Polyoxazoline-drug conjugates with novel pharmacokinetic properties

Abstract

The present disclosure provides polyoxazoline (POZ) conjugates, the conformation of which and the release rate of a drug from the POZ conjugate can be controlled by selecting one or more characteristics of the POZ polymer. Methods for controlling the conformation and release rate of a drug from the POZ conjugate, as well as methods of treatment using such POZ conjugates and methods, are provided. Pharmaceutical compositions containing the POZ conjugates are also provided.

Description

[Background technology]

[0001] The use of polymer conjugates (e.g., polyoxazoline (POZ) conjugates) for drug modification and delivery has attracted increasing research activity in recent years. One aspect of this research involves the attachment of drugs as pendant groups along a polymer backbone, which can be released from the polymer backbone after administration to a subject. The rate at which such drugs are released from the polymer backbone is variable. Applicant has previously demonstrated the slow release of pendant rotigotine from POZ conjugates (attached via a triazole-ester linkage), resulting in a nearly linear pharmacokinetic (PK) profile suitable for once-weekly subcutaneous injection of the POZ-rotigotine conjugate in humans. However, the rate of release of various drugs from POZ polymers has been reported to be variable.

[0002] The ability to control the release rate of a drug from a polymer conjugate is therapeutically useful. For example, slow / sustained release of a drug from a polymer conjugate can reduce local adverse effects, reduce adverse effects associated with peak blood levels, or extend the half-life of the drug. Such sustained release is also associated with the added benefits of convenient dosing, improved compliance, and reduced fluctuations in blood levels during administration. Similarly, fast / immediate release of a drug from a polymer conjugate is useful in achieving high drug concentrations in the body over a short period of time.

[0003] The prior art needs a solution for controlling the release rate of an agent (e.g., a drug) from a POZ conjugate. Additionally, the prior art needs a solution for providing a desired release profile (e.g., a sustained release profile) of an agent from a POZ conjugate. The present disclosure provides a solution to these problems. [Brief explanation of the drawings]

[0004] [Figure 1]1 shows the conformations of selected compounds of the examples. [Figure 2] Figure 1 shows the assigned chemical shifts for the POZ conjugate conformation with rotigotine bound to POZ. Numbers in red italics correspond to 1H and numbers in blue regular font are assigned 13C chemical shifts. [Figure 3] The self-diffusion coefficients of pure POZ (□), POZ-rotigotine (○), and POZ-cholesterol (△) are shown. The dashed line indicates the linearity of POZ diffusion due to occlusion. The inset provides the same data on a linear scale. [Figure 4] 1 shows the hydrolysis rate of POZ-CBD conjugates in human female plasma at 37° C. [Figure 5] Figure 1 shows the pharmacokinetic profile of rotigotine after a single SC injection of the POZ-ROT conjugate at a dose of 1.5 mg / kg in male monkeys. Drug loading is 7.5% (□), 9.7% (△), and 11.8% (○). n=3±SD. [Figure 6] Figure 1 shows the pharmacokinetic profile of cannabidiol following a single SC injection of the POZ-CBD conjugate at a dose of 4.5 mg / kg in male monkeys. Drug loading is 2.8% (○) and 7.1% (□). n=3±SD. [Figure 7] Figure 1 shows the plasma concentrations of POZ cyanine 5 conjugates of different molecular weights after intravenous injection into rats at a dose of 10 mg / kg. The molecular weights tested were 10K (●), 20K (■), 30K (▲), 40K (▼), and 60K (◇). n=3 ± SD. [Figure 8] Figure 1 shows the plasma concentrations of POZ cyanine 5 conjugates of different molecular weights after subcutaneous injection in rats at a dose of 10 mg / kg. The molecular weights tested were 10K (●), 20K (■), 30K (▲), 40K (▼), and 60K (◇). n=3±SD. [Figure 9]Figure 1 shows the pharmacokinetic profile of rotigotine after a single SC injection of rotigotine and POZ-ROT conjugates in male rats: rotigotine, 0.5 mg / kg dose (□), acetate linker, 10.9% loading, 1.6 mg / kg dose (△), and 3-propionate linker, 13.3% loading, 1.6 mg / kg dose (▽). n=3 ± SD. [Figure 10] Figure 1 shows the pharmacokinetic profile of buprenorphine after a single SC injection of POZ-BUP conjugates in male monkeys: 2-propionate linker, 11.2% drug loading, 1.5 mg / kg dose (△) and 3-propionate linker, 13.3% drug loading, 1.5 mg / kg dose (▽). n=3 ± SD. Summary of the Invention [Problem to be solved by the invention]

[0005] (Summary of the Invention) The present disclosure provides POZ conjugates that modulate the conformation of the POZ conjugate. Accordingly, the present disclosure provides POZ conjugates and methods for controlling the conformation of the POZ conjugates. Additionally, the present disclosure provides POZ conjugates and methods for modulating the release of drugs from the POZ conjugates. Additionally, the present disclosure provides POZ conjugates and methods that allow for selection of the release profile of drugs from the POZ conjugates. Additionally, the present disclosure provides compositions, including pharmaceutical compositions, comprising such POZ polymer conjugates. Methods of treatment using the described POZ conjugates, methods, and pharmaceutical compositions are also provided. [Means for solving the problem]

[0006] In a general form, a POZ conjugate of the present disclosure comprises a POZ polymer moiety and a drug. The drug is attached to the POZ polymer by a physiologically degradable linkage (i.e., a linkage between the drug and the POZ polymer). Cleavage of the physiologically degradable linker can be controlled by altering the conformation of the POZ conjugate to increase or decrease the accessibility of a cleavage function (e.g., an enzyme) to the physiologically degradable linker.

[0007] The conformation of the POZ conjugate can be controlled in several ways, as described herein, For example, the conformation of the POZ conjugate can be controlled through selection of the characteristics of the POZ polymer, through selection of the characteristics of the drug, through selection of the loading characteristics, or through a combination of the foregoing. DETAILED DESCRIPTION OF THE INVENTION

[0008] Introduction The POZ conjugates of the present disclosure comprise a POZ polymer moiety and a drug. The drug is attached to the POZ polymer via a physiologically degradable linkage. Cleavage of the physiologically degradable linker can be controlled by modifying the conformation of the POZ conjugate to increase or decrease the accessibility of the cleavage function to the physiologically degradable linker.

[0009] The factors that control the release rate of a drug from a POZ conjugate are not fully understood. In previous studies, Applicants have shown that the manner in which a drug is attached to the POZ polymer portion of a POZ conjugate can affect the release rate of the drug from the POZ conjugate. Specifically, when rotigotine (i.e., the drug) is attached at a pendant position along the polymer backbone of a 20K POZ polymer via a degradable triazine-alkyl ester linkage (i.e., a physiologically degradable linkage), the hydrolysis rate varies depending on the structure of the linkage (see Structure 1 below). * is H and R **is -CH2CH3, a is random, n is typically 190, o is typically 10, and p can be varied to vary the rate of hydrolysis).

[0010] [ka]

[0011] Upon further investigation of the observed differences in drug release rates, applicants unexpectedly discovered that the conformation of the POZ conjugate affects the release rate of the drug from the POZ conjugate.

[0012] Without being bound by any particular theory, it is believed that the water-soluble POZ polymer portion of the POZ conjugate is loosely folded around the drug, forming a shell around the drug. The surrounding POZ polymer shell is flexible and mobile, and can hinder, but not block, the access of the necessary cleavage function (e.g., enzymes, e.g., esterases) to the physiologically degradable linker. This obstruction of access to the cleavage function delays the cleavage of the physiologically degradable linker, and therefore delays the release rate of the drug from the POZ conjugate. When the POZ polymer shell surrounds the drug, the POZ conjugate is in a compact higher-order structure.

[0013] The flexibility and mobility of the POZ polymer shell depends, at least in part, on one or more characteristics of the POZ conjugate. Thus, the release rate of a drug from a POZ conjugate can be controlled by selecting one or more characteristics of the POZ conjugate. Such characteristics include, but are not limited to, POZ polymer characteristics, drug characteristics, loading characteristics, or a combination of the foregoing.

[0014] In one embodiment, the characteristics of the drug (i.e., the nature of the drug) affect the release rate of the drug from the POZ conjugate. Consider two POZ conjugates of Structure 1 above. In the first POZ conjugate, R *is H and R ** is -CH2CH3, a is random, n is 190, o is 10, p is 3, and the drug has a LogP of 7.0. For the second POZ conjugate, the values ​​are the same except that the drug has a LogP of 2.5 (less hydrophobic). For the first POZ conjugate, the hydrophilic POZ polymer portion interacts with more of the hydrophobic drug, so the POZ polymer shell is less flexible and mobile (i.e., more tightly wrapped around the drug and / or core) than for the second POZ conjugate. In this situation, the POZ polymer shell of the first POZ conjugate restricts the access of the cleavage function to the physiologically degradable linker to a greater extent than for the second POZ conjugate, and the release rate of the drug from the first POZ conjugate is slower than that from the second POZ conjugate.

[0015] In another embodiment, the characteristics of the POZ polymer (i.e., the size of the POZ polymer moiety) affect the release rate of the drug from the POZ conjugate. Consider two POZ conjugates of Structure 1. In the first POZ conjugate, R * is H and R ** is -CH2CH3, a is random, n is 390, o is 10, p is 3, and the drug has a LogP of 6.1. In the second POZ conjugate, the values ​​are the same except for n, which is 190 for the second POZ conjugate. In the first POZ conjugate, because the first POZ conjugate has a higher molecular weight, the POZ polymer shell is less flexible and mobile and / or more completely surrounds the drug and / or core compared to the second POZ conjugate. In this situation, the POZ polymer shell of the first POZ conjugate restricts access of the cleavage function to the physiologically degradable linker to a greater extent than in the second POZ conjugate, and the release rate of the drug from the first POZ conjugate is slower than the release rate of the drug from the second POZ conjugate.

[0016] In another embodiment, the loading characteristics (i.e., percentage of loading) affect the release rate of the drug from the POZ conjugate. Consider two POZ conjugates of Structure 1. In the first POZ conjugate, R * is H and R ** is -CH2CH3, a is random, n is 190, o is 15, p is 3, and the drug has a LogP of 4.9. In the second POZ conjugate, the values ​​are the same except for o, which is 5. In the first POZ conjugate, a greater number of drugs are available to interact with the POZ polymer to form a shell, and therefore the POZ polymer shell is less flexible and mobile (i.e., more tightly wrapped around the drug and / or core) than in the second POZ conjugate. In this situation, the POZ polymer shell of the first POZ conjugate limits the access of the cleavage function to the physiologically degradable linker to a greater extent than in the second POZ conjugate, and the release rate of the drug from the first POZ conjugate is slower than the release rate of the drug from the second POZ conjugate. In certain embodiments, agents with more hydrophobic character have a greater impact on the percentage of loading that stimulates the formation of compact conformations.

[0017] In another embodiment, the characteristics of different POZ polymers (i.e., the nature of the pendant groups on the POZ polymer portion of the POZ conjugate) affect the release rate of the drug from the POZ conjugate. Consider two POZ conjugates of Structure 1. In the first POZ conjugate, R * is H and R ** is -CH2CH3, a is random, n is 190, o is 6, p is 3, and the drug has a LogP of 6.1. In the second POZ conjugate, R * is H and R **is 70% -CH2CH3 and 30% -CH3, a is random, n is 190, o is 6, p is 3, and the drug has a LogP of 6.1. The second POZ conjugate contains 30% -CH3 groups and is less hydrophobic than the -CH2CH3 groups on the first POZ conjugate. Due to the more hydrophobic nature of the POZ polymer portion in the first POZ conjugate, the POZ polymer shell is less flexible and mobile (i.e., more tightly wrapped around the drug and / or core) compared to the second POZ conjugate. In this situation, the POZ polymer shell of the first POZ conjugate restricts access of the cleavage function to the physiologically degradable linker to a greater extent than the second POZ conjugate, and the release rate of the drug from the first POZ conjugate is slower than the release rate of the drug from the second POZ conjugate.

[0018] In another embodiment, different POZ polymer characteristics (i.e., the presence of hydrophilic or hydrophobic pendant moieties on the POZ polymer portion of the POZ conjugate) affect the release rate of the drug from the POZ conjugate. Consider two POZ conjugates: a first POZ conjugate having Structure 1 and a second POZ conjugate having Structure 2 below. In the first POZ conjugate, R * is H and R ** is -CH2CH3, a is random, n is 190, o is 6, p is 3, and the drug has a LogP of 6.1. In the second POZ conjugate (structure 2), R * is H and R ** is -CH2CH3, and R ***is a linked propionic acid, a is random, n is 190, o is 6, m is 4, and the drug has a LogP of 6.1. The second POZ conjugate contains four propionic acid pendant moieties (hydrophilic, at least in part, due to C-O bonds) in addition to the 190 -CH2CH3 pendant groups present on the first POZ conjugate. Without being bound by any particular theory, the four pendant hydrophilic moieties attract water to the region near the backbone (core) of the POZ polymer moiety, preventing the POZ polymer shell from surrounding the drug and / or core to the same extent as it would if the hydrophilic pendant moieties were not present (thus making the POZ polymer shell more flexible and mobile within the second POZ conjugate). In this situation, the POZ polymer shell of the first POZ conjugate restricts the access of the cleavage function to the physiologically degradable linker to a greater extent than in the second POZ conjugate, and the release rate of the drug from the first POZ conjugate is slower than the release rate of the drug from the second POZ conjugate.

[0019] [ka]

[0020] Therefore, the conformation of a POZ conjugate is a factor that affects the conformation and / or the release rate of a drug from the POZ conjugate. The release rate of a drug from a POZ conjugate can be adjusted by modifying the conformation of the POZ conjugate. For example, when the compact conformation of a POZ conjugate is inhibited, the release rate of a drug from the POZ conjugate increases (compared to a POZ conjugate whose compact conformation is not inhibited). Conversely, when the compact conformation of a POZ conjugate is stimulated, the release rate of a drug from the POZ conjugate decreases (compared to a POZ conjugate whose compact conformation is not stimulated).

[0021] The present disclosure provides POZ conjugates and methods for controlling the conformation of a POZ conjugate by adjusting the characteristics of the POZ conjugate. The present disclosure further provides POZ conjugates and methods for adjusting the release of a drug from a POZ conjugate by adjusting the characteristics of the POZ conjugate. The present disclosure also provides POZ conjugates and methods for adjusting (i.e., selecting or fine-tuning) the release rate (i.e., release profile) of a drug from a POZ conjugate by adjusting the characteristics of the POZ conjugate. In certain embodiments of the methods, the release rate / release profile of the drug can be selected. The present disclosure also provides POZ conjugates and methods for selecting the release profile of a drug from a POZ conjugate by adjusting the characteristics of the POZ conjugate. Still further, the present disclosure provides compositions, including pharmaceutical compositions, comprising such POZ polymer conjugates. Methods of treatment using the described POZ conjugates, methods, and pharmaceutical compositions are also provided.

[0022] definition All patent applications, patents, and printed publications cited herein are incorporated by reference in their entirety, except for any definitions, disclaimers or disclaimers of subject matter, and except to the extent that the incorporated material conflicts with the express disclosure herein, in the event of a conflict, the language of the present disclosure shall control.

[0023] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0024] As used herein, the terms "active" or "activated," when used in conjunction with a particular functional group, refer to a functional group that readily reacts with an electrophile or nucleophile on another molecule. This is in contrast to those groups that require a catalyst or impractical reaction conditions in order to react (i.e., "nonreactive" or "inert" groups).

[0025] As used herein, the term "agent" refers to any molecule having therapeutic or diagnostic utility, which agent can be attached to a group on a POZ polymer or to a linking group attached to a POZ polymer. Agents include, but are not limited to, therapeutic agents (e.g., but are not limited to, drugs), diagnostic agents, and small organic molecules. In certain embodiments, the agent is hydrophobic or does not dissolve in water (e.g., a hydrophobic drug). In certain embodiments, the agent has a logP value of ≧0.5 or ≧2.0.

[0026] As used herein, the terms "physiologically degradable" or "physiologically releasable" refer to a linkage that contains a cleavable moiety. The terms degradable and releasable do not imply any particular mechanism by which the linker is cleaved.

[0027] As used herein, the term "cleavable moiety" refers to a group that is cleavable in vivo within a subject under physiological conditions in the subject (e.g., after a POZ conjugate of the present disclosure is administered to the subject). In one embodiment, the cleavable moiety is cleaved by a chemical reaction. In an aspect of this embodiment, cleavage occurs by reduction of an easily reduced group in the cleavable moiety, such as, but not limited to, a disulfide. In another aspect of this embodiment, the cleavable moiety is cleaved via hydrolysis (i.e., reaction with water). In one embodiment, the cleavable moiety is cleaved by a substance that is naturally present or induced to be present in the subject. In one aspect of this embodiment, such a substance is an enzyme or polypeptide. Thus, in one embodiment, the cleavable moiety is cleaved by an enzymatic reaction. In one embodiment, the cleavable moiety is cleaved by a combination of the foregoing.

[0028] As used herein, the terms "electrophile" and "electrophilic group" refer to an ion, atom, or collection of atoms, which may be ionic, having an electrophilic center, i.e., a center that is electron-seeking and capable of reacting with a nucleophile.

[0029] As used herein, the phrase "inhibits the formation of compact higher-order structures," when referring to a POZ conjugate, does not mean that the water-soluble POZ polymer portion of the POZ conjugate is completely prevented from folding around the drug and / or core, but rather that the water-soluble POZ polymer portion of the POZ conjugate folds to a lesser extent (i.e., forms a looser shell) around the drug and / or core, for example, compared to a reference POZ conjugate or a POZ conjugate containing a different modification (e.g., a less hydrophobic pendant moiety).

[0030] As used herein, the terms "bond," "bonded," "linked," or "linker," when used in reference to a POZ polymer, POZ conjugate, agent, or compound described herein, or a component thereof, refer to a bond that is usually formed as a result of a chemical reaction and is usually a covalent bond.

[0031] As used herein, the term "hydrophilic" refers to a compound or molecule, or portion thereof, whose interaction with water is thermodynamically more favorable than its interaction with oil or other hydrophobic solvents, e.g., with reference to a hydrophilic moiety. A hydrophilic compound can be dissolved or dispersed in water. Typically, a hydrophilic compound contains one or more oxygen, nitrogen, sulfur, and / or phosphorus atoms and / or one or more polar covalent bonds (e.g., but not limited to, C=O, CN, C=N, OH, and / or C-halogen bonds). Such polar covalent bonds may be arranged asymmetrically.

[0032] As used herein, the term "hydrophobic" refers to a compound or molecule, or portion thereof, whose interaction with water is thermodynamically less favorable than its interaction with oil or other hydrophobic solvent, e.g., with reference to a hydrophobic moiety. A hydrophobic compound can be dissolved or dispersed in oil or other hydrophobic solvent.

[0033] As used herein, the terms "inert" or "non-reactive," when used in conjunction with a particular functional group, refer to a functional group that does not readily react with an electrophile or nucleophile on another molecule, requiring a catalyst or impractical reaction conditions in order to react.

[0034] As used herein, the terms "nucleophile" and "nucleophilic group" refer to an ion, atom, or collection of atoms, which may be ionic, that has a nucleophilic center, i.e., a center capable of donating electrons and reacting with an electrophile.

[0035] As used herein, the term "pendant group" refers to a portion of a POZ polymer moiety formed during polymerization of the POZ polymer moiety. A pendant group is exemplified by X in Formula I described herein.

[0036] As used herein, the term "pendant moiety" refers to a substituent that is attached to a POZ polymer moiety via a linking group. A pendant moiety is exemplified by R1 in Formula I described herein.

[0037] As used herein, the term "pharmaceutically acceptable" refers to a compound that is compatible with the other ingredients of a composition and not harmful to the subject receiving the compound or composition. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal regulatory agency or a state government, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia, for use in animals, and more particularly, in humans.

[0038] As used herein, the term "pharmaceutically acceptable form" is intended to include known forms of a compound or POZ conjugate that may be administered to a subject, including, but not limited to, solvates, hydrates, prodrugs, isomorphs, polymorphs, pseudomorphs, neutral forms, and salt forms of the compound. In certain embodiments, pharmaceutically acceptable forms exclude prodrugs, isomorphs, and / or pseudomorphs. In certain embodiments, pharmaceutically acceptable forms are limited to pharmaceutically acceptable salts, neutral forms, solvates, and hydrates. In certain embodiments, pharmaceutically acceptable forms are limited to pharmaceutically acceptable salts and neutral forms. In certain embodiments, pharmaceutically acceptable forms are limited to pharmaceutically acceptable salts.

[0039] As used herein, the term "polar covalent bond" is a covalent bond in which one of the atoms has a higher affinity for electrons (ie, is more electronegative) than the other atom.

[0040] As used herein, the term "reference POZ conjugate" refers to a POZ conjugate that has not been modified to inhibit or stimulate compact structure formation (i.e., by altering the POZ polymer characteristics, drug characteristics, and / or loading characteristics) and that is identical or similar in all other respects to the POZ polymer of the present disclosure to which it is being compared (the "comparative POZ conjugate"). In one embodiment, the reference POZ conjugate is a POZ conjugate having a structure similar to that of the presently disclosed comparative POZ polymer (the "comparative POZ conjugate"). * is H and R ** is -CH2CH3, a is random, n is 190, o is 3-5, and p is the same between the reference POZ conjugate and the comparative POZ conjugate. * In another embodiment, the reference POZ conjugate is a conjugate of Structure 1 above, in which R, a, n, p, o, and the drug are each selected to be the same on the reference POZ conjugate and the comparative POZ conjugate. *In another embodiment, the reference POZ conjugate is a conjugate of Structure 1 above, in which the a, p, o, and drug are selected to be the same on the reference POZ conjugate and the comparative POZ conjugate, respectively. * In another embodiment, the reference POZ conjugate is a conjugate of Structure 1 above, in which R, a, n, p, and the drug are each selected to be the same on the reference POZ conjugate and the comparative POZ conjugate. * In another embodiment, the reference POZ conjugate is a conjugate of Structure 1 above, where a, n, o, and p are each selected to be the same on the reference POZ conjugate and the comparative POZ conjugate. * , a, n, p, and the drug are selected to be the same on the reference POZ conjugate and the comparative POZ conjugate, respectively, as shown in Structure 2 above.

[0041] As used herein, the term "substantially all," when used herein in reference to a period of time, means 80% or more of that period, for example, 90% or 95% of that period.

[0042] As used herein, the phrase "stimulates the formation of compact higher-order structures," when referring to a POZ conjugate, does not mean that the water-soluble POZ polymer portion of the POZ conjugate is completely folded around the drug and / or core, but rather that the water-soluble POZ polymer portion of the POZ conjugate is folded to a greater extent around the drug and / or core (i.e., forms a more rigid shell), for example, compared to a reference POZ conjugate or a POZ conjugate containing a different modification (e.g., a more hydrophilic pendant moiety).

[0043] As used herein, the term "sustained release profile," when used in connection with a POZ conjugate of the present disclosure, means that the drug is released from the POZ conjugate such that the drug concentration in the body (e.g., plasma concentration) is maintained at a higher level for a period of 12 hours to 4 weeks.

[0044] As used herein, the term "water-soluble" refers to a water-soluble polymer that is soluble in water at room temperature. Typically, a water-soluble polymer transmits at least about 75%, more preferably at least about 95%, of the light transmitted by the same solution after filtration. On a weight basis, the water-soluble polymer is preferably at least about 35% (by weight) water-soluble, more preferably at least about 50% (by weight) water-soluble, even more preferably about 70% (by weight) water-soluble, and even more preferably about 85% (by weight) water-soluble. However, it is most preferred that the water-soluble polymer is about 95% (by weight) water-soluble or completely water-soluble.

[0045] As used herein, the term "water soluble" refers to a water soluble drug and refers to a drug having a logP value equal to or >0.5.

