A polymer based delivery system for administration of corticosteroids

Abstract

The invention relates to polymer drug conjugate comprising dexamethasone or betamethasone, and methods for preparation of dexamethasone or betamethasone derivatives for the treatment of a number of diseases. Moreover, the embodiments of the invention relate to chemical compounds having an anti-inflammatory activity and / or immunosuppressive activity and synthetic intermediates, means for their preparation, pharmaceutical compositions and drug-delivery systems comprising such compounds including dexamethasone or betamethasone, and methods of treatment employing the same.

Description

[0001]A POLYMER BASED DELIVERY SYSTEM FOR ADMINISTRATION OF CORTICOSTEROIDS FIELD OF THE INVENTION This invention relates to polymer drug conjugates according to formula I, methods of preparingthe polymer-drug conjugates and their use for treatment of diseases detailed in the specification.Embodiments of the invention relate to chemical compounds having an anti-inflammatory and / orimmunosuppressive activity and synthetic intermediates, means for their preparation,pharmaceutical compositions and drug-delivery systems comprising such compounds includingdexamethasone and betamethasone, and methods of treatment employing the same. Particularly,the present invention is directed to compositions comprising dexamethasone or betamethasone,and methods for preparation and administration of dexamethasone or betamethasone derivativesfor the treatment of a number of diseases. BACKROUND OF THE INVENTION The World Health Organization (WHO) compiles a comprehensive list of medicines that are highly effective, safe, and economically viable. This list specifically includes important drugs that may require sophisticated diagnostic or monitoring facilities, expert medical care, and / or specializedtraining. Dexamethasone and betamethasone are a well-established corticosteroid drugs that havebeen employed in the treatment of various diseases and disorders and is also featured in the listcompiled by the World Health Organization. The topic of dexamethasone, for instance, isaddressed under the various categories as outlined in this listing such as medicines for common symptoms in palliative care, antiallergics and medicines used in anaphylaxis, antiemeticmedicines, acute lymphoblastic leukaemia, anaplastic large cell lymphoma, Burkitt lymphoma andmultiple myeloma. (Glucocorticoid use in acute lymphoblastic leukemia: comparison ofprednisone and dexamethasone - PMC (nih.gov)).When the dosages of dexamethasone and betamethasone are not adjusted properly, various sideeffects such as hormone balance in the body, unsteady suppression of adrenal glands, loss of appetite, nausea, weakness, fatigue, and hypotension are observed. In recent years, there has been a rise in the importance of research that investigate the use ofpolymer materials as drug carriers. For instance, a prior art, WO2007004067 (A2) disclosescompositions for the delivery of biologically active agents. The invention features a method fordecreasing inflammation at a specific location within a biological organism that requires suchintervention. The method provided in WO2007004067 (A2) includes a method of releasing froma surface an anti-inflammatory substance such as dexamethasone and betamethasone in a sufficientamount.The abrupt withdrawal of dexamethasone or betamethasone treatment, particularly in individualsusing large doses of corticosteroids, might disrupt the hormonal equilibrium of the body. Studies on controlled drug release have become increasingly important as a consequence of theundesirable side effects of therapies that comprise dexamethasone or betamethasone.Given the aforementioned state of the art it is evident that there exists a necessity for thedevelopment of a novel polymer-drug combination including dexamethasone or betamethasonethat possesses diminished side effects and the required pharmacokinetic characteristics. BRIEF DESCRIPTION OF THE INVENTIONAn object of the present invention is to provide a dexamethasone or betamethasone delivery systemand a method of preparation thereof. Another object of the present invention is to provide a polymer-drug conjugate which addresses the problem of drug cleavage before the polymer drug conjugate reaches the tissue.Since the dexamethasone and betamethasone increase the risk of stomach ulcers, it is customaryto concurrently administer antacids and gastric protective medications. Reducing the use of extramedications is another advantage of the present invention. Other adverse effects of dexamethasone and betamethasone as mentioned in the prior art, on the digestive system are reduced by the present invention. The present invention discloses a polymer-drug conjugate as shown in Formula I for delivery of Dexamethasone or betamethasone. Formula I The polymer-drug conjugates disclosed in the present invention comprises a (meth)acrylate based polymer backbone, at least two types of side chains wherein one of the side chains is a oligoethylene glycol (PEG) bearing chain such as -COOCH2CH2(OCH2CH2)nOCH3and the other side chain includes at least one therapeutic agent covalently bonded to a cleavable linker wherein, • R is selected from H or -CH3; • x is a natural number between 15-100; • y is a natural number between 1-20; • n is a number between 2-10; • L is a cleavable linker; • A is an end group; • B is an end group, and• D is a therapeutic agent that is dexamethasone or betamethasone. In a possible embodiment, the linker comprises C1-C10substituted or hetero substituted hydrocarbon including at least one functional group selected from the group comprising of acetal, ester, imine, disulfide, carbonate, carbamate, and hydrazone. In accordance with another embodiment, the linker is selected from a group comprising a poly(ethylene glycol), an amino acid, poly(amino acid), polypeptide and short peptides.In a possible embodiment, the polymer-drug conjugate has a molecular weight between 5 kDa to100 kDa. In another possible embodiment, the polymer-drug conjugate has an average molecular weight in between 10 kDa to 80 kDa.In accordance with an embodiment, dexamethasone or betamethasone is present in an amountbetween 2% to 40% (wt / wt) by the total weight of the polymer-drug conjugate.In accordance with another embodiment, dexamethasone or betamethasone is present in an amountbetween 7% to 29% (wt / wt) by the total weight of the polymer-drug conjugate.In accordance with an embodiment dexamethasone or betamethasone is present in an amountbetween 10% to 20% (wt / wt) by the total weight of the polymer-drug conjugate.In a possible embodiment, a pharmaceutical composition comprising a polymer-drug conjugate offormula I as shown above.In a possible embodiment, a polymer-drug conjugate of formula I as shown above can be for useas a medicament.In a possible embodiment, a polymer-drug conjugate of formula as shown above can be for use inthe treatment of side effects of chemotherapy. In a possible embodiment, a polymer-drug conjugate of formula I as shown above can be for use in the treatment of postoperative nausea and vomiting.DETAILED DESCRIPTION OF THE INVENTIONBefore the present invention is described, it is to be understood that this invention is not limited tothe processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describingthe particular versions or embodiments only and is not intended to limit the scope of embodimentsherein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one ofordinary skill in the art. Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodiments of embodiments herein, the preferred methods, devices, and materials are now described. It is also noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.Considering the prior art, the technical problem underlying the present invention is to providealternative and / or improved means for reducing the side effect and improve the pharmacokineticproperties. This problem is solved by the features of the independent claims. Optional, possible orpreferred or exemplary embodiments of the present invention are provided by the dependent claims.The present invention is based on the surprising finding that the present invention pertains to anovel pharmaceutical composition and method for controlling the release of dexamethasone orbetamethasone in a highly efficient manner.Examples of the polymer drug conjugates comprising dexamethasone or betamethasone, andexemplary embodiments thereof are described.The present invention further provides methods of using dexamethasone or betamethasone, and itspharmaceutical compositions for therapies.The term "polymer-drug conjugate” hereinafter refers to a polymeric structure having a therapeuticagent covalently attached to the polymer.The terms "polymeric backbone" and "polymer backbone” hereinafter can be used interchangeablyand refer to a polymer chain having side chains or pendant groups. For example, a side chain may have an oligo ethylene glycol unit and a pendant group may be bearing one therapeutic agent orany other group that can be utilized to attach a therapeutic and / or diagnostic agent or a targetinggroup.Throughout the text, the term "the polymer-drug conjugate of the invention" hereinafter should beconstrued to mean "a polymer-drug conjugate according to formula I" or "a polymer-drug conjugate of formula I" or "formula I" and these terms can be used interchangeably.The term "agent(s)" hereinafter refers to at least one or more therapeutic agents. “Therapeuticagent" refers to any compound that is suitable for use in treatment of a disease. The terms"therapeutic agent”, or “anti-inflammatory", both refer to the compounds suitable for use intreatment of a disease and these terms can be used interchangeably. Additionally, a "therapeutic agent" also refers to any agent that is suitable for use in treating of a disease. Any therapeutic agent which can be directly or indirectly attached to the polymer-drug conjugate of the invention can beused. The patent application WO2018002761A1 also describe agents and this document isincorporated herein by