appears, it can be ethylidene, propyleneide, or butylidene;

[0348] m ranges from 1 to 300;

[0349] n can be 3 to 8, preferably 3 or 4.

[0350] More specific examples of comonomers of formula (V) may be selected from the group consisting of:

[0351]

[0352] J 1 Having formula C Z H 2Z-1 (Straight chain or branched chain), where z is an integer from 1 to 8, preferably 3 to 8, and most preferably 3 or 4; and

[0353]

[0354] J 2 Having formula C Z H 2z-2 (Straight chain or branch chain) where z is an integer from 1 to 8, preferably from 3 to 8, and most preferably 3 or 4.

[0355] The R group in the linking group (II) of the polymer-prostaglandin conjugate 5 Preferably, it is hydrogen or methyl.

[0356] In the monomer of formula (V), A represents a group containing a terminal functional group, which comprises an alkyne or azide functional group. The azide or alkyne functional group present in the terminal functional group of group "A" is complementary to the azide or alkyne functional group present in the terminal functional group of X in formula (IV), such that when the functional groups in A and X react under linking reaction conditions, a triazole group is formed.

[0357] In monomers of formula (V), which may have formula (Va) or (Vb), n is an integer and at least 2. In some embodiments, n is an integer selected from 2, 3, 4, 5, 6, 7, and 8. In one form, in monomers of formula (V) (which may have formula (Va) or (Vb)), n is 3-8, particularly 3 or 4. Monomers of formula (V) contain at least two A moieties, which may be the same or different each time they appear. When n is 2, the monomer is bifunctional, may be linear, and contains two A moieties. When n is 3 or greater, the monomer is multifunctional and contains three or more A moieties. In such embodiments, monomers of formula (V) (which may have formula (Va) or (Vb)) may be branched monomers. When the monomer is branched, three or more A moieties may be present. Monomers of formula (V) containing at least three terminal functional groups provide a branched structure for the polymer conjugates of the present invention.

[0358] As used herein, the term "group comprising a terminal functional group" encompasses embodiments in which the group itself represents a terminal functional group, as well as embodiments in which the terminal functional group is part of a larger chemical group.

[0359] In formulas (Va) and (Vb), the "J" denotes an optionally substituted linking group. In some embodiments, J may be a divalent group. Alternatively, J may be polyvalent and branched. When monomers of formula (IV) and (Va) or (Vb) are copolymerized, J forms a linking segment in the polymer backbone of the conjugate.

[0360] In some embodiments, J may include a linker moiety selected from optionally substituted straight-chain or branched aliphatic hydrocarbons, optionally substituted carbocyclic groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted polymer segments, and combinations thereof.

[0361] The optional substituted straight-chain or branched aliphatic hydrocarbon linker may be selected from the optional substituted C1-C 20 C1-C 10 These can be C1-C6 straight-chain or branched aliphatic hydrocarbons. Aliphatic hydrocarbons can be saturated or unsaturated.

[0362] The optionally substituted carbocyclic linker portion may have 3-12, 3-8, or 5-6 carbocyclic members.

[0363] The optionally substituted heterocyclic linker may have 3-12, 3-8, or 5-6 ring members and 1, 2, 3, 4, or more heteroatoms as part of the ring. The heteroatoms may be independently selected from the group consisting of O, N, and S.

[0364] The optionally substituted aryl linker may have 3-12, 3-8 or 5-6 carbocyclic members and at least one degree of unsaturation.

[0365] The optionally substituted heteroaryl linker may have 3-12, 3-8, or 5-6 ring members and 1, 2, 3, 4, or more heteroatoms as part of the ring. The heteroatoms may be independently selected from the group consisting of O, N, and S. The heteroaryl linker also has at least one degree of unsaturation.

[0366] The optionally substituted polymer linker can comprise any suitable polymer or copolymer. In some embodiments, it may be desirable for the polymer portion to comprise a biocompatible and / or biodegradable polymer. Those skilled in the art will be able to select suitable biocompatible and / or biodegradable polymers. Exemplary biocompatible polymers may include polyethers, polycarbonates, polyesters, polyamides, polyurethanes, and copolymers thereof, such as poly(ether-ester), poly(urethane-ether), poly(urethane-ester), poly(ester-amide), etc. Preferred biocompatible polymers are polyethers, polyesters, polycarbonates, polyurethanes, and copolymers thereof.

[0367] Exemplary polyethers include polymers of C2-C4 alkylene glycols, such as polyethylene glycol and polypropylene glycol, preferably polyethylene glycol.

[0368] Exemplary polyesters include polycaprolactone, poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid).

[0369] In one form, the polymer linker portion may comprise a biodegradable polymer. Typically, a biodegradable polymer comprises at least one biodegradable moiety. The biodegradable moiety may be selected from ester, urethane, carbonate, amide, carbamate, and disulfide moieties. Biodegradable polymers may comprise combinations of these moieties. Those skilled in the art will understand that such a biodegradable moiety is capable of undergoing degradation or pyrolysis in biological or physiological environments.

[0370] The optionally substituted polymer linker can have any suitable molecular weight, and the desired molecular weight can depend on the type and properties of the polymer. In some embodiments, J comprises a polymer portion with a molecular weight not exceeding 1500.

[0371] In one set of embodiments, J comprises a polyether linker moiety derived from polyethylene glycol (PEG). The polyether segment may be derived from PEG of a suitable molecular weight. In some embodiments, the PEG has a molecular weight of about 200-10,000, preferably about 200-about 3,000.

[0372] In one set of embodiments, J comprises a linker moiety derived from lysine, including lysine ethyl esters, such as ethyl 2,6-bis(((3-azidopropoxy)carbonyl)amino)hexanoate (ELDI), bis(1-pentanol)carbamate of lysine ethyl ester, and bis(1-pentanol)carbamate of lysine 1-pentanol ester.

[0373] In some embodiments, the group "J" in formulas (Va) and (Vb) may contain a functional group. The functional group may be selected from amide, ether, ester, carbamate, urea, and carbonate functional groups. This functional group is typically a cleavable functional group that can degrade in the biological environment.

[0374] In some embodiments of formula (V), J represents an optionally substituted polymer linker portion. The polymer linker portion may comprise the biocompatible and / or biodegradable polymers described herein. In one set of embodiments, B may comprise polyethers, polyesters, polyamides, polyurethanes, or copolymers thereof.

[0375] In one implementation, the comonomer has the formula (Vb).

[0376] J-((OR a ) m -BA) n (Vb)

[0377] in

[0378] J is selected from optionally substituted hydrocarbons or hydrocarbon ethers or polyethers having 2 to 4 hydrocarbon units in each ether unit;

[0379] R a Each time it appears, it can be ethylidene, propyleneide, or butylidene;

[0380] m is 1 to 300, for example, 1 to 100 or 1 to 50;

[0381] n is 2 to 8 (preferably 3 to 8, such as 3 or 4);

[0382] B is a bond, oxygen, a group of the formula -MOC(O)N(H)M'- or a group of the formula (VIa):

[0383]

[0384] in

[0385] M and M' are independently selected from the following groups: bonds, optional substitutions of C1 to C2. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(Rw )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0386] q is 0 or 1; and

[0387] In the monomers of formulas (VIa) and (VIb), the group

[0388] R 3 R 3' R 4 and R 4' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, and

[0389] Where R 3 R 3’ R 4 and R4 ’ One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members.

[0390] In preferred embodiments of the comonomers of formulas (V), (Va), and (Vb), the integer n is at least 3, for example 3-8, most preferably 3 or 4. In this embodiment, the resulting comonomer has three or more arms with reactive terminal groups, resulting in a reaction with a pharmaceutical monomer of formula IV (including formula (IVa)) to form a polymer network comprising pharmaceutical side-group portions covalently linked to the polymer backbone network.

[0391] In a set of preferred embodiments, the drug-polymer conjugate is a copolymer of drug conjugate monomers of formula (IVa):

[0392]

[0393] in

[0394] M is selected from the following groups: bonds, optional substitutions of C1 to C1. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0395] q is 0 or 1;

[0396] X is a terminal functional group containing alkyne or azide;

[0397] R is selected from the following groups: straight-chain or branched hydrocarbons;

[0398] L is a linking group; and

[0399] D is a releasable drug;

[0400] and comonomers of formula (Vb)

[0401] J-((OR a ) m -BA) n (Vb)

[0402] J is selected from optionally substituted hydrocarbons or hydrocarbon ethers or polyethers with 2-4 hydrocarbon units;

[0403] R a Each time it appears, it can be ethylidene, propyleneide, or butylidene;

[0404] m ranges from 1 to 300;

[0405] n is 3 to 8 (preferably 3 or 4);

[0406] B is a bond, oxygen, a group of the formula –MOC(O)N(H)M' or a group of the formula (IV):

[0407]

[0408] in

[0409] M and M' are independently selected from the following groups: bonds, optional substitutions of C1 to C2. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups;

[0410] q is 0 or 1;

[0411] Among the monomers of formulas (Ia) and (Vb),

[0412] R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1' and R 2 R 2' One of the pairs can form a carbon ring or heterocycle with 3 to 6 constituent ring members, wherein the heterocycle can contain 1 to 3 constituent oxygen heteroatom ring members.

[0413] R 3 R 3' and R 4 R 4' One of the pairs can form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle can contain 1 to 3 constituent oxygen heteroatom ring members I.

[0414] In a preferred embodiment, group B has the formula (IVa-1) or (IVb-1):

[0415] or

[0416] In one embodiment, n in the comonomer (V) such as (Va) or (Vb) is 3 or greater, and is therefore branched, resulting in a network copolymer that we have found to provide significant advantages in controlling biodegradation. Therefore, the present invention further provides a drug-polymer conjugate, which is a copolymer, preferably a hyperbranched copolymer network, comprising network segments of formula (XXX):

[0417]

[0418] Wherein the n group is covalently bonded around the J group, and the groups J, R, B, R a T, M, R, L, and D, as well as m and q, are as defined above for formulas (IVa) and (Vb), and n is an integer from 2 to 8, preferably from 3 to 8, and more preferably from 3 or 4. Specific examples of networks of formula XXX include compositions in which L is of formula (II) and D is selected from the prostaglandins in Table 1.