[0046] As used herein, the term "alkyl," whether used alone or as part of a substituent, is a term of art and refers to a saturated aliphatic group that optionally contains one or more heteroatoms (e.g., O, S, or N), which may be optionally substituted, and includes straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C6 for a straight chain). 30 , C3~C for branched chains 30 ), alternatively having about 20 or less, or 10 or less. In certain embodiments, the term "alkyl" refers to a C1-C 10refers to a straight chain alkyl group or a C1-C3 straight chain alkyl group. In certain embodiments, the term "alkyl" refers to a C3-C 12 It refers to a branched alkyl group. In certain embodiments, the term "alkyl" refers to a C3 to C8 branched alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. In certain embodiments, the term "alkyl" refers to a C1 to C8 branched alkyl group containing one or more heteroatoms (e.g., O, S, or N) in place of a carbon atom. 10 "alkyl" refers to a straight chain alkyl group, the heteroatoms of which may be optionally substituted. In certain embodiments, the term "alkyl" refers to a C1-C2 alkyl group substituted with up to five groups selected from the group consisting of OH, NH2, and =O. 10 Refers to a straight chain alkyl group.

[0047] As used herein, the term "alkenyl," whether used alone or as part of a substituent, is a term of art and refers to an unsaturated aliphatic group optionally containing one or more heteroatoms (e.g., O, S, or N), which may be optionally substituted, including straight- or branched-chain hydrocarbon groups containing 2 to 30 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The unsaturated bond(s) in an alkenyl group can be located anywhere in the moiety and can have either the (Z) or (E) configuration around the double bond(s).

[0048] As used herein, the term "alkynyl," whether used alone or as part of a substituent, is a term of art that refers to an unsaturated aliphatic group that optionally contains one or more heteroatoms (e.g., O, S, or N) that may be optionally substituted, including straight- or branched-chain hydrocarbon groups containing 2 to 30 carbon atoms and at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, and 1-butynyl.

[0049] As used herein, the terms "substituted alkyl," "substituted alkenyl," and "substituted alkynyl" refer to alkyl, alkenyl, and alkynyl groups as defined above in which one or more bonds to a carbon(s) or hydrogen(s) have been replaced by a bond to a non-hydrogen or non-carbon atom, for example, but not limited to, halogen atoms in halides such as F, Cl, Br, and I; oxygen atoms in groups such as carbonyl, carboxyl, hydroxyl groups, alkoxy groups, aryloxy groups, heterocyclyloxy groups, and ester groups; thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfur groups, and the like. The terms "polar alkyl," "polar alkenyl," and "polar alkynyl" refer to alkyl, alkenyl, and alkynyl groups substituted with an atom resulting in a polar covalent bond. In another specific embodiment, "polar alkyl," "polar alkenyl," and "polar alkynyl" refer to C1-C5 alkyl, alkenyl, and alkynyl groups substituted with an atom resulting in a polar covalent bond. In certain embodiments, "polar alkyl," "polar alkenyl," and "polar alkynyl" refer to alkyl, alkenyl, and alkynyl groups, such as C1-C5 alkyl, alkenyl, and alkynyl groups substituted with -OH and / or -C(O)-OH groups.

[0050] As used herein, the terms "halo" or "halogen," whether used alone or as part of a substituent, are terms of art and refer to -F, -Cl, -Br, or -I.

[0051] The term "alkoxy," as used herein, whether used alone or as part of a substituent group, is a term of art and refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0052] As used herein, the terms "aralkyl" or "arylalkyl," whether used alone or as part of a substituent, are terms of art that refer to an alkyl group substituted with an aryl group, where the aryl group portion is attached to the parent molecule via the alkyl group. The arylalkyl group may be optionally substituted. "Substituted aralkyl" has the same meaning with respect to unsubstituted aralkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups. However, substituted aralkyl groups also include groups in which a carbon or hydrogen bond in the alkyl portion of the group is replaced with a bond to a non-carbon or non-hydrogen atom.

[0053] As used herein, the terms "heteroaralkyl" or "heteroarylalkyl," whether used alone or as part of a substituent group, are terms of art and refer to an alkyl group substituted with a heteroaryl group, where the heteroaryl group is attached to the parent molecular moiety through the alkyl group. The heteroarylalkyl can be optionally substituted. The term "substituted heteroarylalkyl" has the same meaning with respect to unsubstituted heteroarylalkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups.

[0054] As used herein, the term "heterocyclylalkyl," whether used alone or as part of a substituent, is a term of art and refers to an unsubstituted or substituted alkyl, alkenyl, or alkynyl group in which a hydrogen or carbon bond of the unsubstituted or substituted alkyl, alkenyl, or alkynyl group is replaced with a bond to a heterocyclyl group. A heterocyclylalkyl may be optionally substituted. The term "substituted heterocyclylalkyl" has the same meaning with respect to unsubstituted heterocyclylalkyl groups that substituted aryl groups have with respect to unsubstituted aryl groups. However, substituted heterocyclylalkyl groups also include groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of a heterocyclylalkyl group, such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group.

[0055] As used herein, the term "aryl," whether used alone or as part of a substituent, is a term of art and refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), where at least one of the rings is, for example, an aromatic hydrocarbon, and the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In certain embodiments, the term "aryl" refers to a phenyl group. Aryl groups can be optionally substituted.

[0056] As used herein, the term "cycloalkyl," whether used alone or as part of a substituent, is a term of art and refers to a saturated carbocyclic group containing from 3 to 6 ring carbon atoms, such ring being optionally substituted with a substituted or unsubstituted alkyl group or the substituents described for a substituted alkyl group. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, and 4-ethylcyclohexyl.

[0057] As used herein, the term "heteroaryl," whether used alone or as part of a substituent group, is a term of art that refers to monocyclic, bicyclic, and polycyclic aromatic groups having 3 to 30 total atoms, including one or more heteroatoms, e.g., nitrogen, oxygen, or sulfur, within the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl, or tropanyl, and the like. A "heteroaryl" may be optionally substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, etc. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings"), and at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0058] As used herein, the term "heterocyclyl," whether used alone or as part of a substituent, is a term of art that refers to groups of non-aromatic ring systems, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be fully saturated or contain one or more units of unsaturation, provided that the degree of unsaturation does not result in an aromatic ring system, and have 3 to 15 atoms, including at least one heteroatom, e.g., nitrogen, oxygen, or sulfur. For illustrative purposes, the following are examples of heterocyclic rings, which should not be construed as limiting the scope of the present invention: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, dioxolanyl, oxazolyl, thiazolyl, Triazinyl, isothiazolyl, isoxazolyl, azepine, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.Heterocyclyl groups may be optionally substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like.

[0059] As used herein, the terms "treatment," "treat," and "treating" refer to a course of action (e.g., administering a conjugate described herein or a pharmaceutical composition comprising a conjugate described herein) to prevent, eliminate, or reduce symptoms, aspects, or features of a disease or condition. Taking such a treatment need not be absolutely beneficial. In one embodiment, treatment includes a course of action initiated concurrently with or subsequent to the onset of symptoms, aspects, or features of a disease or condition. In another embodiment, treatment includes a course of action initiated prior to the onset of symptoms, aspects, or features of a disease or condition.

[0060] As used herein, the term "in need of treatment" refers to a determination made by a caregiver that a patient requires or would benefit from treatment. This determination is made based on a variety of factors within the caregiver's realm of expertise, including knowledge that the patient is ill or will be ill as a result of a disease or condition treatable with the methods or compounds of the present disclosure.

[0061] As used herein, the terms "individual," "subject," or "patient" refer to any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans. The terms may specify male or female, or both, or may exclude male or female. In preferred embodiments, the terms "individual," "subject," or "patient" refer to humans.

[0062] As used herein, the term "therapeutically effective amount" refers to an amount of a conjugate, alone or as part of a pharmaceutical composition, that is capable of having any detectable positive effect on any symptom, aspect, or characteristic of a disease or condition. Such effect need not be absolutely beneficial.

[0063] Certain compounds contained in the POZ conjugates of the present disclosure may exist in specific geometric or stereoisomeric forms. In addition, compounds contained in the POZ conjugates of the present disclosure may also be optically active. The present disclosure contemplates that all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0064] For example, if a specific enantiomer of a compound is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting mixture of diastereomers separated, and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the formed diastereomers by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomer.

[0065] It is to be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is consistent with the allowed valence of the substituted atom and substituent, and that the substitution results in a stable compound that is not spontaneously transformed, for example, by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0066] When a group is specified as part of a compound, it is understood that the substitution of the group can be adjusted to accommodate specific bonds. For example, when an alkyl group is linked to two other groups, the alkyl group is considered an alkylene group.

[0067] The term "substituted" is also intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclyl, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. For purposes of this disclosure, heteroatoms, such as oxygen or nitrogen, may have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Illustrative substitutions include, but are not limited to, hydroxy, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0068] Other chemical terms herein are used in accordance with conventional usage in the art as exemplified in The McGraw-Hill Dictionary of Chemical Terms (Parker, S., ed., 1985), McGraw-Hill, San Francisco, incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0069] The term "pharmaceutically acceptable salt," as used herein, includes salts derived from inorganic or organic acids, including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. Pharmaceutically acceptable salt forms can include forms in which the ratio of salt-containing molecules is not 1:1. For example, a salt may contain more than one inorganic or organic acid molecule per base molecule, e.g., two hydrochloric acid molecules per conjugate molecule. As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, e.g., two conjugate molecules per inorganic or organic acid molecule.

[0070] The terms "carrier" and "pharmaceutically acceptable carrier" as used herein refer to a diluent, adjuvant, excipient, or vehicle administered with or formulated for administration of a compound. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary substances, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents can be used. Other examples of suitable pharmaceutical carriers are described in Remington's Science and Practice of Pharmacy (23rd Edition, ISBN9780128200070) and Handbook of Pharmaceutical Excipients (8th Edition, 978-0-85-711271-2), each of which is incorporated herein by reference in its entirety.

[0071] Compositions and methods for controlling the higher-order structure of POZ conjugates and adjusting the release rate of drugs from POZ conjugates The present disclosure provides methods for controlling the conformation of a POZ conjugate, the cleavage of a drug from the POZ conjugate, the release rate of a drug from the POZ conjugate, the selection of a release profile of a drug from the POZ conjugate, or a combination of the foregoing. In a general embodiment, such methods include providing a POZ conjugate, or a pharmaceutically acceptable form thereof, comprising a water-soluble POZ polymer and a drug attached to the water-soluble POZ polymer by a physiologically degradable linkage, wherein the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of a release profile of the drug from the POZ conjugate are controlled by selecting a characteristic of the POZ polymer, a characteristic of the drug, a loading characteristic, or a combination of the foregoing.

[0072] In one embodiment, the method of controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate comprises selecting characteristics of the POZ conjugate to either stimulate the formation of a compact conformation of the POZ conjugate (i.e., reduce the release rate of the drug from the POZ conjugate) or inhibit the formation of a compact conformation of the POZ conjugate (i.e., increase the release rate of the drug from the POZ conjugate). Thus, the release rate of a drug from a POZ conjugate can be controlled by selecting one or more characteristics of the POZ conjugate. Such characteristics include, but are not limited to, characteristics of the POZ polymer, characteristics of the drug, and loading characteristics.

[0073] In one embodiment, a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting the release profile of a drug from a POZ conjugate comprises selecting characteristics of the POZ polymer to inhibit or stimulate the formation of a compact conformation of the POZ conjugate. Suitable POZ polymer characteristics include, but are not limited to, the presence of hydrophilic or hydrophobic pendant moieties on the POZ polymer moiety, the hydrophobic nature of the pendant groups on the POZ polymer moiety (particularly when the POZ polymer moiety lacks hydrophilic or hydrophobic pendant moieties), and the molecular weight of the POZ polymer.

[0074] In one aspect of this embodiment, the method includes including one or more hydrophilic pendant moieties on the POZ polymer portion. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate, the method comprising including hydrophilic pendant groups on the POZ polymer portion of the POZ conjugate. As discussed above, when the POZ polymer portion contains hydrophilic pendant groups, the formation of a compact conformation of the POZ conjugate is inhibited (compared to a reference POZ conjugate lacking hydrophilic pendant moieties). Without being bound by any particular theory, the inclusion of one or more hydrophilic pendant groups inhibits the POZ polymer portion from interacting with the attached drug and / or core, thereby inhibiting the formation of a compact conformation of the POZ conjugate. Furthermore, modifying the number of hydrophilic pendant groups allows for control of the degree to which the formation of a compact conformation of the POZ conjugate is inhibited.

[0075] POZ conjugates containing hydrophilic pendant groups exhibited increased (shorter t) release rates of the drug compared to the base POZ conjugates that did not contain such modifications. 1 / 2 ) shows the release rate of a drug from a POZ conjugate. Thus, the present disclosure provides a method for inhibiting the formation of a compact conformation in a POZ conjugate, the method comprising including a hydrophilic pendant group on the POZ polymer portion of the POZ conjugate. Further, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising including a hydrophilic pendant group on the POZ polymer portion of the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 The present invention provides a method for selecting a release profile having a formula comprising including a hydrophilic pendant group on the POZ polymer portion of the POZ conjugate.

[0076] In another aspect of this embodiment, the method includes including a hydrophobic pendant group on the POZ polymer portion of the POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from the POZ conjugate, controlling the release of a drug from the POZ, and / or selecting the release profile of a drug from a POZ conjugate, the method including including a hydrophobic pendant group on the POZ polymer portion of the POZ conjugate. Without being bound by any particular theory, the inclusion of one or more hydrophobic pendant groups stimulates the POZ polymer portion to interact with the bound drug and / or core, thereby stimulating the formation of a compact conformation of the POZ conjugate (compared to a reference POZ conjugate that does not contain hydrophobic pendants). Furthermore, modifying the number of hydrophobic pendant groups allows for control of the degree to which compact conformation formation is stimulated.

[0077] POZ conjugates containing hydrophobic pendant groups exhibited a reduced (longer t) release rate of the drug compared to that from the reference POZ conjugate that did not contain such modifications. 1 / 2 ) shows the release rate of a drug from a POZ conjugate. Thus, the present disclosure provides a method of stimulating the formation of a compact conformation of a POZ conjugate, the method comprising including a hydrophobic pendant group on the POZ polymer portion of the POZ conjugate. Additionally, the present disclosure provides a method of decreasing the release rate of a drug from a POZ conjugate, the method comprising including a hydrophobic pendant group on the POZ polymer portion of the POZ conjugate. Still further, the present disclosure provides a method of decreasing the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for selecting a release profile having:

[0078] In another aspect of this embodiment, the method comprises eliminating hydrophobic pendant groups on the POZ polymer portion of the POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from the POZ, and / or selecting the release profile of a drug from a POZ conjugate, the method comprising eliminating hydrophobic pendant groups on the POZ polymer portion of the POZ conjugate. When the POZ polymer portion does not contain hydrophobic pendant groups, the formation of a compact conformation of the POZ conjugate is not stimulated (compared to a reference POZ conjugate containing hydrophobic pendant groups).

[0079] Thus, the POZ conjugates lacking hydrophobic pendant groups exhibited an increased drug release rate (shorter t) compared to that from the reference POZ conjugate containing hydrophobic pendants. 1 / 2 ) shows the release rate of a drug from a POZ conjugate. Thus, the present disclosure provides a method for inhibiting the formation of a compact conformation of a POZ conjugate, the method comprising eliminating hydrophobic pendant groups on the POZ polymer portion of the POZ conjugate. Further, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising eliminating hydrophobic pendant groups on the POZ polymer portion of the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 The present invention provides a method for a release profile having a formula comprising eliminating the hydrophobic pendant groups of the POZ polymer portion of the POZ conjugate.

[0080] In another aspect of this embodiment, the method comprises eliminating hydrophilic pendant groups from the POZ polymer portion of the POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate, comprising eliminating hydrophilic pendant groups from the POZ polymer portion of the POZ conjugate. When the POZ polymer portion does not contain hydrophilic pendant groups, the formation of a compact conformation of the POZ conjugate is not inhibited (compared to a reference polypeptide containing hydrophilic pendant groups).

[0081] Thus, the POZ conjugates lacking hydrophilic pendant groups exhibited a reduced (longer t) release rate of the drug compared to the reference POZ conjugate containing hydrophilic pendants. 1 / 2 ) shows the release rate of a drug from a POZ conjugate. Thus, the present disclosure provides a method of stimulating the formation of a compact conformation of a POZ conjugate, the method comprising eliminating hydrophilic pendant groups on the POZ polymer portion of the POZ conjugate. Further, the present disclosure provides a method of increasing the release rate of a drug from a POZ conjugate, the method comprising eliminating hydrophilic pendant groups on the POZ polymer portion of the POZ conjugate. Still further, the present disclosure provides a method of improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for producing a release profile having the formula:

[0082] In the foregoing discussion, the effect of hydrophilic and hydrophobic pendant moieties on a POZ polymer portion is determined relative to a POZ conjugate with substantially the same properties except for the presence / absence of the pendant moiety (e.g., when determining the effect of a hydrophilic pendant moiety on a POZ-CBD conjugate, the effect of the hydrophilic pendant moiety is determined relative to a POZ-CBD conjugate with the same structure and substantially the same properties, e.g., loading percentage and molecular weight, except for the absence of the hydrophilic pendant moiety). In one embodiment, the effect of adding or removing a hydrophilic or hydrophobic pendant moiety is specific to a particular POZ conjugate, and the effect of adding or removing a hydrophilic or hydrophobic pendant moiety may differ qualitatively or quantitatively for another POZ conjugate. Furthermore, in another embodiment, the effect of adding or removing a hydrophilic or hydrophobic pendant moiety may also be affected by other POZ conjugate characteristics, such as those discussed herein, including, but not limited to, the nature of the drug. For example, a drug that generally exhibits low water solubility (e.g., a drug with a LogP value of 6.1) will exhibit greater interaction with the POZ polymer moiety, stimulate the formation of compact conformations, and / or exhibit a reduced release rate compared to a drug in the same POZ conjugate with a lower LogP (e.g., a LogP value of 4.8), despite the presence of hydrophilic pendant moieties.

[0083] In another aspect of this embodiment, the method includes controlling the molecular weight of the POZ polymer portion of the POZ conjugate. Generally, as the molecular weight of the POZ polymer portion increases, the formation of a compact higher-order structure of the POZ conjugate is stimulated and the release rate of the drug from the POZ conjugate decreases (longer t 1 / 2) (each of the foregoing compared to a reference POZ conjugate having a lower molecular weight POZ polymer portion). In one embodiment, a method for controlling the conformation of a POZ conjugate, controlling cleavage of a drug from a POZ conjugate, controlling release of a drug from a POZ conjugate, and / or selecting a release profile of a drug from a POZ conjugate comprises selecting a molecular weight for the POZ polymer portion that stimulates or inhibits the formation of a compact conformation of the POZ conjugate. In one aspect of this embodiment, a molecular weight > 20 kDa (e.g., 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 75 kDa, 100 kDa, or 150 kDa, but less than 1000 kDa) stimulates the formation of compact conformations, while a molecular weight < 20 kDa (e.g., 17.5 kDa, 15 kDa, 12.5 kDa, 10.0 kDa, 8 kDa, 6 kDa, 4 kDa, or 2 kDa, but greater than 1 kDa) inhibits the formation of compact conformations. In another aspect of this embodiment, a molecular weight > 30 kDa stimulates the formation of compact conformations, while a molecular weight < 15 kDa inhibits the formation of compact conformations.

[0084] In one aspect of this embodiment, the present disclosure provides a method for stimulating the formation of a compact conformation in a POZ conjugate, the method comprising providing a POZ conjugate comprising a POZ polymer portion of ≥ 20 kDa. Additionally, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising providing a POZ conjugate comprising a POZ polymer portion of ≥ 20 kDa. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2The present invention provides a method for selecting a release profile having a molecular weight of 20 kDa or less, the method comprising providing a POZ conjugate comprising a POZ polymer segment of ≥ 20 kDa. In certain embodiments of this aspect, the molecular weight of the POZ polymer segment is 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 75 kDa, 100 kDa, or 150 kDa, and less than 1000 kDa. In certain embodiments of this aspect, the molecular weight of the POZ polymer segment is ≥ 20 kDa and ≤ 100 kDa. In certain embodiments of this aspect, the molecular weight of the POZ polymer segment is ≥ 50 kDa and ≤ 150 kDa.

[0085] Furthermore, generally, as the molecular weight of the POZ polymer moiety decreases, the formation of a compact higher-order structure of the POZ conjugate is inhibited, and the release rate of the drug from the POZ conjugate increases (shorter t 1 / 2 ) (comparing each of the foregoing to the higher molecular weight POZ polymer fraction).

[0086] In one aspect of this embodiment, the present disclosure provides a method for inhibiting the formation of compact conformation in a POZ conjugate, the method comprising providing a POZ conjugate comprising a POZ polymer moiety of <20 kDa. Additionally, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising providing a POZ conjugate comprising a POZ polymer moiety of <20 kDa or less. Furthermore, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2The present invention provides a method for selecting a release profile having a molecular weight of 17.5 kDa, 15 kDa, 12.5 kDa, 10.0 kDa, 8 kDa, 6 kDa, 4 kDa, or 2 kDa, and is greater than 1 kDa. In certain embodiments of this aspect, the molecular weight of the POZ polymer portion is ≥ 2 kDa and < 20 kDa. In certain embodiments of this aspect, the molecular weight of the POZ polymer portion is ≥ 10 kDa and < 20 kDa.

[0087] In the foregoing discussion, the effect of the molecular weight of the POZ polymer segment is determined relative to a POZ conjugate with substantially the same properties except for the difference in the molecular weight of the POZ polymer segment (e.g., if the effect of a 60 kDa POZ polymer segment on a POZ-CBD conjugate is determined, the effect of the POZ polymer segment is determined relative to a POZ-CBD conjugate with the same structure and substantially the same properties, e.g., loading percentage, except for the different molecular weight). In one embodiment, the effect of increasing or decreasing the molecular weight of the POZ polymer segment is specific to a particular POZ conjugate, and the effect of increasing or decreasing the molecular weight of the POZ polymer segment can be qualitatively or quantitatively different relative to another POZ conjugate. Furthermore, in other embodiments, the effect of increasing or decreasing the molecular weight of the POZ polymer segment can also be affected by other POZ conjugate characteristics, such as those discussed herein, including, but not limited to, the nature of the drug. For example, a drug exhibiting low water solubility (e.g., a drug with a LogP value of 6.1) will generally exhibit greater interaction with a POZ polymer moiety having a 60 kDa POZ polymer moiety, stimulate the formation of compact higher-order structures, and / or exhibit a reduced release rate compared to a drug in the same POZ conjugate having a lower LogP (e.g., a LogP of 4.8).

[0088] In one aspect of this embodiment, the method includes altering the hydrophobic nature of the pendant group on the POZ polymer portion, particularly when the POZ conjugate has Structure 1 above and lacks a hydrophilic or hydrophobic pendant moiety. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate, comprising modifying the hydrophobic nature of the pendant group on the POZ polymer portion of the POZ conjugate. As discussed above, when the POZ polymer portion contains a pendant group that provides more hydrophobic properties, the formation of a compact conformation of the POZ conjugate is stimulated (compared to the less hydrophobic pendant group of the reference POZ conjugate). For example, a POZ conjugate having a propyl pendant group on the POZ polymer portion has a more hydrophobic nature than a POZ conjugate having a methyl pendant group on the POZ polymer portion. As another example, a POZ conjugate having propyl pendant groups on the POZ polymer moiety has a more hydrophobic nature than a POZ conjugate having 50% ethyl and 50% methyl pendant groups on the POZ polymer moiety. Without being bound to any particular theory, the hydrophobic nature of the pendant groups stimulates interaction of the POZ polymer moiety with the attached drug and / or core, thereby stimulating the formation of a compact conformation of the POZ conjugate. Furthermore, varying the number of hydrophobic pendant groups allows for control of the degree to which the formation of a compact conformation of the POZ conjugate is stimulated.

