JP2016040333A - Method for preparation of controlled release system - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for the preparation of a controlled release system and especially to provide a method for the enclosure of a compound into a polymer carrier for controlled release of active ingredients, preferably bioactive ingredients, such as drugs.SOLUTION: This method results in a system for controlled release of active ingredients and especially for controlled drug delivery. In accordance with the present invention, the term "controlled release" encompasses all kinds of controlled release, including slow release, sustained release, and delayed release. Particularly, the present invention results in active ingredients which are enclosed in or otherwise incorporated in or coupled to polymer carriers, polymeric devices, such as micelles, nanoparticles, and microspheres, or other types of polymer devices for controlled release. The active ingredients are covalently bonded to the polymer carriers or polymeric devices.SELECTED DRAWING: None

Description

  The present invention relates to a method for preparing a controlled release system, and in particular to a method for encapsulating a compound in a polymer carrier for the controlled release of an active ingredient such as a drug, preferably a bioactive ingredient. This method provides a system for controlled release of the active ingredient, particularly controlled drug delivery. According to the present invention, the term “controlled release” encompasses all types of controlled release including sustained release, sustained release and delayed release. In particular, the present invention is encapsulated or otherwise incorporated in polymer carriers or polymeric devices such as micelles, nanoparticles, microspheres, hydrogels and other types of polymer carriers or devices for controlled release. Or active ingredients bound to them. The active ingredient is bound, in particular covalently bound, to the polymer device or carrier.

  Nanoparticulate polymeric carriers such as micelles are considered promising candidates for targeted drug delivery. Such a system can be configured to have a so-called enhanced permeation and retention effect in various affected areas. Such polymeric devices for targeted delivery can include a wide variety of bioactive ingredients such as hydrophobic drugs.

  In this regard, reference may be made to US-B-7,425,581 and EP-A-1 776 400 which describe micelles based on hydrophobically modified PEG-polymethacrylamide block copolymers. Such polymers exhibit a unique combination of temperature sensitivity and biodegradability, each of which provides micelles with properties that allow easy drug loading and controlled release properties.

  Furthermore, Rijcken et al., Biomaterials 28 (incorporation of polymer cross-linking in the micelle core, ie, covalent bonding, was essential to achieve long-term micelle blood circulation after intravenous administration to mice. 2007), revealed on pages 5581-5593. In addition, they found that empty cross-linked micelles accumulate to 6 times higher in tumor tissue when compared to uncross-linked micelles.

  However, encapsulating a drug or other active ingredient non-covalently (physically) in a polymeric micelle (or other device) may cause the active ingredient to achieve its activity, particularly in vivo. The active ingredient often decreases rapidly after being applied to the intended system. This is due to rapid drug diffusion and / or premature degradation of the carrier. This latter mechanism can be prevented or at least delayed by cross-linking micelles, but drug compounds encapsulated non-covalently in the core of such cross-linked micelles can be introduced into the human or animal body, such as by intravenous infusion. There was a tendency for burst release immediately upon ingestion. This rapid release from stabilized micelles is due to drug diffusion.

  Furthermore, as described in US-B-7,425,581 and EP-A-1 776 400 above, the properties of micelles containing non-covalently encapsulated drugs are characterized by aggressive treatments such as freeze drying ( It has been found to be adversely affected as a result of aggressive processing). Particularly in medical applications, specifically in drug delivery applications, good storage stability of the drug-carrying particles is important. The present invention aims to provide a method for providing long-term product stability of a drug delivery system, for example by freeze drying (freeze drying).

  In the prior art, methods have been developed for covalently encapsulating drugs. In covalent encapsulation, active ingredients such as drug molecules are chemically bonded to the polymer chain. Such polymers can be hydrophilic so that such systems are referred to as polymer-drug conjugates that can be administered themselves. Alternatively, the polymer can be amphiphilic and micelles are formed that can be administered themselves in an aqueous environment. Such types of micelles can also suffer from stability problems that lead to degradation into individual components upon intravenous administration. Such polymer modifications can be made, for example, by using organic synthesis.