reference. As used herein, "treat" or "treating" means to inhibit, reduce, modulate, ameliorate, or block at least one symptom that characterizes a pathologic condition, ina subject threatened by, or afflicted with, the condition. The term “treatment” includes eithertherapeutic or prophylactic therapy. The term "dexamethasone”, which is the preferred therapeutic agent in the context of the presentinvention, hereinafter may refer to (8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 – dodecahydro -3H - cyclopenta[a]phenanthrene -3-one), dexamethasone phosphate, dexamethasone sodiumphosphate, dexamethasone acetate, dexamethasone palmitate or dexamethasone dipropionate or esters thereof, or pharmaceutically acceptable salts thereof.The term "acrylate” hereinafter refers to derivatives of acrylic acids. These derivatives include theparent acid (CH2 CHCO2H) and esters, thus the term "acrylate based" defines functional groups having any of the abovementioned acrylate derivatives.The term "methacrylate” hereinafter refers to derivatives of methacrylic acids. These derivativesinclude the parent acid (CH2 C(CH3)CO2H) and esters. Thus the term "methacrylate based" defines functional groups having any of the abovementioned methacrylate derivatives.The term "(meth)acrylate” hereinafter refers to the terms "acrylate" and "methacrylate". Thus, theterm "(meth)acrylate" can be used interchangeably with "acrylate" and "methacrylate" and comprises all features of these terms as described above. The term "(meth)acrylate" should be construed to mean "methacrylate and / or acrylate".The term "PEG" hereinafter refers to a polyether compound having the structure of H-(O-CH2 -CH2)n-OCH3, n being a natural number between 1-20 and R selected from H or -CH3. PEG is defined as an oligomer or polymer of ethylene oxide. The terms "PEG", "polyethylene glycol", "polyethylene oxide", "PEO", "polyoxyethylene" and "POE" refer to the same structure and may be used interchangeably within this text. As shown by formula I the polymer-drug conjugate of the invention comprises PEG side chains. The side chains provide important physicochemical properties to the polymer-drug conjugate of the invention and leads to a polymer-drug conjugate that has better physicochemical properties in comparison to the conjugates that does not have said side chains. As mentioned above "L" in formula I denotes a cleavable linker. The term "cleavable linker" refersto a group that spatially separates drug or a targeting group from the carrier molecule and breaksin the presence of chemical or biological stimuli. The terms "linker", "L" and "cleavable linker"refer to the same entity and can be used interchangeably. The term "random copolymer" refers to a copolymer wherein the monomers forming thecopolymer follow in any order. The polymer-drug conjugates of the invention are in the form of arandom copolymer. The term “end group” refers to functionalities or constitutional units that are at the extremity of a polymer. A and B can optionally be a polymerization initiator or a fragment thereof. Particularlywhen an initiator is used in the polymerization reaction, an initiator fragment may stay as an endgroup on the polymer. The initiator used herein, may be any material suitable for initiating thepolymerization reaction known in the art. The patent application WO2018002761A1 also describethe end groups and this document is incorporated herein by reference. The present invention discloses a polymer-drug conjugate as shown in Formula I for delivery of therapeutic agents including dexamethasone or betamethasone: Formula I The polymer-drug conjugates disclosed in the present invention comprises a (meth)acrylate based polymer backbone, at least two types of side chains wherein one of the side chains is a PEG bearing chain such as -COOCH2CH2(OCH2CH2)nOCH3and the other side chain includes at least one therapeutic agent covalently bonded to a cleavable linker. R is selected from H or -CH3; x is a natural number between 15-250; y is a natural number between 1-20; n is a number between 2-20; L is a cleavable linker; A is an end group; B is an end group, and D is a therapeutic agent that is dexamethasone or betamethasone. The polymer-drug conjugates disclosed in the present invention comprises a (meth)acrylate based polymer backbone, at least two types of side chains wherein one of the side chains is a PEG chain such as -COOCH2CH2(OCH2CH2)nOCH3 and the other side chain includes at least one therapeutic agent covalently bonded to a cleavable linker. The present invention provides a polymer-drug conjugate for delivery of therapeutic agents comprising a (meth)acrylate based polymer backbone characterized in that the polymer comprises at least two types of side chains wherein one of the side chains is a PEG chain such as -COOCH2CH2(OCH2CH2)nOCH3 wherein n is a natural number between 2-20 and R is selected from a group comprising H or -CH3 and the other side chain is comprising at least one therapeutic agent covalently bonded to a cleavable linker as shown in Formula I above.According