LEVODOPA POLYMERIC CONJUGATES, FORMULATIONS THEREOF, AND THEIR USES FOR THE TREATMENT OF PARKINSON'S DISEASE

Abstract

Compounds of formula I: or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof, wherein: R.sub.1 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that the carbonyl group is linked to R.sub.1 through an ester, amide, carbonate or carbamate bond; R.sub.2 is hydrogen, or —(C═O)Rs wherein R.sub.5 is a C.sub.1-3 straight or branched chain alkyl group; and R.sub.3 and R.sub.4 are independently selected from hydrogen, C.sub.1-3 straight or branched chain alkyl group, or —(C=0)Re wherein R.sub.6 is —(O—CH.sub.2—CH.sub.2).sub.n—OCH.sub.3 or a C1-3 straight or branched chain alkyl group, and n is 1 to 5. The compositions are useful for the treatment of Parkinson's disease when administered alone or in combination with carbidopa and/or entacapone.

##STR00001##

Claims

1. A compound of formula I: ##STR00004## or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof, wherein: R.sub.1 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that the carbonyl group is linked to R.sub.1 through an ester, amide, carbonate or carbamate bond; R.sub.2 is hydrogen, or —(C═O)R.sub.5 wherein R.sub.5 is a C.sub.1-3 straight or branched chain alkyl group; and R.sub.3 and R.sub.4 are independently selected from hydrogen, C.sub.1-3 straight or branched chain alkyl group, or —(C═O)R.sub.6 wherein R.sub.6 is —(O—CH.sub.2—CH.sub.2).sub.n—OCH.sub.3 or a C.sub.1-3 straight or branched chain alkyl group, and n is 1 to 5.

2. The compound of claim 2, wherein the pharmaceutically acceptable polymer chain comprising the polymeric moiety R.sub.1 is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialic acid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine) dendrimers, and mixtures, combinations and copolymers thereof.

3. A composition comprising a pharmaceutically effective amount of the compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

4. The composition of claim 3, wherein the composition is injectable, inhalable, or topical.

5. The composition according to claim 3, wherein the composition is in the form of liposomes or micelles.

6. The composition according to claim 3, wherein the pharmaceutically acceptable carrier is castor oil or a derivative thereof.

7. A pharmaceutical composition comprising micro or nano particles comprising: a pharmaceutically effective amount of the compound of formula I; and a second pharmaceutically acceptable polymer, wherein the compound of formula I is encapsulated in the second pharmaceutically acceptable polymer.

8. The pharmaceutical composition according to claim 7, wherein the second pharmaceutically acceptable polymer is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialic acid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine) dendrimers, and mixtures, combinations and copolymers thereof.

9. The pharmaceutical composition according to claim 8, wherein the composition further comprises one or more pharmaceutically acceptable carriers or excipients.

10. The composition of claim 9, wherein the composition is injectable, inhalable, or topical.

11. A method for treating Parkinson's disease comprising administering the composition according to claim 3.

12. The method according to claim 11, wherein the composition is administered intravenously, intramuscularly, intraperitoneally, or subcutaneously.

13. The method according to claim 11, wherein the composition is co-administered with carbidopa and/or entacapone.

14. The method according to claim 12, wherein the composition is administered once daily.

15. The method according to claim 12, wherein the composition is administered twice weekly, thrice weekly, once weekly or biweekly.

16. The method according to claim 12, wherein the composition is administered once monthly.

17. A method for treating Parkinson's disease comprising administering the composition-according to claim 7.

18. The method according to claim 17, wherein the composition is co-administered with carbidopa and/or entacapone.

19. The method according to claim 17, wherein the composition is administered intravenously, intramuscularly, intraperitoneally, or subcutaneously.

20. The method according to claim 17, wherein the composition is administered once daily, twice weekly, thrice weekly, once weekly, biweekly, or once monthly.