[0419] In one set of embodiments of formulas (Va), (Vb), and (XXX), the integer n is 3 to 8, and the branched linker J is a hydrocarbon of the following formula:

[0420] C z H 2z+2–n

[0421] Where z is 1 to 8, preferably 3 to 8, and n is 3 to 8, preferably 3 or 4.

[0422] When n = 2, the comonomer can be linear. Specific examples of the linking base J where n = 2 include C1 to C2. 10 Alkylenes, such as ethylene and 1,2-propylene and 1,3-propylene:

[0423] -CH2-CH2-, -CH2-CH(CH3)- and –CH2-CH2-CH2-.

[0424] Specific examples of the linking basis J where n is 3 to 8 include:

[0425]

[0426] Where n is 3; and

[0427]

[0428] Where n is 4, 6 or 8.

[0429] In formula IIIc, the group (OR) a ) m It is a polymer of one or more of ethylene oxide, propylene oxide, and butane oxide.

[0430] In one set of implementations, the formula (OR) in formula (V), (Va), (Vb) or formula (XXX) a ) m A block copolymer selected from one or more of poly(ethylene oxide), poly(propylene oxide), poly(butane oxide), poly(ethylene oxide), poly(propylene oxide), and poly(butane oxide), and a block copolymer of two or more of poly(ethylene oxide), poly(propylene oxide), and poly(butane oxide), wherein (OR a )m has a molecular weight in the range of 200 to 10,000.

[0431] Specific examples of comonomers of formula (Vb) include:

[0432]

[0433] J 1 Having formula C Z H 2z-1 (straight chain or branched chain), and where z is an integer from 1 to 8, preferably from 3 to 8; and

[0434]

[0435] J 2 Having formula C Z H 2z-2 (straight chain or branch chain), and where z is an integer from 1 to 8, preferably from 3 to 8.

[0436] In formulas (I), (Ia), (Ib), (Ic), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc-1), (Vc-2), and (XXX), some or all of the substituents R exist. 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' Substituent R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' Independently selected from hydrogen, alkyl, alkoxy, and alkoxyalkyl, wherein R 1 R 1’ R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0437] Where R 3 R 3’ R 4 and R4 ’ One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members.

[0438] Particularly preferred is at least one substituent on the carbon atom at the α or β position of the carbonyl carbon, i.e., R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' At least one of them (present in at least one reactive monomer) is not hydrogen.

[0439] Substituents other than hydrogen significantly improve control over main-chain biodegradation. This control allows the main chain of the drug-polymer conjugate to degrade in a controlled manner, and any remaining active pharmaceutical ingredient is diluted systemically in the subject. Biodegradation allows for pre-determining the duration of treatment for the subject. This limitation on treatment duration and main-chain biodegradation is particularly advantageous in embodiments where the drug-polymer conjugate is used for topical treatment of tissues, such as in implant-based drug-polymer conjugates used to treat, for example, glaucoma.

[0440] In some implementation schemes, R 1 and R 1' At least one of them is not hydrogen, and in a further embodiment, R 2 and R 2' At least one of them is not hydrogen.

[0441] In embodiments of the invention in which any one of the monomers of formula (Va) and chain segments of formulas (VIa), (VIb), (VIc), and (VId) exists, then, in which R 1 R 1’ R 2 and R 2’ When at least one of them is not hydrogen, the substituent R 3 R 3' R 4 R 4' It can be hydrogen, or R in it. 1 R 1’ R 2 and R 2’ It is hydrogen, when R 3 R 3' R 4 and R 4' When at least one of the components is not hydrogen, the control of biodegradation is significantly improved. In one set of embodiments, R 1 R 1’ R 2 and R 2’ At least one of them is not hydrogen, and R 3 R 3' R 4 and R 4' At least one of them is not hydrogen.

[0442] To enhance control over degradation, it is generally preferred to have at least one group on the carbon at the α-position of the carbonyl group, i.e., R. 1 R 1' R 3 and R 3' It's not hydrogen.

[0443] When R 1 R 1' R2 R 2' R 3 R 3' R 4 and R 4' When one or more of the groups are not hydrogen, specific examples of substituents other than hydrogen may be selected from C1-C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl; C1-C4 alkoxy groups such as methoxy, ethoxy, propyl, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy; and C1-C4 alkyl groups substituted with C1-C4 alkoxy groups, such as one of the aforementioned C1-C4 alkoxy groups substituted with one of the aforementioned C1-C4 alkyl groups. Biodegradation can be enhanced by gem-substitution with groups other than hydrogen. When the α or β carbon atom of the carbonyl carbon is disubstituted, specific examples of the disubstituted pair may be selected from C1 to C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl; C1 to C4 alkoxy groups such as methoxy, ethoxy, propyl, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy; and C1 to C4 alkyl groups substituted with C1 to C4 alkoxy groups, for example, one of the aforementioned C1 to C4 alkoxy groups substituted with one of the aforementioned C1 to C4 alkyl groups. When the α carbon of the carbonyl carbon is disubstituted, i.e., R 1 R 1' R 3 and R 3' Biodegradation is particularly enhanced when at least one or both of the hydrogen atoms are not hydrogen.

[0444] R 1 R 1’ R 2 and R 2’ The members of the pair can form a carbon ring or heterocycle having 3 to 6 constituent ring members, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and

[0445] Where R 3 R 3’ R 4 and R4 ’ One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members.

[0446] Specific examples of this type of carbon ring include one or more pairs of R rings in which a spirocarbon ring is formed between the pairs via a connecting group. 1 R 1' R 2 R 2' R 3 R 3' and R4 R 4' The linking group is selected from alkylene groups with 2-5 optional substituted methylene groups, wherein the optional substituents are C1 to C4 alkyl or C1 to C4 alkoxy groups, and groups with 2-5 optional substituted methylene groups and 1-3 oxygen atoms, wherein the optional substituents are C1 to C4 alkyl or C1 to C4 alkoxy groups.

[0447] Specific examples include the groups –CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2- and -CH2-CH2-O-CH2-CH2-.

[0448] In formulas (Ia), (IVa), (Va), (Vb), (Vc), (Vd), and (XXX), the linking group M or both M and M' are present in the main chain portion of the monomer or polymer. Groups M and M' are chosen independently, and the presence of M in some pharmaceutical-monomer conjugates and comonomers is also chosen independently. Pharmaceutical-monomer conjugates contain two M linking groups, which can be chosen independently, but in many embodiments, it is convenient that they are the same.

[0449] Groups M and M' are each selected from the group consisting of: bonds, optionally substituted C1 to C2 bonds. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups. Wherein M and M' are C1 to C4 alkyl groups. 10 Preferred examples of embodiments involving aliphatic groups include –(CH2). y - where y is 1-6, preferably 1-4, for example, methylene or ethylene, and where the chain –(CH2) y One or both hydrogens in - can be replaced by a methylene group to form an olefin branch or a C1 to C4 alkyl group. One or both of M and M' are selected from -O (C1 to C4). 10 In embodiments involving straight-chain or branched aliphatic groups, examples include –O-(CH2). y - where y is 1 to 6, preferably 1 to 4, for example, methylene or ethylene. One or both of M and M' are selected from C1 to C2 containing oxygen (-O-) interrupted. 10In embodiments where the ether linkage of a straight-chain or branched aliphatic group is an ether linkage, examples include the group (CH2)-O-(CH2)y, wherein y is 1-6, preferably 1-4, such as methylene or ethylene. Wherein M and / or M' is a group –N(R w )-(C1 to C 10 (straight-chain or branched aliphatic groups) and C1 to C2 groups containing N (Rw) spacers. 10 In embodiments of the ether linkage group of a straight-chain or branched aliphatic group, Rw is selected from hydrogen and C1 to C4 alkyl groups, examples including –N(R w )-–-(CH2)y-, where y is 1 to 6, preferably 1-4, for example, methylene or ethylene. One or both of M and M' are selected from C1 to C2 containing oxygen (-O-) interruptions. 10 In embodiments where the amine linker is a straight-chain or branched aliphatic group, examples include the group (CH2)-N(R). w )-(CH2)y, where y is 1-6, preferably 1-4, for example, methylene or ethylene.

[0450] In several embodiments of formulas (IVa), (IVb), (IVc), and (IVd), s is 0-6 (preferably 0-2). In some examples, the number s can be 0, 1, or 2.

[0451] According to one embodiment, a method for delivering a drug to a subject is provided, the method comprising administering a drug-polymer conjugate according to the invention to the subject.

[0452] "Suitable" polymeric conjugates for administration to subjects are those for which administration to a subject will not result in unacceptable toxicity, including allergic reactions and disease states. The term "subject" refers to an animal or human subject.

[0453] "Administration" of the conjugate to a subject refers to the transfer of the composition to the subject to release the drug. The drug, for example, is selected from one or more of prostaglandins, beta-blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), and quinolones, and is used to treat eye diseases associated with elevated intraocular pressure, such as glaucoma. Preferably, the polymeric conjugate is administered to the affected eye of the subject. Administration to the eye can be intraocular, intravitreal, subchoroidal, or subconjunctival.

[0454] Polymer conjugates may be provided in particulate form and mixed with a pharmacologically acceptable carrier to facilitate administration. "Pharmacologically acceptable" means that the carrier is suitable for administration to a subject in its own right. In other words, administration of the carrier to a subject will not result in unacceptable toxicity, including allergic reactions and disease states. The term "carrier" refers to a carrier containing the conjugate prior to administration.