[0089] POZ conjugates containing pendant groups with more hydrophobic properties exhibited a reduced drug release rate (longer t) compared to the reference POZ conjugate containing pendant groups with less hydrophobic properties. 1 / 2) shows the release rate of a drug from a POZ conjugate. Thus, the present disclosure provides a method of stimulating the formation of a compact conformation in a POZ conjugate, the method comprising including a pendant group having hydrophobic properties on the POZ polymer portion of the POZ conjugate. Additionally, the present disclosure provides a method of reducing the release rate of a drug from a POZ conjugate, the method comprising including a pendant group having hydrophobic properties on the POZ polymer portion of the POZ conjugate. In certain embodiments of the methods described herein, a comparison is made with a POZ polymer of substantially the same properties, except that it has methyl pendant groups.

[0090] In the foregoing discussion, the effect of pendant groups having hydrophobic properties on the POZ polymer portion is determined in relation to a POZ conjugate with substantially the same properties except for the hydrophobic nature of the pendant group (e.g., when determining the effect of propyl pendant groups on a POZ-CBD conjugate, the effect of the propyl pendant group is determined relative to a POZ-CBD conjugate with the same structure and substantially the same properties, e.g., loading percentage and molecular weight, except that it contains a less hydrophobic pendant group, e.g., a methyl pendant group). In one embodiment, the effect of pendant groups having hydrophobic properties on the POZ polymer portion is specific to a particular POZ conjugate, and the effect of pendant groups having hydrophobic properties on the POZ polymer portion may differ qualitatively or quantitatively for different POZ conjugates. Furthermore, in other embodiments, the effect of pendant groups having hydrophobic properties on the POZ polymer portion may also be affected by other POZ conjugate characteristics, such as those discussed herein, including, but not limited to, the nature of the drug. For example, a drug that generally exhibits low water solubility (e.g., a drug with a LogP value of 6.1) will exhibit higher interactions with the POZ polymer moiety containing pendant groups with hydrophobic properties, stimulating the formation of compact conformations and / or exhibiting a reduced release rate compared to a drug in the same POZ conjugate with a lower LogP (e.g., a LogP of 4.8).

[0091] The conformation of a POZ conjugate can also be controlled by selecting drug characteristics. The present disclosure provides methods for controlling the conformation of a POZ conjugate, controlling cleavage of a drug from a POZ conjugate, controlling release of a drug from a POZ conjugate, and / or selecting a release profile of a drug from a POZ conjugate, comprising selecting drug characteristics of the POZ conjugate. Suitable drug characteristics include, but are not limited to, drug solubility, drug molar volume, drug total polar surface area (TPSA), or a combination of the foregoing.

[0092] In one aspect of this embodiment, a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting the release profile of a drug from a POZ conjugate comprises selecting a drug with low water solubility for inclusion in a POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, comprising selecting a drug with low water solubility for inclusion in a POZ conjugate. A drug with low water solubility stimulates the formation of a compact conformation of the POZ conjugate (compared to a reference POZ conjugate having a drug with higher water solubility). POZ conjugates containing a drug with low water solubility exhibit a reduced drug release rate (longer t) compared to a reference POZ conjugate containing a drug with higher water solubility. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0093] Thus, the present disclosure provides a method for stimulating the formation of a compact conformation of a POZ conjugate, the method comprising selecting a drug with low water solubility for inclusion in the POZ conjugate. Further, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug with low water solubility for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for selecting a release profile having a drug with low water solubility for inclusion in a POZ conjugate.

[0094] In certain embodiments of this aspect, the water solubility of a drug is determined by the drug's LogP value. Unless otherwise specified, in this disclosure, LogP value refers to the value determined by partitioning the drug in a two-phase system of n-octanol and water, as described in Dearden et al. (Molecular Informatics, Vol. 7 (3), pp. 133-134, 1988). In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 0.5. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 1.0. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 1.5. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 2.0. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 2.5. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 3.0. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 3.5. In certain embodiments, a poorly water-soluble drug has a LogP value of ≥ 4.0. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧4.5. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧5.0. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧5.5. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧6.0. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧6.5. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧7.0. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧7.5. In certain embodiments, the poorly water-soluble drug has a LogP value of ≧8.0. In certain of the foregoing embodiments, the drug has a LogP value of ≦10. In certain of the foregoing embodiments, the drug has a LogP value of ≦0.5 and ≦10.

[0095] In one aspect of this embodiment, a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting the release profile of a drug from a POZ conjugate comprises selecting a drug with high water solubility for inclusion in the POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, comprising selecting a drug with high water solubility for inclusion in the POZ conjugate. A drug with high water solubility inhibits the formation of a compact conformation of the POZ conjugate (compared to a reference POZ conjugate having a drug with lower water solubility). POZ conjugates containing a drug with high water solubility exhibit an increased drug release rate (shorter t) compared to a reference POZ conjugate containing a drug with lower water solubility. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0096] Thus, the present disclosure provides a method for inhibiting the formation of compact conformations in a POZ conjugate, the method comprising selecting a drug with high aqueous solubility for inclusion in the POZ conjugate. Additionally, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug with high aqueous solubility for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 The present invention provides a method for selecting a release profile having a drug having a high water solubility for inclusion in a POZ conjugate.

[0097] In certain embodiments, drugs with high water solubility have a LogP value of <0.5.

[0098] In another aspect of this embodiment, the method comprises selecting a drug having a large molecular volume for inclusion in a POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting a release profile of a drug from a POZ conjugate, comprising selecting a drug having a large molecular volume for inclusion in a POZ conjugate. Drugs with large molecular volumes inhibit the formation of a compact conformation of the POZ conjugate (e.g., via steric hindrance). POZ conjugates containing drugs with large molecular volumes exhibit increased drug release rates (shorter t) compared to POZ conjugates containing drugs with smaller molecular volumes. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0099] Thus, the present disclosure provides a method for inhibiting the formation of compact conformations of a POZ conjugate, the method comprising selecting a drug with a large molecular volume for inclusion in the POZ conjugate. Additionally, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug with a large molecular volume for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 wherein the method comprises selecting a drug with a large molecular volume for inclusion in a POZ conjugate.

[0100] In certain embodiments of this aspect, the molecular volume is determined based on group contributions obtained by fitting the sum of fragment contributions to the true 3D volume to generate a training set (e.g., about 12,000) of drug-like molecules. The 3D molecular geometries for the training set were fully optimized by the semi-empirical AM1 method (Molinspiration chemoinformatics). In certain embodiments, drugs with large molecular volumes have a molecular volume ≧300. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧350. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧400. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧450. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧500. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧300 and ≦500. In certain embodiments, drugs with large molecular volumes have a molecular volume ≧300 and ≦400.

[0101] In another aspect of this embodiment, the method comprises selecting a drug having a small molecular volume for inclusion in a POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate, comprising selecting a drug having a small molecular volume for inclusion in a POZ conjugate. Drugs with small molecular volumes do not stimulate or inhibit the formation of compact conformation of the POZ conjugate. Thus, POZ conjugates containing drugs with small molecular volumes exhibit increased drug release rates (longer t) compared to POZ conjugates containing drugs with larger molecular volumes. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0102] Thus, the present disclosure provides a method for stimulating the formation of a compact conformation of a POZ conjugate, the method comprising selecting a drug having a small molecular volume for inclusion in the POZ conjugate. Further, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug having a small molecular volume for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for selecting a release profile having a small molecular volume for inclusion in a POZ conjugate.

[0103] In certain embodiments of this aspect, the molar volume is determined as described above. In certain embodiments, drugs with small molecular volumes have a molar volume ≦300. In certain embodiments, drugs with small molecular volumes have a molar volume ≦275. In certain embodiments, drugs with small molecular volumes have a molar volume ≦250. In certain embodiments, drugs with small molecular volumes have a molar volume ≦200. In certain embodiments, drugs with small molecular volumes have a molar volume ≦100. In certain embodiments, drugs with small molecular volumes have a molar volume ≦50. In certain embodiments, drugs with small molecular volumes have a molar volume ≦50<300. In certain embodiments, drugs with small molecular volumes have a molar volume ≧100<300.

[0104] In another aspect of this embodiment, the method comprises selecting a drug with a high TPSA for inclusion in a POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting the release profile of a drug from a POZ conjugate, comprising selecting a drug with a high TPSA for inclusion in a POZ conjugate. Drugs with a high TPSA inhibit the formation of a compact conformation of the POZ conjugate. POZ conjugates containing drugs with a high TPSA exhibit increased drug release rates (shorter t 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0105] Thus, the present disclosure provides a method for inhibiting the formation of compact conformations of a POZ conjugate, the method comprising selecting a drug with a high TPSA for inclusion in the POZ conjugate. Additionally, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug with a low TPSA for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 The present invention provides a method for selecting a release profile having a TPSA of 100 mg / dose, the method comprising selecting a drug with a high TPSA for inclusion in a POZ conjugate.

[0106] In certain embodiments of this aspect, the TPSA is determined as the sum of the O-centered and N-centered polar fragment fragment contributions based on the methodology published by Ertl et al. (J. Med. Chem., Vol. 43, pp. 3714-3717, 2000). In certain embodiments, drugs with high TPSA have a TPSA of ≥ 35. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 40. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 45. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 50. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 55. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 60. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 65. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 35 and ≤ 75. In certain embodiments, drugs with high TPSA have a TPSA of ≥ 40 and ≤ 60.

[0107] In another aspect of this embodiment, the method comprises selecting a drug with a low TPSA for inclusion in a POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling the cleavage of a drug from a POZ conjugate, controlling the release of a drug from a POZ, and / or selecting the release profile of a drug from a POZ conjugate, comprising selecting a drug with a low TPSA for inclusion in a POZ conjugate. Drugs with low TPSA do not stimulate or inhibit the formation of a compact conformation of the POZ conjugate. POZ conjugates containing drugs with low TPSA have a reduced drug release rate (longer t) compared to POZ conjugates containing drugs with larger TPSA. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0108] Thus, the present disclosure provides a method for stimulating the formation of a compact conformation of a POZ conjugate, the method comprising selecting a drug with a low TPSA for inclusion in the POZ conjugate. Further, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising selecting a drug with a low TPSA for inclusion in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for selecting a release profile having a TPSA comprising selecting a drug with a low TPSA for inclusion in a POZ conjugate.

[0109] In certain embodiments of this aspect, the TPSA is determined as described above. In certain embodiments, drugs with a low TPSA have a TPSA < 35. In certain embodiments, drugs with a low TPSA have a TPSA ≤ 30. In certain embodiments, drugs with a low TPSA have a TPSA ≤ 25. In certain embodiments, drugs with a low TPSA have a TPSA ≤ 20. In certain embodiments, drugs with a low TPSA have a TPSA ≤ 15. In certain embodiments, drugs with a low TPSA have a TPSA < 35 and ≥ 15.

[0110] In the foregoing discussion, the impact of a drug characteristic is determined relative to a POZ conjugate of substantially the same properties, except for the difference in the drug characteristic(s) being tested (e.g., if the effect of a drug with a high TPSA is determined relative to a 20 kDa POZ-CBD conjugate, the effect of the high TPSA is determined relative to a POZ-CBD conjugate with the same structure and substantially the same properties, e.g., loading percentage and molecular weight, except that the drug has a lower TPSA). In one embodiment, the impact of a drug characteristic is specific to a particular POZ conjugate, and the impact of a drug characteristic may differ qualitatively or quantitatively relative to another POZ conjugate. Furthermore, in another embodiment, the impact of a drug characteristic may also be affected by other POZ conjugate characteristics, such as those discussed herein, including, but not limited to, loading percentage. For example, a POZ conjugate containing a drug with a high TPSA (e.g., TPSA 62.2) at a loading percentage of 10% generally inhibits the formation of compact higher-order structures of the POZ conjugate to a greater extent and / or exhibits an increased release rate compared to the same POZ conjugate with a lower loading percentage (e.g., 4%).

[0111] The conformation of a POZ conjugate can also be controlled by selecting loading characteristics. Accordingly, the present disclosure provides methods for controlling the conformation of a POZ conjugate, controlling cleavage of a drug from a POZ conjugate, controlling release of a drug from a POZ conjugate, and / or selecting the release profile of a drug from a POZ conjugate, comprising selecting the loading characteristics of the POZ conjugate.

[0112] In one aspect of this embodiment, the method comprises selecting a high loading percentage of drug in the POZ conjugate. Accordingly, the present disclosure provides a method of controlling the conformation of a POZ conjugate, comprising selecting a high loading percentage of drug in the POZ conjugate. POZ conjugates with a higher loading percentage stimulate the formation of compact conformation to a greater extent than a reference POZ conjugate containing a lower loading percentage of drug in the POZ conjugate. POZ conjugates containing a high loading percentage of drug in the POZ conjugate exhibit a reduced drug release rate (longer t) compared to a reference POZ conjugate containing a lower loading percentage of drug in the POZ conjugate. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0113] Thus, the present disclosure provides a method for stimulating the formation of a compact conformation of a POZ conjugate, the method comprising selecting a high loading percentage for the drug in the POZ conjugate. Additionally, the present disclosure provides a method for reducing the release rate of a drug from a POZ conjugate, the method comprising selecting a high loading percentage for the drug in the POZ conjugate. Furthermore, the present disclosure provides a method for improving the release profile of the drug from the POZ conjugate, e.g., a longer t 1 / 2 The present invention provides a method for selecting a release profile having a high loading percentage for the drug in the POZ conjugate.

[0114] In any of the aforementioned methods utilizing a high loading percentage, the agent may have a logP value < 0.5, a molecular volume < 300, and a TPSA < 35. In any of the aforementioned methods utilizing a high loading percentage, the agent may have a logP value ≥ 0.5, a molecular volume > 300, and a TPSA > 35.

[0115] In certain embodiments, a high drug loading percentage is a loading percentage of ≧4.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧5.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧6.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧7.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧8.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧9.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧10.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧11.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧12.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧13.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧14.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧15.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧16.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧4.0% and ≦20.0%. In certain embodiments, a high drug loading percentage is a loading percentage of ≧6.0% and ≦10.0%.

[0116] In one aspect of this embodiment, the method comprises selecting a low loading percentage of drug in the POZ conjugate. Accordingly, the present disclosure provides a method for controlling the conformation of a POZ conjugate, controlling cleavage of a drug from a POZ conjugate, controlling release of a drug from a POZ conjugate, and / or selecting a release profile of a drug from a POZ conjugate, comprising selecting a low loading percentage of drug in the POZ conjugate. POZ conjugates with a lower loading percentage stimulate the formation of compact conformation to a lesser extent than a reference POZ conjugate containing a higher loading percentage of drug in the POZ conjugate. POZ conjugates containing a lower loading percentage of drug in the POZ conjugate exhibit an increased drug release rate (shorter t) compared to a reference POZ conjugate containing a higher loading percentage of drug in the POZ conjugate. 1 / 2 ) shows the release rate of drug from POZ conjugates.

[0117] Thus, the present disclosure provides a method for inhibiting the formation of compact conformation in a POZ conjugate, the method comprising selecting a low loading percentage for the drug in the POZ conjugate. Additionally, the present disclosure provides a method for increasing the release rate of a drug from a POZ conjugate, the method comprising selecting a low loading percentage for the drug in the POZ conjugate. Still further, the present disclosure provides a method for improving the release profile of a drug from a POZ conjugate, e.g., a shorter t 1 / 2 The present invention provides a method for selecting a release profile having a low loading percentage for the drug in the POZ conjugate.

[0118] In any of the aforementioned methods utilizing a low loading percentage, the agent may have a logP value < 0.5, a molecular volume < 300, and a TPSA < 35. In any of the aforementioned methods utilizing a low loading percentage, the agent may have a logP value ≥ 0.5, a molecular volume > 300, and a TPSA > 35.

[0119] In certain embodiments, a low drug loading percentage is a loading percentage < 4.0%. In certain embodiments, a low drug loading percentage is a loading percentage ≦3.5%. In certain embodiments, a low drug loading percentage is a loading percentage ≦3.0%. In certain embodiments, a low drug loading percentage is a loading percentage ≦2.5%. In certain embodiments, a low drug loading percentage is a loading percentage ≦2.0%. In certain embodiments, a low drug loading percentage is a loading percentage ≦1.0%. In certain embodiments, a low drug loading percentage is a loading percentage <4.0% and ≧1.0%.

[0120] In the foregoing discussion, the effect of the loading percentage of the POZ polymer moiety is determined relative to a POZ conjugate having the same properties except for the loading percentage (e.g., when the effect of a high loading percentage on a POZ-CBD conjugate is determined, the effect of the high loading percentage is determined relative to a POZ-CBD conjugate having the same structure and substantially the same properties, e.g., molecular weight, except for the lower loading percentage). In one embodiment, the effect of modifying the loading percentage is specific to a particular POZ conjugate, and the effect of modifying the loading percentage may differ qualitatively or quantitatively for another POZ conjugate. Furthermore, in other embodiments, the effect of increasing or decreasing the loading percentage may also be affected by other POZ conjugate characteristics, such as those discussed herein, including, but not limited to, the nature of the drug. For example, generally, a drug exhibiting low water solubility (e.g., a drug with a LogP value of 6.1) will exhibit higher interactions with the POZ polymer moiety at higher loading percentages (e.g., 8.5%), stimulate compact conformation formation to a greater extent, and / or exhibit a reduced release rate, compared to a drug in the same POZ conjugate with a lower LogP (e.g., LogP 4.8).

[0121] The present disclosure also provides methods for modulating (i.e., selecting or fine-tuning) the release rate of a drug from a POZ conjugate. By modulating the release rate of a drug, a particular release profile for the release of the drug from the POZ conjugate can be selected. The release rate of a drug from a POZ conjugate can be controlled in several ways, as described herein. For example, the release rate of a drug from a POZ conjugate can be controlled through selection of characteristics of the POZ polymer, through selection of characteristics of the drug, through selection of loading characteristics, or through a combination of the foregoing. The release rate can be monitored via determination of the half-life of the drug in vitro or in vivo after administration to a subject using the methods described in the Methods section herein, with a faster release rate correlating with a decreased half-life of the drug.

[0122] The release profile of the drug from the POZ polymer can be selected using one of the above methods or a combination of one or more of the above methods. For example, if a sustained release profile of the drug from the POZ conjugate is desired or if it is desired to reduce the release rate of the drug from the POZ conjugate, one or more of the above methods that stimulate the formation of a compact higher-order structure of the POZ conjugate and / or reduce the release rate of the drug from the POZ conjugate can be selected. Furthermore, if a sustained release profile of the drug from the POZ conjugate is not desired or if it is desired to increase the release rate of the drug from the POZ conjugate, one or more of the above methods that inhibit the formation of a compact higher-order structure of the POZ conjugate and / or increase the release rate of the drug from the POZ conjugate can be selected.

[0123] The present disclosure also provides POZ conjugate compositions for controlling the conformation of the POZ conjugate, controlling the cleavage of a drug from the POZ conjugate, controlling the release rate of a drug from the POZ conjugate, selecting the release profile of a drug from the POZ conjugate, or a combination of the foregoing. In a typical embodiment, such a POZ conjugate composition comprises a water-soluble POZ polymer and a drug attached to the water-soluble POZ polymer by a physiologically degradable linkage, or a pharmaceutically acceptable form thereof, wherein the POZ conjugate comprises one or more of the following characteristics: a hydrophilic or hydrophobic pendant moiety; a pendant group on the POZ polymer moiety having hydrophobic properties, where the hydrophobic properties are determined in relation to a POZ conjugate containing a methyl pendant group (particularly when the POZ polymer moiety lacks a hydrophilic or hydrophobic pendant moiety); a selected molecular weight (i.e., high or low) for the POZ polymer moiety; a drug having a selected aqueous solubility (i.e., high or low); a drug having a selected molecular volume (i.e., large or small); a drug having a selected TPSA (i.e., high or low); a selected drug loading percentage (i.e., high or low); or a combination of the foregoing. Such POZ conjugates can be used in any of the methods described herein.

[0124] In one embodiment, the present disclosure provides a POZ conjugate comprising a hydrophilic or hydrophobic pendant moiety. In one embodiment, the present disclosure provides a POZ conjugate comprising a pendant group with increased hydrophobicity (e.g., increased compared to a methyl pendant group). In one embodiment, the present disclosure provides a POZ conjugate comprising a high or low drug loading percentage. In one embodiment, the present disclosure provides a POZ conjugate comprising a drug with low or high aqueous solubility. In one embodiment, the present disclosure provides a POZ conjugate comprising a drug with a logP value ≥ 0.5 or a drug with a logP value < 0.5. In one embodiment, the present disclosure provides a POZ conjugate comprising a drug with a large or small molecular volume. In one embodiment, the present disclosure provides a POZ conjugate comprising a drug with a high or low TPSA.

[0125] The present disclosure also provides compositions, including pharmaceutical compositions, comprising the POZ conjugates of the present disclosure. Such compositions can contain any of the POZ conjugates described in the preceding methods.

[0126] The present disclosure also provides methods of treatment utilizing any of the methods, POZ conjugates, and pharmaceutical compositions described herein.

[0127] POZ conjugate composition The POZ conjugates of the present disclosure comprise a POZ polymer moiety and a drug. The drug is attached to the POZ polymer by a physiologically degradable linkage. As discussed above, the present disclosure demonstrates that the release rate and release profile of the drug from the POZ conjugate can be controlled by altering the conformation of the POZ conjugate.

[0128] In one embodiment, the POZ conjugates of the present disclosure have the general formula I, as set forth below: The conformation of the POZ conjugates of formula I is controlled, at least in part, by the selection of one or more of the POZ polymer characteristics, the drug characteristics, and the loading characteristics.

[0129] In one embodiment, the selection of the higher-order structure of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the release profile of the drug from the POZ conjugate is controlled, at least in part, by the selection of the characteristics of the POZ polymer.

[0130] In one aspect of this embodiment, the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of the release profile of the drug from the POZ conjugate are controlled, at least in part, by the selection of one or more pendant moieties in the POZ polymer portion (e.g., selection of R1) and / or the number of pendant moieties (e.g., selection of m). The present disclosure demonstrates that the inclusion of one or more hydrophilic or hydrophobic pendant groups modulates the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0131] In another aspect of this embodiment, the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of the release profile of the drug from the POZ conjugate are controlled, at least in part, by the selection of molecular weight (e.g., selection of n or n, and optionally m and o). The present disclosure demonstrates that varying the molecular weight of the POZ conjugate (in one embodiment, varying the molecular weight of the POZ polymer portion) modulates the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0132] In one embodiment, the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of the release profile of the drug from the POZ conjugate are controlled, at least in part, by the selection of drug characteristics. In one aspect of this embodiment, the conformation of the POZ conjugate is controlled, at least in part, by the selection of a drug with low water solubility (e.g., logP value ≧0.5) or high water solubility (e.g., logP < 0.5). The present disclosure demonstrates that varying the water solubility of the drug can modulate the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0133] In another aspect of this embodiment, the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of the release profile of the drug from the POZ conjugate are controlled, at least in part, by selecting a drug with a large molecular volume (e.g., molecular volume ≥ 300) or a small molecular volume (e.g., molecular volume < 300). The present disclosure demonstrates that varying the molecular volume of the drug can modulate the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0134] In another aspect of this embodiment, the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ, and / or the selection of the release profile of the drug from the POZ conjugate are controlled, at least in part, by selecting a drug with a high TPSA (e.g., TPSA ≥ 35) or a low TPSA (e.g., TPSA < 35). The present disclosure demonstrates that varying the TPSA of the drug can modulate the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0135] In one embodiment, the selection of the conformation of the POZ conjugate, the cleavage of the drug from the POZ conjugate, the release of the drug from the POZ conjugate, and / or the release profile of the drug from the POZ conjugate is controlled, at least in part, by the selection of the loading characteristics (i.e., the percentage of loading). The percentage of loading can be determined by varying the "o" parameter relative to the total molecular weight of the POZ conjugate. In one aspect of this embodiment, the conformation of the POZ conjugate is controlled, at least in part, by the selection of a high drug loading percentage (e.g., a loading percentage of ≥ 4% and ≤ 20%) or a low drug loading percentage (e.g., a loading percentage of < 4%). The present disclosure demonstrates that varying the percentage of drug loading can modulate the conformation of the POZ conjugate and / or the release rate of the drug from the POZ conjugate, allowing for the selection of the release profile for the drug.