21-23. (canceled)

Description

DETAILED DESCRIPTION

[0033] The prodrug of levodopa are obtained by using suitable chemical moieties which mask one or both reactive hydroxyl groups in the phenyl ring and/or the amine group of levodopa. In some embodiments, 0-diacetyl derivatives or a short poly ethylene glycol (PEG) unit (repeating unit n=1-5) at 3 and 4 position of levodopa can be employed generating an ester bond which is eventually converted to free Levodopa in the body system. The two hydroxyl groups can also be converted to 0-methoxy groups for prolonged duration of action. It has been established that the amide prodrug of Levodopa in the form of acetamide in which the amine group is converted to acetamide has better C.sub.max, t.sub.max and AUC (the area under the curve describing the variation of a drug concentration in blood plasma as a function of time) as compared to Levodopa upon systemic administration (Jiang et al., J. Pharm. Biomed. Anal. 2010; 53:751-754). So, an N-acetylation reaction can be done with levodopa to employ an acetamide group for improved efficacy. It is worth noting here that, in the majority of prodrug formulations of levodopa, the C.sub.max, AUC and t.sub.max values in the plasma are known. It is not necessary that a better C.sub.max value in plasma of a particular prodrug formulation has better brain uptake. It has been proven that even if there is no difference in C.sub.max and t.sub.max in plasma, an elevated amount of dopamine was observed in the brain with such prodrugs as compared to Levodopa (Ishikura et al., Int. J. Pharm. 1995; 116:51-63).

[0034] An in vivo cleavable bond is generated with the carboxylic acid functional group of levodopa to a biocompatible polymer so that the polymer allows the levodopa to circulate in blood plasma for longer time without clearance. It also reduces the chances of peripheral degradation of levodopa to dopamine by AADC and COMT enzymes, thereby increasing the subsequent availability of levodopa in the brain. The conjugated compound of formula I provides sustained plasma levels of levodopa with increased delivery of levodopa to the brain, resulting in improved efficacy.

[0035] Pharmaceutically acceptable polymers used in the present invention may be non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA (The Food and Drug Administration) approved. The covalent attachment of polymer to a drug can increase its hydrodynamic size (size in solution), which prolongs its circulatory time by reducing renal clearance (Knop et al., Angew. Chemie Int. Ed. 2010; 49(36):6288-6308; Veronese et al., Drug Discov Today. 2005; 10(21):1451-1458; and Harris et al., Nat Rev Drug Discov. 2003; 2(3):214-221). The polymer conjugate compounds of the invention and polymer-encapsulated compositions of the invention have several advantages including increased bioavailability at lower doses; predictable drug-release profile over a defined period of time following each administration; better patient compliance; ease of application; improved systemic availability by avoidance of first-pass metabolism; reduced dosing frequency without compromising the effectiveness of the treatment; decreased incidence of side effects; and overall cost reduction of medical care.

[0036] Polymer conjugates of formula I may be prepared by methods known in the art, for example, Sk U H et al., Biomacromolecules. 2013; 14(3):801-810. Polymer-encapsulated micro/nano particles may be prepared by methods known in the art. For example, Han et al., Front Pharmacol. 2016; 7:185; Qutachi 0 et al., Acta Biomater. 2014; 10(12):5090-5098.

[0037] In some embodiments, the pharmaceutically acceptable polymer chain in compounds of formula I comprises 15-75 monomer units, 20-70 monomer units, or 25-65 monomer units. In other embodiments, the polymer has a molecular weight in the range of 1 kDa to 75 kDa, 2 kDa to 60 kDa, or 3 kDa to 50 kDa.

[0038] In certain other embodiments, the pharmaceutically acceptable polymer chain in the compound of formula I is a straight or branched chain PEG comprising 4-120 monomer units, 4-75 monomer units, 4-50 monomer units, or 4-30 monomer units. In certain other embodiments, the polymer is a straight or branched chain PEG comprising 12-120 monomer units, 12-75 monomer units, 12-75 monomer units, or 12-30 monomer units. In some other embodiments, the polymer chain is a straight or branched chain PEG comprising 11-20 monomer units, 26-42 monomer units, 49-64 monomer units, or 72-111 monomer units. In certain other embodiments, the polymer chain is a straight or branched chain PEG having a molecular weight in the range of 0.4 kDa to 50 kDa, 0.5 kDa to 50 kDa, 0.8 kDa to 50 kDa, or 1 kDa to 50 kDa.

