Drug delivery composition

Abstract

To provide a drug delivery composition that can provide improved drug release.SOLUTION: The present invention provides a drug delivery composition, where the composition comprises a drug and a polymer degrading enzyme embedded into a polymer-based matrix, and where the composition is obtained by incorporation of the drug and the enzyme in the polymer-based matrix during heat treatment at a temperature T at which the polymer is in a partially or totally molten state.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a drug delivery composition comprising at least one drug and one polymer-degrading enzyme contained, preferably embedded, in a polymer-based matrix. The present invention also relates to a method for making the drug delivery composition. Furthermore, the present invention relates to a drug delivery device, preferably a medical device, made from or molded from the drug delivery composition. [Background technology]

[0002] Drug delivery devices or compositions are well known in the medical field. Among them, drug delivery devices have been developed that allow for the in vivo release of drugs at a somewhat controlled rate. In most cases, drugs are bound to a polymer used as a drug vehicle. For example, some delivery devices are composed of biodegradable polymers in which the drug is coated on the outer surface of the polymer structure. Alternatively, some delivery devices are composed of polymer structures in which the drug is incorporated using a solvent. The use of solvents is limited to the incorporation of drugs soluble in solvents that can solubilize the polymer. For example, drugs that are only soluble in water cannot be incorporated into water-insoluble polymers, such as those used in sutures, tissue engineering, scaffolds, and other applications requiring specific mechanical properties. The amount of drug incorporated is also limited to the solubility threshold. Furthermore, few solvents are available for use in the medical field. Furthermore, manufacturing methods using solvents are crude, and quality is important. In fact, manufacturing methods include solvent drying and composition washing steps to ensure that the final device is completely free of traces of solvent. The manufacturing process is also generally carried out in batches, each of which requires strict quality control. Some other drug delivery devices are composed of polymer structures containing liquid-filled pores that are permeable to the drug. However, the use of porous polymers does not result in non-uniform drug content in the polymer structure. The use of solid drugs, which require an additional liquid medium or carrier for drug diffusion, is eliminated in these devices.

[0003] A method for dispersing drugs into polymer structures by hot-melt extrusion is also known. Hot-melt extrusion allows the production of a wide variety of dosage forms and formulations, such as granules, pellets, tablets, intraocular inserts, implants, stents, or transdermal systems, and offers several advantages over solvent-based manufacturing methods, including a continuous process and the elimination of solvents that previously had to be removed using costly and time-consuming processes. In any case, until now, the relationship between the drug release rate and the amount and nature of the polymer in the drug delivery device has not been fully controlled. Drug delivery devices do not provide satisfactory controllable and / or long-term drug delivery.

[0004] Thus, there remains a need for drug delivery compositions that can provide improved drug release by virtue of controlling the degradation rate of the drug-containing material. Summary of the Invention

[0005] The present invention now provides a drug delivery composition that includes both a drug and a polymer-degrading enzyme within a polymer structure, where the polymer-degrading enzyme can degrade at least one polymer of the polymer structure, resulting in a more controlled rate of polymer degradation and improved drug release.

[0006] It is therefore an object of the present invention to provide a drug delivery composition comprising a polymer-based matrix, at least one drug and at least one polymer-degrading enzyme, wherein the drug and the enzyme are contained in, and more preferably embedded in, the polymer-based matrix.

[0007] Another object of the present invention is to provide a drug delivery composition comprising a drug and a polymer-degrading enzyme contained, more preferably embedded, in a polymer-based matrix, wherein the composition is obtainable by incorporating the drug and the enzyme into the polymer-based matrix during heat treatment at a temperature T at which the polymer is partially or completely molten.

[0008] The present invention also relates to drug delivery devices made from such compositions.

[0009] It is a further object of the present invention to provide a method for preparing a drug delivery composition comprising a polymer-based matrix, a drug, and a polymer-degrading enzyme, the method comprising incorporating the drug and the enzyme into the polymer-based matrix during heat treatment of the polymer at a temperature T while the polymer is in a partially or completely molten state, allowing for the maintenance of enzyme and drug activity.

[0010] The invention also relates to a drug delivery device obtainable by such a method.