[0455] For guidance only, those skilled in the art may consider that "pharmacologically acceptable" means an entity approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more particularly in humans. Suitable pharmacologically acceptable vehicles are described in Martin, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, (1990).

[0456] Polymer drug conjugates may also be formed as part of or in an article or device, or applied as a coating to an article or device and implanted into a subject. “Implantation” means that the article or device is introduced, wholly or partially, into a subject and is intended to remain there after surgery.

[0457] The appropriate dosage of the drug and the dosing regimen of the polymer conjugate can be determined by the physician and can depend on the specific condition being treated, the release rate of the polymer backbone, the severity of the condition, and the subject's general age, health, and weight.

[0458] The form of drug-polymer conjugates can be tuned to suit desired applications, such as coatings, films, pellets, capsules, fibers, laminates, foams, etc. Differences in conjugate form provide a means to modify drug release profiles. For example, the amounts of polymer and drug can be the same in two different structures; however, differences in surface area and volume, hydration rate, and diffusion pathways from different physical forms or structures can lead to different rates of drug release from essentially the same polymer.

[0459] Adjusting the form of polymer conjugates to suit the application and further adjusting the form to further control drug release offers additional advantages over pure composition and polymer structure methods for controlling drug release profiles.

[0460] Some compositional / structural means of controlling drug release include: controlling drug loading; and compositions of other comonomers that adjust criteria such as hydrophobicity, flexibility, degradation sensitivity, ability of fragments to autocatalytically degrade polymers, polymer thermal stability, moldability, and polymer solubility that facilitates casting.

[0461] In one set of embodiments, the drug can be released from the polymer conjugate, thereby providing a sustained drug delivery system. In its simplest form, this delivery system can be a polymer conjugate provided in a desired shape, such as a pellet or a more complex shape. To facilitate surface area contact of the polymer conjugate under physiological conditions or with the biological environment, it can also be provided in the form of a foamed product or a coating on a substrate.

[0462] "Continuous partial drug delivery" refers to the release of a drug from a conjugate over a period of time, such as 10 minutes or longer, 30 minutes or longer, 60 minutes or longer, more than 2 hours, more than 4 hours, more than 12 hours, more than 24 hours, more than 2 days, more than 5 days, more than 10 days, more than 30 days, more than 2 months, more than 4 months, or more than 6 months.

[0463] The drug-polymer conjugates of the present invention can be incorporated into drug delivery systems, therapeutic articles, devices, or formulations and pharmaceutical products for treating intraocular pressure.

[0464] The drug-polymer conjugates of the present invention can be blended with one or more other polymers (e.g., biodegradable polymers).

[0465] The pharmaceutical-polymer conjugates according to the invention can be formed into articles or devices. Articles or devices can be manufactured in various forms. Suitably, the articles or devices are medical devices, preferably ocular implants. The polymer conjugates according to the invention can also be incorporated into or formulated as coatings for in vitro and in vivo application.

[0466] The pharmaceutical-polymer conjugates according to the present invention can be used to form articles or devices suitable for application to the eye.

[0467] In some implementations, the drug-polymer conjugate may be in the form of a solid article (e.g., granules, rods, balls, or pellets), a semi-solid, a deformable solid, a gel, or a liquid for placement in the eye of a subject.

[0468] In another aspect, the present invention provides an ocular implant for treating glaucoma comprising a pharmaceutical-polymer conjugate of any of the embodiments described herein.

[0469] In another aspect, the present invention provides an ocular implant for treating or preventing endophthalmitis or ocular inflammatory glaucoma, comprising a pharmaceutical-polymer conjugate of any of the embodiments described herein.

[0470] In one form, the implant is rod-shaped or spherical and can be accommodated within the lumen of a needle, such as a 20-27 gauge needle. The outer diameter of the implant is less than 0.5 mm, preferably about 0.4 mm, and more preferably 0.3 mm. The length of the rod-shaped implant can be selected to deliver the desired dose of drug.

[0471] Implants can have a variety of different structural forms. Ocular implants can be solid, semi-solid, or even gel. Solid implants will contain materials with a melting point above 37°C, while semi-solid implants will have a glass transition temperature equal to or just below 25-37°C. Gels can be formed by appropriately formulating polymer conjugates with suitable plasticizers. In one set of embodiments, the implant can be a hydrogel.

[0472] In another aspect, the present invention provides an injectable article for placement in the eye of a subject, wherein the injectable article comprises a drug-polymer conjugate of any of the embodiments described herein. In one form, the injectable article is an injectable gel.

[0473] The envisioned ocular implant could be a two-component polymer structure, incorporating a drug-polymer conjugate into either the outer or inner layer of the two-component structure. The drug-polymer conjugate can be incorporated into the outer layer to achieve a measured dosage. Alternatively, the inner polymer layer can provide structural integrity to allow for needle delivery. Furthermore, the inner polymer can be engineered to degrade faster or slower than the polymer conjugated layer. This can alter the rate of bio-erosion or the implant itself.

[0474] Possible devices for producing rod-shaped implants include:

[0475] • The drug-polymer conjugate or material containing the drug-polymer conjugate is melt-extruded through a forming mold.

[0476] • Formed in situ in the mold during the polymerization process.

[0477] • The drug-polymer conjugate and other materials forming the outer or inner layer are simultaneously extruded in two components through a suitable die.

[0478] • Subsequently, one polymer is sequentially coated and extruded with another polymer. For example, the core polymer fibers of PLGA can be melt-coated with a polymer containing a drug-polymer conjugate.

[0479] • It is also possible to solution-coat a suitable internal polymer carrier material (e.g., PLGA) with a solution containing a drug-polymer conjugate.

[0480] Possible devices for producing rod-shaped or spherical implants include:

[0481] • Injection molding of the drug-polymer conjugate or materials containing the drug-polymer conjugate.

[0482] • Casting of the solution in a mold containing the drug-polymer conjugate or a material containing the drug-polymer conjugate.

[0483] In another aspect, the present invention provides an injectable article for placement in the eye of a subject, wherein the injectable article comprises a drug-polymer conjugate of any of the embodiments described herein. In one form, the injectable article is in gel form.

[0484] In this specification, "optionally substituted" means that the group may or may not be substituted or may be fused with one, two, three or more organic and inorganic groups (i.e., optional substituents) to form a fused polycyclic group, wherein the organic and inorganic groups include those selected from: alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, heteroaryl, acyl, aralkyl, alkylaryl, alkylheterocyclic, alkylheteroaryl, alkylcarbocyclic, halogen, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halocarbocyclic, haloheterocyclic, haloheteroaryl, haloacyl, haloarylalkyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycarbocyclic, hydroxyaryl, hydroxyheterocyclic, hydroxyheteroaryl, hydroxyacyl, hydroxyaralkyl, alkoxy Alkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbocyclic, alkoxyaryl, alkoxyheterocyclic, alkoxyheteroaryl, alkoxyacyl, alkoxyaralkyl, alkoxy, alkenyloxy, alkynyloxy, carbocyclic alkoxy, aralkyloxy, heteroaryloxy, heterocyclic alkoxy, acyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy, halocarbocyclic alkoxy, haloaralkyloxy, haloheteroaryloxy, haloheterocyclic alkoxy, haloacyloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclic, nitroheteroaryl, nitrocarbocyclic, nitroacyl, nitroaralkyl, amino (NH2), alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, aralkyl Amino, diarylalkylamino, amide, diamide, heterocyclic amino, heteroarylamino, carboxyl, carboxyl ester, amide, alkylsulfonyloxy, arylsulfinyloxy, alkylsulfinyl, arylsulfinyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, arylalkylthio, carbocyclic thio, heterocyclic thio, heteroaryl thio, acylthio, sulfoxide, sulfonyl, sulfonamide, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocarbocyclic, aminoaryl, aminoheterocyclic, aminoheteroaryl, aminoacyl, aminoaralkyl, thioalkyl, thioalkenyl, thioalkynyl, thiocarbonyl, thioaryl, thioheterocyclic, thioaryl, thioacyl, thioaralkyl, carboxylalkyl, carboxylalkenyl, carboxylalkynyl, carboxylcarbocyclic, carboxyl Aryl, carboxyheterocyclic, carboxyheterocyclic, carboxyacyl, carboxyaralkyl, carboxy ester alkyl, carboxy ester alkenyl, carboxy ester kyneyl, carboxy ester carbocyclic, carboxy ester aryl, carboxy ester heterocyclic, carboxy ester heterocyclic, carboxy ester acyl, carboxy ester aryl, acylaminoalkyl, acylaminoalkenyl, acylaminokyneyl, acylaminocarbocyclic, acylaminoaryl, acylaminoheterocyclic, acylaminoheterocyclic, acylaminoacyl, acylaminoaralkyl, formylalkyl, formylaminoalkenyl, formylaminokyneyl, formylcarbocyclic, formylaryl, formylheterocyclic, formylheterocyclic, formylacylacyl, formylaralkyl, acylalkyl, acylalkenyl, acylkyneyl, acylcarbocyclic, acylaryl, acylheterocyclic, acylheterocyclic, acylacyl, acylaralkylSulphinyl alkenyl, sulfinyl alkynyl, sulfinyl carbocyclic, sulfinyl aryl, sulfinyl heterocyclic, sulfinyl heteroaryl, sulfinyl acyl, sulfinyl aralkyl, sulfonyl alkyl, sulfonyl alkenyl, sulfonyl alkynyl, sulfonyl carbocyclic, sulfonyl carbocyclic, sulfonyl aralkyl, sulfonylamino alkyl, sulfonylamino alkenyl, sulfonylamino alkynyl, sulfonylamino carbocyclic, sulfonylamino aryl, sulfonylamino heterocyclic, sulfonylamino heteroaryl, sulfonylamino acyl, sulfonylamino aralkyl, nitroalkyl, nitroalkenyl, nitroalkynyl, nitro carbocyclic, nitroaryl, nitro heterocyclic, nitro heteroaryl, nitroyl, nitroaralkyl, cyano, sulfate, and phosphate.

