WO2009078978A2

WO2009078978A2 - Compositions containing polyglycidol-based polymers and uses thereof

Info

Publication number: WO2009078978A2
Application number: PCT/US2008/013728
Authority: WO
Inventors: Lorraine Reeve
Original assignee: Phrixus Pharmaceuticals Inc
Current assignee: Phrixus Pharmaceuticals Inc
Priority date: 2007-12-14
Filing date: 2008-12-15
Publication date: 2009-06-25
Anticipated expiration: 2010-06-14
Also published as: WO2009078978A3

Abstract

The present invention provides a therapeutic composition for treatment of heart failure, comprising a therapeutically acceptable carrier and a polyglycidol-based polymer as a therapeutic agent. Also provides by this invention are methods of using the therapeutic compositions for treating heart conditions.

Description

COMPOSITIONS CONTAINING POLYGLYCIDOL-BASED POLYMERS AND USES THEREOF

[001] This application claims the priority of U.S. Serial No. 61/013,756 filed on December 14, 2007. The entire contents of U.S. Serial No. 61/013,756 are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

[002] Heart failure (HF) is a pathological condition in which the heart is unable to pump blood at a rate required for normal metabolism and physical activity. Frequently, the exact causes of HF (particularly chronic HF) are unknown, but may be one or more of hypertension, myocardial injury, ischemic heart disease, cardiac valve abnormalities, coronary artery diseases, and abnormal electrical conduction within the heart. Alone or in combination, these conditions cause an increased chronic load on the heart which triggers three major compensatory mechanisms: the adrenergic system, the renin-angiotensin-aldosterone system, and ventricular hypertrophy. Although these mechanisms allow the heart to adapt and maintain adequate cardiac output, over time, they also bring about deleterious effects on the heart and cardiovascular system. These deleterious effects include cardiac myocyte hypertrophy leading to wall thickening and reduced contractility, elevated cytosolic calcium, causing impaired myocardial relaxation, vasoconstriction and aldosterone-induced salt and water retention, both of which may cause hypertension and additional load on the heart.

[003] In current medical practice, patients are treated with one or more drugs that reduce stress on the heart. These drugs include vasodilators, diuretics, angiotensin receptor blockers, and beta-blockers. In combination with a healthy life style, these drug regimens improve symptoms and quality of life for the patient. Nevertheless, the pathophysiological changes in the heart progress over time causing debilitation of the heart, decreasing mobility and declining quality of life for the patient.

[004] Poloxamers, especially Poloxamer-188 (P-188), have been shown to improve cardiac output and reverse the heart failure associated with muscular dystrophy in a mouse cell model. Cardiac muscle fibers exhibited a contractile defect that resulted from sustained high levels of cellular cytosolic calcium. P-188, when added to an in vitro cardiac muscle preparation, appeared to seal tears in the muscle cell membrane, and thereby prevent an influx of calcium thus allowing cells to normalize their calcium levels. All of these affects of P-188 on cardiac muscle cells were observed in vitro, by placing the cell in a solution containing a fairly high concentration of P- 188. Following exposure to P- 188 treatment, heart muscle tissue exhibited an improved ability to relax which would be expected to correlate with improved diastolic function and increased cardiac output in vivo. However, it is unknown whether these results are applicable to heart failure other than that associated with muscular dystrophy. [005] In addition to the poloxamers, there are a number of other classes of biocompatible polymers that have been extensively studied for various biomedical applications. Polyglycidol- based polymers are relatively new, and some polyglycidol copolymers have been found to be biocompatible. However, their biomedical or therapeutic applications have yet to be explored.

SUMMARY OF THE INVENTION

[006] In one aspect, the present invention provides therapeutic compositions for treatment of heart failure, each comprising a therapeutically acceptable carrier and a polyglycidol-based polymer as a therapeutic agent.