[0136] Any of the parameters described in the previous section can be used above.

[0137] In one embodiment, the POZ conjugates of the present disclosure have the general formula I, or a pharmaceutically acceptable form thereof: R-{[N(CO-L1-R1)CH2CH2] m -[N(COR2-A)CH2CH2]0-[N(COX)CH2CH2] n} a -T [In the formula, R is an initiating group; R1 is a hydrophilic or hydrophobic pendant moiety of a pendant moiety containing a hydrophilic or hydrophobic moiety; L1 is a linking group that attaches R1 to the POZ polymer, or is absent; R2 is the direct bond of the linking group connecting the POZ polymer and A; X is a pendant group; A is a drug; a is ran indicating a random copolymer or block indicating a block copolymer; m is an integer from 0 to 100; n is an integer from 0 to 1000, provided that when m is 0, n is an integer from 1 to 1000; o is an integer from 1 to 50; T is a terminal group.

[0138] In one embodiment, m is 0. In one embodiment, m is an integer of 1 to 50 or 1 to 10.

[0139] In one embodiment, o is an integer from 1 to 20 or 1 to 10.

[0140] In one embodiment, n is an integer from 0 to 500, 0 to 250, 50 to 500, 50 to 250, or 100 to 200.

[0141] In one embodiment, m is an integer from 1 to 50, and o is an integer from 1 to 20 or 1 to 10. In one aspect of such an embodiment, n is an integer from 0 to 500, 0 to 250, 50 to 500, 50 to 250, or 100 to 200. In one embodiment, m is an integer from 1 to 10, and o is an integer from 1 to 20 or 1 to 10. In one aspect of such an embodiment, n is an integer from 0 to 500, 0 to 250, 50 to 500, 50 to 250, or 100 to 200.

[0142] R is an initiating group and is derived from the cationic initiator used to initiate the living cationic polymerization of the POZ polymer. Thus, the identity of the R group depends on the selection of the cationic initiator. Exemplary R groups include, but are not limited to, hydrogen, unsubstituted alkyl, and substituted alkyl. In one embodiment, the initiating group is an alkyl group, e.g., a C1-C4 alkyl group. In certain embodiments of the foregoing, the initiating group is a methyl group. In another embodiment, the initiating group is H. In yet another embodiment, the initiating group is selected to lack a functional group. Additional exemplary initiating groups are disclosed in U.S. Patent Nos. 7,943,141, 8,088,884, 8,110,651, and 8,101,706, each of which is incorporated herein by reference for such teachings.

[0143] When present, R1 is selected to modulate the release rate of the drug from the POZ conjugate. As discussed above, R1 is a pendant moiety containing a hydrophilic or hydrophobic moiety. In certain embodiments, R1 can contain a single hydrophilic or hydrophobic moiety or two or more hydrophilic or hydrophobic moieties. When R1 contains two or more hydrophilic or hydrophobic moieties, the number can be from 2 to 8.

[0144] In certain embodiments, R1 is L1-R1, where L1 is a linking group connecting the POZ conjugate and R1. In certain embodiments, L1 can contain one or more hydrophilic or hydrophobic moieties, for example, 2 to 7 hydrophilic moieties. In certain embodiments, L1 contains at least one or at least two hydrophilic or hydrophobic moieties. In certain embodiments, L1 does not contain a hydrophilic or hydrophobic moiety. In certain embodiments, L1 includes a physiologically degradable linkage. In certain embodiments, L1 does not contain a physiologically degradable linkage.

[0145] A variety of hydrophilic groups or compounds can be used. Such hydrophilic groups can be introduced after the POZ polymer is synthesized. In one embodiment, R1 is independently selected from a water-soluble polymer, a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted aralkyl, or a substituted heterocyclylalkyl group for each repeat unit. In another embodiment, R1 is independently selected from a C1-C5 substituted alkyl, a substituted alkenyl, or a substituted alkynyl for each repeat unit. In another embodiment, R1 is independently selected from a polar alkyl, a polar alkenyl, or a polar alkynyl, particularly a C1-C5 polar alkyl, a polar alkenyl, or a polar alkynyl, for each repeat unit. In another embodiment, R1 is independently selected from a water-soluble polymer, a substituted alkyl, and a polar alkyl, particularly a C1-C5 substituted alkyl or polar alkyl, for each repeat unit. In another embodiment of the POZ conjugate of Formula I, R1 is independently selected from a C1-C5 alcohol for each POZ repeat unit. In another embodiment of the POZ conjugate of Formula I, R1 is independently selected from a C2-C4 alcohol for each POZ repeat unit. In another embodiment of the POZ conjugate of Formula I, R1 is independently selected from a C1-C5 carboxylic acid for each POZ repeat unit. In another embodiment of the POZ conjugate of Formula I, R1 is independently selected from a C2-C4 carboxylic acid for each POZ repeat unit. In one embodiment, when R1 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aralkyl, and / or substituted heterocyclylalkyl, R1 contains one or more oxygen, nitrogen, sulfur, and / or phosphorous atoms. In one embodiment, R1 is selected from one or more polar covalent bonds (such as, but not limited to, C=O, CN, C = N, OH, and / or C-halogen bonds).

[0146] A variety of hydrophobic groups or compounds can be used. Such hydrophobic groups can be introduced during the POZ polymer polymerization process (i.e., as a substituent on the 2-oxazoline monomer), or can be introduced after the POZ polymer is synthesized, or can be introduced by a combination of the foregoing. In one embodiment, R1 is independently selected from a C5-C20 substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aralkyl, or substituted heterocyclylalkyl group for each repeat unit. In another embodiment, R1 is independently selected from a C5-C20 substituted alkyl, substituted aralkyl, or substituted heterocyclylalkyl group for each repeat unit. In another embodiment, R1 is independently selected from a C5-C20 unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl group for each repeat unit. In another embodiment, R1 is independently selected from a C5-C20 unsubstituted alkyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl group for each repeat unit. Preferably, the hydrophobic group or compound is not a polar alkyl, polar alkenyl, or polar alkynyl.

[0147] When R1 is a water-soluble polymer, any water-soluble polymer can be used. Suitable water-soluble polymers include, but are not limited to, POZ, poly(alkylene glycol), copolymers of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefin alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), or any combination of the foregoing. In certain embodiments, the water-soluble polymer is selected from the group consisting of polyethylene glycol, poly(propylene glycol), copolymers of ethylene glycol and propylene glycol, and POZ. In one embodiment of any of the foregoing, the water-soluble polymer contains 1 to 30 repeating units, e.g., 1 to 20, 1 to 15, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 repeating units.

[0148] In certain embodiments, at least one hydrophilic or hydrophobic moiety of R1 is located within 50 angstroms of the N group to which R1 is attached. In certain embodiments, when R1 contains more than one hydrophilic or hydrophobic moiety, at least two hydrophilic or hydrophobic moieties of R1 are located within 50 angstroms of the N group to which R1 is attached. In certain embodiments, all of the hydrophilic or hydrophobic moieties of R1 are located within 50 angstroms of the N group to which R1 is attached.

[0149] In certain embodiments, at least one hydrophilic or hydrophobic moiety of R1 is located within 30 angstroms of the N-group to which R1 is attached. In certain embodiments, when R1 contains more than one hydrophilic or hydrophobic moiety, at least two hydrophilic moieties of R1 are located within 30 angstroms of the N-group to which R1 is attached. In certain embodiments, all of the hydrophilic or hydrophobic moieties of R1 are located within 30 angstroms of the N-group to which R1 is attached.

[0150] In certain embodiments, at least one hydrophilic or hydrophobic moiety of R1 is located within 20 angstroms of the N group to which R1 is attached. In certain embodiments, when R1 contains more than one hydrophilic or hydrophobic moiety, at least two hydrophilic moieties of R1 are located within 20 angstroms of the N group to which R1 is attached. In certain embodiments, all of the hydrophilic or hydrophobic moieties of R1 are located within 20 angstroms of the N group to which R1 is attached.

[0151] In certain embodiments, R1 is an inert group.

[0152] X is a pendant group. In one embodiment, X is selected to be non-reactive (i.e., inert). In another embodiment, X is selected to be reactive (i.e., contains a reactive functional group). In one embodiment, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl. In one embodiment, X is independently selected for each repeat unit from unsubstituted alkyl, unsubstituted alkenyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl. In another embodiment, X is unsubstituted alkyl. In another embodiment, X is C1-C20 unsubstituted alkyl. In another embodiment, X is C1-C10 unsubstituted alkyl. In another embodiment, X is C1-C5 unsubstituted alkyl. In another embodiment, X is C1-C2 unsubstituted alkyl. In certain embodiments, X is methyl, ethyl, propyl, or butyl, or X is methyl or ethyl.

[0153] In another embodiment, when m is 0, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group, preferably unsubstituted. In another embodiment, when m is 0, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group, preferably unsubstituted.

[0154] In another embodiment, when m is 0, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups, preferably unsubstituted; up to 90% of the X groups (i.e., 90% of n) are C5-C20 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted); and the remainder of the X groups (i.e., 50% of n) are C1-C4 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted).

[0155] In another embodiment, when m is 0, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups, preferably unsubstituted; up to 50% (e.g., 5%, 10%, 15%, 20%, or 25%) of the X groups are C5-C20 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted); and the remainder of the X groups (i.e., 50% of n) are C1-C4 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted).

[0156] The terminal group can be any nucleophilic group capable of terminating the living cationic polymerization of the POZ polymer. In one embodiment, T is a thioalkyl carboxylic acid, a thiocarboxylic acid ester, or a hydroxyl.

[0157] In one embodiment, T is ZBQ, where Z is S, O, or N; B is an optional linking group; and Q is a terminal nucleophile or a terminal portion of a nucleophile. In certain embodiments, Q is inert (i.e., does not contain a functional group); in other embodiments, Q contains a functional group.

[0158] Exemplary B groups include, but are not limited to, alkylene groups. In certain embodiments, B is -(CH) y - and y is an integer selected from 1 to 16. In certain embodiments, y is an integer selected from 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In certain embodiments, y is 2. In certain embodiments, Z is S. POZ conjugates containing a sulfur group as described herein can be prepared by terminating a cation at the end of a polyoxazoline polymer with a mercaptide reagent, such as, but not limited to, a mercapto-ester (e.g., -S-CH2CH2-CO2CH3 or -S-CH2CH2-CO2H), an amine (e.g., -S-CH2CH2-NH2), or a mercapto-protected amine (e.g., -S-CH2CH2-NH-tBoc). Such POZ conjugates provide efficient, large-scale purification by ion exchange chromatography (to remove secondary amines) and allow for control of polydispersity values ​​(polydispersity values ​​of 1.10 or less) and the creation of POZ conjugates in which the POZ polymer has a higher molecular weight. In another embodiment, Z is N. In a further embodiment, Z is O.

[0159] As described above, Q may be inert or may contain a functional group. When Q contains a functional group, exemplary functional groups include, but are not limited to, alkynes, alkenes, amines, oxyamines, aldehydes, ketones, acetals, thiols, ketals, maleimides, esters, carboxylic acids, activated carboxylic acids (e.g., but not limited to, N-hydroxysuccinimidyl (NHS) and 1-benzotriazine activated esters), activated carbonates, chloroformates, alcohols, azides, vinyl sulfones, or orthopyridyl disulfides (OPSS). When Q contains a functional group, the functional group can be chemically orthogonal to one or more or all other functional groups present in the conjugate. When Q is a non-reactive group, any non-reactive group can be used, including, but not limited to, unsubstituted alkyl and —CH.

[0160] The nature of the agent is described in further detail herein. In one embodiment, A is a compound containing a phenol group. The agent can be any compound useful in the treatment of a disease or condition or in the diagnosis of a disease or condition. In certain embodiments, the agent is a diagnostic or therapeutic agent. In certain embodiments, the therapeutic agent is a small organic molecule or a polypeptide.

[0161] In one embodiment, the agent is a compound useful in the treatment of PD or other diseases or conditions associated with a deficiency of dopamine in the peripheral or central nervous system.

[0162] In one embodiment, the agent is a compound useful for the treatment of a disorder that would benefit from agonism or antagonism of a CB1 receptor, a CB2 receptor, a 5H1-a receptor, a 5H2-a receptor, a TRP-V1 receptor, a TRP-V2 receptor, a TRP-V3 receptor, an adenosine A2A receptor, a GPR55 receptor, a GPR18 receptor, a PPAR-α receptor, a PPAR-γ receptor, or a combination of the foregoing.

[0163] In one embodiment, the agent is selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, cancer pain, neurodegenerative diseases, post-traumatic stress disorder, agitation associated with dementia, insomnia, REM sleep behavior disorder, excessive daytime sleepiness, nightmares associated with post-traumatic stress disorder, obstructive sleep apnea, essential tremor, Tourette's syndrome, depression, fibromyalgia, ischemic disease, stroke, cardiac ischemia, coronary artery disease, thromboembolism, myocardial infarction, brain injury, traumatic brain injury, diffuse axonal injury, and concussion. , contusion, anoxic brain injury, hypoxic brain injury, age-related inflammatory disease, age-related autoimmune disease, cachexia, AIDS wasting disease, weight loss associated with cancer, weight loss associated with chronic obstructive pulmonary disease, weight loss associated with infection, nausea, vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergies, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia, and nephritis.

[0164] In one embodiment, the agent is a drug for treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, multiple sclerosis ataxia / spasticity syndrome, syndrome), dystonia associated with Parkinson's disease, dystonia associated with Huntington's disease, frontotemporal dementia, prion disease, dementia with Lewy bodies, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, progressive supranuclear palsy, parafragile X tremor / ataxia syndrome, parafragile X behavior disorder, autism spectrum disorder, vascular dementia, normal pressure hydrocephalus, traumatic spinal cord injury, HIV dementia, alcohol-induced neurotoxicity, Down syndrome, epilepsy, partial seizures, generalized seizures, tonic-clonic seizures, absence seizures, atonic seizures, treatment-resistant epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, Ohtahara syndrome, West syndrome, Dossé syndrome, CDKL5 encephalopathy, Landau-Kleffner syndrome, hypoxic-ischemic encephalopathy, early myoclonic epilepsy, Rett syndrome, and febrile infection-associated epilepsy syndrome.

[0165] In certain embodiments, R2 is a direct bond between the drug and a functional group (e.g., a functional group described herein) on the POZ polymer moiety such that a physiologically degradable linkage is formed. In certain embodiments, R2 is a linking group L2 that attaches the drug to the POZ polymer moiety, where L2 contains a physiologically degradable linkage (including the formation of a physiologically degradable linkage by attachment of the drug to L2). In some preferred embodiments, the drug is attached to the POZ polymer moiety by L2.

[0166] In one embodiment, R1 is R1-L1, where L1 optionally comprises a physiologically degradable linkage, and R2 is L2, where L2 comprises a physiologically degradable linkage.

[0167] In one embodiment, R1 is R1-L1, where L1 optionally comprises a physiologically degradable linkage, and R2 is L2, where L2 comprises a physiologically degradable linkage: Z is S and B is -(CH2) y -, Q is -COOH; Z is O and B is -(CH) y - and Q is -COOH; or Z is N and B is -(CH) y - and Q is -COOH; Z is S and B is -(CH2) y -, Q is -COOCH3; Z is O and B is -(CH2) y - and Q is -COOCH; or Z is N and B is -(CH) y - and Q is -COOCH; or Z is S and B is -(CH) y -, Q is -NH; Z is O and B is -(CH) y and Q is -NH2; or Z is N, B is -(CH2)y- and Q is -NH2.

[0168] In any of the foregoing embodiments, the cleavable portion of the physiologically degradable linkage can be an ester group. In any of the foregoing, y is 1 to 3.

[0169] In any of the foregoing embodiments, L1 and L2, when present, can each comprise a component of a group originally present in the POZ polymer and / or R1 or the drug. Suitable parameters for L1 and L2 are described herein. In any of the foregoing embodiments, L1 comprises a physiologically degradable linkage. In any of the foregoing embodiments, L1 does not comprise a physiologically degradable linkage. In any of the foregoing embodiments, L2 comprises a physiologically degradable linkage.

[0170] In any of the foregoing embodiments, controlling the release rate of the drug from the POZ conjugate provides the ability to select the release profile for the drug. As discussed above, in certain embodiments, the release rate of the drug from the POZ conjugate is controlled by selection of R1, the hydrophobic character of the pendant group (particularly when m is 0), selection of the drug, selection of m (i.e., percentage loading), selection of n, and optionally m and / or o (i.e., molecular weight of the POZ polymer portion), or a combination of the foregoing.

[0171] In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 24 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 48 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 72 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 96 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 120 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 144 hours. In any of the foregoing embodiments, the release profile is sustained over a period of 12 to 168 hours.

[0172] In any of the foregoing embodiments, the release profile is sustained for 1 week or more. In any of the foregoing embodiments, the release profile is sustained for 1-2 weeks. In any of the foregoing embodiments, the release profile is sustained for 1-3 weeks. In any of the foregoing embodiments, the release profile is sustained for 1-4 weeks.

[0173] In any of the foregoing, the release profile over the aforementioned period exhibits zero-order release kinetics.

[0174] L group In certain embodiments described above, the drug and / or R1 are attached to the POZ polymer moiety by linkages L2 and L1, respectively, where L2 comprises a physiologically degradable linkage and L1 optionally comprises a physiologically degradable linkage. In certain embodiments, L2 is the same in each repeating unit of the POZ polymer moiety and / or L1 is the same in each repeating unit of the POZ polymer moiety. In certain embodiments, L1 and L2 are the same in each repeating unit of the POZ polymer moiety. Exemplary cleavable moieties that may be contained in the physiologically degradable linkage include, but are not limited to, ester, carboxylate ester (-C(O)-O-), carbonate ester (-OC(O)-O-), carbamate (-OC(O)-NH-), amide (-C(O)-NH-), disulfide (SS), and peptide (e.g., a peptide of 2 to 10 amino acids); other cleavable moieties are discussed herein. In certain embodiments, the cleavable moiety is an ester group. In another particular embodiment, the cleavable moiety is a carboxylate ester.

[0175] In one embodiment, L2 is a disubstituted triazole that includes a first cleavable moiety at one of the R3 or R4 groups, preferably at the R4 group.

[0176] In specific embodiments, the disubstituted triazole has the structure:

[0177] [ka] [In the formula, R3 is a linker that connects the triazole moiety to the POZ polymer chain. R3 can be partially defined by the functional groups in the polymer chain; in other words, R3 can comprise part of the functional groups in the polymer chain. In one embodiment, R3 is -C(O)-R5-, where (i) R5 is absent; (ii) R5 is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group; (iii) R5 is an unsubstituted alkyl, unsubstituted alkenyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl group; (iv) R5 is an unsubstituted alkyl; or (v) or R5 is a straight-chain unsubstituted alkyl. In any of the above (i)-(v), the unsubstituted or substituted alkyl or unsubstituted or substituted alkenyl can be 1 to 10 carbons in length or 1 to 5 carbons in length.

[0178] R4 is a linker that connects the triazole moiety to the drug. R4 can be partially defined by a functional group on the drug; in other words, R4 can include part of a group / functional group on the drug, such as the O atom of a phenolic hydroxyl group. In one embodiment, R4 is -R6-R7-R8-, where R6 is substituted or unsubstituted alkyl, substituted or unsubstituted aralkyl, or oligo(ethylene oxide) (e.g., -(CH2CHO) e - (wherein e is an integer from 1 to 10 or 1 to 4), R7 is a cleavable moiety or a group comprising a portion of a cleavable moiety, and R8 is absent or O. In certain embodiments, R7 and R8 can combine to form a cleavable moiety. In one embodiment, R7 is -R a -C(O)-R b -, -R a -OC(O)-R b -, -R a -C(O)-OR b , -R a -C(O)-NH-cyclic-OC(O)-R b- (wherein cyclic represents a substituted or unsubstituted aryl, heterocylalkyl, heteroaryl, heterocyclyl, or cycloalkyl), -R a -C(O)-NH-(C6H4)-OC(O)-R b -, -R a -OC(O)-NR 10 -R b -(In the formula, R 10 is H or substituted or unsubstituted C1-C5 alkyl), -R a -CH(OH)-OR b -, -R a -SSR b -, -R a -OP(O)(OR9)-OR b - (wherein R9 is H or substituted or unsubstituted C1-C5 alkyl), or -R a -C(O)-NR 10 -R b -(In the formula, R 10 is H or substituted or unsubstituted C1-C5 alkyl, and R a and R b are each independently absent or substituted or unsubstituted alkyl. a and R b are each independently absent or a C1-C16 or C1-C6 substituted or unsubstituted alkyl.

[0179] In one embodiment of the foregoing, R6 is a straight chain substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R7 is -R a -C(O)-R b - and R8 is -O-. In one embodiment of the foregoing, R6 is a straight chain substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R7 is -R a -C(O)-OR b - and R8 is absent. In any of the foregoing, R a and R b is non-existent.

[0180] In one embodiment of the foregoing, R6 is a straight chain substituted or unsubstituted C1-C4 alkyl or a branched substituted or unsubstituted C1-C4 alkyl, and R7 is -R a -C(O)-R b - and R8 is -O-. In one embodiment of the foregoing, R6 is a straight chain substituted or unsubstituted C1-C4 alkyl or a branched substituted or unsubstituted C1-C4 alkyl, and R7 is -R a -C(O)-OR b - and R8 is absent. In any of the foregoing, R a and R b is non-existent.

[0181] In certain embodiments, R3 is -C(O)-(CH2)3 and R4 is -(CH2) d -C(O)-O-, -CH2-C(O)-O-, -CH2-CH2-C(O)-O-, -CH2-CH2-CH2-C(O)-O-, -CH2(CH3)-C(O)-O-, wherein d is an integer from 1 to 10, or a combination of the foregoing.

[0182] In certain embodiments, R3 is -C(O)-(CH2)3 and R4 is -(CH2) d -C(O)-, -CH2-C(O)-, -CH2-CH2-C(O)-, -CH2-CH2-CH2-C(O)-, -CH2(CH3)-C(O)-, wherein d is an integer from 1 to 10, or a combination of the foregoing.

[0183] In one embodiment, L1 is a disubstituted triazole optionally containing a first cleavable moiety, if present, in one of the R3 or R4 groups, preferably in the R4 group.

[0184] In specific embodiments, the disubstituted triazole has the structure:

[0185] [ka] [In the formula, R3 * R3 is a linker that connects the triazole moiety to the POZ polymer chain. * can be partially defined by the functional groups in the polymer chain; in other words, R * may comprise a portion of the functional group in the polymer chain. * is -C(O)-R5 * - and R5 * is (i) absent; (ii) unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group; (iii) unsubstituted alkyl, unsubstituted alkenyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl group; (iv) unsubstituted alkyl; or (v) straight-chain unsubstituted alkyl. In any of the foregoing (i) to (v), the unsubstituted or substituted alkyl or unsubstituted or substituted alkenyl can be 1 to 10 carbons in length or 1 to 5 carbons in length.

[0186] R4 * is R1 or a linker connecting the triazole moiety to R1. * is the linker connecting the triazole moiety to R1, then R4 * may be as described for R4 in L2 above.

[0187] In certain embodiments, R * is —C(O)—(CH2)3, and R1 is a C1-C5 alcohol, a C1-C5 carboxylic acid, a C1-C5 substituted or unsubstituted alkyl, alkenyl, or alkynyl, a C1-C5 substituted or unsubstituted polar alkyl, polar alkenyl, or polar alkynyl, or a combination of the foregoing.