[0485] Preferred optional substituents include the reactive functional groups or moieties described above, polymer chains, and alkyl groups (e.g., C14, C24, C34, C44, C44, C54, C6 ... 1-6 Alkyl groups such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl groups (e.g., methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, etc.), and alkoxy groups (e.g., C...). 1-6 Alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halogens, trifluoromethyl, trichloromethyl, tribromomethyl, hydroxyl, phenyl (which can be further substituted, for example: C...). 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 alkyl and amino), benzyl (wherein the benzyl group itself can be further converted, for example, C 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substitutions), phenoxy groups (wherein the phenyl group itself can be further substituted, for example, C... 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substituted), benzyloxy (wherein the benzyl group itself can be further substituted, for example, C 1-6 Alkyl, halogen, hydroxyl substitution, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino), amino, alkylamino (e.g., C1-6 Alkyl groups, such as methylamino, ethylamino, propylamino, etc., and dialkylamino groups (such as C44, ... 1-6 Alkyl groups, such as dimethylamino, diethylamino, dipropylamino, acylamino (e.g., NHC(O)CH3), phenylamino (wherein the phenyl group itself can be further converted to, for example, C... 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substituted), nitro, formyl, -C(O)-alkyl (e.g., C 1-6 Alkyl groups, such as acetyl groups), OC(O)-alkyl groups (e.g., C10) 1-6 Alkyl groups, such as acetoxy groups, and benzoyl groups (wherein the phenyl group itself can be further converted to, for example, C40) 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substitution), CH2 replaced by C=O, CO2H, CO2alkyl (e.g., C 1-6 Alkyl groups such as methyl ester, ethyl ester, propyl ester, butyl ester), CO2 phenyl (wherein the phenyl group itself can be further converted, for example, by C 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substituted), CONH2, CONHphenyl (wherein the phenyl itself can be further substituted, for example, C 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substituted), CONH benzyl (wherein the benzyl group itself can be further substituted with, for example, C 1-6 Alkyl, halogen, hydroxyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyano, nitro OC(O)C 1-6 Alkyl and amino substituted), CONH alkyl (e.g., C 1-6 Alkyl groups such as methylamide, ethylamide, propylamide, butylamide) CONH dialkyl (e.g., C 1-6 Alkyl) aminoalkyl (e.g., HNC) 1-6 Alkyl-, C1-6 Alkyl HN-C 1-6 Alkyl- and (C 1-6 Alkyl)2N-C 1-6 Alkyl-), thioalkyl (e.g., HSC) 1-6 Alkyl-), carboxylalkyl (e.g., HO2CC) 1-6 alkyl-), carboxylic acid ester alkyl (e.g., C10) 1-6 Alkyl O2CC 1-6 Alkyl-), amide-alkyl (e.g., H2N(O)CC) 1-6 Alkyl-, H(C) 1-6 alkyl)N(O)CC 1-6 alkyl-), formylalkyl (e.g., OHCC) 1-6 alkyl-), acylalkyl (e.g., C10) 1-6 Alkyl(O)CC 1-6 alkyl-), nitroalkyl (e.g., O2NC) 1-6 alkyl-), sulfoxide alkyl (e.g., R) 3 (O)SC 1-6 Alkyl, such as C 1-6 Alkyl(O)SC 1-6 alkyl-), sulfonylalkyl (e.g., R) 3 (O)2SC 1-6 Alkyl-, for example, C 1-6 Alkyl(O)2SC 1-6 alkyl-), sulfonamide alkyl (e.g., 2HRN(O)SC) 1-6 Alkyl, H(C) 1-6 Alkyl)N(O)SC 1-6 alkyl-).

[0486] It should be understood that the compounds of the present invention (including monomers and polymers) can exist in one or more stereoisomeric forms (e.g., enantiomers, diastereomers). The invention encompasses all such stereoisomers, either isolated (e.g., enantiomer isolation) or in combination (including racemic mixtures).

[0487] The following examples are intended to illustrate the scope of the invention and to enable reproduction and comparison. They are not intended to limit the scope of this disclosure in any way.

[0488] Example

[0489] General experimental methods

[0490] The following compounds, essential to this invention, are prepared using methods described in the literature or, unless otherwise described, techniques well known to those skilled in the art.

[0491] 2-(prop-2-yn-1-yl)pentan-4-yn-1-ol (CAS 432027-96-8); (2-hydroxypropane-1,3-diylbis(hexyl-5-ynyl ester) (CAS 1627101-87-4); 1,3-bis(prop-2-yn-1-yloxy)prop-2-ol (CAS16169-22-5) are all based on WO Preparation according to the procedure described in 2014134689A1, September 12, 2014. 2-(hydroxymethyl)-2-methylpropane-1,3-diyldiyne ester was synthesized by treating a solution of 2-(hydroxymethyl)-2-methylpropane-1,3-diol and carboxylic acid (2 eq) in THF for 16 h with DCC (2 (equivalent) eq) and DMAP (0.1 eq). The crude material was filtered and purified by rapid chromatography to obtain the desired 2-(hydroxymethyl)-2-methylpropane-1,3-diyldiyne ester.

[0492] Linear poly(ethylene glycol) bis(azide) of different molecular weights were purchased from commercial sources or prepared using standard literature methods.

[0493] Monomer Synthesis

[0494] Formation of chloroalkyl reagents

[0495] Method 1

[0496] Example 1 illustrates 1-chloroethyl (2-(prop-2-yn-1-yl)pent-4-yn-1-yl) carbonate

[0497] 1-Chloroethyl chloroformate (4.70 mL, 43.4 mmol) was added dropwise to a solution of 2-(prop-2-yn-1-yl)pentan-4-yn-1-ol (2.649 g, 21.7 mmol) in anhydrous pyridine (50 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 days. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and washed with water and brine. The organic phase was then dried over Na₂SO₄, filtered, concentrated, and dried under vacuum. The crude residue was purified by rapid chromatography.

[0498] Method 2

[0499] To an ice-cold solution of 2-(prop-2-yn-1-yl)pentan-4-yn-1-ol (2.0 g, 16.37 mmol) and DMAP (3.0 g, 24.55 mmol) in anhydrous dichloromethane (60 mL), 1-chloroethyl chloroformate (3.4 mL, 31.4 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 18 h. The solvent was removed under reduced pressure. The crude product was slurried with ethyl acetate and passed through a silica stopper. The title compound was isolated as a clear amber liquid (3.01 g, 80% yield).

[0500] Formation of [alkoxycarbonyl)oxy]alkyl esters

[0501] Method 3

[0502] Example 6 illustrates 1-((((2-(prop-2-yn-1-yl)pent-4-yn-1-yl)oxy)carbonyl)oxy)ethyl(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid ester.

[0503] Add K₂CO₃ (3.66 mmol) to a 0°C solution of latanoprost free acid (1.80 mmol) in DMF (5 mL). After 5 minutes, add a DMF (20 mL) solution of alkyl chloride (e.g., 1-chloroethyl (2-(prop-2-yn-1-yl)pent-4-yn-1-yl) carbonate 5.98 mmol) through a sleeve. Warm the resulting solution to room temperature and stir for 5 days or until the reaction is complete. Add EtOAc and a saturated aqueous NH₄Cl solution to extract the product (EtOAc), wash (H₂O, then brine), dry (Na₂SO₄), filter, and concentrate under reduced pressure. Rapid chromatography (20%-100% EtOAc / gasoline gradient elution) yielded 1-(((((2-(prop-2-yn-1-yl)pent-4-yn-1-yl)oxy)carbonyl)oxy)ethyl(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (643.4 mg, 1.10 mmol, 61%) as a colorless, viscous oil. f =0.60(EtOAc).

[0504] Preparation of drug monomer precursors

[0505] Using the methods described above and methods known to those skilled in the art, the following structural unit precursors of pharmaceutical monomers are prepared.

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514] Preparation of drug-polymer conjugates

[0515] Preparation of comonomers

[0516] Method 4: General Method A: Used for preparing PEG azide comonomers: esters

[0517] Example 44 is used to illustrate the point.

[0518]

[0519] 4-arm PEG 2000 -OH (5 g, 2.5 mmol), TEA (3.1 mL, 4.4 eq), and DCM (50 mL) were introduced into a round-bottom flask equipped with a rubber septum and a magnetic stir bar and placed under a nitrogen atmosphere. The solution was stirred and cooled to 0 °C in an ice bath. A mixture of 3-chloro-2,2-dimethylpropionyl chloride (2.6 mL, 8 eq) in 10 mL of DCM was added dropwise using a syringe with a needle. The solution was warmed to room temperature and stirred overnight. After filtration, DCM was removed under vacuum, and the product was purified by rapid chromatography (EtOAc:[DCM / MeOH95 / 5]100:0->0:100) to give the product (5.14 g, 83%), which was analyzed by MALDI-ToF mass spectrometry (Mn = 2458.3 g·mol⁻¹). -1 Mw = 2474.8 g·mol -1 (D = 1.007)

[0520] C-(PEG-OCO-C(CH3)2-CH2-Cl)4 (5.135, 2.09 mmol), NaN3 (5.43 g, 40 eq), and DMF (75 mL) were introduced into a round-bottom flask equipped with a rubber septum and a magnetic rod. The solution was stirred at 50 °C for 24 hours. The solvent was evaporated, and the polymer was purified by rapid chromatography (EtOAc:acetone 100:0 -> 0:100), and dried under vacuum to give the product (Example 44) (3.48 g, 67%). MALDI-ToF mass spectrometry (Mn = 2439.7 g·mol⁻¹) was used. -1 Mw = 2451.7 g·mol -1 (D = 1.005); 1¹H NMR (C-(CH₂-CH₂-O)-CO-C(CH₃)₂-CH₂-N₃)₄: 1.30 ppm (6H, (CH₃)₂; 3.4 ppm-3.8 ppm (44H, -CH₂-CH₂-O); 4.28 ppm (-CH₂-N₃)). Overall yield = 56%.