  Ulbrich et al., J. Contr. Rel. 87 (2003), 33-47, describe a water-soluble HPMA copolymer conjugated with the anticancer drug doxorubicin. Doxorubicin is attached to the polymer support through a hydrolytically unstable spacer that contains either a hydrazone bond or a cis-aconitic acid residue.

  Rihova et al., J. Contr. Rel. 74 (2001), pages 225-232, and Kovar et al., J. Contr. Rel. 99 (2004) pages 301-314, hydrolysable release doxorubicin. Also described are composites containing.

  Nakanishi et al. Describe a polymer micelle carrier system for doxorubicin in J. Contr. Rel. 74 (2001) pages 295-302. First, doxorubicin is coupled to a block copolymer of polyethylene glycol and polyaspartic acid. The micelle carrier system is then formed by dissolving the modified polymer in an aqueous environment. This carrier system further includes free (physically encapsulated) doxorubicin.

  Panarin et al., Pharmaceutical Chemistry Journal 23, (1989), pages 689-694, disclose derivatives of glucocorticoids derivatized with water-soluble polymers. Specifically, it is disclosed that hydrocortisone, prednisolone or dexamethasone is acylated with a copolymer of vinyl pyrrolidone with maleic anhydride to form the glucocorticoid polyester described above.

  During polymer synthesis, drug molecules can also be covalently bonded by copolymerizing polymerizable drug derivatives. In Davaran et al., J. Contr. Rel. 58, 1999, pages 279-287, drug-containing monomers are free-radically copolymerized with methacrylic acid or hydroxyethyl methacrylate. The main chain of the acrylic polymer has drug units as side chain substituents attached via hydrolyzable bonds such as ester or amide bonds.

  Disadvantages of these known systems are the need to perform organic synthesis to attach drug molecules to high molecular weight polymer chains (which results in problems), as well as the applicability of new polymer platform technologies. There is a need to develop new polymers for each limited drug molecule. Furthermore, since a water-soluble polymer is mainly used for the covalent bond of a drug molecule in a polymer-drug complex, application of such a polymer-drug complex to a water-soluble drug is often limited. In addition, since the hydrophilic polymer-drug complex remains in contact with the aqueous solution, its stability is reduced in the aqueous solution and is thus easily degraded.

US-B-7,425,581 EP-A-1 776 400

Rijcken et al., Biomaterials 28 (2007), pages 5581-5593. Ulbrich et al., J. Contr. Rel. 87 (2003), pp. 33-47. Rihova et al., J. Contr. Rel. 74 (2001), pp. 225-232 Kovar et al., J. Contr. Rel. 99 (2004) 301-314 Nakanishi et al., J. Contr. Rel. 74 (2001) 295-302 Panarin et al., Pharmaceutical Chemistry Journal 23, (1989), pp. 689-694. Davaran et al., J. Contr. Rel. 58, 1999, pp. 279-287 Kim et al., Polym. Adv. Technol., 10 (1999), pp. 647-654 Lee et al., Macromol. Biosci. 6 (2006) 846-854 Hu et al., Macromol. Biosci. 9 (2009), pages 456-463. Kim et al., J. Control. Rel. 138 (2009) 197-204 Bontha et al., J. Control. Rel. 114 (2006) 163-174 Lee et al., Angew. Chem 121 (2009) 5413-4516 Nishiyama et al., Cancer Res. 63 (2003), 8977-8893 Miyata et al., J. Control. Rel. 109 (2005) 15-23 Chemical Reviews 1971, volume 71, number 6

  The present invention provides a method that overcomes the above disadvantages. That is, a method is provided wherein an active ingredient such as a drug molecule is first non-covalently encapsulated in a polymer phase, particularly a rich polymer phase, in an aqueous environment and then bound to a 3D-polymer network.