to an optional embodiment, the polymer drug conjugate comprises -CH3 as R anddexamethasone or betamethasone as a therapeutic agent. According to another optionalembodiment, the polymer drug conjugate comprises -H as R, and dexamethasone orbetamethasone as a therapeutic agent.The inventors have surprisingly found that in addition to overcoming the disadvantages of the prior art drug delivery systems comprising polymer-drug conjugates; the polymer of the presentinvention allows the dose of dexamethasone or betamethasone to be adjusted as needed, ensureshormone balance in the body, prevents unbalanced suppression of the adrenal glands andeliminates various side effects such as loss of appetite, nausea, weakness, fatigue and hypotension.Moreover, the invention provides certain degree of water solubility along with the longer half-life.The aqueous solubility is important to reach the target inflammation site without getting trappedand accumulating in the other organs. This, in turn, provides a polymer-drug conjugate that haslower toxicity. Moreover, the present invention enables the maintenance of the body's hormonalequilibrium. The linkers are cleavable so that the therapeutic agent can be released, for example, under reducing conditions, oxidizing conditions or by hydrolysis of an ester, carbonate, carbamate, dithiane, orsimilar linkage that forms the covalent bond between the linker and the therapeutic agent.Additionally, the type of linker may augment the selective toxicity (and thus improve thetherapeutic index) aspect by permitting selective release of the therapeutic agent adjacent to orinside the cell.The cleavable linker can be any hydrocarbon or substituted hydrocarbon-based compound whichis capable of dissociating under physiological conditions. A physiological condition can be definedas one that has a temperature range of 20–40 degrees Celsius, an atmospheric pressure of 1, and apH between 6-8. In a more limited scope, it is to be comprehended that the pH levels within thehuman body are confined within the range of 7.35 to 7.45.In a possible embodiment, the linker can be selected from compounds that are cleaved under theacidic conditions (such as any C1-C10 substituted hydrocarbon comprising an acetal or an esterfunctional group) or with the help of the overexpressed enzymes which may be present in anintercellular or intracellular matrix of the cells. In an exemplary embodiment, the linker is a C1-C10 substituted or hetero substituted hydrocarbon.The C1-C10 substituted or hetero substituted hydrocarbon comprises at least one functional groupselected from the group consisting of acetal, ester, imine, disulfide, carbonate, carbamate, and hydrazone. In another exemplary embodiment, the linker comprises two or more functional groups selected from the group consisting of acetal, ester, imine, disulfide, carbonate, carbamate, and hydrazone. The term “C1-C10 hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in thebackbone. The term “C1-C10 substituted hydrocarbon” refers to a hydrocarbon chain having 1 to10 C atoms in the backbone wherein one or more of its hydrogen atoms replaced by atoms of groups of other elements such as alcohol, amine, carboxyl, thiol etc. The term “C1-C10 heterosubstituted hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein at least one of the C atoms is substituted with an atom other than C such as nitrogen, oxygen, phosphorus, sulfur or a halogen atom. These substituents include but not limited to lower alkoxy such as methoxy, ethoxy, butoxy; ethers; acetals; esters; heteroaryl; heterocyclic, hydroxyl; protected hydroxyl; acyl; acyloxy; amino; amido; imine, disulfide, carbonate, carbamate, hydrazone. In an exemplary embodiment of the invention, the polymer drug conjugate comprises -CH3 as R,dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one disulfide functional group. In an exemplary embodiment of the invention, the polymer drug conjugate comprises -H as R,dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one disulfide functional group.In another exemplary embodiment of the invention, the polymer drug conjugate comprises -CH3as R, dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one acetal functional group. In another exemplary embodiment of the invention, the polymer drug conjugate comprises -H asR, dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one acetal functional group. In yet another exemplary embodiment of the invention, the polymer drug conjugate comprises -CH3 as R, dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10hetero substituted hydrocarbon comprising at least one ester functional group. In yet another exemplary embodiment of the invention, the polymer drug conjugate comprises -Has R, dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one ester functional group. In an embodiment of the invention, the polymer drug conjugate comprises -CH3 as R,dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one imine functional group. In an embodiment of the invention, the polymer drug conjugate comprises -H as R, dexamethasoneor