[007] In some embodiments, the polyglycidol-based polymer is a linear polyglycidol (LPG). In some embodiments, the polyglycidol-based polymer is a branched (e.g., hyperbranched) polyglycidol. In some embodiments, the polyglycidol-based polymer is a linear polymer. In some embodiments, the polyglycidol-based polymer is a copolymer containing polyglycidol. In some further embodiments, the polyglycidol-based polymer is a copolymer containing polyglycidol and poly(alkylene oxide) {e.g., poly(propylene oxide) or poly(methylene oxide)]. In some embodiments, the polyglycidol-based polymer is a block copolymer, polyglycidol- poly(propylene oxide)-polyglycidol ("PG-PPO-PG"). In some embodiments, the poly(propylene oxide) block of the copolymer includes 20-50 propylene oxide units. In some embodiments, the poly(propylene oxide) block of the copolymer includes an average of 34 propylene oxide units. In some embodiments, each of the two polyglycidol blocks of the polymer comprise glycidol and ethylene-oxide units. In some embodiments, each of the two polyglycidol blocks of the copolymer includes 4 to 80 glycidol units. In some embodiments, each of the two polyglycidol blocks of the copolymer includes 6, 8, 13, 17, 26, 51, or 70 glycidol units. In some embodiments, the two polyglycidol blocks of the copolymer have the same average number of glycidol units. In some embodiments, each of the two polyglycidol blocks of the copolymer includes 4 to 80 glycidol units. In some embodiments, the therapeutically acceptable carrier is an aqueous buffer (e.g., phosphate buffer, phosphate buffered saline, TRIS). In some embodiments, the aqueous buffer has a pH between 6.0 and 8.0 (e.g., 7.4). In some further embodiments, the composition contains 5-30% of the copolymer. [008] In another aspect, the present invention provides a method for improving the functioning of a diseased heart in a patient, wherein the method includes administering to the patient a therapeutic composition comprising a therapeutically effective amount of a polyglycidol-based polymer.

[009] In some embodiments, the therapeutic composition improves the functioning of the diseased heart continuously for at least 24 hours (e.g., for at least 48 hours, at least 7 days, at least one month) following each administration of the therapeutic composition. [0010] In some other embodiments, the therapeutic agent improves the functioning of a diseased heart independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

[0011] In some embodiments, the polyglycidol-based polymer is a linear polymer, a linear polyglycidol or a branched polyglycidol. In some further embodiments, the polyglycidol-based polymer is a block copolymer containing polyglycidol (e.g., a copolymer containing polyglycidol and poly(alkylene oxide)). In some embodiments, the polyglycidol-based polymer is a copolymer containing polyglycidol and poly(propylene oxide). In some further embodiments, the polyglycidol-based polymer is polyglycidol-poly(propylene oxide)-polyglycidol. In still other embodiments, the polyglycidol-based polymer is a copolymer containing a poly(propylene oxide) center block flanked by mixed blocks of poly(ethylene oxide) and polyglycidol. In some embodiments the poly(ethylene oxide) and polyglycidol units are interspersed with each other. In other embodiments the poly(ethylene oxide) and polyglycidol subunits are arranged within the flanking polymer blocks to provide increasing polarity at the distal ends of the molecule. [0012] In some further embodiments, the therapeutic composition is administered by injection or infusion.

[0013] In still some further embodiments, the disease of the heart is heart failure (e.g., chronic heart failure or acute heart failure), such as ischemic or idiopathic heart failure. In some other embodiments, the disease of the heart is muscular dystrophy. [0014] In yet still some further embodiments, the amount of the polyglycidol-based polymer can range from about 0.4 to about 500 mg/kg (e.g., 0.46 mg/kg, 4.6 mg/kg, 10 mg/kg, 100 mg/kg, or 460 mg/kg).

[0015] The present invention further provides a method of treating, ameliorating, or preventing heart failure in a patient, which includes administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, decreasing left ventricular end-diastolic dimension, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

[0016] In some embodiments, the therapeutic composition improves the heart condition continuously for at least 24 hours (e.g., at least 48 hours, at least 7 days, or at least one month) following each administration of the therapeutic composition.

[0017] In some other embodiments, the therapeutic composition improves the heart condition independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

[0018] Another aspect of the present invention relates to a method for restoring the integrity of heart muscle cell membrane in a heart failure patient, which includes administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

[0019] Still another aspect of the present invention relates to a method for improving the function of the membrane of cardiac muscle cells in a heart failure patient, which includes administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

[0020] Yet still another aspect of the present invention provides a method for lowering and maintaining intracellular calcium concentration at normal levels in a heart failure patient, comprising administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

DETAILED DESCRIPTION OF THE INVENTION

[0021] In one aspect, the present invention provides compositions for the treatment of heart failure which contains a therapeutically acceptable carrier and at least a polyglycidol-based polymer as the therapeutic agent. In other aspects, the invention also provides methods for using these compositions.

[0022] Unless otherwise provided, all terms herein have the meanings as commonly known in the field to which the present invention relates.