[0521] Method 5:

[0522] Preparation of PEG azide comonomers: General method B for esters

[0523] Example 37 is used to illustrate the point.

[0524]

[0525] 4-arm PEG 2000 -OH (5.0 g, 2.5 mmol), TEA (2.23 g, 3.1 mL, 22 mmol, 8.8 eq), and DCM (50 mL) were introduced into a round-bottom flask equipped with a stir bar and placed under nitrogen. The solution was stirred and cooled to 0 °C. A mixture of 5-bromopentanoyl chloride (3.99 g, 2.68 mL, 20.0 mmol, 8 eq) in 10 mL of DCM was added dropwise. The solution was stirred overnight and warmed to room temperature. After filtration, 30 mL of brine was added to the mixture, and the aqueous phase was washed three times with DCM (3 × 100 mL). The organic phases were combined, dried (MgSO4), and vacuum-sealed. The product was purified by column chromatography (EtOAc:Hex = 40:60 to 100:0).

[0526] C-(PEG-Br)4 (4.36 g, 1.64 mmol), NaN3 (4.27 g, 65.7 mmol), and DMF (50 mL) were introduced into a round-bottom flask. The solution was stirred at room temperature for 24 hours. The solvent was evaporated, the mixture was dissolved in acetone and filtered. The acetone was evaporated, brine (50 mL) was added, and the mixture was washed with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over MgSO4, and then dried under vacuum.

[0527] Method 6: A general method for preparing PEG azide comonomers: carbamates C

[0528] Example 49 is used to illustrate the point.

[0529] Four-arm PEG 2000 -Carbamate tetraazide comonomer

[0530]

[0531] 4-arm PEG 2000-OH (6 g, 3 mmol), dibutyltin dilaurate (0.19 g, 0.3 mmol), and dichloromethane (18 mL) were introduced into an RBF equipped with a diaphragm and a magnetic rod. 3-chloropropyl isocyanate (2.15 g, 18.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated and... 1 The products were analyzed by HNMR and MALDI-TOF spectrometry.

[0532] 4-arm PEG 2000 -OCONH-C3H6-Br (4.56 g, 3.91 mmol), NaN3 (10.2 g, 157 mmol), and DMF (120 mL) were introduced into a round-bottom flask. The solution was stirred at 50 °C for 48 hours. The solvent was evaporated, the mixture was dissolved in EtOAc (50 mL), filtered, washed with brine (25 mL), dried over NaSO4, and the solvent was removed under vacuum. The product was purified by rapid chromatography (EtOAc:Hex = 40:60 to 100:0, then acetone 100).

[0533] Method 7: Preparation of PEG azide comonomer amides: General methods for amides

[0534] Example 47 is used to illustrate the point.

[0535]

[0536] 4-Amino-PEG (2.5 g, 1.25 mmol), TEA (1.53 mL, 11 mmol, 8.8 eq), and DCM (28 mL) were introduced into a two-necked round-bottom flask equipped with a pressure-balanced feeding funnel and placed under nitrogen. The solution was stirred and cooled to 0 °C. Then, a mixture of 2-bromopropionyl bromide (1.05 mL, 10 mmol, 8 eq) in 2 mL of DCM was added dropwise through a dropping funnel. The solution was stirred overnight and allowed to warm to room temperature. The mixture was dried, dissolved in 50 mL of EtOAc, filtered, and washed with brine (25 mL). The aqueous phase was washed twice with EtOAc, the organic phases were combined, dried with MgSO4, and then dried under vacuum. MALDI-ToF: Mn = 2437.4 g / mol; Mw = 2440.7 g / mol;

[0537] (Br-CONH-PEG-)4-C (0.792 g, 0.325 mmol), NaN3 (0.845 g, 1.3 mmol, 40 eq), and DMF (10 mL) were introduced into a round-bottom flask. The solution was stirred at room temperature for 24 hours. The solvent was evaporated, the mixture was dissolved in 50 mL of ethyl acetate, filtered, washed with brine (25 mL), dried over Na2SO4, and then dried under vacuum. MALDI-ToF: Mn = 2185.5 g / mol; Mw = 2191.6 g / mol;

[0538] The following azide monomers in Table 5 were prepared using the methods described above.

[0539] Table 5

[0540]

[0541]

[0542]

[0543] Polymer Synthesis

[0544] Linear Polytriazole Synthesis

[0545] Method 8: Copper (II)

[0546] Dialkyl-drug-monomer (1.0 eq), diazide copolymer monomer (1.0 eq), and sodium ascorbate (0.45 eq) were placed in a vial equipped with a stir bar, and then... Seal. Anhydrous DMF pre-purged with N2 or argon was introduced into the vial, and the mixture was stirred under a constant inert atmosphere to form a clear solution. A stock solution of catalyst (2 mL of DMF solution of CuBr2 (14.2 mg) and PMDETA (11.0 mg)) was added to the mixture, resulting in a final reaction mixture containing 0.15 equivalents of CuBr2 and 0.15 equivalents of PMDETA. The solution was stirred at room temperature under a constant N2 flow for 24 hours. At the end of the reaction, the solution was diluted with THF and passed through a neutral alumina column. The column was further washed with THF, followed by washing with DCM to collect the remaining polymer. The solution was then concentrated to approximately 1 mL, precipitated in diethyl ether, and dried under vacuum to obtain the desired polymer.

[0547] Method 9: Copper (I)

[0548] The diyne-drug-monomer (1 eq) and the diazide copolymer monomer (1 eq) were placed in a 4 mL vial equipped with a stir bar, and then... Seal. Introduce 0.5 mL of toluene pre-purged with N2 into the vial and stir the mixture under a constant N2 flow to form a clear solution. Then, add 0.2 mL of CuBr (0.15 eq) and PMDETA (0.15 eq) stock solution (20 mg / mL, in toluene, stirred under N2 for 30 min prior to use) to the reaction mixture and stir the solution at room temperature under a constant N2 flow for 24 h. At the end of the reaction, dilute the solution with 3 mL of THF and pass it through a neutral alumina column. Wash the column further with 20 mL of THF to ensure all polymer is collected. The solution is then concentrated to approximately 1 mL, precipitated in 40 mL of diethyl ether, and dried under vacuum.

[0549] Method 10: Ruthenium-catalyzed linking reactions

[0550] Dialkyl-drug-monomer (1 eq), diazidide comonomer (1 eq), and DMF were introduced into the vial using a stir bar, and then... Seal the container. Before adding 14.7 mg Cp*RuCl(PPh3)2, purge the solution with argon for 10 minutes and heat the reaction mixture at 35°C for 24 hours under argon. Add the reaction mixture dropwise to diethyl ether to precipitate the product, and then dry under vacuum overnight.

[0551] Synthesis of cross-linked polytriazole

[0552] Method 11: Cross-linked or hyperbranched polymers

[0553] Dialkyl-drug-monomer (1 eq), tetraazide copolymer (0.5 eq) or triazide copolymer (0.66 eq), sodium ascorbate (0.45 eq), and DMF were introduced into a vial equipped with a magnetic stir bar. A catalyst stock solution (CuBr2 (14.2 mg) and PMDETA (11.0 mg) in 2 mL DMF) was added to the mixture, yielding 0.15 eq CuBr2 and 0.15 eq PMDETA in the final reaction mixture. The vial was sealed with a rubber septum and stirred at room temperature under nitrogen for 24 hours. The resulting gel was dialyzed in acetonitrile (3 × 1 L) and dried under high vacuum.

[0554] Method 12: Synthesis of cross-linked rods and bulk polymers

[0555] Dialkyl-drug-monomer (1 eq), tetraazide copolymer monomer (0.5 eq) or triazide copolymer monomer (0.66 eq), sodium ascorbate (0.45 eq), and DMF were introduced into a vial containing a magnetic stir bar and PTFE tubing (φ = 0.35 mm, l = 10 mm, 100 tubes). A catalyst stock solution (CuBr2 (14.2 mg) and PMDETA (11.0 mg) in 2 mL DMF) was added to the mixture to obtain 0.15 eq of CuBr2 and 0.15 eq of PMDETA in the final reaction mixture. The vial was sealed with a rubber septum and degassed (5 nitrogen / vacuum cycles) to remove trapped air bubbles from the tubing. The solution was then stirred under nitrogen at room temperature for 24 hours, during which time a gel formed. The tubing was separated from the bulk gel and immersed in isopropanol for at least 16 hours, and the rod was pushed out of the tubing using a 0.305 mm probe / wire. The resulting rods were washed in acetonitrile (3 × 250 mL) and the bulk gel was washed with 3 × 1 L of acetonitrile for 24 hours and dried under high vacuum.

[0556] Method 13: Cross-linked or hyperbranched polymers - ruthenium catalysis

[0557] Dialkyl-drug-monomer (1 eq.), tetraazide copolymer monomer (0.5 eq.), and DMF were introduced into a vial equipped with a stir bar, and then... The mixture was then sealed. It was then purged with argon for 5 minutes, followed by the addition of the Cp*RuCl(PPh3)2 catalyst. The mixture was heated at 35°C for 24 hours under argon atmosphere, then the temperature was increased to 50°C and heated for another 24 hours. The resulting gel was dialyzed in acetonitrile (3 × 1 L) and vacuum dried overnight.