betamethasone as a therapeutic agent wherein the linker is a C1-C10 hetero substitutedhydrocarbon comprising at least one imine functional group. In an embodiment of the invention, the polymer drug conjugate comprises -CH3 as R,dexamethasone or betamethasone as a therapeutic agent wherein the linker is a C1-C10 heterosubstituted hydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention, the polymer drug conjugate comprises -H as R, dexamethasoneor betamethasone as a therapeutic agent wherein the linker is a C1-C10 hetero substitutedhydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention, the polymer drug conjugate comprises -H as R, dexamethasoneor betamethasone as a therapeutic agent wherein the linker is a C1-C10 hetero substitutedhydrocarbon comprising at least one carbamate functional group. In an embodiment of the invention, the polymer drug conjugate comprises -H as R, dexamethasoneor betamethasone as a therapeutic agent wherein the linker is a C1-C10 hetero substitutedhydrocarbon comprising at least one hydrazone functional group. In an exemplary embodiment of the invention, the polymer drug conjugate comprises -CH3 as R,dexamethasone or betamethasone as a therapeutic agent wherein the linker may comprise a C1-C10substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising acetal, ester, imine, disulfide, carbonate, carbamate, hydrazone.The invention presents a polymer-drug conjugate according to formula 1 for use as a medicament.The invention presents a polymer-drug conjugate according to formula 1 for use in the treatmentof postoperative nausea and vomiting.The invention presents a polymer-drug conjugate according to formula 1 for use in the treatmentof nausea and vomiting induced by chemotherapy.The invention presents a polymer-drug conjugate according to formula 1 for use in the treatmentof nausea and vomiting.The invention presents a polymer-drug conjugate according to formula 1 for use in the treatmentof side effects of the cancer treatment. Some embodiments are directed to the use of a pharmaceutical composition according to an embodiment herein in the treatment of at least one disease or condition selected from the groupcomprising of primary immune thrombocytopenia, postoperative nausea and vomiting, nausea andvomiting induced by chemotherapy. Some other embodiments are directed to the use of a pharmaceutical composition according to an embodiment herein in the treatment of postoperative nausea. Some other embodiments are directed to the use of a pharmaceutical composition according to an embodiment herein in the treatment of postoperative vomiting. Some embodiments are directed to the use of a pharmaceutical composition according to an embodiment herein in the treatment of nausea and vomiting induced by chemotherapy. The present invention provides a usage of polymer drug conjugate for the preparation of compositions for therapeutic treatments of diseases selected from pathologies of inflammatory-type diseases.The present invention further provides a drug-delivery system which is formulated for localdelivery to the subject.When dexamethasone or betamethasone is selected as a therapeutic agent, the therapeutic agentcan be present in an amount between 2% to 40% by weight of the polymer-drug conjugate, preferably in an amount between 3% to 35% by weight of the drug-polymer conjugate, and most preferably in an amount between 3% to 30% by weight of the drug-polymer conjugate. Thetherapeutic agent can be present in an amount for example, 5% to 25% or 6% to 24% or 8% to23% or 11% to 22%, or 13% to 20% by weight of the drug-polymer conjugate.In an aspect of the invention the dexamethasone or betamethasone can be present in an amount at10% by weight of the polymer-drug conjugate.In an aspect of the invention the dexamethasone or betamethasone can be present in an amount at20% by weight of the polymer-drug conjugate.In an exemplary embodiment, the present invention provides a use of a dexamethasone orbetamethasone in a polymer drug conjugate or in a drug delivery system.A composition in accordance with the present invention can be formed by combining one or more pharmacologically active agents with Formula (I). The present invention further discloses polymer drug conjugates or drug delivery systems that are capable of being formulated for oral administration, such as in the form of liquid dispersions or aqueous or oily suspensions. Additionally, said polymer drug conjugates or drug delivery systemsmay further be prepared for parenteral administration, including but not limited to subcutaneous,intravenous, intramuscular, intrasisternal, intraperitoneal, intradermal, intratympanic or transdermal. The polymer drug conjugates can be configured for inhalation administration in the form of an aerosol or a solution. Said arrangement may be supplied employing inhaler or nebulizer equipment.In accordance with an aspect of the invention, the polymer-drug conjugate of the invention has anaverage molecular weight in between 5 kDa to 100 kDa. In accordance with another aspect of