[0039] The term “encapsulated” in the context of the present invention means coated by, covered by, or surrounded by, such that about 20% to about 80% of the compound of formula I is enclosed/covered/coated by the polymer.

[0040] In some embodiments, PLGA and mixture of PLGA with other polymers, such as PLA, PGA and PVA, in different ratios are used to encapsulate compounds of the invention to form microparticles. Due to its excellent biocompatibility, PLGA is a pharmaceutically acceptable biodegradable polymer widely used for encapsulation of a broad range of therapeutic agents including hydrophilic and hydrophobic small molecule drugs, DNA, and proteins. Other additives can be used to enhance the drug loading and efficiency in PLGA microparticles, such as PEG, poly(orthoesters), chitosan, alginate, caffeic acid, hyaluronic acid etc. PLGA can be a varying composition of PLA and PGA with a ratio from 20 to 80% PGA in PLA and vice versa.

[0041] In some embodiments, the amount of compound of formula I in the compositions of the invention is in the range of 100 mg to 2000 mg equivalent of levodopa administered once daily. Compositions comprising 10-200 mg of carbidopa and/or 200-1600 mg of entacapone may be used in combination with the compositions of the invention for treatment of PD. In some embodiments, compositions of the invention may include carbidopa and/or entacapone in addition to the compound of formula I. The amount of carbidopa co-administered with levodopa may be in a ratio of 1:10 to 1:4 with respect to the amount of levodopa. Entacapone may be co-administered with levodopa in a dose of 200 mg and the dosage repeated as required. Carbidopa in an amount of 10 mg to 200 mg/day and/or entacapone in an amount of 200 mg to 1600 mg/day may be co-administered with the compounds or compositions of the invention.

[0042] In some embodiments, dosage forms of the composition of the invention are adapted for administration to a patient parenterally, including subcutaneous, intramuscular, intraperitoneal, intravenous or intradermal injections. In other embodiments, the composition may be administered as a depot. Upon parenteral injection of levodopa polymer conjugates of formula I, enzymatic cleavage may occur generating levodopa and/or its prodrugs, and the respective polymer used in the conjugation.

[0043] In some embodiment, the compositions of the invention further comprise one or more pharmaceutically effective carriers or excipients. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0044] The compositions may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

EXAMPLES

[0045] a) Preparation of Polymer Conjugates of Formula I

[0046] Levodopa may be prepared by methods known in the art or obtained from commercial sources. All prodrug of Levodopa (ester at 3,4-position and amide at 2-position) may also be prepared by methods known in the art.

[0047] Dissolve levodopa or its prodrug in anhydrous dimethylformamide (DMF) under nitrogen atmosphere. Add: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and Dimethylamino) pyridine (DMAP) dissolved in DMF to the reaction mixture and stir the reaction mixture for 30 minutes. Add a calculated amount of linear, branched PEG or any other carboxylate-functionalized globular polymer dissolved in DMF to the reaction mixture and stir the reaction mixture for 2 days under nitrogen atmosphere. Evaporate the solvent and dialyze the resulting reaction mixture for 24 hours using dialysis membrane (MWCO 1 kDa) and then with water. Lyophilize the resulting water to get the final levodopa polymer conjugates. Check the purity of the conjugate by reverse-phase high performance liquid chromatography (HPLC) and characterize/calculate the loading of the polymeric conjugate by proton nuclear magnetic resonance (NMR), and matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectroscopy.

[0048] b) Preparation of Microparticles of Compound of Formula I

[0049] Nanoprecipitation technique is used for the preparation of the levodopa microparticles. Briefly, either levodopa or levodopa prodrug and a polymer (e.g., PLGA) are dissolved in a suitable solvent (e.g., dichloromethane) in different ratios, the mixture being subjected to sonication for 5-10 minutes to achieve dissolution, if required. Dissolve a hydrophilic non-ionic surfactant (for example a triblock copolymer), such as Pluronic F127, in 50 mL of deionized water and add the levodopa/PLGA solution dropwise using a syringe with a flow rate of 1 mL/10 min with stirring at varying speed. Centrifuge, and lyophilize the obtained nanosuspension with cryoprotectant (e.g., 2% sucrose). Characterize the microparticle with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-Ray diffraction (XRD).