[0558] Method 14: Synthesis of crosslinking rods and bulk polymers containing two different crosslinking agents

[0559] Dialkyl-drug-monomer (1 eq), tetraazide copolymer 1 (0.25 eq), another tetraazide copolymer 2 (0.25 eq), sodium ascorbate (0.45 eq), and DMF were introduced into a vial containing a magnetic stir bar and PTFE tubing (φ = 0.35 mm, 1 = 10 mm, 100 tubes). A catalyst stock solution (CuBr2 (14.2 mg) and PMDETA (11.0 mg) in 2 mL DMF) was added to the mixture to obtain 0.15 eq of CuBr2 and 0.15 eq of PMDETA in the final reaction mixture. The vial was sealed with a rubber septum and degassed (5 nitrogen / vacuum cycles) to remove trapped air bubbles from the tubing. The solution was then stirred under nitrogen at room temperature for 24 hours to form a gel. The tubing was separated from the bulk gel and immersed in isopropanol for at least 16 hours, and the rod was pushed out of the tubing using a 0.305 mm probe / wire. The resulting rods were washed in acetonitrile (3 × 250 mL) and the bulk gel was washed with 3 × 1 L of acetonitrile for 24 hours and dried under high vacuum.

[0560] Method 15: Cross-linked or hyperbranched polymers containing two different drug monomers

[0561] Diyne-drug-monomer (1) (0.5 eq) and diyne-drug-monomer (2) (0.5 eq), tetraazide copolymer (0.5 eq) or triazide copolymer (0.66 eq), sodium ascorbate (0.45 eq), and DMF (introduced into a vial equipped with a magnetic stir bar) were added to the mixture. A catalyst stock solution (CuBr2 (14.2 mg) and PMDETA (11.0 mg) in 2 mL of DMF) was added to the final reaction mixture to obtain 0.15 equivalents of CuBr2 and 0.15 equivalents of PMDETA in the final reaction mixture. The vial was sealed with a rubber septum and stirred at room temperature under nitrogen for 24 hours. The gel was dialyzed in acetonitrile (3 × 1 L) and dried under high vacuum.

[0562] Method 16: Polymer conjugates prepared using diazide-drug-monomer

[0563] The diazidide-drug monomer (1 eq.) and dialkyl comonomer (1 eq.) were dissolved in a solvent of choice. The solution was purged with argon for 30 min, and then copper(II) bromide (CuBr2) (0.05 mol equivalent), PMDETA (0.05 mol equivalent), and sodium ascorbate (0.15 mol equivalent) were added to the solution. The heterogeneous mixture was stirred vigorously overnight at room temperature until the starting material was completely consumed, as shown by TLC. The mixture was diluted with water and any precipitate formed was collected. The product was purified by precipitation from DMF and further purification on a Sephadex LH-20 to give the title drug-polymer conjugate. The product was analyzed by IR, 1 HNMR and 13 CNMR and GPC analysis of drug-polymer conjugates.

[0564] Method 17: Linear block polymer conjugates prepared from dialkyl-drug-monomers with additives.

[0565] Dialkyl pharmaceutical monomers and diazide comonomers 1 and 2 were dissolved in a chosen solvent while maintaining an equimolar ratio of alkyne and azide units. The solution was purged with argon for 30 minutes, and then copper(II) bromide (CuBr2) (0.05 mol equivalent), PMDETA (0.05 mol equivalent), and sodium ascorbate (0.15 mol equivalent) were added. The heterogeneous mixture was stirred overnight under argon atmosphere and then stirred at room temperature for 24 hours. The reaction mixture was then passed through a basic alumina column to remove the CuBr2 catalyst, followed by vacuum concentration and precipitation several times in excess diethyl ether to obtain the desired polymer in solid form. 1 HNMR and GPC analysis of drug-polymer conjugates.

[0566] Method 18: Polymer conjugates prepared using acetylene-azide-drug-reagent conjugate monomers (drug monomers only).

[0567] The acetylene-azide drug-monomer (1 eq.) was dissolved in a solvent of choice. The solution was purged with argon for 30 min, and then copper(II) bromide (CuBr2) (0.05 mol equivalent), PMDETA (0.05 mol equivalent), and sodium ascorbate (0.15 mol equivalent) were added to the solution. The heterogeneous mixture was stirred vigorously overnight until the starting material was completely consumed, as shown by TLC. The mixture was diluted with water and any precipitate formed was collected. The product was purified by precipitation from DMF and further purification on a Sephadex LH-20 to give the title drug-polymer conjugate. The product was analyzed by IR... 1 HNMR and 13 CNMR and GPC analysis of drug-polymer conjugates.

[0568] Method 19: Polymer conjugates prepared using acetylene-azide-drug-monomer (and comonomer).

[0569] The acetylene-azide-drug-monomer (1 eq.) and the acetylene-azide comonomer (1 eq.) were dissolved in a solvent of choice. The solution was purged with argon for 30 min, and then copper(II) bromide (CuBr2) (0.05 mol equivalent), PMDETA (0.05 mol equivalent), and sodium ascorbate (0.15 mol equivalent) were added to the solution. The heterogeneous mixture was stirred vigorously overnight until the starting material was completely consumed, as shown by TLC. The mixture was diluted with water and any precipitate formed was collected. The product was purified by precipitation from DMF and further purification on a Sephadex LH-20 to give the title drug-polymer conjugate. The product was analyzed by IR, 1 HNMR and 13 CNMR and GPC analysis of drug-polymer conjugates.

[0570] The following polymers in Table 6 were prepared using the methods described above.

[0571]

[0572]

[0573]

[0574] Using the above method, the following comonomers listed in Table 7 can also be prepared.

[0575] Table 7

[0576]

[0577]

[0578] The above methods can also be used to prepare the following polymers listed in Table 8.

[0579] Table 8

[0580]

[0581]

[0582] Drug release methods

[0583] In vitro drug release from polymer samples was tested according to the guidelines recommended by the International Organization for Standardization (ISO). The sample was placed on a wire mesh folded into an M-shape and suspended in isotonic phosphate buffer (IPB) at pH 7.4 or pH 8.4 (Table 1), and stirred at 37°C or 55°C. Aliquots of the receptor solution were collected at predetermined time points until the drug was exhausted from the polymer.

[0584] Preparation of in vitro release samples

[0585] 15 mL of isotonic phosphate buffer (pH 7.4) was added to approximately 10 mg of the bulk polymer material and stirred in a 37°C water bath in the dark. At defined time points, 100 μL aliquots of each sample were removed. After each aliquot removal, 100 μL of isotonic phosphate buffer was returned to each sample. The amount of drug in the aliquots was quantified by reversed-phase high-performance liquid chromatography (HPLC) combined with UV detection. Analytes were separated on a C18 column using solvent mixtures, as described in Table 9 below for each drug category.

[0586] Table 9

[0587]

[0588] Preparation of degradation samples

[0589] In vitro degradation of cross-linked polymers

[0590] The degradation sample consisted of 3-4 cross-linked polymer rods (total polymer mass = 0.5-1.1 mg) wrapped in a stainless steel mesh, placed in an amber glass bottle containing 15 mL of isotonic phosphate buffer (pH 7.4) and equipped with a stir bar and a PTFE / silicone diaphragm cap. The initial mass of the mesh and rods was recorded.

[0591] Place 10-12 of these samples in a constant temperature water bath at 37°C or 55°C equipped with multiple stirring plates. Stir the samples at 300 rpm at the desired temperature and remove them at predetermined time points. Remove the polymer from the samples and wash the sieve with the rods twice with milliQ water and dry under vacuum. Weigh the rods. If the rods cannot be removed from the sieve (rod jamming), weigh the sieve with the rods. Additionally, measure the drug concentration in the buffer solution by HPLC.

[0592] Drug release from samples undergoing biodegradation was also determined. Aliquots of 100 μL each were taken at specified time points. The amount of drug in the aliquots was quantified by reversed-phase high-performance liquid chromatography (HPLC) combined with UV detection, as described below.

[0593] In vitro degradation of linear polymers

[0594] The degradation samples consisted of carefully weighed polymer (~10 mg) in 8 mL vials filled with 5 mL of isotonic phosphate buffer (pH 7.4) and equipped with a stir bar and a PTFE / silicone diaphragm cap. Four to five samples of each polymer were placed in a constant-temperature water bath at 37°C or 55°C equipped with multiple stir plates. The samples were stirred at 300 rpm at the desired temperature and removed at predetermined time points. A 100 μL aliquot was taken from each sample, and the amount of drug in the aliquot was quantified by reversed-phase high-performance liquid chromatography (HPLC) combined with UV detection, as described below. The remaining solution was then freeze-dried for 72 hours. Gel permeation chromatography (GPC) analysis was performed on each sample to determine the molecular weight of the polymer.

[0595] GPC Analysis:

[0596] Gel permeation chromatography (GPC) analysis of polymer samples was performed on a Shimadzu liquid chromatography system equipped with a Shimadzu RID-10A differential refractive index detector (λ = 633 nm) and a Shimadzu SPD-20A ultraviolet detector. The Shimadzu SPD-20A ultraviolet detector was connected to a 5.0 μm bead-sized guard column (50 × 7.8 mm), followed by three Shodex KF-805L columns (300 × 8 mm). Bead size: 10 μm, maximum pore size: The operation was performed continuously at 40°C. The eluent was N,N-dimethylacetamide (HPLC grade, containing 0.03% w / v LiBr) and the flow rate was 1 mL / min. A narrow molecular weight distribution of 500-2 × 10⁻⁶ was used. 6 Molecular weight calibration curves were prepared for polystyrene standards within the Da range.

[0597] Drug release from samples undergoing biodegradation was also determined. 100 μL aliquots of each sample were collected at defined time points. The amount of drug in the aliquots was quantified by reversed-phase high-performance liquid chromatography (HPLC) combined with UV detection, as described below.

[0598] Table 10 Drug Release from Polymers

[0599]

[0600] Research methods for intraocular pressure and pupil size in dogs

[0601] The in vivo properties of the selected drug polymer conjugate were investigated in dogs (domestic dogs) that were homozygous for the G661R missense mutation in ADAMTS10, thus affecting primary angular glaucoma.