theinvention, the polymer-drug conjugate of the invention has an average molecular weight inbetween 20 kDa to 80 kDa. In accordance with yet another aspect of the invention, the polymer- drug of the invention has an average molecular weight in 30 kDa to 50 kDa.As an exemplary embodiment, the polymer drug conjugate comprises the disulfide functionalgroup as the linker (L), -H as R, and dexamethasone or betamethasone as a therapeutic agent.As an exemplary embodiment the polymer drug conjugate an acetal functional group as the linker(L), -H as R, and dexamethasone or betamethasone as a therapeutic agent.As an exemplary embodiment the polymer drug conjugate comprises an ester functional group asthe linker (L), -H as R, and dexamethasone or betamethasone as a therapeutic agent.As an exemplary embodiment the polymer drug conjugate comprises a carbonate functional groupas the linker (L), -H as R and dexamethasone or betamethasone as a therapeutic agent.As an exemplary embodiment the polymer drug conjugate comprises C1-10 hetero substituted hydrocarbon comprising a carbonate functional group as the linker (L), -CH3 as R anddexamethasone or betamethasone as a therapeutic agent.As an exemplary embodiment the polymer drug conjugate comprises a carbamate functional groupas the linker (L), -H as R and dexamethasone or betamethasone as a therapeutic agent. As can be seen from aforementioned explanation, the polymer drug conjugates in accordance withdisclosed embodiments provides regulated release of dexamethasone or betamethasone; supportsanti-inflammatory and immunosuppressive properties; adjusts dexamethasone or betamethasonedosage to prevent adverse or side effects such hormone imbalance, adrenal gland suppression, lossof appetite, nausea, weakness, fatigue, and hypotension; reduces the administration of antacids andstomach protecting medicines; minimizes the use of additional drugs; and lowers the overdoseeffects of dexamethasone or betamethasone on the digestive system.In accordance with yet another aspect of the invention there is also provided a method (Method I)for preparation of the polymer-drug conjugate of the invention of Formula I which comprisespolymerization of PEG (meth)acrylate monomer of Formula II: Formula II and at least one type of (meth)acrylate-L-D monomer of Formula IIIa: Formula IIIawherein R is selected from H or -CH3, L is a cleavable linker, D is dexamethasone orbetamethasone, and n is a natural number between 2-20 for providing formula I.The invention also provides another method (Method II) for preparation of the polymer-drugconjugate of the invention of formula I comprising (i) polymerization of PEG (meth)acrylatemonomer of Formula II and (meth)acrylate-L. monomer of Formula IIIb;Formula IIIbwherein R is selected from H or -CH3, n is a natural number between 2-20, and L is a cleavablelinker that comprises a reactive group for providing a copolymer as shown in formula IV.Moreover, the reactive group shown as Q is a group that may react with dexamethasone orbetamethasone, and may be selected from reactive groups such as perfluorophenoxy, maleimide,carbonate, thiazolidone-2-thione, N-oxybenzotriazole, imidazolyl, o / p-nitrophenol, pentachlorophenol, N-hydroxysuccinimide, acetates, formates, 2,3,5-trichlorophenol, 8- hydroxyquinoline, Cl, Br for providing a copolymer as shown in formula IV. The exemplary reactive groups are shown in the examples below; wherein x is a natural number between 15-100 and y is a natural number between 1-20, A is anend group that is optionally a polymerization initiator or a fragment thereof, B is an end group thatis optionally a polymerization initiator or a fragment thereof, and then (ii) reacting formula IVwith the therapeutic agent (D) wherein the therapeutic agent is dexamethasone or betamethasone,or pharmaceutically acceptable salts thereof, for instance dexamethasone palmitate or estersthereof, so as to provide the polymer-drug conjugate shown in formula I. In some other cases, a method (method III) for preparation of the polymer-drug conjugate of the invention (formula I) comprises (i) polymerization of PEG (meth)acrylate monomer of Formula II and a (meth)acrylate monomer; wherein n is a natural number between 2-20; R is selected from H or -CH3; Q is selected from carbonyl activating groups such as perfluorophenoxy, carbonate,thiazolidone-2- thione, N-oxybenzotriazole, imidazolyl, o / p-nitrophenoxy, pentachloro-phenoxy,N-hydroxysuccinimide, acetates, formates, 2,3,5-trichlorophenol, 8-hydroxyquinoline, OH, Cl,Br, for providing a copolymer as shown in formula IV; wherein x is a natural number between 15-250 and y is a natural number between 1-20, A is an end group that is optionally a polymerizationinitiator or a fragment thereof or A may be null, B is an end groups that is optionally a polymerization initiator or a fragment thereof or B may be null and (ii) reacting formula V with alinker (L) for providing a copolymer as shown in formula IV; wherein (iii) reacting formula IVwith dexamethasone or betamethasone (D) for providing the polymer conjugate shown