[0011] The present invention also relates to a method of delivering a drug to a subject or organism, comprising administering the drug delivery device described above to the subject or organism.

[0012] The present invention also relates to a method for delivering a drug to a subject or organism, comprising providing a drug, incorporating the drug into a polymer-based matrix with a polymer-degrading enzyme during thermal treatment of the polymer at a temperature T at which the polymer is partially or completely molten, and administering the incorporated drug to the subject or organism.

[0013] The present invention further relates to a drug delivery device as described above for use in a method of treating a subject or organism.

[0014] The present invention can be used with a wide variety of drugs and polymers and has broad application in the medical field. [Brief explanation of the drawings]

[0015] [Figure 1]1 shows PLA degradation and ibuprofen release for a drug delivery composition of the present invention comprising PLA, 10% ibuprofen, and 10% PLA-degrading enzyme compared to a control composition comprising only PLA and ibuprofen. [Figure 2] 1 shows PLA degradation and naltrexone release of a drug delivery composition of the present invention comprising PLA, 8% naltrexone, and 5% PLA-degrading enzyme compared to a control composition comprising only PLA and naltrexone. [Figure 3] 1 shows the PLA degradation and estradiol release of a drug delivery composition of the present invention comprising PLA, 5% estradiol, and 5% PLA-degrading enzyme compared to a control composition comprising only PLA and estradiol. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention relates to a novel drug delivery composition comprising or consisting essentially of a polymer-based matrix, at least one enzyme capable of degrading the polymer of the polymer-based matrix, and at least one drug incorporated therein. The drug delivery composition of the present invention exhibits good dispersion of both the enzyme and the drug in the polymer-based matrix, allowing for control of the degradation rate of the at least one polymer contained in the polymer-based matrix. Depending on the application of the drug delivery composition, the polymer of the polymer-based matrix can be tailored to take into account, for example, the safety of by-products for humans and / or the amount of drug. Furthermore, compatibility of the polymer's natural degradation conditions with the physiological properties of the target (i.e., the drug delivery device to be implanted in the body) is no longer a fundamental parameter to consider when selecting a polymer. In fact, enzymes promote polymer degradation even in the absence of natural degradation conditions. Enzymes also enable the use of polymers that are not biodegradable under physiological conditions (i.e., at about 37°C and pH 7). Therefore, the present invention is particularly suitable for polymers that are not naturally degradable but slowly degrade under physiological conditions. For example, PLA biodegrades slowly in the human body if its molar mass (Mw) is low, preferably less than 100,000 g / mol. Otherwise, its biodegradation is too slow for medical applications, limiting its use to long-term applications. Furthermore, low-molecular-mass PLA exhibits weak mechanical properties for medical devices that must exhibit high resistance to compression. Therefore, until now, PLA has not been used for all types of intracorporeal medical devices. According to the present invention, high-molecular-mass PLA, preferably with a Mw greater than 100,000 g / mol, more preferably greater than 150,000 g / mol, can be used for applications that utilize its mechanical properties, such as implants. In fact, incorporating an enzyme capable of degrading PLA accelerates its biodegradation, even at high molar masses. Furthermore, the biodegradation rate can be adjusted by varying the amount and / or nature of the enzyme incorporated.

[0017] (definition) The present disclosure will be best understood by reference to the following definitions.

[0018] Within the context of this invention, the term "drug delivery composition" refers to any composition in liquid, gel, or solid form that comprises at least one polymer-based material containing at least one polymer and at least one drug to be released from the composition.

[0019] In the context of the present invention, the term "drug delivery device" refers to any item made from at least one polymer-based material, preferably in solid form, such as plastic sheets, tubes, rods, profiles, shapes, pellets, macroblocks, fabrics, fibers, scaffolds, etc., containing at least one polymer and at least one drug to be released. More preferably, the drug delivery device is a medical device.

[0020] "Polymer" refers to a chemical compound or mixture of compounds whose structure is composed of multiple repeating units linked by covalent bonds. Within the context of the present invention, the term polymer includes natural or synthetic polymers composed of a single type of repeating unit (i.e., homopolymers) or a mixture of different repeating units (i.e., heteropolymers and copolymers). Within the context of the present invention, the term polymer preferably refers to thermoplastic polymers.