[0023] As used herein, the term "heart failure" refers to a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body. As used herein, the term "chronic heart failure" refers to a sustained inability of the heart to pump blood forward at a sufficient rate to meet metabolic demands. Examples of chronic heart failure include systolic dysfunction, diastolic dysfunction and right-sided heart failure, idiopathic and ischemic heart failure. As used herein, the term "acute heart failure" refers to acute decompensation episodes in chronic heart failure patients.

[0024] As used herein, the term "polyglycidol-based polymers" refers to polymers which contains polyglycidol, either just polyglycidol itself or a copolymer containing polyglycidol. [0025] A polyglycidol itself can be a linear polyglycidol (LPG) or a branched polyglycidol (BPG), the structures of which are shown below.

(linear) (hyperbranched)

[0026] Both LPG and BPG can be used to practice the present invention. Synthesis of these two polymers have been described in, e.g., R. K. Kainthan et al., Biomacromolecules, 2006, 7, 703-709; which is incorporated herein by reference in its entirety.

Preparation of Linear Polyglycidol (LPG)

[0027] LPG can be synthesized by following a known procedure as described in, e.g., S. Stiriba et al., J. Am. Chem. Soc, 2002, 124, 9698-9700, the contents of which are incorporated herein by reference in its entirety. Specially, ethoxy ethyl glycidyl ether dissolved in a solvent (e.g., THF) is added to a solution of potassium t-butoxide (KO¹Bu) in diglyme under a heated condition. The mixture is stirred for a period of time, e.g., 12 hours, and then the solvent is removed and the polymer is dissolved in a solvent and further stirred with the presence of acid (e.g., HCl) to give a polymer precipitate. The precipitated polymer can be washed and purified with suitable solvent (e.g., THF, acetone, methanol, or their combination), and then further purified by dialysis against water, e.g., by using a regenerated cellulose membrane with a preferred molecular weight cutoff (e.g., 1,000 g/mol) and then freeze-dried. Shown below is a scheme of the synthesis.

Preparation of Branched Polyglycidol (BPG)

[0028] BPG can be synthesized according to procedures described in literature, e.g., Sunder,

A. et al., Macromolecules, 1999, 32, 4240, the contents of which are incorporated herein by reference in its entirety. The polymer thus prepared can be purified by dialysis against water by using a regenerated cellulose membrane with a desired molecular weight cutoff (e.g., 1,000 g/mol). The degrees of branching and of polymerization of the branched polymer can be determined by, e.g., ¹³C NMR spectrometry, and the polydispersity can be determined by gel permeation chromatography (GPC).

[0029] Shown below in Table 1 are some physical data of examples of LPG and BPG.

Table 1. Polymer Characterization Data intrinsic viscosity polyglycidol M_n MJM_n (mL/g) (nm) R_n (nm) branched 6400 1.28 4.7 2 .36 1 .81 linear 6400 1.60 7.3 2.82 2.16

The ratio Mw/Mn indicates the molecular weight distribution of the polymer molecules. A uniform polymer having a narrow dispersity (less than approximately 1.5) is desirable in medical applications. In some embodiments, polyglycidol-containing polymers are fractionated to obtain a uniform polymer having a dispersity value of less than 1.5, by using column chromatography, high pressure liquid chromatography, supercritical fluid extraction, alcohol/salt extraction, fractionation using aqueous two phase extraction, or any other appropriate method known in the art.

PG Copolymers

[0030] A polyglycidol-containing copolymer is a copolymer that contains one or more polyglycidol blocks and one or more blocks of other repeating units. For example, copolymers of A and B (e.g., polyA-co-polyB) have the structure of (A)_m-(B)_n, or (A)_1n-(B)_n-(A)₀ wherein m, n, and o can be the same or different. Examples of polyglycidol-containing copolymers include polyglycidol-poly(alkylene oxide)-polyglycidol ("PG-PAO-PG"). Specific examples of the PG- PAO-PG copolymers include polyglycidol-poly(propylene oxide)-polyglycidol, in which the numbers of glycidol and propylene oxide units can range from 2 to 80 (e.g., 3, 6, 8, 13, 17, 26, 34, 51, or 70). Specific examples of the PG-PPO-PG copolymers are listed in Table 2 below. [0031] Polyglycidol-polyCpropylene oxide)-polyglycidol ("PG-PPO-PG") copolymers are a family of linear and symmetric tri-block copolymers each including a center block of poly(propylene oxide) between two blocks of polyglycidol. Their structures can be shown as