in formulaI. As disclosed above, methods for preparing the polymer drug conjugate of formula I (Method I, IIand III) comprise at least one polymerization step, wherein monomers of formula II and monomersof formula Illa or IIIb are polymerized. In an embodiment of the invention, these polymerizationsteps further comprise an initiator and / or a solvent. In an embodiment of the invention PEG(meth)acrylate (Formula II) has an average molecular weight in between 200-2000 g / mol. In another embodiment of the invention PEG (meth)acrylate (Formula II) has an average molecular weight in between 250-1500 g / mol. In yet another embodiment of the invention PEG(meth)acrylate (Formula II) has an average molecular weight 300- 1100 g / mol.The polymer-drug conjugate of the invention can be prepared by any of the known polymerization methods. Any suitable initiators and / or catalysts known in the art can be used for the preparation of the polymer-drug conjugate of the present invention. Where a polymerization initiator is used, the initiator or a fragment thereof may be present in the resulting polymer-drug conjugate. The polymerization technique used for the preparation of the polymer-drug conjugate of the present invention may propagate through free-radical polymerization or controlled / living freeradical polymerization. Herein the term “controlled / living free radical polymerization” refers toatom transfer radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT) polymerization, iodine transfer polymerization (ITP), selenium centered radical mediated polymerization, telluride mediated polymerization (TERP), nitroxide mediated polymerization (NMP). In a preferred embodiment of the invention RAFT polymerization is used to prepare the polymer-drug conjugates of the invention. A polymerization initiator as used herein refers to a chemical compound that reacts with a monomer to form an intermediate compound capable of linking successively with a large number of other monomers into a polymeric compound. In an embodiment of the invention a polymerization initiator selected from the group disclosed in the above paragraphs of thisdocument. In an embodiment of the invention methods I, II, and / or III used to prepare the polymer-conjugate of formula I comprises use of AIBN as initiator in the polymerization reactions. The specific embodiments described herein are offered by way of example, not by way oflimitation. Any subtitles herein are included for convenience only and are not to be construed aslimiting the disclosure in any way. Example 1:To introduce a polymerizable methacrylate group, dexamethasone is reacted with methacryloylchloride. A is a fragment of a polymerization initiator that is a part of phenyl dithioester; and B isa fragment of a polymerization initiator that is a part of azobisisobutyronitrile (AIBN). Thereaction scheme which illustrates a polymer drug conjugate comprising dexamethasone as atherapeutic agent and ester functional group as a cleavable linker is presented below: Example 2: To introduce a polymerizable methacrylate group, the reactive agent including NHS is reacted with dexamethasone and a monomer containing a carbonate functional group is provided. A is fragment of a polymerization initiator that is a part of phenyl dithioester; and B is a fragment of apolymerization initiator that is a part of azobisisobutyronitrile (AIBN).The reaction scheme which illustrates a polymer drug conjugate comprising dexamethasone as atherapeutic agent and carbonate functional group as a cleavable linker is presented below: Example 3:To introduce a polymerizable methacrylate group, dexamethasone is reacted with an agentcontaining an isocyanate functional group, resulting in a carbamate-containing monomer. A is afragment of a polymerization initiator that is a part of phenyl dithioester; and B is a fragment of apolymerization initiator that is a part of Azobisisobutyronitrile (AIBN).The reaction scheme which illustrates a polymer drug conjugate comprising dexamethasone as atherapeutic agent and carbamate functional group as a cleavable linker is presented below: Example 4:To introduce a polymerizable methacrylate group, the dexamethasone is introduced with apolymerizing agent containing the ester and disulfide functional group. The polymer is thencovalently bonded to the main chain. A is a fragment of a polymerization initiator that is a part ofphenyl dithioester; and B is a fragment of a polymerization initiator that is a part of Azobisisobutyronitrile (AIBN).The reaction scheme which illustrates a polymer drug conjugate comprising dexamethasone as atherapeutic agent and disulfide and ester functional group as a cleavable linker is presented below:Figure 1, is a release graph of the polymer-drug conjugates according to Example 4 in the presenceof D-Dopachrome Tautomerase (DDT) Peptide. This Figure is related to a polymer drug conjugatecomprising Poly(oligo(ethylene glycol) methyl ether methacrylate) POEGMEMA, dexamethasone as a therapeutic agent, disulfide functional group as a part of cleavable linker.