[0602] A rod-shaped implant containing the selected conjugate is inserted into the anterior chamber of the limbus by penetrating the conjunctiva, sclera, and cornea. The needle is moved as far into the anterior chamber as possible, with its tip approaching the inferior iridocorneal angle. The implant is expelled from the needle and placed into the inferior iridocorneal angle by moving the core needle toward the needle tip. The needle is then removed from the anterior chamber, and the conjunctiva around the injection site is held with forceps for 1–2 minutes to minimize aqueous humor leakage.

[0603] Through the rebound tonometer (TONOVET) TM (Epimedium Finland Ltd). IOP was measured at 8:00 AM, 12:00 PM, and 4:00 PM, and the average of all measurements was calculated to determine the average daily IOP.

[0604] Pupil diameter was measured using a Jameson™ caliper. Pupil size was assessed at the same time points as the IOP measurement (08:00, 12:00, and 16:00) and immediately after the tonometer measurement. Indoor lights and a red LED headlight were turned off; this red LED headlight was used to reveal the basic reflection of the pupil outline through backlighting. Pupil dimensions were measured at 8:00 AM, 12:00 PM, and 4:00 PM to calculate the average pupil size.

[0605] Example 150

[0606] Discussion of attached figures

[0607] Referring to the accompanying drawings, which illustrate specific embodiments demonstrating the effects of monomer variations and the presence of each of the biodegradable groups in monomers such as formula (IVa) and formula (V) when present (IVa, b, c, or d).

[0608] exist Figure 1 These figures illustrate the cumulative release (μg / 10 mg) of latanoprost free acid from a drug-polymer conjugate exposed to isotonic phosphate buffer (pH 7.4) at 37.0 °C over time. This drug-polymer conjugate has the same backbone segment Q as the exemplary drug-polymer conjugate, but with different chemical properties in and around segment Q. Examples 60 (n-alkyl ester) and 65 (α,α-dimethyl ester) are derived from common 4-arm PEG500 azide comonomers, but with different ester moieties in QX. Despite the differences in QX chemistry, the same zero-order release rate is consistently achieved, and linker chemistry can be used to modify the drug release rate. Preparation of the drug-polymer conjugates of Examples 60 and 65: Latanoprost free acid drug monomer and common 4-arm PEG500 azide. A combination of two stoichiometric products of the comonomer. The structures of each pharmaceutical monomer are as follows:

[0609]

[0610] In both cases, the drug release rate was shown to be of order zero (see [reference]). Figure 1 This provides a product that delivers a constant daily dose throughout treatment. The actual daily dose can be selected by controlling the weight of the product being administered. Furthermore, latanoprost free acid release rates vary, providing products with different treatment durations.

[0611] exist Figure 2 In the figures, the curves show the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugate over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C and 55.0°C, respectively. This drug-polymer conjugate has the same linker (L) as the drug-polymer conjugate in the examples but with different comonomers. Compared to Examples 67 and 68, Examples 53 and 66 have a proportionally larger PEG content relative to the drug monomer, indicating that PEG content can still be used to modify the drug release rate even when using different polymer chemistry. Examples 53 and 66 use the same PEG content in the drug monomer, ester, and carbamate, but with different QX components, respectively, indicating that the linker (L) of prostaglandin to the main chain is the main determinant of the drug release rate, rather than a change in the QX chemistry. Examples 67 and 68 have the same chemical composition, but Example 68 has a higher crosslinking density, indicating that crosslinking density has no significant effect on the drug release rate.

[0612] Preparation of drug-polymer conjugates in Examples 53, 66, 67, and 68. The compositions of all four examples were derived from the free latanoprost acid drug monomer. Example 6:

[0613]

[0614] Examples 67 and 68 are stoichiometric products of Example 6 and common 4-arm PEG200 azide. Compositions of comonomers. Example 67 was prepared using a 0.09 M reactant concentration, and Example 68 was prepared using a 0.18 M reactant concentration to ensure that Example 68 had a higher crosslinking density. Example 53 was a composition of the stoichiometric product of Example 6 and the comonomer 4-arm PEG500 ester azide, while Example 66 was a composition of the stoichiometric product of Example 6 and the comonomer 4-arm PEG500 urethane azide. The composition.

[0615] In all cases, the drug release rate is displayed. Figure 2The product is grade zero to provide a constant daily dose throughout treatment. The actual daily dose can be selected by controlling the weight of the administered product. Examples 53 and 66 use the same PEG content but different QX components in the pharmaceutical monomer, ester, and carbamate, respectively, indicating that the linker (L) is the primary determinant of drug release rate, rather than a change in QX chemistry. Compared to Examples 67 and 68, Examples 53 and 66 have a proportionally larger PEG content relative to the pharmaceutical monomer, indicating that PEG content can still be used to modify drug release rate even when using different polymer chemistry. Examples 67 and 68 have the same chemical composition, but Example 68 has a higher crosslinking density, indicating that crosslinking density has no significant effect on drug release rate.

[0616] In Figure 3, the curves show the a) cumulative release (μg / 10mg) and b) mass loss % of latanoprost free acid exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C from the drug-polymer conjugate over time. This drug-polymer conjugate has the same linker (L) as the drug-polymer conjugate of the examples, but with a different comonomer. Examples 56, 53, and 62 are derived from the same drug-monomer as in Example 6, but use a 4-arm PEG500 azide comonomer containing an alkyl ester and C3, C4, and C5 methylene chains around the ester, respectively. The release rate does not change significantly with the alkyl ester of the comonomer, but only over time until complete mass loss. Furthermore, the mass loss is non-linear, initially small but accelerating after a hysteresis period. This distribution allows for the preparation of products that ensure minimal mass loss during treatment and rapid mass loss after treatment. Drug-polymer conjugates of Examples 56, 53, and 62 were prepared. The compositions of all four examples were derived from conventional latanoprost free acid drug monomers, Example 6:

[0617]

[0618] And 4-arm PEG200 azide comonomers containing n-alkyl esters with C3, C4, and C5 methylene groups surrounding the ester. The following are the structures of the comonomers used in each construct:

[0619]

[0620] In all cases, the drug release rate ( Figure 4This product is presented as grade zero to provide a constant daily dose throughout treatment, and although the chemical degradation rate varies significantly (mass loss % relative to exposure to isotonic phosphate buffer at pH 7.4 at 55.0°C), the release rate does not change significantly with variations in the n-alkyl ester of the comonomer. Mass loss is non-linear, initially small but accelerating after a hysteresis period. This distribution allows for the preparation of products to ensure minimal mass loss during treatment and rapid mass loss after treatment.

[0621] exist Figure 4 These figures show the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugate over time upon exposure to isotonic phosphate buffer (pH 7.4) at 37.0°C, the drug-polymer conjugate having a linker (L) of the same but different comonomer as the drug-polymer conjugates in the examples. Examples 59 and 57 contain a common drug monomer and a similar comonomer, both using esters with different R-groups at the α-position of the carbonyl group. Example 54 uses an oxalyl moiety adjacent to the carbonyl group. These are compared to Example 53, which has no substituent R-group at the α-position of the carbonyl group in a simple n-alkyl ester. The drug release rates of Examples 54, 59, and 57 are rapid compared to Example 53. Such a system would be suitable for controlled drug delivery in applications with short therapeutic periods. Drug-polymer conjugates of Examples 54, 59, and 57 were prepared for comparison with Example 53. The compositions of all four examples were derived from the free acid monomer of conventional latanoprost, Example 6:

[0622]

[0623] Example 53 uses a C4 ester containing n-alkyl groups. The 4-arm PEG500 azide comonomers used in Examples 54, 59, and 57 contain branched esters at positions similar to those in Example 53 relative to the azide. The structures of the comonomers used in each construct are as follows:

[0624]

[0625] The drug release rates of Examples 54, 59, and 57 are the same as those of Example 53 (see Example 53). Figure 4 Compared to other methods, this is faster, and it is noted that the chemobiodegrades into a completely soluble product within 7 days. Such a system would be suitable for controlled drug delivery in applications with short therapeutic periods.

[0626] exist Figure 5These figures show the cumulative release (μg / 10mg) of latanoprost free acid from the drug-polymer conjugate over time when exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C, the drug-polymer conjugate having a linker (L) common to the drug-polymer conjugates of the examples. Examples 63, 64, and 58 comprise a combination of a common drug monomer and two comonomers with different chemical properties. It is shown that the polymer chemistry can be altered to introduce other features (e.g., biodegradation) while maintaining preferred drug release. The drug-polymer conjugates of Examples 63, 64, and 58 were prepared. The compositions of all four examples were derived from the common latanoprost free acid drug monomer. Example 6:

[0627]

[0628] The following are the structures of the comonomers used for each building block:

[0629] Example 63

[0630]

[0631] Example 64

[0632]

[0633] Example 58

[0634]

[0635] For each construct, the composition comprises a stoichiometric amount of each comonomer in an equimolar ratio to the drug monomer, as described in Example 6. The drug release rates of Examples 63, 64, and 58 are comparable (see Example 63). Figure 5 Furthermore, it was shown that the polymer chemistry could be altered to introduce other features (e.g., biodegradation) while still maintaining the preferred drug release rate.

[0636] exist Figure 6 The figure shows the miotic response (mm) in the eyes of dogs treated with Examples 66 and 63, each having a common drug monomer fragment Q. These results demonstrate the release of therapeutic levels of the drug (latanoprost free acid). Rod-shaped implants of Examples 66 and 63 were prepared, suitable for administration to dogs using a 27G needle. The implants were administered to dogs and pupil size (mm) was measured. The dog pupils showed a minimal response to the prostaglandin analogue. Pupillary responses were measured weekly after administration (see [link to original text]). Figure 6In both cases, therapeutic concentrations of the prostaglandin analogue latanoprost free acid were observed during near-zero order release, as indicated by pupil sizes less than 4 mm. In the case of Example 66, pupillary response was observed to decrease at approximately 37 weeks, consistent with the depletion of latanoprost free acid from the material following a prolonged drug release period. Such results demonstrate that the chemistry of the linker (L) can be used to alter the therapeutic duration of the product.