in which a, b, and c are integers and a and c can be the same or different. In some examples, the integers a and c are the same and can be, e.g., 3, 6, 8, 13, 17, 26, 51, or 70. In some other examples, the integer b can be 17, 20, 34, or 40. These polyglycidol-containing copolymers are water soluble, and above a critical micelle concentration characteristic for each molecule, self-associate to form micelles in aqueous solution. The hydrophobic poly(propylene oxide) regions associate with each other and are sequestered in the interior of the micelle. The polyglycidol blocks of the molecule are oriented toward the exterior of the micelle and form hydrogen bonds with neighboring water molecules stabilizing the micellar structure.

These PG-PPO-PG copolymers can be synthesized in varying molecular weight ranges and having varying ratios of polyglycidol and poly(propylene oxide). See, e.g., S. Halacheva et al., Macromolecules, 2006, 39, 6845-6852, the entire contents of which are incorporated herein by reference.

Preparation of PG-PPO-PG Copolymers

[0032] Preparation of a PG-PPO-PG copolymer can be conducted in three steps: (1) preparation of the PPO macroinitiator, (2) synthesis of the poly(ethoxyethyl glycidol ether)-PPO- poly(ethoxyethyl glycidol ether) precursor, and (3) synthesis of PG-PPO-PG copolymer. Shown below is a scheme of the preparation process.

^{«ΛΛΛΛAΛ}' PPO chain

[0033] In the first step, PPO (e.g., of a molecular weight of 2000) is first partially deprotonated with a deprotonated agent such as cesium hydroxide (CsOH) and the resultant water is removed, so that part of the hydroxyl groups (e.g., 80%) are converted to alkoxide, thus giving a PPO macroinitiator.

[0034] In the second step, ethoxyethyl glycidol ether (EEGE) is introduced to the macroinitiator for ring-opening polymerization to give the precursor PEEGE-PPO-PEEGE. The block structures of the resulting PEEGE-PPO-PEEGE precursor can be proved by gel permeation chromatography (GPC) which also gives polydispersity of the copolymer precursor.

[0035] In the third step, the PEEGE-PPO-PEEGE precursor can be treated with aluminum chloride (AlCl₃) in methanol, e.g., for an hour at room temperature, to give rise to the PG-PPO-

PG copolymer.

[0036] The PG-PPO-PG copolymers of different molecular weights can be prepared by using the similar procedure, e.g., with different PPO and under slightly different condition for different period of time. [0037] Shown below in Table 2 are targeting and characterization data of the PG-PPO-PG copolymers and the corresponding PEEGE-PPO-PEEGE Precursors, all of which contain a PPO block of 34 propylene oxide units.

Table 2. Targeting and Characterization Data of the PG-PPO-PG copolymers and the Corresponding PEEGE-PPO-PEEGE Precursors total degree of polymerization of the

PEEGE moieties targeting PG copolymer experimental PG content (\vt %) theoretical experimental* composition* content (wt %)^r abbreviation

20 7 6 3-34-3 IS LGP62

30 12 11 6-34-6 29 LGP63

40 18 16 8-34-8 37 LGP64

50 27 26 13-34-13 49 LGP65

60 40 35 17-34-17 56 LGP66

70 63 52 26-34-26 66 LGP67

80 108 102 51-34-51 79 LGP68

90 242 141 70-34-70 84 LGP68+

^• Determined from the ¹H NMR data of PEEGE- PPO-PEEGE precursors in CDCl₃ ^b 34 is the average degree of polymerization of the middle PPO block The degrees of polymerization of the flanking blocks are the same for the precursors and final copolymers ' Determined from the ¹H NMR data of PG-PPO-PG precursors in DMSO-rft

[0038] Shown below in Table 3 are some physical and chemical data of additional PG-PPO- PG copolymers that can be used for the methods of this invention.