[0021] "Polymer-based matrix" refers to a matrix that contains one or more polymers as a main component. The polymer-based matrix comprises at least 51% by weight of polymer, preferably at least 60, 70, 80, 90, or 95% by weight, based on the total weight of the composition. The polymer-based matrix may further comprise additional compounds, such as additives. In certain embodiments, the polymer-based matrix comprises at least 96, 97, 98, or 99% by weight of polymer, based on the total weight of the composition.

[0022] "Drug" refers to any substance that is biologically active, i.e., that can have an effect on living organisms, including mammals, birds, viruses, fungi, and microorganisms. In particular, the term drug encompasses mineral or organic active substances that can have prophylactic or therapeutic activity in mammals, substances with antifungal and / or antimicrobial activity, and the like. For example, drugs are active substances such as pharmaceutical substances, herbal medicines, antibiotics, anticancer drugs, antiviral drugs, anti-inflammatory drugs, hormones, growth factors, etc., antigens, vaccines, adjuvants, etc. Drugs can also consist of cosmetic substances.

[0023] As used herein, the term "by weight" refers to a percentage based on the total weight of the composition or product under consideration.

[0024] In the context of the present invention, the term "about" refers to a margin of ±5%, preferably ±1%, or within the tolerance of the appropriate measuring device or apparatus.

[0025] (polymer-based matrix) The present invention relates to a drug delivery composition made of a polymeric material. More specifically, the polymeric material is composed of a polymer-based matrix that can be molded into a desired shape depending on the purpose of the composition (e.g., the nature of a medical device). For example, devices obtained from such compositions can be molded into sutures, stents, prostheses, patches, screws or bone plates, intrauterine devices, scaffolds, implants, pumps, etc.

[0026] Advantageously, both the drug to be released and the polymer-degrading enzyme capable of degrading at least one polymer of the polymer-based matrix are added to the polymer-based matrix so that they are contained in the matrix, preferably embedded. Advantageously, both the drug and the enzyme are uniformly embedded in the polymer-based matrix. In the context of the present invention, "uniformly embedded" means that the drug and the enzyme are uniformly distributed in the polymer-based matrix. Such uniform distribution in the polymer-based matrix results in a final drug delivery composition that exhibits uniform redistribution of the drug and the enzyme, thereby enabling controlled release of the drug. Such uniform distribution can be obtained, for example, by heating the polymer-based matrix until it is at least partially melted, allowing the drug and the enzyme to be incorporated into the molten composition. The final drug delivery composition is advantageously in a solid state. However, it is possible to provide a drug delivery composition in a molten state or even in a liquid state.

[0027] The polymer base matrix can be made from various polymers. Preferably, the polymer base matrix comprises at least one polymer selected from polyester, polyether, or ester-ether copolymer. Polyesters include, for example, polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), stereocomplex PLA (scPLA), polyhydroxyalkanoic acid (PHA), poly(3-hydroxybutanoic acid) (P(3HB) / PHB), poly(3-hydroxyvaleric acid) (P(3HV) / PHV), poly(3-hydroxyhexanoic acid) (P(3HHx)), poly(3-hydroxyoctanoic acid) (P(3HO)), poly(3-hydroxydecanoic acid) (P(3HD)), 3-hydroxybutanoic acid-3-hydroxyvaleric acid copolymer (P(3HB-co-3HV) / PHBV), 3-hydroxybutanoic acid-3-hydroxyhexanoic acid copolymer (P(3HB-co-3HHx) / (PHBHHx)), 3-hydroxybutanoic acid-5-hydroxyhexanoic acid copolymer (P(3HB-co-3HHx) / (PHBHHx)), 3-hydroxybutanoic acid-5-hydroxyvaler ... The polymer may be selected from hydroxyvaleric acid copolymer (PHB5HV), 3-hydroxybutanoic acid-3-hydroxypropionic acid copolymer (PHB3HP), hydroxybutanoic acid-hydroxyoctanoic acid copolymer (PHBO), hydroxybutanoic acid-hydroxyoctadecanoic acid copolymer (PHBOd), 3-hydroxybutanoic acid-3-hydroxyvaleric acid-4-hydroxybutanoic acid copolymer (P(3HB-co-3HV-co-4HB)), polyglycolic acid (PGA), polybutylene succinate (PBS), polybutylene succinate adipate (PBSA), polybutylene adipate terephthalate (PBAT), polycaprolactone (PCL), poly(ethylene adipate) (PEA) or copolymers thereof, such as lactic acid-glycolic acid copolymer (PLGA), and blends / mixtures of these materials. The polyether may be selected from, for example, polyethylene glycol (PEG), preferably PEG with a molecular weight greater than 600 g / mol, polyethylene oxide (PEO), or copolymers and blends / mixtures thereof. The ester-ether copolymer may be selected from, for example, polydioxanone (PDS).