[0188] In certain embodiments, R * is —C(O)—(CH2)3, and R1 is a C1 to C5 alcohol, a C1 to C5 carboxylic acid, or a combination of the foregoing.

[0189] POZ Conjugate Properties The POZ polymer characteristics, drug characteristics, and loading characteristics described in this section entitled "Compositions and Methods for Controlling the Conformation of a POZ Conjugate and Modulating the Release Rate of an Agent From a POZ Conjugate" are applicable to the POZ conjugates described herein. Each can be applied individually, or they can be applied in combination.

[0190] In one embodiment, where it is desirable to inhibit the formation of compact conformations and / or increase the rate of drug release from the POZ conjugate, the POZ conjugate has a drug loading percentage of 4% to 20%. In certain embodiments, the POZ conjugate has a drug loading percentage of ≥4.0% and ≤16.0% or a drug loading percentage of ≥6.0% and ≤10.0%. In certain embodiments, the POZ conjugate has a drug loading percentage of ≥4.0%, ≥5.0%, ≥6.0%, ≥7.0%, ≥8.0%, ≥9.0%, ≥10.0%, ≥11.0%, ≥12.0%, ≥13.0%, ≥14.0%, ≥15.0%, or ≥16.0% (each of the foregoing with a loading percentage ≤20.0%).

[0191] In one embodiment, when it is desired to inhibit the formation of compact conformation and / or increase the rate of drug release from the POZ conjugate, the POZ conjugate has a drug loading percentage of ≦4%. In one embodiment, when it is desired to inhibit the formation of compact conformation and / or increase the rate of drug release from the POZ conjugate, the POZ conjugate has a drug loading percentage of less than 4%. In certain embodiments, the POZ conjugate has a drug loading percentage of ≦4.0% or a drug loading percentage of ≧1.0% and ≦4.0%.

[0192] In one embodiment, when it is desirable to stimulate the formation of compact conformations and / or slow the rate of drug release from the POZ conjugate, the POZ polymer portion of the POZ conjugate has a molecular weight of ≧20 kDa. In one embodiment, the POZ polymer portion has a molecular weight of 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 75 kDa, 100 kDa, or 150 kDa. In another embodiment, the molecular weight of the POZ polymer portion is ≧20 kDa and ≦100 kDa. In another embodiment, the molecular weight of the POZ polymer portion is ≧50 kDa and ≦150 kDa.

[0193] In one embodiment, when it is desirable to inhibit the formation of compact conformations and / or increase the rate of drug release from the POZ conjugate, the POZ conjugate comprises a hydrophilic pendant moiety (R1). R1 ​​can be as described above. In certain embodiments, R1 is a C1-C5 alcohol, a C1-C5 carboxylic acid, a C1-C5 substituted or unsubstituted alkyl, alkenyl, or alkynyl, a C1-C5 substituted or unsubstituted polar alkyl, polar alkenyl, or polar alkynyl, or a combination of the foregoing. In certain embodiments, R1 is a C1-C5 alcohol, a C1-C5 carboxylic acid, or a combination of the foregoing.

[0194] In one embodiment, when it is desirable to stimulate the formation of compact conformations and / or slow the rate of release of the drug from the POZ conjugate, the POZ conjugate includes a pendant group having hydrophobic characteristics (e.g., a pendant group other than methyl). In another embodiment, particularly when m is 0, X is independently selected for each repeat unit from unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups, preferably unsubstituted, and 50% to 90% of the X groups are C5 to C20 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted), with the remainder of the X groups (i.e., 50% of n) being C1 to C4 unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl groups (preferably unsubstituted).

[0195] In one embodiment, when it is desirable to promote the formation of compact conformations and / or slow the rate of release of the drug from the POZ conjugate, the POZ conjugate comprises a hydrophobic pendant moiety (R1). R1 ​​can be as described above. In one embodiment, R1 is independently selected for each repeat unit from a C5-C20 unsubstituted alkyl, unsubstituted aralkyl, or unsubstituted heterocyclylalkyl group.

[0196] Drugs In one embodiment, the agent is a therapeutic agent.

[0197] In one embodiment, the drug is a dopamine agonist.Non-limiting examples of dopamine agonists include, but are not limited to, apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.The above-mentioned are useful for treating dopamine-responsive conditions.

[0198] In one embodiment, the agent is an anticholinergic (e.g., but not limited to, trihexyphenidyl, biperiden, and hyoscyamine), a monoamine oxidase-B inhibitor (e.g., but not limited to, serigiline and rasagiline), a catechol-O-methyltransferase (COMT) inhibitor (e.g., but not limited to, tolcapone and entacapone), or adenosine A 2A Receptor antagonists (such as, but not limited to, preladenant, theophylline, and istradefylline) are useful for treating dopamine-responsive states.

[0199] In one embodiment, the agent is a GABA reuptake inhibitor. Non-limiting examples of GABA reuptake inhibitors are tiagabine and nipecotic acid. The foregoing are useful for treating excessive GABA reuptake or disorders characterized by GABA reuptake.

[0200] In one embodiment, the agent is a compound isolated from a plant of the Cannabis species. In another embodiment, the agent is a phytocannabinoid (a compound that is naturally derived and can be found in a plant of the Cannabis species). In another embodiment, the agent is a compound listed in Table 1 of Brenneisen (Chapter 2, Forensic Science and Medicine: Marijuana and the Cannabinoids; MA ElSohly ed., Humana Press, Inc., Townsend NJ). In another embodiment, the agent is cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiol monomethyl ether, cannabidiol-C4, cannabidarinic acid, cannabidivarin, cannabidiol or cannabigerol propyl variants, cannabichromene, cannabichromene acid, cannabichromevarin, cannabinol, cannabicyclol, tetrahydrocannabivarin, Δ 9 -THC, adulemic acid and dexanabinol.

[0201] In one embodiment, the agent is buprenorphine. In another embodiment, the agent is an analog of buprenorphine. Suitable analogs of buprenorphine include, but are not limited to, BU08028 (as disclosed in Li, PNAS Vol. 113 (No. 37), pp. 10225-10227, 2016), WO / 2014 / 087226, WO / 2013 / 084060, or WO / 2012 / 084060, or compounds disclosed in HS-559.

[0202] In one embodiment, the agent is useful for treating dopamine-responsive states, including, but not limited to, diseases or conditions associated with a lack of dopamine in the peripheral or central nervous system. In another embodiment, the agent is useful for treating Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopamine states, SSRI-induced sexual dysfunction, depression, obesity, and type 2 diabetes. Other diseases and conditions that can be treated are described in Rubi et al. (Endocrinology, Vol. 151 (12), 5570-5581, 2010).

[0203] In one embodiment, the agent is a compound useful for treating excessive GABA reuptake or a disorder characterized by GABA reuptake, hi certain embodiments, the agent is a compound useful for treating anxiety disorders, social anxiety disorder, panic disorder, neuropathic pain (including useful in poorly understood disorders such as fibromyalgia), chronic pain, muscle tremors, muscle spasms, epileptic seizures, convulsions, and / or epilepsy.

[0204] In one embodiment, the agent is a compound useful for the treatment of a disorder that would benefit from agonism or antagonism of a CB1 receptor, a CB2 receptor, a 5H1-a receptor, a 5H2-a receptor, a TRP-V1 receptor, a TRP-V2 receptor, a TRP-V3 receptor, an adenosine A2A receptor, a GPR55 receptor, a GPR18 receptor, a PPAR-α receptor, a PPAR-γ receptor, or a combination of the foregoing.

[0205] In one embodiment, the agent is selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, cancer pain, neurodegenerative diseases, post-traumatic stress disorder, agitation associated with dementia, insomnia, REM sleep behavior disorder, excessive daytime sleepiness, nightmares associated with post-traumatic stress disorder, obstructive sleep apnea, essential tremor, Tourette's syndrome, depression, fibromyalgia, ischemic disease, stroke, cardiac ischemia, coronary artery disease, thromboembolism, myocardial infarction, brain injury, traumatic brain injury, diffuse axonal injury, and concussion. , contusion, anoxic brain injury, hypoxic brain injury, age-related inflammatory disease, age-related autoimmune disease, cachexia, AIDS wasting disease, weight loss associated with cancer, weight loss associated with chronic obstructive pulmonary disease, weight loss associated with infection, nausea, vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergies, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia, and nephritis.

[0206] In one embodiment, the agent is a therapeutic agent for treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, multiple sclerosis ataxia / spasticity syndrome, dystonia associated with Parkinson's disease, dystonia associated with Huntington's disease, frontotemporal dementia, prion disease, dementia with Lewy bodies, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, progressive supranuclear palsy, fragile X-associated tremor / ataxia syndrome, fragile X-associated behavior disorder, autism spectrum disorder, vascular dementia, normal pressure hydrocephalus, traumatic spinal cord injury, The compounds are useful for treating a neurodegenerative disease selected from the group consisting of spinal cord injury, HIV dementia, alcohol-induced neurotoxicity, Down's syndrome, epilepsy, partial seizures, generalized seizures, tonic-clonic seizures, absence seizures, atonic seizures, treatment-resistant epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, Ohtahara syndrome, West syndrome, Dossé syndrome, CDKL5 encephalopathy, Landau-Kleffner syndrome, hypoxic-ischemic encephalopathy, early myoclonic epilepsy, Rett syndrome, and febrile infection-associated epilepsy syndrome.

[0207] For clarity, the agent can be any of the aforementioned classes of compounds or another class of compounds having suitable chemical functionality to form a physiologically degradable linkage with the POZ polymer or linking group of the present disclosure. The foregoing examples are provided by way of illustration and are not intended to be limiting.

[0208] Furthermore, the drugs can be used to treat a variety of diseases or conditions. The selection of drugs should not be limited to the treatment of the exemplified diseases or conditions. Any drug that would benefit from the methods described herein can also be used. The foregoing examples are provided by way of illustration and are not intended to be limiting.

[0209] In one embodiment, when it is desirable to stimulate the formation of compact conformation and / or slow the rate of release of the drug from the POZ conjugate, the POZ conjugate includes a drug with low water solubility. In certain embodiments, the drug with low water solubility has a logP value of ≧0.5, ≧1.0, ≧1.5, ≧2.0, ≧2.5, ≧3.0, ≧3.5, ≧4.0, ≧4.5, ≧5.0, ≧5.5, ≧6.0, ≧6.5, ≧7.0, ≧7.5, or ≧8.0. In certain embodiments of the foregoing, the drug has a logP value of ≦10. In certain embodiments of the foregoing, the drug has a logP value of ≧4.5 and ≦10.

[0210] In one embodiment, when it is desirable to inhibit the formation of compact conformations and / or increase the rate of release of the drug from the POZ conjugate, the POZ conjugate comprises a highly water-soluble drug. In certain embodiments, a highly water-soluble drug has a logP value of <0.5.

[0211] In one embodiment, when it is desirable to inhibit the formation of compact conformations and / or increase the rate of release of the drug from the POZ conjugate, the POZ conjugate comprises a drug with a large molecular volume. In certain embodiments, the drug with a large molecular volume has a molecular volume of ≧300, ≧350, ≧400, ≧450, or ≧500. In certain embodiments, the drug with a large molecular volume has a molecular volume of ≧300 and ≦500. In certain embodiments, the drug with a large molecular volume has a molecular volume of ≧300 and ≦400.

[0212] In one embodiment, when it is desirable to stimulate the formation of compact conformations and / or slow the rate of release of the drug from the POZ conjugate, the POZ conjugate comprises a drug with a low molecular volume. In certain embodiments, a drug with a low molecular volume has a molecular volume of <300, ≦250, ≦200, ≦150, ≦100, or ≦50. In certain embodiments, a drug with a low molecular volume has a molecular volume of ≧50<300. In certain embodiments, a drug with a low molecular volume has a molecular volume of ≧100<300.

[0213] In one embodiment, when it is desirable to inhibit the formation of compact conformations and / or increase the rate of drug release from the POZ conjugate, the POZ conjugate comprises a drug with a high TPSA. In certain embodiments, a drug with a high TPSA has a TPSA of ≧35, ≧40, ≧45, ≧50, ≧55, ≧60, or ≧65. In certain embodiments, a drug with a high TPSA has a TPSA of ≧35 and ≦75. In certain embodiments, a drug with a high TPSA has a TPSA of ≧40 and ≦60.

[0214] In one embodiment, when it is desired to stimulate the formation of compact conformations and / or slow the rate of release of the drug from the POZ conjugate, the POZ conjugate comprises a drug with a low TPSA. In certain embodiments, a drug with a low TPSA has a TPSA of <30, ≦25, ≦20, or ≦15. In certain embodiments, a drug with a low TPSA has a TPSA of <35 and ≧15.

[0215] Treatment method The present disclosure also provides methods of treatment using the methods, POZ conjugates, and compositions described herein. In the methods of treatment described below, the POZ conjugates can be administered alone or as part of a composition, preferably a pharmaceutical composition.

[0216] In one embodiment, the disclosure provides a method of treating a disorder as described herein in a subject, the method comprising administering to the subject a composition comprising a polyoxazoline (POZ) conjugate, or a single dose of a pharmaceutically acceptable form thereof, according to a dosing interval over a treatment period, wherein the phytocannabinoid-polymer conjugate comprises a water-soluble POZ polymer, a phytocannabinoid attached to the POZ polymer by a physiologically degradable linkage, and optionally a pendant moiety containing a hydrophilic or hydrophobic moiety attached to the POZ polymer, and wherein the administered dose contains a therapeutically effective amount of the POZ conjugate.

[0217] In certain embodiments, the POZ conjugate comprises 1.6%±1.0% to 9.6%±1.0% of the drug (w / w of drug to POZ polymer). In certain embodiments, the dosage of the composition comprising the POZ conjugate is administered as a single dose. In certain embodiments, the dosage of the composition comprising the POZ conjugate is administered in multiple doses.

[0218] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate ranges from i) about 0.05 mg / kg to about 10 mg / kg; ii) about 0.05 mg / kg to about 8 mg / kg; iii) about 0.05 mg / kg to about 6 mg / kg; iv) about 0.05 mg / kg to about 4 mg / kg; v) about 0.05 mg / kg to about 2 mg / kg; or vi) about 0.5 mg / kg to about 8 mg / kg.

[0219] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 1 mg / kg to about 30 mg / kg; ii) about 1 mg / kg to about 25 mg / kg; iii) about 1 mg / kg to about 20 mg / kg; iv) about 1 mg / kg to about 15 mg / kg; v) about 1 mg / kg to about 10 mg / kg; or vi) about 1 mg / kg to about 5 mg / kg.

[0220] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 10 mg / kg to about 30 mg / kg; ii) about 10 mg / kg to about 25 mg / kg; iii) about 10 mg / kg to about 20 mg / kg; iv) about 10 mg / kg to about 18 mg / kg; v) about 10 mg / kg to about 16 mg / kg; or vi) about 10 mg / kg to about 14 mg / kg.

[0221] In certain embodiments, the plasma concentration of the agent in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1,500 ng / ml.

[0222] In certain embodiments, the plasma concentration of the drug in the subject exceeds the minimum therapeutic level for all or substantially all of the dosing interval or treatment period, and a single dose of the POZ conjugate is administered. In certain embodiments, the plasma concentration of the drug in the subject exceeds the minimum therapeutic level for all or substantially all of the dosing interval or treatment period, and multiple doses of the POZ conjugate are administered, and the dose interval is twice weekly or once weekly. In one aspect of these embodiments, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1,500 ng / ml.

[0223] In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous, hi certain embodiments, the administration interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0224] In one embodiment, the disclosure provides a method of treating a disorder in a subject that would benefit from agonism or antagonism of the CB1 receptor, CB2 receptor, 5H1-a receptor, 5H2-a receptor, TRP-V1 receptor, TRP-V2 receptor, TRP-V3 receptor, adenosine A2A receptor, GPR55 receptor, PPAR-α receptor, PPAR-γ receptor, or a combination of the foregoing, the method comprising administering to the subject a composition comprising a polyoxazoline (POZ) conjugate, or a single dose of a pharmaceutically acceptable form thereof, according to a dosing interval over a treatment period, the phytocannabinoid-polymer conjugate comprising a water-soluble POZ polymer, a phytocannabinoid attached to the POZ polymer by a physiologically degradable linkage, and optionally a pendant moiety containing a hydrophilic or hydrophobic moiety attached to the POZ polymer, the administered amount containing a therapeutically effective amount of the POZ conjugate. In one embodiment, the therapeutically effective amount is 0.25 mg eq / kg to 5 mg eq / kg of the phytocannabinoid.

[0225] In certain embodiments, the plant cannabinoid is cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiol monomethyl ether, cannabidiol-C4, cannabidalic acid, cannabidivarin, cannabidiol or cannabigerol propyl variants, cannabichromene, cannabichromenic acid, cannabichromevaric acid, cannabichromevarin, cannabinol, cannabicyclol, tetrahydrocannabivarin, Δ 9 -THC, adulemic acid and dexanabinol.

[0226] In certain embodiments, the POZ conjugates contain 1.6%±1.0% to 9.6%±1.0% phytocannabinoids (w / w phytocannabinoids relative to the POZ polymer). In certain embodiments, the POZ conjugates contain 1.6%±1.0% to 9.6%±1.0% CBD (w / w CBD relative to the POZ polymer).

[0227] In certain embodiments of any of the methods of treatment described herein, the dosage of the composition comprising the POZ conjugate is administered in a single dose. In certain embodiments, the dosage of the composition comprising the phytocannabinoid-polymer conjugate is administered in multiple doses.

[0228] In certain embodiments, the dose of the POZ conjugate contains between 0.25 mg eq / kg and 2.5 mg eq / kg of a phytocannabinoid. In certain embodiments, the phytocannabinoid is CBD. Such a dose may be delivered as a single dose or multiple doses.

[0229] In certain embodiments, the dose of the POZ conjugate contains between 0.25 mg eq / kg and 2.5 mg eq / kg of a phytocannabinoid, and multiple doses of the POZ conjugate are administered twice weekly or once weekly. In certain embodiments, the phytocannabinoid is CBD.

[0230] In certain embodiments, a dose of the POZ conjugate contains between 2.5 mg eq / kg and 5.0 mg eq / kg of a phytocannabinoid. In certain embodiments, the phytocannabinoid is CBD. Such a dose may be delivered as a single dose or multiple doses.

[0231] In certain embodiments, the dose of the POZ conjugate comprises between 2.5 mg eq / kg and 5.0 mg eq / kg of a phytocannabinoid, and multiple doses of the POZ conjugate are administered, with the doses administered twice weekly or once weekly. In certain embodiments, the phytocannabinoid is CBD.

[0232] In certain embodiments, the plasma concentration of phytocannabinoids in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, hi one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, or 1000 ng / ml.

[0233] In certain embodiments, the plasma concentration of the phytocannabinoid in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, the dose of the POZ conjugate comprises between 2.5 mg eq / kg and 5.0 mg eq / kg of the phytocannabinoid, and the dose is administered twice weekly or once weekly. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1500 ng / ml. In another aspect of this embodiment, the phytocannabinoid is CBD.

[0234] In certain embodiments, the plasma concentration of the phytocannabinoid in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, the dose of the POZ conjugate comprises between 0.25 mg eq / kg and 2.5 mg eq / kg of the phytocannabinoid, and the dose interval is twice weekly or once weekly. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, or 1000 ng / ml. In another aspect of this embodiment, the phytocannabinoid is CBD.

[0235] In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous, hi certain embodiments, the administration interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0236] In any of the foregoing embodiments, the disease or condition is selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, cancer pain, neurodegenerative disease, post-traumatic stress disorder, agitation associated with dementia, insomnia, REM sleep behavior disorder, excessive daytime sleepiness, nightmares associated with post-traumatic stress disorder, obstructive sleep apnea, essential tremor, Tourette's syndrome, depression, fibromyalgia, ischemic disease, stroke, cardiac ischemia, coronary artery disease, thromboembolism, myocardial infarction, brain injury, traumatic The disease is selected from the group consisting of brain injury, diffuse axonal injury, concussion, contusion, anoxic brain injury, hypoxic brain injury, age-related inflammatory disease, age-related autoimmune disease, cachexia, AIDS wasting disease, weight loss associated with cancer, weight loss associated with chronic obstructive pulmonary disease, weight loss associated with infection, nausea, vomiting, glaucoma, movement disorder, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia, and nephritis.

[0237] In any of the foregoing embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, multiple sclerosis ataxia / spasticity syndrome, dystonia associated with Parkinson's disease, dystonia associated with Huntington's disease, frontotemporal dementia, prion disease, dementia with Lewy bodies, motor neuron disease, spinal muscular atrophy, spinocerebellar ataxia, progressive supranuclear palsy, fragile X-associated tremor / ataxia syndrome, fragile X-associated behavior disorder, autism spectrum disorder, vascular The disease is selected from the group consisting of dementia, normal pressure hydrocephalus, traumatic spinal cord injury, HIV dementia, alcohol-induced neurotoxicity, Down syndrome, epilepsy, partial seizures, generalized seizures, tonic-clonic seizures, absence seizures, atonic seizures, treatment-resistant epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, Ohtahara syndrome, West syndrome, Dossé syndrome, CDKL5 encephalopathy, Landau-Kleffner syndrome, hypoxic-ischemic encephalopathy, early myoclonic epilepsy, Rett syndrome, and febrile infection-associated epilepsy syndrome.

[0238] In another embodiment, the disclosure provides a method of treating excessive GABA reuptake or a disorder characterized by GABA reuptake in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition, or a pharmaceutically acceptable dosage form thereof, comprising a polyoxazoline (POZ) conjugate, the POZ conjugate comprising a water-soluble POZ polymer, a GABA reuptake inhibitor attached to the POZ polymer by a physiologically degradable linkage, and an optional pendant moiety containing a hydrophilic or hydrophobic moiety attached to the POZ polymer.

[0239] In one embodiment, the dosages are administered according to a dosing interval over the treatment period. In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous. In certain embodiments, the dosing interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0240] In one embodiment, the GABA reuptake inhibitor is tiagabine or nipecotic acid.

[0241] In one embodiment, the excessive GABA reuptake or disorder characterized by GABA reuptake is anxiety disorder, social anxiety disorder, panic disorder, neuropathic pain (including fibromyalgia), chronic pain, muscle tremors, muscle spasms, epileptic seizures, convulsions, and epilepsy.

[0242] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate ranges from i) about 0.05 mg / kg to about 10 mg / kg; ii) about 0.05 mg / kg to about 8 mg / kg; iii) about 0.05 mg / kg to about 6 mg / kg; iv) about 0.05 mg / kg to about 4 mg / kg; v) about 0.05 mg / kg to about 2 mg / kg; or vi) about 0.5 mg / kg to about 8 mg / kg.

[0243] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 1 mg / kg to about 30 mg / kg; ii) about 1 mg / kg to about 25 mg / kg; iii) about 1 mg / kg to about 20 mg / kg; iv) about 1 mg / kg to about 15 mg / kg; v) about 1 mg / kg to about 10 mg / kg; or vi) about 1 mg / kg to about 5 mg / kg.

[0244] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 10 mg / kg to about 30 mg / kg; ii) about 10 mg / kg to about 25 mg / kg; iii) about 10 mg / kg to about 20 mg / kg; iv) about 10 mg / kg to about 18 mg / kg; v) about 10 mg / kg to about 16 mg / kg; or vi) about 10 mg / kg to about 14 mg / kg.

[0245] In another embodiment, the present disclosure provides a method of treating a dopamine-responsive state in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition, or a pharmaceutically acceptable dosage form thereof, comprising a polyoxazoline (POZ) conjugate, the POZ conjugate comprising a water-soluble POZ polymer, a drug attached to the POZ polymer by a physiologically degradable linkage, and an optional pendant moiety containing a hydrophilic or hydrophobic moiety attached to the POZ polymer.