Specifically, according to the present invention, a method for preparing a controlled release system comprising a polymer matrix incorporating an active ingredient, comprising:
(i) mixing an active ingredient comprising a reactive moiety with an aqueous solution or dispersion comprising a polymer chain comprising at least one reactive moiety capable of reacting with the reactive moiety of the active ingredient, wherein the polymer chain further comprises molecules Crosslinkable within or between molecules, and steps;
(ii) simultaneously with the formation of the polymer matrix, subjecting the mixture to crosslinking under conditions such that the active ingredient is encapsulated in the polymer matrix, i.e. the formed polymer network, to form a polymer matrix The method was found. In step (i), the polymer chains preferably interact with each other (see below herein) to form a polymer partial phase in the aqueous phase. That is, a phase that is relatively rich in polymer chains and a phase that is relatively poor in polymer chains are created. In the best form, the active ingredient is preferably present in the rich polymer chain phase. The sub-location of the active ingredient in the polymer rich partial phase is caused by the physical interaction between the active ingredient and the polymer chain. In step (i), the active ingredient does not form a covalent bond with the polymer chain. Only in the crosslinking step (ii) the active ingredient and the polymer chain come together to form a 3D-network.

FIG. 6 is a graph showing biodistribution profile and tumor accumulation after intravenous administration of dexamethasone, noncovalently and covalently encapsulated in free drug, stabilized polymeric micelles, to mice, 6, 24 or 48 Slaughtered after hours.

  Simultaneously with the crosslinking of the polymer forming the polymeric carrier or device, the active ingredient is covalently bound to the polymeric carrier. Crosslinked active ingredient-polymer composites formed using the method of the present invention exhibit higher thermodynamic stability than uncrosslinked polymer particles. Furthermore, covalent binding to the polymeric carrier prevents rapid release of the encapsulated drug molecule.

  The method of the present invention does not require the drug molecules to be directly attached directly to a single polymer chain, which allows the initial use of the polymer used, such as thermosensitive properties and / or ease of drug-loaded micelle formation. The characteristics are completely retained. The use of certain types of polymers, such as biodegradable thermosensitive block copolymers, provides a widely applicable platform technology that can quickly and easily change / optimize the composition of drug-carrying devices.

  The method is applicable to any active ingredient that interacts non-covalently with polymer chains that can form a polymeric carrier after crosslinking. In the aqueous phase, it is preferred that the polymer chains (before the cross-linking step) be built as a specific structure, or at least as a polymer rich domain, and the active ingredient is localized in such a construct. Although any type of physical interaction is possible (see below), in a preferred embodiment, the active ingredient is rather hydrophobic, or at least non-hydrophilic.

  Another requirement is only that the active ingredient includes a moiety that can react (or can be modified with a reactive substituent) with the portion of the polymer chain that forms the base of the polymeric device or carrier.

  Covalently encapsulating drug molecules in the carrier core, such as in the micelle core, will benefit the drug from the long-term blood circulation of the crosslinked carrier in the body, resulting in tumor tissue. Drug concentration increases. Thus, the present invention has advantages over US-B-7,425,581 and EP-A-1 776 400 cited above.

  Furthermore, the long-term product stability of this product can be obtained by subjecting the product prepared by the method of the present invention to lyophilization. For example, drug-loaded micelles prepared by the method of the present invention can be easily freeze-dried without loss of morphology and then resuspended, providing long-term storage as a dry powder.

  Thus, the present invention relates to a method for non-covalently encapsulating (drug) molecules in a polymeric carrier in an aqueous environment, whereby the polymer chain of the polymeric carrier comprises at least one reactive moiety. . This non-covalent encapsulation is optional but generally followed by a simultaneous cross-linking reaction between the modified (drug) molecule and the polymer chain, thereby forming an intertwined network.

  The resulting drug-carrying polymer devices such as micelles did not show an early release of the active ingredient and showed a long blood circulation. This, for example, promotes (to a great extent) tumor accumulation.

  Encapsulation of the drug via a degradable linker ensures a sustained release of the therapeutically active compound. Described and detailed herein, by cleaving a linker or linking group, preferably degradable, between an active ingredient such as a drug molecule and a polymeric carrier under physiological conditions Controlled release of (drug) molecules from the carrier is achieved by such local environmental factors or external stimuli. Furthermore, this encapsulation prevents blood from being exposed to toxic high drug peak levels that would otherwise occur immediately after the free drug is administered intravenously. More importantly, acute toxic effects can be reduced by preventing the transfer of drugs to normal tissues. Conversely, (drug) molecules are fully protected from the above environment by confining them within a formed three-dimensional network of cross-linked polymer carriers, such as cross-linked micelle cores, thereby premature degradation and / or Prevent clearance. These unique aspects deliver the drug at the expected and effective dose in time and in place.