Table 3. PG Content, Composition, Total Copolymer Molecular Weight, and Codes of the Copolymers

PG total content molecular

(wt %) composition weight code

30 (G)₆(PO)₃₄(G)₆ 2900 LGP63

40 (G)₈(PO)₃₄(G)₈ 3200 LGP64

50 (G)I₃(PO)₃₄(G)J₃ 3900 LGP65

60 (G)₁₇(PO)₃₄(G)₃₇ 4500 LGP66

70 (G)₂₆(PO)₃₄(G)₂₆ 5800 LGP67

80 (G)₅I(PO)₃₄(G)₅I 9500 LGP68

84 (G)₇O(PO)₃₄(G)₇O 12400 LGP68+

Uses of PG-Based Polymers

[0039] BPG and LPG have been tested to be biocompatible. See, e.g., R. K. Kainthan et al., Biomacromolecules, 2007, 7, 703-709. Thus, they are expected to have biomedical applications similar to other biocompatible polymers such as poloxamers. As such, it is expected that BPG and LPG can be used for the treatment, amelioration, or prevention of heart failure. [0040] By the same token, there exist substantial similarities of chemical composition and physical properties between the PG-PPO-PG copolymer and poloxamers (e.g., Poloxamer 188, which has the structures of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) with a molecular weight of about 8,500 Daltons). Thus, some of the PG copolymers, e.g., PG- PPO-PG with a molecular weight in the range of approximately 4000 and 15,000 Daltons, may have biomedical applications including acting as membrane sealants. A center block of PPO having a molecular weight between approximately 1200 and 5000 would be expected to insert into a lipid bilayer cellular membrane, as has been shown for, e.g., Poloxamer 188. Additionally, the polyglycidol blocks would remain in the aqueous environment, and form hydrogen bonds with water molecules. Because of additional hydroxyl substituents on the polyglycidol blocks of the molecule, hydrogen bonding to surrounding water molecules would be more extensive than that observed for Poloxamer 188. This additional hydrogen bonding would be expected to stabilize the association between the lipid bilayer and the PG molecule(s) compared to Poloxamer 188, possibly making the PG copolymers stronger and longer acting sealants than Poloxamer 188.

[0041] PG-PPO-PG copolymers having a PPO content and molecular weight similar to Poloxamer 188 may also be useful for treating heart failure by decreasing left ventricular end diastolic pressure with or without an increase in left ventricular ejection fraction, which has been found for Poloxamer 188 at such a low dosage as 4.6 mg/kg.

Uses of the Compositions of this Invention

[0042] The compositions of this invention can be used for treating or ameliorating a diseased heart in a patient or to prevent certain pathologies of heart disease in a subject (e.g., a human patient or animal). The disease can be heart failure, e.g., chronic heart failure (such as ischemic heart failure) or acute heart failure.

[0043] For instance, a composition of this invention can be injected or infused into the blood vessel of a patient (or a subject) with a diseased heart and in need of the treatment. The therapeutic agent in the composition (e.g., a PG-PPO-PG) then circulates into the heart. Not wishing to be bound by this theory, the therapeutic agent contained in the compositions of this invention may decrease the contractile stress of the heart muscle, and in a condition of low membrane dystrophin levels, may even decrease membrane damage enough to allow the heart to repair itself. In other words, the therapeutic composition may aid in the repair of membrane damage in a diseased heart without the need of a surgical procedure and with or without therapeutic agents to reduce the load on the heart.

[0044] Efficacy of the compositions of this invention in treating, ameliorating, or even preventing the heart disease can be determined by methods known in the art, e.g., by measuring the blood flow rate or volume in vitro or in an animal model or the pharmacokinetics of the therapeutic agent in the composition. See, e.g., J. M. Grindel et al., Biopharm. Drugs Dispos.,

2002, 23: 87-103.

[0045] Set forth below are some examples that illustrate uses of the compositions of this invention. These examples are intended only to be illustrated of, not in any way limiting, this invention.

[0046] All publications cited herein are incorporated by reference in their entireties.

Example 1. Effect on Heart Failure.

[0047] In a rat myocardial infarction (MI) heart failure model, the left anterior descending coronary artery (LAD) is tied off to produce an infarction of greater than 40%. The rats become stable after 1 to 3 weeks and in 3 weeks exhibit significant left ventricular (LV) dysfunction. 8- weeks post-MI rats are used due to their loss of dystrophin. Control groups include untreated heart failure rats, sham-operated animals where the LAD was exposed but not tied off as well as rats that did not undergo the surgery (normal).

[0048] On the day of treatment, rats can be infused with a PG-PPO-PG copolymer at a dose ranging from 0.46 mg/kg to 460 mg/kg over a 30-minute period and the heart catheterized and hemodynamics monitored over a 4-hour period.