[0028] In particular, the polymer-based matrix comprises at least one polymer selected from polymers that are not naturally degradable under physiological conditions, i.e., do not undergo decomposition into monomers and / or oligomers under physiological conditions in less than 10 years.The use of enzymes in drug delivery compositions allows the decomposition of such polymers to begin in less than 10 years.In another specific embodiment, the polymer-based matrix comprises at least one polymer selected from polymers that are partially degradable under physiological conditions, i.e., do not undergo complete decomposition into monomers and / or oligomers under physiological conditions in less than 10 years, preferably less than 5 years, more preferably less than 2 years.In this case, the use of enzymes in drug delivery compositions allows the decomposition process of polymers to be accelerated.

[0029] In certain embodiments, the polymer base matrix comprises at least one polymer selected from polylactic acid (PLA), polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoic acid (PHA), polyglycolic acid (PGA), polybutylene succinate (PBS), polycaprolactone (PCL), poly(ethylene adipate) (PEA), dextran, gelatin, starch, cellulose and its derivatives, polybutylene succinate adipate (PBSA), polydioxanone (PDS), polyethylene glycol (PEG), preferably PEG with a molecular weight greater than 600 g / mol, polyethylene oxide (PEO) or copolymers thereof, and blends / mixtures.

[0030] In another particular embodiment, the polymer base matrix comprises at least one polymer with a molecular weight (Mw) greater than 100,000 g / mol.

[0031] In further specific embodiments, the polymer base matrix comprises PLA. In particular, such PLA has an Mw of more than 100,000 g / mol, preferably more than 150,000 g / mol. In certain embodiments, the polymer base matrix comprises PLA with an Mw of 180,000 g / mol. Such a polymer base matrix may further comprise at least one additional polymer, preferably selected from polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoic acid (PHA), polyglycolic acid (PGA), polybutylene succinate (PBS), polycaprolactone (PCL), poly(ethylene adipate) (PEA), dextran, gelatin, starch, cellulose and its derivatives, and blends / mixtures thereof, more preferably PBAT or PCL. Alternatively, the polymer base matrix contains PLA as the only polymer, preferably PLLA and / or PDLA.

[0032] In one embodiment, the polymer base matrix comprises a lactic acid copolymer, preferably selected from PLA-based heteropolymers, more preferably selected from lactic acid-glycolic acid copolymer (PLA-co-PGA or PLGA), lactic acid-caprolactone copolymer (PLA-co-PCL), lactic acid-ethylene glycol copolymer (PLA-co-PEG), lactic acid-ethylene oxide copolymer (PLA-co-PEO) or grafted PLA (PLA-g-gelatin).

[0033] In another specific embodiment, the polymer base matrix contains PCL.This polymer base matrix can further contain at least one additional polymer, preferably selected from polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoic acid (PHA), polyglycolic acid (PGA), polybutylene succinate (PBS), polylactic acid (PLA), poly(ethylene adipate) (PEA), dextran, gelatin, starch, cellulose and its derivatives, and blends / mixtures of these polyesters or copolymers.Alternatively, the polymer base matrix contains PCL as the only polymer.

[0034] In another specific embodiment, the polymer base matrix contains PGA.Such a polymer base matrix can further contain at least one additional polymer, preferably selected from polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoic acid (PHA), polycaprolactone (PCL), polybutylene succinate (PBS), polylactic acid (PLA), poly(ethylene adipate) (PEA), dextran, gelatin, starch, cellulose and its derivatives, and blends / mixtures of these polyesters or copolymers.Alternatively, the polymer base matrix contains PGA as the only polymer.