  The stepwise method of the present invention involves two basic sequential steps.

  In the first step, the crosslinkable polymer and the active ingredient are mixed in an aqueous environment. That is, it is preferably achieved by adding the active ingredient in a suitable solvent, optionally a water or a lower alcohol such as ethanol or a water miscible solvent such as tetrahydrofuran, to the aqueous polymer solution or dispersion. The polymer and active ingredient present are selected so that the polymer and active ingredient are in intimate contact, and in preferred embodiments, the active ingredient is preferably in contact with the polymer chain. In other words, in the first step, the physical non-covalent interaction between the polymer chain and the active ingredient results in selective localization of the compound in a specific region of the polymer device.

  As a result of the first step, the molecules forming the active ingredient are non-covalently encapsulated within and between polymer chains in solution. As used herein and in the appended claims, the term “non-covalent interaction” refers to any interaction that is not covalent, ie, any weak bond between atoms, or a bond that does not involve the sharing of an electron pair. Means. Examples of non-covalent interactions include hydrophobic, aromatic, hydrogen bonding, static electricity, stereocomplex and metal ion interactions.

  In the second basic step of the method of the invention, the non-covalently encapsulated active ingredient is covalently bound to the newly formed / formed polymer network. That is, a reaction occurs in which the polymer chain is crosslinked. This can occur both intermolecularly and intramolecularly, but any step where intermolecular crosslinking is clearly preferred and intermolecular crosslinking is preferred is a preferred embodiment of the claimed method. Simultaneously with the cross-linking step, the reactive portion of the active ingredient is also co-cross-linked to form an intertwined network of polymer and active ingredient.

  This step often requires an initiator, but the physical environment can cause reactions to form crosslinks and composites. If an initiator is required, the initiator may be added to the polymer solution along with the active ingredient, but may be added to the reaction system in the previous or subsequent stage.

  A suitable amount of active ingredient is an amount of 0.1-30 wt.%, Preferably 0.5-15 wt.%, Such as an amount of 1-10 wt. Since the degree of incorporation of the active ingredient can be as high as 95-100%, a similar amount can be incorporated into the 3D-network formed.

According to a preferred method of the invention, the amphiphilic polymer may be completely dissolved in the solvent;
The (biological) active compound may be included in the solvent or added after dissolving the polymer, which will be distributed throughout the polymer solution;
The system can then be subject to certain environmental (e.g., temperature, pH, solvent) changes, resulting in a state where at least some of the polymer behaves differently from the rest of the polymer, Clustering occurs;
Due to the physical properties of (biological) active agents, these agents are localized to specific regions of the newly formed clustered polymer solution;
After this localization, cross-linking takes place and the (bio) active compound is immobilized in its preferred area.

  In a preferred embodiment of the method of the present invention, a heat sensitive block copolymer is used. For example, the active ingredients are mixed in an aqueous environment, where there are also uncrosslinked thermosensitive block copolymers at temperatures below the lower critical solution temperature (LCST) or below the critical micelle formation temperature (CMT). ing. At any temperature below this LCST, the system is in solution and no micelle formation occurs at any temperature below this CMT. However, such systems, particles or micelles are formed by heating, thereby encapsulating the hydrophobic active ingredient in the hydrophobic core. The cross-linking reaction, which then forms a network of entangled micelles further in the core, occurs at higher temperatures than LCST or CMT. This crosslinking reaction can be facilitated by adding an initiator either before heating the polymer solution or after formation of uncrosslinked particles or micelles.