[0246] In one embodiment, the dopamine-responsive state is a disease or condition associated with a lack of dopamine in the peripheral or central nervous system, hi one embodiment, the dopamine-responsive state is Parkinson's disease, restless legs syndrome, schizophrenia, attention deficit hyperactivity disorder, hypodopamine states, SSRI-induced sexual dysfunction, depression, obesity, and type 2 diabetes.

[0247] In one embodiment, the dosages are administered according to a dosing interval over the treatment period. In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous. In certain embodiments, the dosing interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0248] In one embodiment, the agent is an anticholinergic agent (e.g., but not limited to, trihexyphenidyl, biperiden, and hyoscyamine), a monoamine oxidase-B inhibitor (e.g., but not limited to, selegiline and rasagiline), a catechol-O-methyltransferase (COMT) inhibitor (e.g., but not limited to, tolcapone and entacapone), or adenosine A 2A In one embodiment, the drug is a dopamine agonist. Non-limiting examples of dopamine agonists include, but are not limited to, apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.

[0249] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate ranges from i) about 0.05 mg / kg to about 10 mg / kg; ii) about 0.05 mg / kg to about 8 mg / kg; iii) about 0.05 mg / kg to about 6 mg / kg; iv) about 0.05 mg / kg to about 4 mg / kg; v) about 0.05 mg / kg to about 2 mg / kg; or vi) about 0.5 mg / kg to about 8 mg / kg.

[0250] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 1 mg / kg to about 30 mg / kg; ii) about 1 mg / kg to about 25 mg / kg; iii) about 1 mg / kg to about 20 mg / kg; iv) about 1 mg / kg to about 15 mg / kg; v) about 1 mg / kg to about 10 mg / kg; or vi) about 1 mg / kg to about 5 mg / kg.

[0251] In certain embodiments, the therapeutically effective amount of the drug in the POZ conjugate is in the range of: i) about 10 mg / kg to about 30 mg / kg; ii) about 10 mg / kg to about 25 mg / kg; iii) about 10 mg / kg to about 20 mg / kg; iv) about 10 mg / kg to about 18 mg / kg; v) about 10 mg / kg to about 16 mg / kg; or vi) about 10 mg / kg to about 14 mg / kg.

[0252] In any of the methods of treatment described herein, the POZ conjugate comprises an optional pendant moiety that comprises a hydrophilic or hydrophobic moiety.

[0253] In any of the methods of treatment described herein, any of the methods for controlling the conformation of the POZ conjugate, controlling the cleavage of the drug from the POZ conjugate, controlling the release of the drug from the POZ, and / or selecting the release profile of the drug from the POZ conjugate can be used.

[0254] In any of the methods of treatment described herein, any of the POZ conjugates described herein can be used.

[0255] In any of the methods of treatment described herein, the dosage of the POZ conjugate comprises a therapeutically effective amount. In any of the methods of treatment described herein, the dosage of the POZ conjugate is administered in a therapeutically effective amount per day. Suitable therapeutically effective amounts are described in further detail herein.

[0256] In any of the methods of treatment described herein, a single dose of the POZ conjugate is administered during treatment, and the dose preferably comprises a therapeutically effective amount of the POZ conjugate. Such a dose can be administered in a single dose (qd) or in multiple doses on the same day (e.g., but not limited to, bid or tid). When the dose is divided into multiple doses on a given day, the dose can be divided evenly, or the dose can be divided unequally within each administration. Any given dose can be delivered in a single dosage form or in two or more dosage forms (e.g., tablets).

[0257] In any of the methods of treatment described herein, multiple doses of a POZ conjugate are administered during treatment, with at least one dose or all doses preferably containing a therapeutically effective amount of the POZ conjugate. Each dose can be administered as a single dose (qd), or such doses can be administered as multiple doses on the same day (e.g., but not limited to, bid or tid). When the dose is divided into multiple doses per day, the doses can be divided evenly, or the doses can be divided unequally within each administration. Any given dose can be delivered in a single dosage form or in two or more dosage forms (e.g., tablets). The therapeutically effective amount administered in each dosage need not be the same. For example, in some embodiments, a treatment course includes administering at least one loading dose and at least one maintenance dose, where the loading dose contains more POZ conjugate than the maintenance dose (e.g., but not limited to, 2- to 10-fold higher).

[0258] In any of the methods of treatment described herein, multiple doses of the POZ conjugate are administered during treatment, with treatment courses delivering doses daily, every other day, twice a week, once a week, once every 10 days, once every two weeks, once every three weeks, or once every four weeks.

[0259] In any of the methods of treatment described herein, the POZ conjugate can be administered in a pharmaceutically acceptable form. In any of the methods of treatment described herein, the POZ conjugate can be administered as part of a pharmaceutical composition.

[0260] In any of the methods of treatment described herein, the POZ conjugate is administered parenterally. In any of the methods of treatment described herein, the POZ conjugate is administered subcutaneously. In any of the methods of treatment described herein, the POZ conjugate is administered intramuscularly. In any of the methods of treatment described herein, the POZ conjugate is administered intravenously.

[0261] Methods for maintaining plasma concentrations of drugs In one embodiment, the present disclosure provides a method for achieving a plasma concentration of a drug in a subject that exceeds a minimum therapeutic level for all or substantially all of a dosing interval or treatment period, the method comprising administering to the subject, over the dosing interval, a dosage of a water-soluble polyoxazoline (POZ) polymer, a drug attached to the POZ polymer by a physiologically degradable linkage, and an optional pendant moiety attached to the POZ polymer that contains a hydrophilic or hydrophobic moiety, or a pharmaceutically acceptable form thereof.

[0262] In one embodiment, the agent is a plant cannabinoid. In one embodiment, the agent is cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiol monomethyl ether, cannabidiol-C4, cannabidalic acid, cannabidivarin, cannabidiol or cannabigerol propyl variants, cannabichromene, cannabichromenic acid, cannabichromevaric acid, cannabichromevarin, cannabinol, cannabicyclol, tetrahydrocannabivarin, Δ 9-THC, adulemic acid, and dexanabinol.

[0263] In one embodiment, the agent is an anticholinergic (e.g., but not limited to, trihexyphenidyl, biperiden, and hyoscyamine), a monoamine oxidase-B inhibitor (e.g., but not limited to, selegiline and rasagiline), a catechol-O-methyltransferase (COMT) inhibitor (e.g., but not limited to, tolcapone and entacapone), or adenosine A 2A In one embodiment, the drug is a dopamine agonist. Non-limiting examples of dopamine agonists include, but are not limited to, apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.

[0264] In one embodiment, the agent is a GABA reuptake inhibitor. Non-limiting examples of GABA reuptake inhibitors include, but are not limited to, tiagabine or nipecotic acid.

[0265] In certain embodiments, the POZ conjugate contains 1.6%±1.0% to 9.6%±1.0% phytocannabinoid (w / w of drug to POZ polymer).

[0266] In certain embodiments of any of the methods, the dose of the composition comprising the POZ conjugate is administered as a single dose. In certain embodiments, the dose of the composition comprising the POZ conjugate is administered in multiple doses.

[0267] In certain embodiments, the plasma concentration of the agent in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1,500 ng / ml.

[0268] In certain embodiments, the plasma concentration of the drug in the subject exceeds the minimum therapeutic level for all or substantially all of the dosing interval or treatment period, and a single dose of the POZ conjugate is administered. In certain embodiments, the plasma concentration of the drug in the subject exceeds the minimum therapeutic level for all or substantially all of the dosing interval or treatment period, and multiple doses of the POZ conjugate are administered, and the dose interval is twice weekly or once weekly. In one aspect of these embodiments, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1,500 ng / ml.

[0269] In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous, hi certain embodiments, the administration interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0270] In certain embodiments, the agent is a phytocannabinoid. In certain embodiments, the POZ conjugate contains 1.6%±1.0% to 9.6%±1.0% phytocannabinoid (w / w of phytocannabinoid relative to the POZ polymer). In certain embodiments, the POZ conjugate contains 1.6%±1.0% to 9.6%±1.0% CBD (w / w of CBD relative to the POZ polymer).

[0271] In certain embodiments of any of the methods of treatment described herein, the dosage of the composition comprising the POZ conjugate is administered in a single dose. In certain embodiments, the dosage of the composition comprising the phytocannabinoid-polymer conjugate is administered in multiple doses.

[0272] In certain embodiments, a dose of the POZ conjugate contains between 0.25 mg eq / kg and 2.5 mg eq / kg of a phytocannabinoid. In certain embodiments, the phytocannabinoid is CBD. Such a dose may be delivered as a single dose or multiple doses.

[0273] In certain embodiments, the dose of the POZ conjugate contains between 0.25 mg eq / kg and 2.5 mg eq / kg of a phytocannabinoid, and multiple doses of the POZ conjugate are administered, with the dosing intervals being twice weekly or once weekly. In certain embodiments, the phytocannabinoid is CBD.

[0274] In certain embodiments, the dose of the POZ conjugate contains between 2.5 mg eq / kg and 5.0 mg eq / kg of a phytocannabinoid. In certain embodiments, the phytocannabinoid is CBD. Such a dose may be delivered as a single dose or multiple doses.

[0275] In certain embodiments, the dose of the POZ conjugate contains between 2.5 mg eq / kg and 5.0 mg eq / kg of a phytocannabinoid, and multiple doses of the POZ conjugate are administered, with the doses administered twice weekly or once weekly. In certain embodiments, the phytocannabinoid is CBD.

[0276] In certain embodiments, the plasma concentration of phytocannabinoids in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, hi one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, or 1000 ng / ml.

[0277] In certain embodiments, the plasma concentration of the phytocannabinoid in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, the dose of the POZ conjugate comprises between 2.5 mg eq / kg and 5.0 mg eq / kg of the phytocannabinoid, and the dose is administered twice weekly or once weekly. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, 1000 ng / ml, or 1500 ng / ml. In another aspect of this embodiment, the phytocannabinoid is CBD.

[0278] In certain embodiments, the plasma concentration of the phytocannabinoid in the subject exceeds the minimum therapeutic level during all or substantially all of the dosing interval or treatment period, the dose of the POZ conjugate comprises between 0.25 mg eq / kg and 2.5 mg eq / kg of the phytocannabinoid, and the dose interval is twice weekly or once weekly. In one aspect of this embodiment, the minimum therapeutic level is 5 ng / ml, 50 ng / ml, 150 ng / ml, 500 ng / ml, or 1000 ng / ml. In another aspect of this embodiment, the phytocannabinoid is CBD.

[0279] In certain embodiments, the treatment period is from 7 days to 60 months, or the treatment period is continuous, hi certain embodiments, the administration interval is daily, every other day, twice a week, once a week, once every two weeks, or once every four weeks.

[0280] In any of the above methods, the POZ conjugate comprises an optional pendant moiety that comprises a hydrophilic or hydrophobic moiety.

[0281] In any of the above methods, any of the methods for controlling the conformation of the POZ conjugate, controlling the cleavage of the drug from the POZ conjugate, controlling the release of the drug from the POZ conjugate, and / or selecting the release profile of the drug from the POZ conjugate can be used.

[0282] In any of the above methods, any of the POZ conjugates described herein can be used.

[0283] In any of the above methods, the dose of the POZ conjugate comprises a therapeutically effective amount. In any of the above methods, the dose of the POZ conjugate is administered in a therapeutically effective amount per day. Suitable therapeutically effective amounts are described in further detail herein.

[0284] In any of the above methods, a single dose of the POZ conjugate is administered during the treatment course, and the dose preferably comprises a therapeutically effective amount of the POZ conjugate. Such a dose can be administered in a single dose (qd) or in multiple doses on the same day (e.g., but not limited to, bid or tid). When the dose is divided into multiple doses on a given day, the dose can be divided evenly, or the dose can be divided unequally within each administration. Any given dose can be delivered in a single dosage form or in two or more dosage forms (e.g., tablets).

[0285] In any of the above methods, multiple doses of the POZ conjugate are administered during the treatment course, with at least one dose or all doses preferably comprising a therapeutically effective amount of the POZ conjugate. Each dose can be administered as a single dose (qd), or such doses can be administered as multiple doses on the same day (e.g., but not limited to, bid or tid). When the dose is divided into multiple doses per day, the doses can be divided equally, or the doses can be divided unequally within each dose. Any given dose can be delivered in a single dosage form or in two or more dosage forms (e.g., tablets). The therapeutically effective amount administered in each dosage need not be the same. For example, in some embodiments, the treatment course includes administering at least one loading dose and at least one maintenance dose, where the loading dose contains more POZ conjugate than the maintenance dose (e.g., but not limited to, 2- to 10-fold higher).

[0286] In any of the above methods, multiple doses of the POZ conjugate are administered during a treatment course, the treatment course delivering a dose every day, every other day, twice a week, once a week, once every 10 days, once every two weeks, once every three weeks, or once every four weeks.

[0287] In any of the above methods, the POZ conjugate can be administered in a pharmaceutically acceptable form. In any of the above methods, the POZ conjugate can be administered as part of a pharmaceutical composition.

[0288] In any of the above methods, the POZ conjugate is administered parenterally. In any of the above methods, the POZ conjugate is administered subcutaneously. In any of the above methods, the POZ conjugate is administered intramuscularly. In any of the above methods, the POZ conjugate is administered intravenously.

[0289] Pharmaceutical Compositions and Routes of Administration Pharmaceutical compositions are provided that include an amount of a conjugate of the present disclosure. In one embodiment, such pharmaceutical compositions contain a therapeutically effective amount of a conjugate of the present disclosure. In certain embodiments, the conjugate of the present disclosure is a conjugate of Formula I. In addition, other active agents may be included in such pharmaceutical compositions. The additional active agents included can be selected based on the disease or condition being treated.

[0290] The disclosed pharmaceutical compositions can include one or more conjugates of the present disclosure, alone or in combination with additional active agents, in combination with a pharmaceutically acceptable carrier. Examples of such carriers and methods of formulation can be found in Remington's Science and Practice of Pharmacy (23rd Edition, ISBN 9780128200070) and Handbook of Pharmaceutical Excipients (8th Edition, 978-0-85-711271-2). Such conjugates and pharmaceutical compositions can be used to manufacture medicaments for use in the treatment methods described herein. The conjugates of the present disclosure are useful in both free form and pharmaceutically acceptable salt form.

[0291] Pharmaceutically acceptable carriers described herein, including but not limited to vehicles, adjuvants, excipients, or diluents, are well known to those skilled in the art. Pharmaceutically acceptable excipients are also well known to those skilled in the art. The choice of excipient is determined in part by the particular conjugate(s) and the particular method used to administer the formulation. Thus, there are a wide variety of suitable formulations of pharmaceutical compositions. The following methods and excipients are merely exemplary and in no way limiting. Suitable carriers and excipients include solvents such as water, alcohol, polyethylene glycol, glycofurol, and propylene glycol, solid absorbents and diluents, surfactants, suspending agents, tableting binders, lubricants, flavorings, and coloring agents. Pharmaceutically acceptable carriers can include polymers and polymer matrices. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water. Typically, a pharmaceutically acceptable carrier is chemically inert to the active agent in the composition and has no adverse side effects or toxicity under the conditions of use. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal regulatory agency or state government, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia, for use in animals, more particularly in humans.

[0292] In one embodiment, such pharmaceutical compositions contain a therapeutically effective amount of a POZ conjugate of the present disclosure. In certain embodiments, the POZ conjugate is a conjugate of Formula I. In addition, other active agents may be included in such pharmaceutical compositions. The additional active agents included can be selected based on the disease or condition being treated.

[0293] The disclosed pharmaceutical compositions can include one or more of the disclosed POZ conjugates, alone or in combination with additional active agents, in combination with a pharmaceutically acceptable carrier.

[0294] The POZ conjugates of the present disclosure and pharmaceutical compositions containing such POZ conjugates can be administered by any conventional method available for use with pharmaceuticals, either as individual therapeutic agents or in combination with additional therapeutic agents. Suitable methods are available for administering the conjugates of the present disclosure to patients, either alone or as pharmaceutical formulations, and while more than one route can be used, those skilled in the art will recognize that certain routes may provide a more immediate and effective response than others.

[0295] In one embodiment, the conjugate of the present disclosure, alone or as part of a pharmaceutical composition, is administered in a therapeutically effective amount. The therapeutically effective amount and dosage administered will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health, and weight of the recipient, the severity and stage of the disease state or condition, the type of concurrent treatment, the frequency of treatment, and the desired effect.

[0296] The total amount of the POZ conjugate administered, alone or as part of a pharmaceutical composition, will also be determined by the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the conjugate and the desired physiological effect. It will be recognized by those skilled in the art that various conditions or pathologies, particularly chronic conditions or pathologies, may require long-term treatment, including multiple administrations.

[0297] In one embodiment of the pharmaceutical composition, the POZ conjugate(s) of the present disclosure are typically present in an amount of about 0.5-95% by weight based on the total weight of the composition. Multiple dosage forms may be administered as part of a single treatment.

[0298] The POZ conjugates of the present disclosure can be administered enterally, alone or as part of a pharmaceutical composition, in solid dosage forms such as capsules, tablets, and powders, or in liquid dosage forms such as milk, elixirs, syrups, and suspensions. The conjugates of the present disclosure can also be administered parenterally in sterile liquid dosage forms, alone or as part of a pharmaceutical composition. The conjugates of the present disclosure can also be administered intranasally (nose drops) or via the pulmonary system by inhalation, for example, via a spray-based metered-dose inhaler or dry powder inhalation device, either alone or as part of a pharmaceutical composition. Other dosage forms include topical administration, for example, transdermal administration via a patch mechanism or ointment.

[0299] Formulations suitable for enteral or oral administration may be liquid solutions, e.g., a therapeutically effective amount of the conjugate dissolved in a diluent, such as milk, water, saline, buffer, infant formula, other suitable carrier, or a combination thereof. Thus, the conjugate may be mixed with a diluent immediately prior to administration. In alternative embodiments, formulations suitable for enteral or oral administration may be capsules, sachets, tablets, lozenges, and troches. In each embodiment, the formulation may contain a predetermined amount of the conjugate of the present disclosure as a solid or granular form, a powder, a suspension, or a suitable emulsion. Liquid formulations may contain diluents, e.g., water and alcohols, e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, and polyethylene alcohol, with or without a pharmaceutically acceptable surfactant, suspending agent, or emulsifier. Capsule forms may be, for example, conventional hard- or soft-shell gelatin types containing surfactants, lubricants, and inert fillers, e.g., lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacologically compatible carriers.

[0300] Lozenge forms can include the conjugate in a flavoring agent, usually sucrose and acacia or tragacanth; pastilles, which include the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia; emulsions and gels containing such carriers in addition to the active ingredient are known in the art.

[0301] For parenteral administration, the POZ conjugate can be combined with a sterile aqueous solution isotonic with the subject's blood. Such formulations can be prepared by dissolving the POZ conjugate in water containing physiologically compatible substances, such as sodium chloride and glycine, and having a buffered pH compatible with physiological conditions to form an aqueous solution, followed by sterilization of the solution. The formulation can be presented in a unit-dose form, such as a sealed ampoule or vial. The formulation can be delivered by any injection mode, including, without limitation, epifascial, intracapsular, intracerebral, intradermal, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, soft tissue, subcutaneous, or sublingual route, or by a catheter into the subject's body. The preferred injection mode is subcutaneous.

[0302] Parenteral administration includes aqueous and non-aqueous-based solutions. Examples include water, saline, aqueous sugar or sugar alcohol solutions, alcohols (e.g., ethyl alcohol, isopropanol, glycols), ethers, oils, glycerides, fatty acids, and fatty acid esters. In some embodiments, water is used for parenteral administration. In some embodiments, saline is used for parenteral administration. Oils for parenteral injection include animal, vegetable, synthetic, and petroleum-based oils, mineral oil, petrolatum, soybean, corn, cottonseed, peanut, and the like. Examples of sugars for solutions include sucrose, lactose, glucose, mannose, and the like. Examples of fatty acids and esters include oleic acid, myristic acid, stearic acid, isostearic acid, and their esters. Parenteral formulations can also be sterile lyophilized powders that require reconstitution in WFI, normal saline, or 5% glucose solution. The lyophilized powder contains the drug together with excipients such as monosaccharides, disaccharides, and trisaccharides. Examples include glucose, sucrose, raffinose, trehalose, mannitol, sorbitol, etc. Such formulations for parenteral administration may also contain pharmaceutically acceptable surfactants such as a soap or detergent, suspending agents such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0303] Parenteral formulations typically contain about 0.5% to about 50% by weight of the conjugate in solution. Suitable preservatives and buffers can be used in such formulations. To minimize or eliminate irritation at the injection site, such compositions can contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol.

[0304] method material Ethyl oxazoline monomer was purchased from Polymer Chemistry Innovation, Tucson, Arizona. Functional pentynyl monomers were prepared at Serina Therapeutics. Solvents used for the synthesis and extraction of polymers and polymer conjugates were ACS anhydrous grade or higher and were obtained from EMD Chemicals. Initiators, reagents, and catalysts used for the synthesis of polymers and polymer conjugates were obtained from Sigma-Aldrich, St. Louis, MO. Samples of active molecules used in POZ conjugation included rotigotine (obtained from Sai Chemicals, Hyderabad, India), cannabidiol, Δ 9 -THC, cannabigerol, and buprenorphine (obtained from PuriSys / Noramco, Wilmington, DE) and dexanabinol (from Cayman Chemical, Ann Arbor, MI). Polyethylene glycol (PEG) reagents with four-arm and eight-arm chains were obtained from Creative PEGWorks, Chapel Hill, NC, and dextran six-arm polymers were synthesized at Serina Therapeutics.

[0305] In vitro release of drugs from polymer conjugates Approximately 50 mg of a sample of POZ / PEG / dextran drug conjugate was accurately weighed and added to a 5 mL volumetric flask, and 5% w / w glucose solution was added to dissolve and dilute the sample. Under a laminar flow hood, 300 μL of this solution was added to 3 mL of chilled plasma (rat, monkey, or human) and gently mixed by inversion several times. Using an Eppendorf pipettor, 200 μL of the plasma solution was aliquoted into separate screw-cap microcentrifuge tubes and incubated at 37°C in a shaking water bath to allow in vitro hydrolysis of the drug from the POZ conjugate. Experiments were performed in triplicate.

[0306] At each time point, a series of tubes was removed and the samples were quenched by adding 1000 μL of 0.1% trifluoroacetic acid (TFA) in acetonitrile (ACN). The suspension was vortexed to extract the POZ-drug conjugate and released drug from the disrupted plasma proteins. The solution was centrifuged at 14,000 rpm for 5 minutes, and the supernatant (500 μL) was added to 500 μL of 0.1% TFA in HO and placed in an HPLC vial.

[0307] Samples were analyzed by HPLC using a Zorbax 300SB C-8 column, 5 mm × 4.6 × 150 mm, and a UV detector, with gradient elution using 0.1% TFA in HO (mobile phase A) and 0.1% TFA in acetonitrile (mobile phase B). Standard curves were generated for each drug tested using peak area versus concentration curve to determine the concentration of hydrolyzed drug at each time point.

[0308] Chemical synthesis of POZ-cyanine-5 (POZ-Cy5) conjugates POZ polymer conjugates of different molecular weights containing cyanine-5 as the agent were synthesized as described below. Poly(2-ethyl-2-oxazoline) (PEOZ) polymers with an average of 10 alkyne pendants per POZ polymer were synthesized as described in Example 1. Cyanine 5-azide-fluorophore (Cy5, Lumiprobe Corp, Hunt Valley, MD) was attached to the alkyne pendants of the POZ polymer using a quantitative "click chemistry" reaction (generally described in Example 2). The average number of Cy5 fluorophores attached to each POZ polymer ranged from 1.4 to 1.8. 1 The purity of each compound was determined by RP-HPLC.