Claims

AMENDED CLAIMS received by the International Bureau on 05 November 2025 (05.11 .2025)1. A polymer-drug conjugate of Formula I in the form of a random co-polymer;wherein• R is selected from H or -CH3;• x is a natural number between 15-100;• y is a natural number between 1-20;• n is a natural number between 2-10;• L is a cleavable linker;• D is a therapeutic agent that is dexamethasone or betamethasone,• A is an end group that is a polymerization initiator or a fragment thereof; and,• B is an end group that is optionally a polymerization initiator or a fragment thereof.

2. The polymer-drug conjugate according to claim 1, wherein the linker comprises C1-C10substituted or hetero substituted hydrocarbon including at least one functional group selected from the group consisting of acetal, ester, imine, disulfide, carbonate, carbamate, and hydrazone.

3. The polymer-drug conjugate according to claim 1, wherein the linker is selected from a group consisting of a poly(ethylene glycol), an amino acid, poly(amino acid), polypeptide and short peptides.

4. The polymer-drug conjugate according to any one of the preceding claims, wherein the polymer- drug conjugate has a molecular weight between 5 kDa to 100 kDa.

5. The polymer-drug conjugate according to claim4, wherein the polymer-drug conjugate has an average molecular weight in between 10 kDa to 80 kDa.

6. The polymer-drug conjugate according to any one of the preceding claims, wherein the dexamethasone or betamethasone is present in an amount between 2% to 40% (wt / wt) by the total weight of the polymer-drug conjugate.

7. The polymer-drug conjugate according to claim 6, wherein the dexamethasone or betamethasone is present in an amount between 7% to 29% (wt / wt) by the total weight of the polymer-drug conjugate.

8. The polymer-drug conjugate according to any one of the preceding claims, wherein the dexamethasone or betamethasone is present in an amount between 10% to 20% (wt / wt) by the total weight of the polymer-drug conjugate.

9. The polymer-drug conjugate according to any one of the preceding claims, wherein the therapeutic agent is dexamethasone.

10. A pharmaceutical composition comprising a polymer-drug conjugate of Formula I according to any one of claims 1-9.

11. A polymer-drug conjugate of Formula I according to any one of the claims 1-9 for use as a medicament.

12. A polymer-drug conjugate of Formula I according to any one of the claims 1-9 for use in the treatment of side effects of chemotherapy.

13. A polymer-drug conjugate of Formula I according to any one of the claims 1-9 for use in the treatment of postoperative nausea and vomiting.

14. A method for preparation of polymer drug conjugate of Formula I according to any one of the claims 1 to 9 comprising polymerization of PEG (meth)acrylate monomer of Formula II;and at least one type of (meth)acrylate-L-D monomer of Formula Illa;wherein R is selected from H or -CH3, L is a cleavable linker, D is dexamethasone or betamethasone, and n is a number between 2-10 for providing Formula I.

15. A method for preparation of polymer drug conjugate of Formula I according to any one of the claims 1 to 9 comprising (i) polymerization of a PEG (meth)acrylate monomer of Formula II;and a (meth)acrylate-L monomer of Formula Illb;wherein R is selected from H or -CH3, n is a natural number between 2-10, and L is a cleavable linker that comprises a reactive group Q, wherein Q is selected from perfluorophenoxy, maleimide, carbonate, thiazolidone-2-thione, N-oxybenzotriazole, imidazolyl, o / p-nitrophenol, pentachloro-phenol, N-hydroxysuccinimide, acetates, formates, 2,3,5- trichlorophenol, 8-hydroxyquinoline, Cl, Br and H,for the formation of a copolymer of Formula IV:wherein x is a natural number between 15-100, y is a natural number between 1-20, n is a natural number between 2-10, A is an end group that is a polymerization initiator or a fragment thereof, B is an end group that is a polymerization initiator or a fragment thereof, and then (ii) reacting Formula IV with the therapeutic agent (D) wherein the therapeutic agent is dexamethasone or betamethasone so as to provide the polymer-drug conjugate shown in formula I.

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