  Suitable polymer chains that can be used in the present invention are, for example, heat-sensitive block copolymers. In particular, copolymers based on PEG-b-poly (N-hydroxyalkylmethacrylamide-oligolactate) with partially methacrylated oligolactate units are preferred. A variety of other (meth) acrylamide esters can be used in the construction of thermosensitive block copolymers, e.g., esters of HPMAm (hydroxypropyl methacrylamide) or HEMAm (hydroxyethyl methacrylamide), preferably (oligo) lactic acid esters and N -(Meth) acryloyl amino acid ester. Suitable thermosensitive block copolymers are obtained from monomers containing functional groups that can be modified by methacrylate groups, such as HPMAm-lactic acid ester polymers.

  Other types of functional thermosensitive (co) polymers that can be used are hydrophobically modified poly (N-hydroxyalkyl) (meth) acrylamide, a copolymer of N-isopropylacrylamide (NIPAAm) with monomers containing reactive functional groups Compositions (eg, other moieties such as acidic acrylamide and N-acryloxy succinimide) or similar poly (alkyl) 2-oxazoline copolymers.

  Another suitable thermosensitive group can be based on NIPAAm and / or alkyl-2-oxazoline, where the monomer comprises a (meth) acrylamide or (meta) containing a hydroxyl, carboxyl, amine or succinimide group. It can react with monomers containing reactive functional groups such as acrylates.

  Suitable thermosensitive polymers are described in US-B-7,425,581 and EP-A-1 776 400.

  However, it is not necessarily thermosensitive, and other types of amphiphilic block copolymers or ionic micelles that contain or may be modified with a crosslinkable reactive group may be used. In such cases, micelles can be formed using state of the art methods such as direct lysis, dialysis and solvent evaporation.

  Such other polymer containing a reactive moiety or containing a reactive moiety that forms a rich polymer phase in water (e.g., by hydrophobic or ionic interactions) Types of polymers include, for example, PEG-PLA-methacrylate (eg, as described in detail in Kim et al., Polym. Adv. Technol., 10 (1999), pages 647-654) (eg, Lee Et al., Macromol. Biosci. 6 (2006), pages 846-854) (for example, Hu et al., Macromol. Biosci. 9 (2009), 456- Other reactive moieties including methacrylated PEG-polycaprolactone (as described on page 463) and (block co) polymers based on polylactic acid, polylactic glycolic acid and / or polycaprolactone.

  In addition, polymers that can form micelles by ionic interactions can be used, such as block ionomer complexes of poly (ethylene oxide) -b-poly (methacrylic acid) copolymers and divalent metal cations. (See, for example, Kim et al., J. Control. Rel. 138 (2009) pp. 197-204, and Bontha et al., J. Control. Rel. 114 (2006) pp. 163-174. A) polyionic complexes based on block copolymers of poly (ethylene glycol) and poly (amino acids) (e.g. Lee et al. Angew. Chem 121 (2009) 5413-4516; Nishiyama et al., Cancer Res. 63 (2003), 8977-8893, or Miyata et al., J. Control. Rel. 109 (2005) 15-23, etc.).

  In general, any polymer that can create different partial phases in a suitable solvent system can be used with a bioactive agent that can selectively localize to such partial phases.

  Active ingredients encapsulated in the polymer include, but are not limited to, drug molecules, peptides / proteins, contrast agents, genetic material, or combinations of such compounds. Preferably, such active ingredients should be of a nature that tends to interact in a physical non-covalent manner with the polymer chains of the polymers described hereinabove. . When using a thermosensitive polymer in a preferred embodiment, the present invention is particularly useful for encapsulating hydrophobic compounds. Good results are obtained with an active ingredient with a log P of more than 1, preferably more than 2. Refer to Chemical Reviews 1971, volume 71, number 6 for the definition of logP.

  Polymer chains and active ingredients include, but are not limited to, reactive and / or polymerizable moieties including terminal double bonds (e.g., vinyl groups, (meth) acrylates, (meth) acrylamides), In particular, it may contain or be modified to contain free radically polymerizable moieties as well as unsaturated compounds (eg, straight chain containing carbon-carbon double bonds). Of course, the active ingredient is selected or modified such that a bond is formed from the reactive group only by a free radical initiation reaction. This ensures that the active ingredient maintains the desired effect in the intended end use.

  The polymer used should contain sufficiently many reactive substituents to crosslink and react with the reactive groups of the active ingredient. For example, 10-15% of the polymer monomer units have reactive substituents with suitable results, but up to 100% of the monomer units may be derivatized with reactive substituents.