[0309] Pharmacokinetics of POZ polymers with different molecular weights The pharmacokinetics of different molecular weight POZ polymer conjugates (10, 20, 30, 40, and 60 kDa) was investigated in male Sprague-Dawley rats using the POZ-Cy5 conjugate (synthesized as described herein). The in-house institutional animal care and use committee (IACUC) reviewed and approved the experimental protocol before the start of the experiment. After arrival at the animal facility, rats were placed in rat cages and allowed to acclimate for at least 3 days before the start of dosing. Thirty animals were divided into 10 groups, with three animals per group. Five groups of rats were placed in a restraining device, and the POZ-Cy5 conjugate was intravenously injected into the tail vein of each animal using a 25G BD precision Glide needle. The remaining five groups of rats received the POZ-Cy5 conjugate via subcutaneous injection (using a restraining device) into the left flank using a 23G BD precision glide needle. The dose was 10 mg / kg, the dose volume was 1 mL / kg (approximately 0.25 mL), and the duration of each injection was approximately 10–15 seconds. Serial venous blood samples (100 μL) were collected from the tail vein of each animal at the following time points: 0.25, 1, 3, 8, 12, 24, 48, 72, 96, 120, 144, 168, 240, 336, 408, 504, 576, and 672 hours post-dose. Blood was transferred to a 1.5 mL Eppendorf tube containing a fixed volume (150 μL) of 1x PBS with 1.2% 0.2 N EDTA solution. The sample was quickly mixed by repeated pipetting up and down. The samples were immediately placed on ice and covered to minimize exposure to light. The samples were then centrifuged at 10,000 rpm at 4°C for 3 minutes. The supernatant (100 μL) from each tube was removed and placed in a cryotube. The samples were immediately frozen on dry ice and then transferred to a -80°C freezer.

[0310] The amount of POZ-Cy5 conjugate in each sample was measured using fluorescence spectrophotometry. The excitation and emission wavelengths of the Cy5 fluorophore were 650 nm and 670 nm, respectively. Aliquots of the thawed samples were placed in a 96-well plate, and absorbance data were recorded between 660 and 750 nm at 1 nm intervals.

[0311] Stock solutions were prepared for each molecular weight of POZ-Cy5 conjugate by dissolving a known weight of the conjugate in PBS-EDTA stock solution. Dilutions of the stock solution were made in PBS-EDTA to yield final concentrations of 20, 10, 5, 1, 0.5, 0.1, and 0.05 μg / mL. 150 μL of each standard solution was placed in a 1.5 mL centrifuge tube, and 50 μL of freshly drawn whole blood was placed in each tube. The solution was gently mixed and centrifuged at 3000 rpm for 3 minutes. 75 μL of the supernatant from each standard was pipetted and placed in the top row of a 96-well plate. Standards were prepared fresh each day before each measurement. One plate was prepared for each molecular weight of POZ-Cy5 conjugate. The plates were placed in the spectrophotometer holder at a time, and emission absorbance values ​​were recorded at 670 nm with signal gains set at 80, 100, 120, and 150 (Au). A calibration curve equation (peak area vs. concentration curve with linear regression) was calculated for each POZ molecular weight standard. These measurements were performed in duplicate for each time point. Plasma concentrations of POZ Cy5 at each time point were calculated from this equation.

[0312] Pharmacokinetics of drug released from POZ conjugates After a single subcutaneous injection of each of these POZ conjugates with different linkers and drug loadings (wt%), plasma levels of drug released into the bloodstream were measured in rodents (Sprague-Dawley rats) and non-human primates (Macaca fascicularis, cynomolgus monkeys). The in-house Institutional Animal Care and Use Committee (IACUC) reviewed and approved each experimental protocol before the start of the experiment.

[0313] Male untreated Sprague-Dawley rats (8-9 weeks old, body weight 200-250 g) were obtained and placed in rat cages. They were allowed to acclimate for at least 3 days before the start of dosing. Each test group contained three rats. POZ conjugate was dissolved in 5% glucose injection, and the pH of the solution was adjusted to approximately 4.0 with 0.1 N hydrochloric acid. Each animal received a single subcutaneous (SC) injection of the test solution into the left flank using a 23G BD precision glide needle at a dose equivalent to 1.5-1.6 mg / kg (drug equivalent basis) and a volume of 1 mL / kg. The duration of each injection was approximately 10-15 seconds. Serial venous blood samples of 400-500 μL were collected from the tail vein of each animal at the following time points: 3, 6, 12, 24, 48, 72, 96, and 168 hours post-dose. All blood samples were collected into pre-labeled BD Microtiter tubes containing NaF / disodium EDTA, mixed gently, and placed in an ice bath. Plasma was collected by centrifugation at 3000 rpm for 15 minutes at 4°C. 100 μL of plasma aliquots were collected into separate tubes containing 10 μL of 3N HCl acid solution, mixed gently, immediately frozen, and stored at -70°C.

[0314] Previously treated female cynomolgus monkeys (age >2 years, weight 2.5-3.5 kg) were obtained and placed in cages for the experiment. Animals (n=3 per group) had a washout period of at least 30 days after the completion of the previous experiment. POZ conjugate was dissolved in 5% glucose injection, and the pH of the solution was adjusted to approximately 4.0 with 0.1 N hydrochloric acid. Each animal received a single subcutaneous (SC) injection of the test solution into the right shoulder using a 23G BD precision glide needle at a dose equivalent to 1.5 mg / kg (drug equivalent basis) and a volume of 0.3 mL / kg. The duration of each injection was approximately 10-15 seconds. Approximately 1000 μL of blood samples were collected from a peripheral vein of each animal at the following time points: 3, 6, 12, 24, 48, 72, 96, 120, 144, 168, 240, and 336 hours post-dose. All blood samples were collected into pre-labeled BD Microtiter tubes containing NaF / disodium EDTA, mixed gently, and placed in an ice bath. Plasma was collected by centrifugation at 3000 rpm for 15 minutes at 4°C. 250 μL of plasma aliquots were collected into separate tubes containing 10 μL of 3N HCl acid solution, mixed gently, immediately frozen, and stored at -70°C.

[0315] Plasma samples were processed using cold acetonitrile with a "protein crush" method. Samples were mixed and centrifuged at 13,000 rpm for 15 minutes, and the organic phase was sampled and assayed for either rotigotine, buprenorphine, or cannabidiol using a standard LC-MS / MS method. Internal standards of rotigotine-d3, buprenorphine-d4, and cannabidiol-d3 were used in the assay.

[0316] Chemical synthesis of POZ and POZ conjugates Methods for the synthesis of POZ polymers and POZ polymer conjugates have been described in the art. POZ polymers are generally prepared by reacting an appropriate stoichiometric amount of one or more 2-alkyl-2-oxazoline monomers with an electrophilic initiator (e.g., but not limited to, methyl triflate; MeOTF) or a strong acid (e.g., triflic acid; HOTf), followed by termination with a nucleophile (e.g., but not limited to, a mercaptan / mercaptide, hydroxide, thiol, or amine). Exemplary mercaptans include, but are not limited to, mercapto-esters (e.g., but not limited to, S-CHCH-COCHCH) and mercapto-protected amines (e.g., but not limited to, -S-CHCH-NH-tBoc). In certain embodiments, when a mercapto-ester is used as a terminating agent, efficient, extensive purification by ion exchange chromatography (to remove impurities, e.g., secondary amines) after hydrolysis of the ester can be used to generate carboxylic acids or other groups suitable for use in ion exchange chromatography. The resulting POZ polymer exhibits low polydispersity and low levels of impurities. The nature of the 2-alkyl-2-oxazoline monomers used to generate the POZ polymer can be the same, resulting in a homopolymer (e.g., but not limited to, poly(methyloxazoline) or poly(ethyloxazoline)). Two or more 2-alkyl-2-oxazoline monomers can be used to generate the POZ polymer, resulting in a copolymer, e.g., but not limited to, a random copolymer or a block copolymer.

[0317] Methods for synthesizing POZ polymers having a single functional group on the terminus of the polymer are described in U.S. Pat. No. 7,943,141, and methods for synthesizing POZ polymers having pendant functional groups and POZ polymer conjugates having drugs attached to the pendant functional groups are described in U.S. Pat. No. 8,393,093, which is specifically incorporated herein for such teachings.

[0318] An exemplary synthesis of a POZ random copolymer is provided below. The desired 2-alkyl-2-oxazoline monomers (e.g., 2-(4-pentynyl)-2-oxazoline; PtynOZ; ethyl oxazoline; EOZ; and methyl t-propionate oxazoline; TMPOZ) are prepared in a suitable solvent (e.g., chlorobenzene) at room temperature. The percentage of each monomer is controlled by reacting appropriate stoichiometric amounts of the 2-alkyl-2-oxazoline monomers. To this solution, an initiator (e.g., MeOTF) is added, as described below. The solution is stirred at room temperature for a period of time (e.g., 5 minutes to 120 minutes) and then heated (e.g., at 70°C to 130°C for 10 minutes to 12 hours). The mixture is cooled to 0°C and then terminated using the desired nucleophile (e.g., a mercaptoester). The mixture is stirred to terminate the polymerization reaction. The POZ polymer is then recovered.

[0319] An exemplary synthesis of a POZ block polymer is provided below. An initiator (e.g., MeOTf) is added to a solution of a first 2-alkyl-2-oxazoline monomer (e.g., PtynOZ) in a suitable solvent (e.g., chlorobenzene) at room temperature. The solution is stirred at room temperature for a period of time (e.g., 5 to 120 minutes) and then heated (e.g., at 70°C to 130°C for 10 minutes to 12 hours). A second 2-alkyl-2-oxazoline monomer (e.g., EOZ) is added to the reaction, and the mixture is stirred and heated (e.g., at 70°C to 130°C for 10 minutes to 12 hours). The mixture is cooled to room temperature and quenched by the addition of piperidine (0.4 mL, 0.004 mol). The mixture is stirred to quench the polymerization reaction. The POZ polymer is then recovered.

[0320] Exemplary syntheses of random POZ polymers with pendant functional groups and POZ conjugates are provided in Examples 1 and 2 herein. [Example]

[0321] [Example 1] Random H-[(Ptyn) 10 (EOZ) 190Exemplary Synthesis of ]-T-CO2H(POZ10p20k)

[0322] [ka]

[0323] In this example, H-[(Ptyn) 10 (EOZ) 190 The synthesis of ]-T-COH is described here. However, other POZ polymers with different molecular weights, different initiating and terminal groups, and different groups at the pendant positions can also be produced by this method. Additionally, in addition to the random copolymers described in this example, block copolymers can also be produced.

[0324] H-[(Ptyn) 10 (EOZ) 190 For the synthesis of ]-T-COH, triflic acid (HOTf, 173.3 μL, 1.96 mmol) was added to a solution of 2-pentynyl-2-oxazoline (PtynOZ, 3.76 g, 27.4 mmol, 14 equiv.) and 2-ethyl-2-oxazoline (EOZ, 46.61 g, 470.2 mmol, 240 equiv.) in chlorobenzene (124 mL). After stirring for 5 minutes at room temperature, the mixture was heated to 80 °C for 10 hours and then cooled to room temperature. In a separate flask, the terminating reagent was prepared by the dropwise addition of methyl 3-mercaptopropionate (1.23 mL, 0.0114 mol) to a suspension of sodium hydride (60% in mineral oil, 0.272 g, 0.0068 mol) in chlorobenzene (34 mL). The mixture was stirred for 7 hours and then H-(Ptyn) 10 (EOZ) 200 +A solution of living polymer was added. The resulting mixture was then stirred for 18 hours. The solvent was removed by rotary evaporation to produce a white residue. This residue was dissolved in water, and the pH was adjusted to 12.0. The resulting aqueous solution was purified by ion exchange chromatography using DEAE Sepharose FF. The aqueous solution was saturated with NaCl (15% w / w) and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated using a rotary evaporator. The residue was precipitated by adding the dichloromethane concentrate to diethyl ether. The precipitated material was collected and dried under vacuum to give 22.8 g of the desired product as a white powder (50% yield).

[0325] 1 H NMR (Varian, 500 MHz, 10 mg / mL CDC13) showed the usual backbone peaks at 1.13 ppm (m, 3H, CH3CH2CO-); 2.32 ppm (m) and 2.41 (s) (full region 2H, CH3CH2CO-); and 3.47 ppm (m, 4H, -NCH2CH2N-). End group peaks appear at 2.63 ppm (m, 2H, -SCH2CH2CO2H), 2.74 ppm (m, 2H, -CH2SCH2CH2CO2H), and 2.85 ppm (m, 2H, -SCH2CH2CO2H). Pendant pentynyl group peaks appear at 1.85 ppm (m, 2H, -CH2CH2C≡CH) and 2.03 ppm (br s, 1H, -CH2CH2C≡CH). The number of pendant groups, Ptyn, was determined to be 8.5 by comparing the integrals of the terminal acetylene protons and the polymer backbone protons. GPC gave Mn = 19,500 Da and Mp = 20,800 Da, with a PDI of 1.07.

[0326] Example 2: General preparation of POZ conjugates The synthesis of POZs bearing pendant functional groups and pendant releasable drugs (usually ester linkers to phenolic drugs) via the route shown in the reaction scheme below has been described in several inventors' publications and patents [4,7].

[0327] [ka]

[0328] POZ conjugates of phenolic drugs, as shown in Figure 1, were prepared using this procedure. An azidoalkyl carboxylic acid linker was first coupled to the phenolic -OH of the small molecule drug to generate a monoester. Drugs such as cannabidiol and cannabigerol have two latent phenolic -OH groups, and the diester formed was removed by preparative chromatography. The azidoalkyl esters of these drugs were then "clicked" onto the pentynyl pendants of the POZ polymer. Examples of alkyl carboxylic acid linkers include, but are not limited to, acetic acid, 2-propionic acid, and 3-propionic acid. The number of drug molecules loaded can vary and depends on the number of equivalents (equivalents) of drug-linker-azide used in the click reaction. When 10 equivalents were used, conjugates were found to fully click onto all 10 pendants of the POZ polymer chain. Conjugates with lower drug loadings were also prepared using less than 10 equivalents, i.e., 8 and 6 equivalents of drug-linker-azide compound. The percentage of drug loading (% w / w) was assayed by chromatography and then calculated using the molecular weight of the small molecule drug.

[0329] PEG and dextran conjugates of rotigotine were also prepared using click chemistry conditions similar to those used for the POZ polymer, and the procedures for purifying and assaying these conjugates were the same.

[0330] Example 3: The presence of hydrophilic propionic acid pendant moieties increases the rate of hydrolysis As discussed above, it is hypothesized that the presence of a hydrophilic pendant moiety increases the rate of hydrolysis of the drug from the POZ polymer conjugate, resulting in a shorter half-life of the POZ polymer conjugate in vivo. To determine whether the hydrophilic pendant moiety affected the in vitro hydrolysis rate of the drug from the POZ polymer conjugate, two pairs of paired POZ polymer conjugates with a 2-propionate linker containing cannabidiol (CBD) as the drug were prepared with and without a hydrophilic propionic acid pendant moiety (POZ-CBD conjugates).

[0331] The first pair of POZ-CBD conjugates contained six pendant CBD molecules, with and without four pendant propionic acid groups. The second pair of POZ-CBD conjugates contained eight pendant CBD molecules, with and without two pendant propionic acid groups. The structures of the POZ-CBD conjugates are shown below:

[0332] [ka] [In the formula, o is 6 for the first pair of POZ-CBD conjugates or 8 for the second pair of POZ-CBD conjugates; p is 190; a is random; R is H; R3 is -CH2CH3; m is 4 for the first pair of POZ-CBD conjugates or 2 for the second pair of POZ-CBD conjugates; Z is

[0333] [ka] (if the POZ-CBD conjugate lacks a hydrophilic propionic acid group) or

[0334] [ka] (When the POZ-CBD conjugate contains a hydrophilic propionic acid group) either].

[0335] The half-life (t 1 / 2 ) was determined as described in the Methods section herein. The results are presented in Figure 2 and the table below. Figure 2 shows that in POZ-CBD conjugates with hydrophilic pendant moieties, the CBD molecule hydrolyzed faster from the POZ-CBD conjugate compared to POZ-CBD conjugates without hydrophilic moieties. The half-life for each conjugate is shown in the table below:

[0336] [Table 1]

[0337] For the POZ-CBD conjugates with six pendant CBD molecules, the presence of hydrophilic pendant moieties 1 / 2 The hydrolysis time was reduced from 64 to 54 hours, indicating a more rapid hydrolysis of the CBD molecules from the POZ-CDB conjugate. The same increased hydrolysis rate was also observed for the POZ-CDB conjugate with eight pendant CBD molecules, where the presence of two hydrophilic pendant moieties increased the hydrolysis time. 1 / 2 The t decreased from 87 hours to 74 hours, again indicating a more rapid hydrolysis of the CBD molecules from the POZ-CBD conjugate. Furthermore, as discussed above, increasing drug loading (from 6 to 8 CBD molecules) reduced the hydrolysis rate. The POZ-CBD conjugate with 8 pendant CBD molecules showed an increased t compared to the POZ-CBD conjugate with 6 pendant CBD molecules. 1 / 2 (both with and without the presence of hydrophilic pendants).

[0338] Example 4: The presence of hydrophilic PEG pendant moieties increases the rate of hydrolysis To further investigate the role of hydrophilic pendant moieties on the in vitro hydrolysis rate of drugs from POZ polymer conjugates, POZ-CBD conjugates were prepared with and without hydrophilic propionic acid pendant moieties and polyethylene glycol (PEG7-OH). Different batches of human female plasma were used in this Example 4 compared to Example 3. The half-lives measured for certain POZ-CBD conjugates used in both Examples were slightly different, but the trends remained the same. The slight differences were attributed to different levels of butyrylcholinesterase activity in the blood.

[13]

[0339] POZ-CBD conjugates with eight pendant CBD molecules were prepared, along with POZ-CBD conjugates with eight pendant CBD molecules and either i) two pendant propionic acid groups; or ii) two pendant PEG7-OH moieties. POZ-CBD conjugates with ten pendant CBD molecules and no hydrophilic pendants were also prepared. The structures of the POZ-CBD conjugates are as shown in Example 5, except that when the POZ-CBD conjugate contains a hydrophilic group, Z is:

[0340] [ka] or

[0341] [ka] Except that it is one of the following.

[0342] t of each POZ-CBD conjugate 1 / 2was determined as described in the Methods section herein. The results are presented in the table below and show that in POZ-CBD conjugates with hydrophilic pendant moieties, the CBD molecule hydrolyzes faster from the POZ-CBD conjugate compared to POZ-CBD conjugates without hydrophilic pendant moieties. The half-life for each conjugate is shown in the table below:

[0343] [Table 2]

[0344] For the POZ-CBD conjugate with 10 pendant CBD molecules, t 1 / 2 At 70 hours, the t of the POZ-CBD conjugate with eight pendant CBD molecules 1 / 2 It has increased more.

[0345] For the POZ-CBD conjugates with eight pendant CBD molecules, the presence of the hydrophilic propionic acid pendant moiety 1 / 2 The presence of the hydrophilic PEG7-OH pendant moiety reduced the t 1 / 2 The hydrolysis time was reduced from 61 hours to 39 hours. These results again indicate a more rapid hydrolysis of the CBD molecules from the POZ-CDB conjugate. Furthermore, these results demonstrate that various hydrophilic pendant moieties are effective in increasing the hydrolysis rate, as pendant propionic acid and pendant PEG7-OH groups were equally effective.

[0346] Example 5: Presence of hydrophilic pendant moieties on POZ conjugates bearing relatively hydrophilic drugs To further investigate the role of hydrophilic pendant moieties on the in vitro hydrolysis rate of the drug from POZ polymer conjugates, POZ polymer conjugates of buprenorphine (POZ-BUP) bearing a 3-propionate linker, with and without hydrophilic propionic acid pendant moieties and polyethylene glycol (PEG7-OH), were prepared.

[0347] POZ-BUP conjugates with eight pendant BUP molecules were prepared, along with POZ-BUP conjugates with eight pendant BUP molecules and either i) two pendant propionic acid groups; or ii) two pendant PEG7-OH moieties. POZ-BUP conjugates with 10 pendant BUP molecules and no hydrophilic pendants were also prepared. The structures of the POZ-BUP conjugates are shown below, where o = 10 or 8, p = 190, a = random, R = H, R = -CH2CH3, m = 2 or = 0 (if the POZ-BUP conjugate does not contain hydrophilic pendants), and Z is

[0348] [ka] (when the POZ-BUP conjugate lacks a hydrophilic group) or

[0349] [ka] (When the POZ-BUP conjugate contains a hydrophilic group) either].

[0350] [ka]

[0351] t of each POZ-BUP conjugate 1 / 2 was determined as described in the Methods section herein, and the results are presented in the table below.

[0352] [Table 3]

[0353] In this case, human plasma hydrolysis rates showed the following pattern: 10BUP pendant, 17 hours; 8BUP pendant, 11 hours; 8BUP and 2 propionic acid pendants, 14 hours; and 8BUP and 2 PEG7-OH pendants, 12 hours. Thus, conjugates with pendant propionic acid and pendant PEG have approximately the same hydrolysis rates, but they do not hydrolyze any faster than the corresponding conjugates without these pendants. This result, in contrast to the results above for cannabidiol conjugates, appears to contradict the folding hypothesis.

[0354] Buprenorphine and cannabidiol conjugates do exhibit some interesting differences in physical properties. Buprenorphine is more hydrophilic than cannabidiol (LogP at 25°C). oct / wat In this study, it was observed that buprenorphine conjugates readily dissolve in aqueous media, whereas cannabidiol conjugates dissolve slowly in buffers and are sparingly soluble in water. In addition, cannabidiol conjugates with very high drug loadings tend to exhibit "cloud point" behavior [14-16]. Based on these differences, it is not surprising that plasma hydrolysis occurs much more rapidly for buprenorphine conjugates than for cannabidiol conjugates, indicating that the buprenorphine conjugates are less tightly folded and more open to enzymatic access.

[0355] In view of the foregoing, tightly folded conjugates, e.g., conjugates formed with the relatively hydrophobic cannabidiol, will respond to the introduction of inert hydrophilic groups and will swell substantially upon the introduction of these groups, whereas loosely folded conjugates, e.g., conjugates formed with the relatively hydrophilic buprenorphine, will not swell substantially upon the introduction of hydrophilic pendants and therefore will not exhibit enhanced enzymatic hydrolysis upon the introduction of these groups.

[0356] Example 6: Drug loading affects hydrolysis rates in human and rat plasma As discussed above, the amount of drug loaded onto the POZ polymer conjugate is hypothesized to affect the rate of drug hydrolysis from the POZ polymer conjugate, with higher drug loading resulting in a longer half-life and lower drug loading resulting in a shorter half-life. The effect of ester linkages has been previously described [4, 7], and as noted, plasma hydrolysis rates decrease in the order acetate > 2-propionate > 3-propionate. To determine the effect of drug loading on the in vitro hydrolysis rate of drugs from POZ polymer conjugates, POZ polymer conjugates (PEOZ-20K-10P-COOH) were prepared with cannabidiol (POZ-CBD; drug loadings 1.6% to 10.3%), rotigotine (POZ-ROT; drug loadings 7.5% to 11.8%), d9-tetrahydrocannabinol (POZ-d9THC; drug loadings 6.1% to 10.3%), buprenorphine (POZ-BUP; drug loadings 11.3% to 15.5%), cannabigerol (POZ-CBG; drug loadings 4.3% to 10.5%), and dexanabinol (POZ-DEX; drug loading 8.8%).

[0357] The following table shows the t for POZ-polymer conjugates in human female plasma at 37°C. 1 / 2Values ​​(determined as described in the Methods section) are shown. As can be seen, the hydrolysis half-life is longer for the highly loaded conjugates. For the POZ-CBD conjugate with a 2-propionate linker, an increase in drug loading from 1.6% to 8.9% increased the hydrolysis half-life from 10 hours to 87 hours. An increase in hydrolysis half-life was also observed for the POZ-ROT conjugate (with a 3-propionate linker), where an increase in drug loading from 7.5% to 11.8% increased the hydrolysis half-life from 17 hours to 76 hours, and for the POZ-d9THC conjugate (with a 3-propionate linker), an increase in drug loading from 6.1% to 10.3% increased the hydrolysis half-life from 49 hours to 107 hours over a 7-day period.