[0035] The selection of polymer can be adjusted by those skilled in the art according to the purpose and use of drug delivery composition.For example, for the medical device made of said composition and dedicated to be implanted in the mammalian body, polymer should preferably be harmlessly degraded or decomposed as safe unit structure.In fact, for the medical device that must be implanted in the body, it may be interesting to consider the molar mass of monomer (produced by polymer degradation) to ensure that it can be biologically removed (for example, renal excretion, hepatic excretion, etc.).

[0036] According to the present invention, the polymer base matrix may further contain additives such as acid neutralizers, preferably selected from carbonates, calcium phosphates, hydrotalcites, talc, mica and clays.

[0037] (polymer-degrading enzyme) According to the present invention, the drug delivery composition contains at least one polymer-degrading enzyme capable of degrading at least one polymer of the polymer-based matrix. The incorporation of the polymer-degrading enzyme can increase the degradability of the polymer-based matrix, thereby improving the release of the drug.

[0038] In certain embodiments, the drug delivery composition comprises one or more enzymes capable of degrading all of the polymers contained in the polymer base matrix.

[0039] For example, in certain embodiments, the polymer base matrix is ​​composed of one polymer and the drug delivery composition contains one or more enzymes that degrade the polymer.

[0040] In another specific embodiment, the polymer base matrix comprises two different polymers and the drug delivery composition contains one or more enzymes that degrade both polymers.

[0041] In another specific embodiment, the polymer base matrix comprises two different polymers and the drug delivery composition contains one or more enzymes that degrade only one of the polymers.

[0042] In the context of the present invention, a "polymer-degrading enzyme" refers to an enzyme suitable for hydrolyzing chemical bonds between monomers of at least one polymer. Preferably, the polymer-degrading enzyme is suitable for depolymerizing at least one polymer of a drug delivery device to oligomers and / or monomers. Advantageously, the oligomers and / or monomers are harmless to the human body. In certain embodiments, the degrading enzyme can depolymerize the polymer of the drug delivery composition to monomers. Such embodiments may be particularly interesting for medical devices implanted in the body to facilitate the biological excretion of by-products of the medical device.

[0043] The polymer-degrading enzyme may be selected depending on the nature of the polymer. Preferably, the polymer-degrading enzyme is suitable for depolymerizing at least one polyester of the drug delivery device to oligomers and / or monomers.

[0044] In certain embodiments, the degradative enzyme is suitable for depolymerizing at least one polymer of the drug delivery device to oligomers and / or monomers under physiological conditions. Preferably, the degradative enzyme is active at 37°C and / or pH 7-7.5. In another specific embodiment, the degradative enzyme is selected from enzymes with an optimum pH close to physiological pH, i.e., pH 6-8.

[0045] The degradative enzymes are preferably selected from cutinases (EC 3.1.1.74), lipases (EC 3.1.1.3), esterases, carboxylesterases (EC 3.1.1.1), serine proteases (EC 3.4.21.64), proteases and oligomeric hydrolases.

[0046] Serine proteases (e.g., proteinase K from Tritirachium album, or PLA depolymerase from Amycolatopsis sp., Actinomadura keratinilytica, Laceyella sacchari LP175, Thermus sp., or Bacillus licheniformis, or any reconstituted commercially available enzyme known for degrading PLA, such as Savinase®, Esperase®, Everlase®, or any enzyme from the subtilisin CAS 9014-01-1 family, or any functional variant thereof), lipases (e.g., Candida Antarctica An esterase (e.g., from Thermobifida halotolerans) or a variant thereof can be used to depolymerize a drug delivery composition containing polylactic acid (PLA).

[0047] Cutinase (e.g., from Thermobifida fusca or Thermobifida alba or Fusarium solani pisi) and lipase (e.g., lipase PS from Burkholderia cepacia) or variants thereof can be used to depolymerize drug delivery compositions containing PCL.

[0048] Proteases (eg, carboxypeptidase, clostridiopeptidase, α-chymotrypsin, trypsin, or ficin) or esterases or variants thereof can be used to depolymerize drug delivery devices containing PGA.