[0049] Compared with untreated MI rats, the PG copolymer treatment may cause a significant decrease in left ventricular end-diastolic pressure (LVEDP), suggesting an increased ability of the heart to relax. It may also cause left ventricular end-diastolic dimension, an echocardiography seregate for left ventricular end-diastolic volume, to decrease. It may also cause a significant increase in left ventricular ejection fraction (LVEF), a measurement that indicates the ability of the heart to empty its content during systole. Additionally, one may also observe a significant decrease in isovolumic relaxation (LV-dP/dt), a measure of the rate of fall in pressure. The heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular isovolumic contraction (LV +dP/dt), and left ventricular end systolic volume may not change significantly.

[0050] The passive pressure- volume relationships also can be determined in treated hearts from rats with heart failure (HF), normal rats, sham-operated rats and untreated HF rats. These measurements permit the calculation of myocardial compliance (dV/dP) and give indications of remodeling. The pressure-volume relationships in the HF rats can be obtained from hearts arrested in diastole. The untreated HF rats (chronic HF) exhibit dilation due to remodeling of the heart with decreased compliance compared with untreated normal rats. By contrast, treatment with PG-copolymer may shift the PV curve to the right at low doses (0.46 mg/kg to 15 mg/kg) while still returning the heart to near indicating that PG copolymer may have an effect on the dilated ventricle, returning it to normal dimensions.

Example 2. Duration of Action

[0051] HF rats can be infused with a single dose of PG-PPO-PG copolymer and monitored by echocardiography at 2, 24, and 48 hour post infusion. Blood samples can also be taken to determine serum concentrations of the P- 188.

[0052] As in Example 1, treatment of rats with severe HF with PG copolymer at 460 mg/kg may result in a significant increase in left ventricular ejection fraction at 2 hr, which may be maintained out to 48 hr of treatment. Left ventricular fractional shortening, the change in diameter of the LV chamber from end-diastole to end-systole divided by the LVED diameter, may increase significantly as well. Left ventricular dimension in both diastole and systole may not change during the first 24 hours.

Other Embodiments

[0053] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A therapeutic composition for the treatment of heart failure, comprising a therapeutically acceptable carrier and a polyglycidol-based polymer as a therapeutic agent.

2. The therapeutic composition of claim 1, wherein the polyglycidol-based polymer is a linear polyglycidol polymer.

3. The therapeutic composition of claim 1, wherein the polyglycidol-based polymer is a branched polyglycidol polymer.

4. The therapeutic composition of claim 1, wherein the polyglycidol-based polymer is a linear polymer.

5. The therapeutic composition of claim 4, wherein the polyglycidol-based polymer is a copolymer containing polyglycidol.

6. The therapeutic composition of claim 5, wherein the polyglycidol-based polymer is a copolymer containing polyglycidol and poly(alkylene oxide).

7. The therapeutic composition of claim 6, wherein the polyglycidol-based polymer is a block copolymer containing polyglycidol and poly(propylene oxide).

8. The therapeutic composition of claim 7, wherein the polyglycidol-based polymer is polyglycidol-poly(propylene oxide)-polyglycidol.

9. The therapeutic composition of claim 8, wherein the poly(propylene oxide) block of the copolymer includes 20-50 propylene oxide units.

10. The therapeutic composition of claim 9, wherein the poly(propylene oxide) block of the copolymer includes an average of 34 propylene oxide units.

11. The therapeutic composition of claim 10 wherein each of the two polyglycidol blocks of the polymer comprise glycidol and ethylene-oxide units

12. The therapeutic composition of claim 10, wherein each of the two polyglycidol blocks of the copolymer includes 4 to 80 glycidol units.

13. The therapeutic composition of claim 12, wherein each of the two polyglycidol blocks of the copolymer includes an average of 6, 8, 13, 17, 26, 51, or 70 glycidol units.

14. The therapeutic composition of claim 13, wherein the two polyglycidol blocks of the copolymer have the same average number of glycidol units.

15. The therapeutic composition of claim 9, wherein each of the two polyglycidol blocks of the copolymer includes 4 to 80 glycidol units.

16. The therapeutic composition of claim 1, wherein the therapeutically acceptable carrier is an aqueous buffer.

17. The method of claim 16, wherein the aqueous buffer has a pH between 6.0 and 8.0.

18. The method of claim 17, wherein the aqueous buffer has a pH of about 7.4.

19. A method for improving the functioning of a diseased heart in a patient, comprising administering to the patient a therapeutic composition comprising a therapeutically effective amount of a polyglycidol-based polymer.