  The release rate of the active ingredient can be easily controlled by using different types of linkers to attach the reactive moiety to the active ingredient. Well known suitable types of degradable linker molecules are not limited to esters, but include carbonates, carbamates, succinic acid or orthoesters, ketals, acetals, hydrazones and enzymatically degradable linkers (e.g., peptide ) Or a combination thereof. In addition, all known types of stimuli sensitive linkers, such as photosensitive / temperature sensitive / ultrasound-sensitive, and other linkers can be used. When modifying a bioactive ingredient, care is taken in the type of binding so that only the original molecule is released and no derivative is released upon release, in order to ensure its therapeutic activity. By using a biodegradable bond, a specific controlled release profile releases the original active ingredient, such as a drug molecule, and then exerts its activity, particularly its therapeutic effect.

  The products obtained by the method of the present invention are for controlled release, such as polymeric carriers such as micelles, nanoparticles, microspheres, hydrogels and other types of polymeric carriers, or devices encapsulated and coated with active ingredients. A device containing an active ingredient encapsulated or otherwise incorporated.

  As mentioned above, crosslinking and bonding is achieved in the second basic step of the method of the invention. This includes, but is not limited to, KPS (potassium persulfate) / TEMED, photoinitiators, thermo labile initiators, redox initiators and open-circuits due to cross-linking by polymerization. Several (free radical) initiators containing metal ligands for ring metathesis polymerization may be used. In addition, living free radical polymerization techniques may be utilized (eg, atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT)). Depending on the end use of the encapsulated active ingredient, the initiator residues can be removed by repeated washing or by other known techniques.

  By way of example, the formation of a specific embodiment of the method of the invention will be described. In this embodiment, it is initiated from a copolymer based on PEG-b-poly (N-hydroxyalkylmethacrylamide-oligolactate) with partially methacrylated oligolactate units. Hydrophobic (drug) molecules are derivatized with a polymerizable moiety attached to the drug molecule via a degradable linker such as a carbamate. The aqueous solution of the heat-sensitive block copolymer is then a water-miscible organic solvent (preferably a low boiling point such as ethanol or tetrahydrofuran) of a (slightly) hydrophobic drug molecule at a temperature below the CMT of the polymer, i.e., at a temperature that does not form micelles Etc.) with a small amount of concentrated solution (typically 10: 1 volume ratio). Thereafter, the initiator solution (KPS-TEMED) is added and then immediately heated until the critical micelle formation temperature (CMT) is exceeded. As a result, monodisperse polymer micelles (about 70 nm in size) are formed. In this, (drug) compounds are non-covalently localized to the hydrophobic core by hydrophobic interactions. After micelle formation, a nitrogen atmosphere is created. This causes the initiator radicals to induce polymerization of the methacrylated polymer and the polymerizable drug compound having a reactive moiety. As a result of this cross-linking process, an intertwined network is formed and the drug is covalently immobilized within the core of the micelle without affecting the size or uniformity of the micelle.

  Thus, (drug) molecules are covalently encapsulated in cross-linked micelles. The micelles in this embodiment swell by hydration after (partial) hydrolysis of unmodified oligolactate units in a physiological environment, after which the drug is released when the degradable linker is cleaved. This cutting may be due to local environmental factors or external stimuli.

The method of the present invention is not limited to the use of polymers capable of forming micelles. This also allows non-covalent encapsulation of the (drug) molecule in the polymer nanoparticle, microsphere, hydrogel or coating and subsequent covalent cross-linking. For the application of such devices comprising (drug) compounds, the present invention encompasses the following non-limiting embodiments:
(a) Controlled release of (drug) molecules encapsulated in cross-linked micelles upon administration in vivo, e.g. by oral application, injection into the bloodstream or direct injection into an organ or tumor;
(b) controlled release of drugs and / or proteins encapsulated in cross-linked polymeric microspheres or hydrogels upon topical administration; and
(c) Controlled release of (drug) molecules during device coating with encapsulated drug molecules. This is due to subsequent cross-linking and solvent, such as by double spraying an ice-cold aqueous polymer solution and (organic solvent) drug solution onto a medical device that is maintained above the phase transition temperature of the thermosensitive polymer. After evaporation of a cross-linked coating is formed.