[0358] There is a correlation between log P values ​​and hydrolysis rates, with higher log P resulting in slower hydrolysis and longer half-lives. For example, rotigotine, with a log P of 4.9 and a 3-propionate linker and 7.5% loading, hydrolyzes faster (half-life of 17 hours) than THC, with a log P of 7.2 (half-life of 90 hours), as expected. However, there are some exceptions to the table. For example, with a 3-propionate linker and 6.1% loading, cannabidiol, with a log P of 6.1, has a half-life of 168 hours, while the more hydrophobic THC, with a log P of 7.0, has a half-life of 49 hours, which is the opposite of the general trend. While our folding hypothesis suggests that increasing log P should result in a more rigid core and slower hydrolysis rate, varying the pendant drug is also expected to affect more factors than log P. For example, even though the point of attachment in all cases is a phenolic group on the drug and the ester linkage is the same, the size and shape of these molecules vary significantly. This variation is expected to result in different steric effects on folding and esterase binding. There are also likely small but significant differences in electronic effects for different drugs, which also affect the hydrolysis rate for the ester linkage. Thus, it is not surprising that the correlation between drug logP and hydrolysis half-life is rough, due to the difficulty of controlling steric and electronic effects between different drugs.

[0359] [Table 4]

[0360] Example 7: Drug loading affects hydrolysis rate in vivo The data in Example 6 showed that increasing the percentage of drug loading decreased the in vitro hydrolysis half-life of five exemplary POZ conjugates. In general, slowing the plasma hydrolysis rate of a POZ-drug conjugate can be expected to result in a longer in vivo plasma presence for the released drug. To determine the effect of drug loading on the in vivo hydrolysis rate and pharmacokinetics of the drug from a POZ conjugate, POZ conjugates (drugs attached using a 3-propionate ester linkage) were prepared with cannabidiol (POZ-CBD; drug loading 2.8% or 7.1%) and rotigotine (POZ-ROT; drug loading 7.5% to 11.8%). The polymer conjugates were administered to animals, and plasma samples were analyzed for released drug as described in the Methods section.

[0361] Figure 3 shows the plasma concentrations of free rotigotine released from POZ-ROT conjugates after a single injection of POZ-ROT with drug loading percentages of 7.5%, 9.7%, and 11.8%. As can be seen in Figure 3, the POZ-ROT conjugate with 7.5% drug loading provided a higher initial concentration of free rotigotine from days 1 to 3 (compared to the POZ-ROT conjugates with 9.7% and 11.8% drug loadings), and the concentration then decreased from days 3 to 5. This indicates that rotigotine was released more rapidly (i.e., t 1 / 2The POZ-ROT conjugates with 9.7% and 11.8% drug loadings provided lower initial concentrations of free rotigotine during days 1 to 3 (compared to the POZ-ROT conjugate with 7.5% drug loading), but maintained higher concentrations from days 3 to 5. This suggests that rotigotine was released more slowly (i.e., t 1 / 2 These results are consistent with the data from Example 7, suggesting that the POZ-ROT conjugate at 7.5% drug loading exhibited a shorter t compared to the POZ-ROT conjugate at 11.8% drug loading. 1 / 2 This shows that the

[0362] Figure 4 shows the plasma concentrations of free cannabidiol released from POZ-CBD conjugates after a single injection of POZ-CBD at drug loading percentages of 2.8 and 7.1%. As can be seen in Figure 4, the POZ-CBD conjugate with 2.8% drug loading provided a higher initial peak concentration of free cannabidiol between days 1 and 2 (compared to the POZ-CBD conjugate with 7.1% drug loading), which then decreased between days 2 and 14. This indicates that cannabidiol was released more rapidly (i.e., t 1 / 2 The POZ-CBD conjugate with 7.1% drug loading provided a lower initial concentration of free cannabidiol between days 1 and 2 (compared to the POZ-CBD conjugate with 2.8% drug loading), but maintained a higher concentration between days 3 and 14. This suggests that cannabidiol was released more slowly (i.e., t 1 / 2These results are consistent with the data from Example 7, suggesting that POZ-CBD conjugates with lower drug loading percentages exhibited shorter t compared to POZ-CBD conjugates with higher drug loading percentages. 1 / 2 This indicates that the value was

[0363] Example 8: Effect of POZ polymer molecular weight on in vivo circulation lifetime As discussed above, the POZ polymer moiety of the POZ conjugate is hypothesized to affect the rate of drug hydrolysis from the POZ conjugate, with higher molecular weight POZ polymer moieties resulting in longer half-lives and lower molecular weight POZ polymer moieties resulting in shorter half-lives. It was also of interest to determine the effect of POZ molecular weight on in vivo circulatory life. POZ conjugates of 10, 20, 30, 40, and 60 kD were prepared with the fluorescent dye cyanine-5 attached via a non-degradable linkage. The labeled POZ conjugates were injected intravenously and subcutaneously into male rats, and blood levels of cyanine-5 were monitored over time via fluorescence spectrophotometry as described in the Methods section.

[0364] The results are shown in Figures 7 and 8. As can be seen from Figures 7 and 8, the expected molecular weight-dependent clearance pattern was observed [Yamaoka et al., J. Pharm Sci., Vol. 83, pp. 601-606, 1994]. After 3 days, 10 kD POZ-cyanine concentrations fell into the subdetectable range, and 40 and 60 kD POZ-cyanine concentrations remained significant at 28 days, when the experiment was terminated. The 20 and 30 kDa POZ polymers provided stable blood levels for 14 and 21 days, respectively. The cutoff for glomerular filtration of POZ has been reported to be around 40 kD (Wyffels et al., J. Cont. Rel., Vol. 235, pp. 63-71 (2016)).

[0365] Example 9: Fine tuning of the pharmacokinetics of POZ-conjugates in vivo Previous examples have shown that the POZ-drug in vitro hydrolysis rate can be altered (i.e., fine-tuned) to generate specific release profiles by changing the linker, altering the % drug loading, and adding inert hydrophilic pendant moieties. To explore the effects of these parameters in vivo, several POZ conjugates were investigated. In vivo pharmacokinetics is complicated by many factors, including, but not limited to, renal and hepatic clearance. In many cases, a once-weekly injection with a flat steady-state PK profile would be of significant benefit, especially for drugs with short half-lives in vivo.

[0366] In general, a slower in vitro plasma hydrolysis rate of a drug from a POZ conjugate would be expected to result in a longer in vivo plasma presence for the released drug, as observed in the experiments of this example. Figure 9 shows the pharmacokinetic (PK) profiles of rotigotine in rats after a single SC injection of rotigotine with an acetyl (drug loading 10.9%) and a 3-propionyl (drug loading 13.3%) ester linkage and POZ-rotigotine (Structure 1). The POZ-ROT conjugate was administered at a dose of 1.6 mg / kg, and free rotigotine was administered at a dose of 0.5 mg / kg. As shown in Example 7, the 3-propionate ester undergoes plasma hydrolysis substantially slower than the acetate ester, and as expected, the in vivo steady-state PK profiles in Figure 9 show that the 3-propionate ester has a longer blood residence time and a lower initial Cmax "burst effect" than the acetate ester. Injection of rotigotine alone is eliminated from the body in less than 24 hours.

[0367] Figure 10 shows the pharmacokinetic (PK) profiles of buprenorphine after a single SC injection of POZ-BUP with 2-propionyl (drug loading 11.2%) and 3-propionyl (drug loading 13.3%) ester linkages in male monkeys. The POZ-ROT conjugate was administered at a dose of 1.5 mg / kg. As expected, the in vivo steady-state PK profiles in Figure 10 show that the 3-propionate ester has a longer blood residence time and a lower initial Cmax "burst effect" than the acetate ester. In both rats and monkeys, plasma levels for buprenorphine are essentially flat for 4 to 5 days (based on buprenorphine equivalents) at the 1.5 mg / kg dose. These profiles suggest that the POZ conjugates are suitable compounds for weekly subcutaneous injection to treat postoperative pain.

[0368] Example 10: The presence of hydrophobic octyl pendant moieties reduces the rate of hydrolysis To examine the effect of the hydrophobic pendant moiety on plasma hydrolysis rate, three different POZ conjugates were prepared. All had sufficient pendant pentynyl groups to link a drug to the POZ conjugate: (1) PEOZ-20K with 10 buprenorphine molecules and no hydrophobic pendant moiety; (2) PEOZ-20K with 8 buprenorphine molecules and no hydrophobic pendant moiety; and (3) PEOZ-20K(C8) with 8 buprenorphine molecules and two hydrophobic octyl pendant moieties. The hydrolysis rate in human female plasma at 37°C was determined, and the half-life of each POZ conjugate was also determined.

[0369] The results were as follows: PEOZ-20K with 10 buprenorphine molecules and no hydrophobic pendant moieties (half-life 16 hours); PEOZ-20K with 8 buprenorphine molecules and no hydrophobic pendant moieties (half-life 12 hours); and PEOZ-20K with 8 buprenorphine molecules and 2 hydrophobic pendant moieties (half-life 15 hours). These results confirm the results of previous examples, which show that increasing the percentage of drug loading reduces the release rate of the drug from the POZ conjugate. In addition, these results show that, as expected, the presence of hydrophobic pendant moieties reduces the rate of hydrolysis of the drug from the POZ polymer moiety. Thus, hydrophobic pendant moieties can be used to reduce the release rate of the drug from the POZ conjugate and select a desired release profile of the drug from the POZ conjugate.

[0370] Example 11: Increasing the molecular weight of the POZ polymer moiety reduces the rate of hydrolysis of the drug from the POZ conjugate To investigate the effect of molecular weight of the POZ polymer moiety on plasma hydrolysis rate, two different POZ conjugates were prepared. All had sufficient pendant pentynyl groups to link a drug to the POZ conjugate: (1) PEOZ-20K and (2) PEOZ-8K. CBD was conjugated to the POZ polymer moiety via an acetate ester linker, resulting in an 8.7% drug loading for each POZ conjugate. The hydrolysis rate in human female plasma at 37°C was determined, and the half-life of each POZ conjugate was determined.

[0371] The results were as follows: POZ-8K (half-life 5 hours) and POZ-20K (half-life 11 hours). These results confirm that, as expected, increasing the molecular weight of the POZ polymer segment decreases the rate of hydrolysis of the drug from the POZ polymer segment. Therefore, adjusting the molecular weight of the POZ polymer segment can be used to increase or decrease the release rate of the drug from the POZ-conjugate and select the desired release profile of the drug from the POZ conjugate.

[0372] Example 12: Increasing the hydrophobic nature of the pendant groups on the POZ polymer moiety reduces the rate of hydrolysis of the drug from the POZ conjugate To investigate the effect of the hydrophobic nature of the pendant groups on the POZ polymer moiety on plasma hydrolysis rate, two different polyoxazolines were prepared. All had sufficient pendant pentynyl groups to link a drug to the POZ conjugate: (1) PEOZ-20K, and (2) a copolymer of polyoxazoline with 15% methyloxazoline and 85% ethyloxazoline (Co-POZ-20K). CBD was conjugated to the POZ polymer moiety via an acetate ester linker, resulting in an 8.7% drug loading for each POZ conjugate. Hydrolysis rates were determined in human female plasma at 37°C, and the half-life of each POZ conjugate was determined. POZ conjugate 1 had a more hydrophobic nature, with 85% of the pendant groups (approximately 160) being ethyl groups and the remainder being methyl, as all pendant groups (approximately 190) were the more hydrophobic ethyl groups.

[0373] The results were as follows: CoPOZ-20K (half-life 8 hours), and POZ-20K (half-life 11 hours). These results confirm that, as expected, increasing the hydrophobic nature of the pendant groups on the POZ polymer moiety reduces the rate of hydrolysis of the drug from the POZ polymer moiety. Therefore, adjusting the hydrophobic nature of the pendant groups on the POZ polymer moiety can be used to increase or decrease the release rate of the drug from the POZ-conjugate and to select a desired release profile of the drug from the POZ conjugate.

Claims

1. A water-soluble polyoxazoline (POZ) conjugate comprising a POZ polymer and a drug attached to the water-soluble POZ polymer by a physiologically degradable linkage, POZ conjugates are The following structure R-{[N(CO-L １ -R １ )CH ２ CH ２ ] ｍ -[N(COR ２ -A)CH ２ CH ２ ] ｏ -[N(COX)CH ２ CH ２ ]n} ａ -T wherein A is a drug; R is hydrogen, unsubstituted alkyl or substituted alkyl; R １ is an inert pendant group, the inert pendant group comprising one or more hydrophilic pendant moieties; L １ is a linking group; R ２ is a pendant moiety comprising a physiologically degradable linkage; X is a pendant group; T is a terminal group; a is ran indicating a random copolymer or block indicating a block copolymer; m is an integer from 1 to 50; n is an integer from 0 to 1000; and o is an integer from 1 to 50. and The release rate of the drug from the POZ conjugate is R １ POZ conjugates controlled by

2. The drug is a plant cannabinoid, a dopamine agonist, an anticholinergic, a monoamine oxidase B inhibitor, a catechol-O-methyltransferase (COMT) inhibitor, or an adenosine A ２Ａ 2. The POZ conjugate of claim 1, which is a receptor antagonist or a GABA uptake inhibitor.

3. The plant cannabinoid may be cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiol monomethyl ether, cannabidiol-C4, cannabidalic acid, cannabidivarin, cannabidiol or cannabigerol propyl variants, cannabichromene, cannabichromenic acid, cannabichromevaric acid, cannabichromevarin, cannabinol, cannabicyclol, tetrahydrocannabivarin, Δ ９ 3. The POZ conjugate of claim 2, wherein the POZ conjugate is selected from the group consisting of THC, adulemic acid and dexanabinol.

4. 3. The POZ conjugate of claim 2, wherein the dopamine agonist is selected from the group consisting of apomorphine, albutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone or (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, and bromocriptine.

5. 3. The POZ conjugate of claim 2, wherein the anticholinergic drug is selected from the group consisting of trihexyphenidyl, biperiden, and hyoscyamine.

6. 3. The POZ conjugate of claim 2, wherein the monoamine oxidase B inhibitor is selected from the group consisting of serigiline and rasagiline.

7. 3. The POZ conjugate of claim 2, wherein the COMT inhibitor is selected from the group consisting of tolcapone and entacapone.

8. Adenosine A ２Ａ 3. The POZ conjugate of claim 2, wherein the receptor antagonist is selected from the group consisting of preladenant, theophylline, and istradefylline.

9. 3. The POZ conjugate of claim 2, wherein the GABA uptake inhibitor is selected from the group consisting of tiagabine and nipecotic acid.

10. 10. The POZ conjugate of any one of claims 1 to 9, wherein the release rate of the drug from the POZ conjugate is further controlled by selecting the drug loading percentage.

11. 11. The POZ conjugate of any one of claims 1 to 10, wherein the release rate of the drug from the POZ conjugate is further controlled by selecting the drug with a selected solubility in water, selecting the drug with a selected molecular volume, selecting the drug with a selected total polar surface area, or a combination of the foregoing.

12. 4. The POZ conjugate of any one of claims 1 to 3, wherein the agent is a phytocannabinoid and the POZ conjugate comprises a phytocannabinoid loading percentage of 1.6%±1% to 9.6%±1% (w / w of phytocannabinoid to POZ polymer), and wherein the release rate of the phytocannabinoid from the POZ conjugate is further controlled by selecting the loading percentage.

13. 2. The POZ conjugate of claim 1, wherein X is independently selected for each repeat unit from an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl, or an unsubstituted or substituted heterocyclylalkyl group.

14. 2. The POZ conjugate of claim 1, wherein X is independently selected from unsubstituted alkyl for each repeat unit.

15. 2. The POZ conjugate of claim 1, wherein T is a thioalkyl carboxylic acid, a thiocarboxylic acid ester, or a hydroxyl.

16. 2. The POZ conjugate of claim 1, wherein T is Z-B-Q, Z is S, O, or N, B is an optional linking group, and Q is a terminal nucleophile or a terminal portion of a nucleophile.

17. B is -(CH ２ ) ｙ - and y is an integer selected from 1 to 16.

18. 17. The POZ conjugate of claim 16, wherein Q is an alkyne, alkene, amine, oxyamine, aldehyde, ketone, acetal, thiol, ketal, maleimide, ester, carboxylic acid, activated carboxylic acid, activated carbonate, chloroformate, alcohol, azide, vinyl sulfone, orthopyridyl disulfide, or an inert group.

19. T is -S-CH ２ CH ２ -CO ２ CH ３ , -S-CH ２ CH ２ -CO ２ H), —S—CH ２ CH ２ -NH ２ or -S-CH ２ CH ２ 17. The POZ conjugate of claim 16, which is -NH-tBoc.

20. L １ The POZ conjugate of claim 1 , wherein is a non-degradable linkage.

21. R １ The POZ conjugate of claim 1 , wherein comprises one or more polar covalent bonds.

22. R １ 2. The POZ conjugate of claim 1, wherein for each repeat unit, is independently selected from a water soluble polymer, a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted aralkyl, or a substituted heterocyclylalkyl group.

23. 23. The POZ conjugate of claim 22, wherein the substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aralkyl, or substituted heterocyclylalkyl group contains one or more oxygen atoms, nitrogen atoms, sulfur atoms, phosphorus atoms, or combinations of the foregoing.

24. 23. The POZ conjugate of claim 22, wherein the water-soluble polymer is poly(alkylene glycol), a copolymer of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamide), poly(hydroxyalkyl methacrylate), poly(saccharide), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), or a combination of any of the foregoing.

25. 25. The POZ conjugate of claim 24, wherein the water-soluble polymer comprises 1 to 30 repeating units.

26. R １ 2. The POZ conjugate of claim 1, wherein for each repeating unit, is independently selected from a C1-C5 alcohol, a C1-C5 carboxylic acid, or a poly(alkylene glycol) comprising 2 to 10 repeating units.

27. R １ wherein one or more hydrophilic pendant moieties of R １ The POZ conjugate of claim 1 , wherein is located within 50 angstroms of the attached N group.

28. R ２ L ２ 17. The POZ conjugate of claim 16, wherein L2 is a linking group containing a physiologically degradable linkage.

29. L １ is an indecomposable linkage, and L ２ is a linking group containing a physiologically degradable linkage, wherein the physiologically degradable linkage comprises a cleavable moiety selected from the group consisting of ester, carboxylate ester, carbonate ester, carbamate, amide, disulfide, and peptide.

30. L １ is an indegradable linkage, Z is S, and B is -(CH ２ ) ｙ -, y is an integer from 1 to 3, and Q is -COOCH ３ , —COOH or —NH ２ 29. The POZ conjugate of claim 28, wherein:

31. L １ and L ２ 30. The POZ conjugate of claim 28, wherein each is independently a disubstituted triazole.

32. L ２ wherein the disubstituted triazole has the following structure: 【Chemistry 1】 [In the formula, R ３ is a linker attaching the triazole moiety to the POZ polymer; R ４ is a linker that attaches the triazole moiety to the drug.

32. The POZ conjugate of claim 31, having:

33. R ３ But -C(O)-R ５ - and R ５ 33. The POZ conjugate of claim 32, wherein is absent or is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group.

34. R ５ 34. The POZ conjugate of claim 33, wherein is absent or is an unsubstituted alkyl of 1 to 10 carbons in length.

35. R ４ But, -R ６ -R ７ -R ８ - and R ６ is a substituted or unsubstituted alkyl, a substituted or unsubstituted aralkyl, or —(CH ２ CH ２ O) ｅ -, e is an integer from 1 to 10, and R ７ is a cleavable moiety or a group comprising a portion of a cleavable moiety, and R ８ The POZ conjugate of claim 32, wherein is absent or O.

36. R ６ is a straight chain substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R ７ is —C(O)—, and R ８ is —O—, or R ６ is a straight chain substituted or unsubstituted C1-C10 alkyl or a branched substituted or unsubstituted C1-C10 alkyl, and R ７ is —C(O)—O—, and R ８ The POZ conjugate of claim 35, wherein is absent.

37. R ３ is -C(O)-(CH ２ ) ３ and R ４ For each repeating unit, -(CH ２ ) ｄ -C(O)-, -CH ２ -C(O)-, -CH ２ -CH ２ -C(O)-, -CH ２ -CH ２ -CH ２ -C(O)-, -CH ２ (CH ３ )-C(O)-,-(CH ２ ) ｄ -C(O)-O-, -CH ２ -C(O)-O-, -CH ２ -CH ２ -C(O)-O-, -CH ２ -CH ２ -CH ２ —C(O)—O— or —CH ２ (CH ３ )-C(O)-O-, wherein d is an integer from 1 to 10.

38. L １ wherein the disubstituted triazole has the following structure: 【Chemistry 2】 [In the formula, R ３ ＊ is a linker attaching the triazole moiety to the POZ polymer; R ４ ＊ is a triazole moiety R １ or R ４ is R １ is] 32. The POZ conjugate of claim 31, having:

39. R ３ ＊ But -C(O)-R ５ - [wherein, R ５ is absent or is an unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted aralkyl, or unsubstituted or substituted heterocyclylalkyl group.

40. R ５ 40. The POZ conjugate of claim 39, wherein is absent or is an unsubstituted alkyl of 1 to 10 carbons in length.

41. R ３ ＊ is -C(O)-(CH ２ ) ３ and R ４ ＊ are independently selected from a C1-C5 alcohol, a C1-C5 carboxylic acid, or a poly(alkylene glycol) comprising 2 to 10 repeating units for each repeating unit.

42. The structure: 【Transformation 3】 [In the formula, R １ are independently selected for each repeat unit from a C1-C5 alcohol, a C1-C5 carboxylic acid, or a poly(alkylene glycol) containing 2 to 10 repeat units; R 4 is independently selected for each repeat unit from —(CH 2 ) d —C(O)—, —CH 2 —C(O)—, —CH 2 —CH 2 —C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—, —CH 2 (CH 3 )—C(O)—, —(CH 2 ) d —C(O)—O—, —CH 2 —C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH 2 —CH 2 —CH 2 —C(O)—O— or —CH 2 (CH 3 )—C(O)—O—; d is an integer from 1 to 10; The release rate of the drug from the POZ conjugates is further controlled by the percentage of drug loading.

2. The POZ conjugate of claim 1, having:

43. The following structure: 【Chemistry 4】 [In the formula, f is an integer from 1 to 10; R ４ is -(CH ２ ) ｄ -C(O)-, -CH ２ -C(O)-, -CH ２ -CH ２ -C(O)-, -CH ２ -CH ２ -CH ２ -C(O)-, -CH ２ (CH ３ )-C(O)-,-(CH ２ ) ｄ -C(O)-O-, -CH ２ -C(O)-O-, -CH ２ -CH ２ -C(O)-O-, -CH ２ -CH ２ -CH ２ —C(O)—O— or —CH ２ (CH ３ )—C(O)—O—; d is an integer from 1 to 10; The release rate of the drug from the POZ conjugate is further controlled by the loading percentage.

2. The POZ conjugate of claim 1, having:

44. R ４ But -CH ２ —C(O), —CH ２ -CH ２ —C(O)— or —CH ２ (CH ３ )-C(O), and m and n are each an integer independently selected from 2 to 8.

45. The drug is a plant cannabinoid, a dopamine agonist, an anticholinergic, a monoamine oxidase B inhibitor, a catechol-O-methyltransferase (COMT) inhibitor, or an adenosine A ２Ａ 44. The POZ conjugate of any one of claims 1 to 43, which is a receptor antagonist or a GABA uptake inhibitor.

46. 44. The POZ conjugate of any one of claims 1 to 43, wherein the drug is cannabidiol (CBD) and the POZ conjugate contains 1.6%±1% to 9.6%±1% CBD (w / w of CBD to POZ polymer).

Images