20. The method of claim 19, wherein the therapeutic composition comprising 5-30% of the copolymer

21. The method of claim 19, wherein the therapeutic composition improves the functioning of the diseased heart continuously for at least 24 hours following each administration of the therapeutic composition.

22. The method of claim 21, wherein the therapeutic composition improves the functioning of a diseased heart continuously for at least 48 hours following each administration of the therapeutic composition.

23. The method of claim 22, wherein the therapeutic composition improves the functioning of a diseased heart continuously for at least 7 days following each administration of the therapeutic composition.

24. The method of claim 23, wherein the therapeutic composition improves the functioning of a diseased heart continuously for at least one month following each administration of the therapeutic composition.

25. The method of claim 19, wherein the therapeutic agent improves the functioning of a diseased heart independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

26. The method of claim 19, wherein the polyglycidol-based polymer is a linear polyglycidol.

27. The composition of claim 26, wherein the polyglycidol-based polymer is a branched polyglycidol.

28. The composition of claim 27, wherein the polyglycidol-based polymer is a linear polymer.

29. The composition of claim 28, wherein the polyglycidol-based polymer is a block copolymer containing polyglycidol.

30. The composition of claim 29, wherein the polyglycidol-based polymer is a copolymer containing polyglycidol and poly(alkylene oxide).

31. The composition of claim 30, wherein the polyglycidol-based polymer is a copolymer containing polyglycidol and poly(propylene oxide).

32. The composition of claim 31, wherein the polyglycidol-based polymer is polyglycidol-poly(propylene oxide)-polyglycidol.

33. The composition of claim 31, wherein the polyglycidol-based polymer is a copolymer containing a poly(propylene oxide) center block flanked by mixed blocks of poly(ethylene oxide) and polyglycidol.

34. The method of claim 19, wherein the therapeutic composition is administered by injection or infusion.

35. The method of claim 19, wherein the disease of the heart is heart failure.

36. The method of claim 35, wherein the disease of the heart is chronic heart failure or acute heart failure.

37. The method of claim 19, wherein the disease of the heart is ischemic or idiopathic heart failure.

38. The method of claim 19, wherein the disease of the heart is muscular dystrophy.

39. The method of claim 19, wherein the therapeutic composition comprises an amount of polyglycidol-based polymer that can range from about 0.4 to about 500 mg/kg.

40. The method of claim 39, wherein the therapeutic composition comprises about 0.46 mg/kg of polyglycidol-based polymer.

41. The method of claim 39, wherein the therapeutic composition comprises about 4.6 mg/kg of polyglycidol-based polymer.

42. The method of claim 39, wherein the therapeutic composition comprises about 10 mg/kg of polyglycidol-based polymer.

43. The method of claim 39, wherein the therapeutic composition comprises about 100 mg/kg of polyglycidol-based polymer.

44. The method of claim 39, wherein the therapeutic composition comprises about 460 mg/kg of polyglycidol-based polymer.

45. A method of treating, ameliorating, or preventing heart failure in a patient, comprising administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, decreasing left ventricular end- diastolic dimension, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

46. The method of claim 45, wherein the therapeutic composition improves the heart condition continuously for at least 24 hours following each administration of the therapeutic composition.

47. The method of claim 46, wherein the therapeutic composition improves the heart condition continuously for at least 48 hours following each administration of the therapeutic composition.

48. The method of claim 47, wherein the therapeutic composition improves the heart condition continuously for at least 7 days following each administration of the therapeutic composition.

49. The method of claim 48, wherein the therapeutic composition improves the heart condition continuously for at least one month following each administration of the therapeutic composition.

50. The method of claim 49, wherein the therapeutic composition improves the heart condition independently of its concentration in the blood for at least 24 hours following each single administration of the therapeutic composition.

51. A method for restoring the integrity of heart muscle cell membrane in a heart failure patient, comprising administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

52. A method for improving the function of the membrane of cardiac muscle cells in a heart failure patient, comprising administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.

53. A method for lowering and maintaining intracellular calcium concentration at normal levels in a heart failure patient, comprising administering to the patient a therapeutic composition comprising an aqueous buffer, and a polyglycidol-based polymer that improves the functioning of a diseased heart by decreasing left ventricular end-diastolic pressure, left ventricular end-diastolic volume, or increasing left ventricular ejection without affecting the blood pressure or heart rate.