  The invention will now be illustrated by the following non-limiting examples.

  In this example, dexamethasone was selected as the model drug compound. This is due to the down-regulation of dexamethasone's dual mechanism of action: inflammatory cytokines and pro-oncogenic signals. For this reason, dexamethasone has been widely used as an anti-inflammatory drug, and recently the remarkable antitumor effect of corticosteroids has been confirmed after targeted delivery to the tumor.

Specifically, ³ H-dexamethasone is modified with methacrylate units via a degradable carbamate linker, and ¹⁴ C to track the pharmacokinetics and biodistribution of drugs and carriers individually by liquid scintillation counting of blood and tissue samples Labeled polymer was used. Modified by the specific embodiment described above based on PEG-b-poly (N-2-hydroxypropylmethacrylamide-oligolactate) (CMT is 11 ° C.) with partially methacrylated oligolactate units Dexamethasone was physically encapsulated and then covalently attached to the core of the cross-linked micelle. Free drug, or dexamethasone encapsulated non-covalently or covalently in cross-linked polymeric micelles, was administered intravenously to mice bearing B16F10 tumors, and the mice were sacrificed after 6, 24 or 48 hours. The results are shown in FIG. FIG. 1 shows the biodistribution profile and tumor accumulation of free drug, non-covalently encapsulated dexamethasone and covalently encapsulated dexamethasone in micelles after intravenous administration to mice. These mice are sacrificed after 6, 24 or 48 hours.

  Encapsulating unmodified dexamethasone non-covalently in cross-linked micelles did not prolong the blood circulation of the drug. However, in the case of covalently encapsulated dexamethasone, there was still more than 95% covalent drug-loaded micelles in the bloodstream after 6 hours compared to 0.3% of free dexamethasone. In addition, 10 percent of the dose of covalently bound dexamethasone accumulated per gram of subcutaneous tumor. This is 23 times more compared to free dexamethasone. Ultimately, the biodegradable linker between the drug and micelle determines the therapeutic activity of the encapsulated drug.

Claims (12)

  A controlled release system that is an entangled polymer network cross-linked three-dimensionally, covalently linked to the three-dimensional cross-linked entangled polymer network via a degradable linker, and entangled cross-linked to the three-dimensional The three-dimensionally entangled polymer network comprising an active ingredient encapsulated in a polymer network is constituted by a cross-linked polymer of a polymer chain containing a polymerizable moiety and a polymerizable moiety linked to the active ingredient. Controlled release system.   2. The controlled release system of claim 1, wherein the polymer chain is a thermosensitive polymer chain.   3. The controlled release system of claim 2, wherein the thermosensitive polymer chain is a (co) polymer comprising a hydrophobically modified ester of N-hydroxyalkyl- (meth) acrylamide or N- (meth) acryloyl amino acid.   4. The controlled release system according to any one of claims 1 to 3, wherein the polymer chain includes a functional group that has been methacrylated.   5. The controlled release system of claim 4, wherein the polymer chain comprises a (co) polymer of N-hydroxyalkyl methacrylamide-oligo lactate.   6. The controlled release system according to any one of claims 2 to 5, wherein the thermosensitive polymer chain comprises a monomer derived from N-isopropylacrylamide and / or alkyl-2-oxazoline.   7. The controlled release system according to any one of claims 1 to 6, wherein the polymer chain is a di- or triblock copolymer with PEG.   8. A controlled release system according to any one of claims 1 to 7, which is in the form of a hydrogel, nanoparticles or microspheres.   9. The controlled release system according to any one of claims 1 to 8, wherein the active ingredient is a drug molecule, a contrast agent or a combination of these compounds.   10. A controlled release system according to claim 9, wherein the active ingredient is hydrophobic.   11. The controlled release system according to claim 9 or 10, wherein the active ingredient is a corticosteroid.   11. A controlled release system according to claim 10, wherein the active ingredient is dexamethasone.

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