[0637] The curves in Figure 7 show a) the cumulative release (μg / 10mg) of the drug-polymer conjugate from the preferred examples over time, and b) the percentage of mass loss, of latanoprost free acid exposed to isotonic phosphate buffer (pH 7.4) at 37.0°C and 55.0°C. Examples 58, 62, 63, and 64 are derived from the same drug-monomer, Example 6, but using different 4-arm PEG-azide comonomers. The release rate does not change significantly with the comonomer, but rather with the time until complete mass loss. Furthermore, the mass loss is preferably a non-linear curve with a predictive period up to complete mass loss in mammalian eyes, preferably 20 to 45 weeks. The drug-polymer conjugates of Examples 58, 62, 63, and 64 were prepared. The compositions of all four examples were derived from the common latanoprost free acid drug monomer, Example 6:

[0638]

[0639] The following are the structures of the comonomers used in each building block:

[0640] Example 58

[0641]

[0642] Example 62

[0643]

[0644] Example 63

[0645]

[0646] Example 64

[0647]

[0648] For each construct, the composition comprises a stoichiometric amount of each comonomer in an equimolar ratio to the pharmaceutical monomer, Example 6.

[0649] In all cases, the drug release rate (Figure 7) is shown as zero order to provide a product that delivers a constant daily dose throughout the treatment period, and the release rate does not change significantly with variations in polymer chemistry caused by the use of different comonomers. Furthermore, the mass loss is preferably a non-linear curve with a predicted period up to complete mass loss in the mammalian eye, preferably 20 to 45 weeks. This curve allows for the production of a product that provides a preferred effective treatment period of 20–45 weeks.

Claims

1. A polymer-prostaglandin conjugate comprising: Polymer backbone containing multiple groups of formula (I): in: T represents the triazole group; Q is chosen independently each time it appears and may or may not be present, and when present, it represents the linking group Q in the formula QX, where QX is selected from the following groups: Where X represents the connection to T, and s is an integer from 0 to 10; R is selected from the following groups: straight-chain or branched hydrocarbons; D is selected from prostaglandin analogues; and L is a group of formula (II). Where R 5 Selected from hydrogen and C1 to C6 alkyl groups; (R) indicates the end of a group bonded to the R group; and (D) indicates the end of the group attached to group D; Among them, prostaglandin analog D is of formula (Xb). in: Indicates the junction of prostaglandin analogues with L; Indicates a double bond or a single bond; Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups; R 9 and R 11 It is a hydroxyl group; and W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group.

2. The polymer-prostaglandin conjugate according to claim 1, wherein Q is absent, thereby providing Formula I having formula (Ib):

3. The polymer-prostaglandin conjugate according to claim 1, wherein s is an integer from 0 to 6.

4. A polymer-prostaglandin conjugate, which is a copolymer of at least one monomer of formula (IV): in: X can be the same or different each time it appears, and represents a terminal functional group containing alkyne or azide; Q is chosen independently each time it appears and may or may not be present, and when present, it represents the linking group Q in the formula QX, where QX is selected from the following groups: s is an integer from 0 to 10; R is selected from the following groups: straight-chain or branched hydrocarbons; D is selected from prostaglandin analogues of formula (Xb): in: Indicates the junction of prostaglandin analogues with L; Indicates a double bond or a single bond; Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups; R 9 and R 11 It is a hydroxyl group; and W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group; L is a group of the following formula: Where R 5 Selected from hydrogen and C1 to C6 alkyl groups, (R) indicates the end of a group bonded to the R group; and (D) indicates the end of the group attached to group D; and Monomer of formula (Va): J-(Y–A) n (Go) in, J represents the connecting functional group. n is between 2 and 8; Y is a chain containing one or more groups selected from the group consisting of: straight or branched chains C1 to C2. 10 Alkylene, amino, alkylamino, ether (-O-), ester, amide, carbonate, and carbamate; and A may be the same or different each time it appears, and represents a group containing a terminal functional group, which includes an alkyne or azide functional group, wherein the terminal functional group is complementary to the terminal functional group X of formula (IV).

5. The polymer-prostaglandin analog according to claim 4, wherein in formula (Va), group J comprises a polyether linker portion derived from polyethylene glycol (PEG).

6. The polymer-prostaglandin analog according to claim 4, wherein in formula (Va), group J comprises polyethylene glycol with a molecular weight of about 200 to about 10,000.

7. The polymer-prostaglandin conjugate according to claim 4, wherein n in the monomer (Va) is 3 or 4.

8. The polymer-prostaglandin analog according to claim 4, wherein s is an integer from 0 to 6.

9. The polymer-prostaglandin conjugate according to claim 4, wherein the group Q in formula (IV) is absent.

10. The polymer-prostaglandin conjugate according to any one of claims 4 to 9, wherein the comonomer of formula (Va); Y includes the formula (OR) a ) m polyether, wherein R a Independently ethylene, propylene, and butylene, m is 1-300, and the polyether has one or more groups on the chain, said one or more groups being selected from the group consisting of: optionally substituted linear or branched C1 to C2 groups. 10 Alkylene, amino, ether, ester, amide, carbonate and carbamate.

11. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein the comonomer of formula (Va) has formula (Vb). J-((OR a ) m -B-A) n (Vb) in A may be the same or different each time it appears and represents a group containing a terminal functional group, the terminal functional group comprising an alkyne or azide functional group, wherein the alkyne or azide functional group in the terminal functional group is complementary to the alkyne or azide functional group present in the terminal functional group X on the monomer of formula (IV). J represents the connecting functional group. R a Selected from ethylene, propylene, butene, and mixtures thereof; m ranges from 1 to 300; n is between 2 and 8; B is a bond, a group of the formula –MOC(O)N(H)M'-, –MOC(O)OM'-–MC(O)NHM'-, wherein the group formula is selected from (VIa), (VIb), (VIc) and (VId): or M and M' are independently selected from the following groups: bonds, optional substitutions of C1 to C2. 10 Straight-chain or branched aliphatic, with -O- (C1 to C1) groups. 10 Straight-chain or branched aliphatic, containing C1 to C2 chains separated by oxygen spacers (-O-). 10 Straight-chain or branched aliphatic ether linkage groups, group –N(R w )-(C1 to C 10 Straight-chain or branched aliphatic) and containing N(R) groups w ) interval C1 to C 10 A straight-chain or branched aliphatic amine linker, wherein R w Selected from hydrogen and C1 to C4 alkyl groups; q is 0 or 1; and In the monomers of formulas (IV), (Va), and (Vb), the group R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' Independently selected from the group consisting of: hydrogen, alkyl, alkoxy, alkoxy-alkyl, amino, alkylamino, dialkylamino, amino-alkyl, alkylamino-alkyl, dialkylamino-alkyl, and wherein R 1 R 1 R 2 and R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups; and Where R 3 R 3’ , and R 4 R4 ’ One of the pairs may form a carbon ring or heterocycle with 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent heteroatom ring members selected from oxygen and nitrogen, and nitrogen may optionally be substituted with C1 to C6 alkyl groups.

12. The polymer-prostaglandin conjugate according to claim 11, wherein in the monomers of formula (IV), (Va), and (Vb): Group R 1 R 1' R 2 R 2' R 3 R 3' R 4 and R 4' Independently selected from the group consisting of: hydrogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkoxy-(C1 to C6 alkyl), and wherein R 1 R 1’ and R 2 R 2’ One of the pairs may form a carbon ring or heterocycle having 3 to 6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1 to 3 constituent oxygen heteroatom ring members; and R 3 R 3’ , and R 4 R4 ’ One of the pairs may form a carbon ring or heterocycle with 3-6 constituent ring members between the members of the pair, wherein the heterocycle may contain 1-3 constituent oxygen heteroatom ring members.

13. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein the monomer of formula (Va) or (Vb) is selected from the group consisting of: J 1 Having formula C Z H 2z-1 (Straight or branched), where z is an integer from 1 to 8; and J 2 Having formula C Z H 2z-2 (straight chain or branch chain), where z is an integer from 1 to 8.

14. The polymer-prostaglandin conjugate according to claim 13, wherein z is an integer from 3 to 8.

15. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein the prostaglandin comprises at least one formula selected from the group consisting of: as well as 16. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein the prostaglandin analog has the following formula:

17. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein R is a straight-chain or branched hydrocarbon with 1-12 carbon atoms.

18. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein R 5 Choose from the group consisting of: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

19. The polymer-prostaglandin conjugate according to any one of claims 4-9, wherein R 5 It is either hydrogen or methyl.

20. A monomer-prostaglandin conjugate, formula (IV): in: X can be the same or different each time it appears, and represents a terminal functional group containing alkyne or azide; Q is chosen independently each time it appears and may or may not be present, and when present, it represents the linking group Q in the formula QX, where QX is selected from the following groups: s is an integer from 0 to 10; R is selected from the following groups: straight-chain or branched hydrocarbons; L is a group in the following formula: Where R 5 Selected from hydrogen and C1 to C6 alkyl groups; (R) indicates the end of a group bonded to the R group; and (D) indicates the end of the group attached to group D; D is selected from prostaglandin analogues of formula (Xb). in: Indicates the junction of prostaglandin analogues with L; Indicates a double bond or a single bond; Y is an optional substitution of C4 to C4. 10 Hydrocarbon group or optional substituted C4 to C 10 Hydroxyl groups; R 9 and R 11 It is a hydroxyl group; and W is a hydroxyl group and U is hydrogen, or both W and U are fluorine, or W and U together form an oxo group.

21. The polymer-prostaglandin conjugate according to claim 20, wherein the group Q in formula (IV) is absent.

22. The polymer-prostaglandin analog according to claim 20, wherein s is an integer from 0 to 6.

23. An eye implant comprising a polymer-prostaglandin conjugate according to any one of claims 1-19.

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