[0049] Thus, in a preferred embodiment, the present invention relates to a drug delivery composition, eg, a drug delivery device, comprising a PLA-based matrix, a drug, and a PLA-degrading enzyme, preferably selected from a serine protease, lipase, or esterase.

[0050] In another preferred embodiment, the present invention relates to a drug delivery composition, eg, a drug delivery device, comprising a PCL-based matrix, a drug, and a PCL-degrading enzyme, preferably selected from cutinase or lipase.

[0051] In another preferred embodiment, the present invention relates to a drug delivery composition, eg, a drug delivery device, comprising a PGA-based matrix, a drug, and a PGA-degrading enzyme, preferably selected from a protease or an esterase.

[0052] (drugs) According to the present invention, a drug is selected to act on a biological target. In the context of the present invention, a "biological target" refers to any living organism that can be directly or indirectly affected by a drug. The biological target may be the whole body, organs, tissues, specific cells, etc. of an animal, such as a mammal, or a bird, a microorganism, a virus, etc.

[0053] Preferably, the drug is a chemical compound, a pharmaceutical compound, a nutraceutical compound, an amino acid, a peptide, a protein, a polysaccharide, a lipid derivative, an antibiotic, an analgesic, a vaccine, a vaccine adjuvant, an anti-inflammatory drug, an antitumor drug, a hormone, a cytokine, an antifungal drug, an antiviral drug, an antibacterial drug, an antidiabetic drug, a steroid, a vitamin, a provitamin, an antioxidant, a mineral salt, a trace element, a specific enzyme inhibitor, a growth stimulant, an immunosuppressant, an immunomodulatory drug, an antihypertensive drug, an antiarrhythmic drug, a cardiotonic drug, an addiction therapy drug, an antiepileptic drug, an anti-aging drug, a neurotransmitter ... the drug is selected from drugs for the treatment of allopathy or pain, lipid-lowering drugs, anticoagulants, antibodies or antibody fragments, antigens, antidepressants or psychotropic drugs, neuromodulators, drugs for the treatment of diseases selected from brain diseases, liver diseases, lung diseases, heart diseases, stomach diseases, intestinal diseases, ovarian diseases, testicular diseases, urinary diseases, genital diseases, bone diseases, muscle diseases, endometrial diseases, pancreatic diseases and / or kidney diseases, ophthalmic drugs, antiallergic drugs, contraceptives or luteinizing drugs, enzymes, herbal medicines, nutrients, cosmetics and mixtures of at least two of these drugs.

[0054] In certain embodiments, the drug is selected from a chemical substance, a pharmaceutical compound, an amino acid, a peptide, a protein, an antibiotic, an analgesic, a vaccine, a vaccine adjuvant, an anti-inflammatory drug, an antitumor drug, a hormone, a cytokine, an antifungal drug, an antiviral drug, an antibacterial drug, an antidiabetic drug, a steroid, a specific enzyme inhibitor, a growth stimulant, an immunosuppressant, an immunomodulatory drug, an antihypertensive drug, an antiarrhythmic drug, a cardiotonic drug, an addiction therapy drug, an antiepileptic drug, an antiaging drug, a drug for the treatment of neuropathy or pain, a lipid-lowering drug, an anticoagulant, an antibody or antibody fragment, an antigen, an antidepressant or psychotropic drug, a neuromodulatory drug, a drug for the treatment of a disease selected from a brain disease, a liver disease, a lung disease, a heart disease, a stomach disease, an intestinal disease, an ovarian disease, a testicular disease, a urinary disease, a genital disease, a bone disease, a muscle disease, an endometrial disease, a pancreatic disease and / or a kidney disease, an ophthalmic drug, an antiallergic drug, a contraceptive or luteinizing drug, an enzyme, and a mixture of at least two of these drugs.

[0055] In certain embodiments, the drug is selected from among compounds that have therapeutic or prophylactic purpose in mammals, more particularly in humans.

[0056] In certain embodiments, the drug is selected from compounds having a denaturation temperature of less than 120° C., preferably less than 100° C. In the context of the present invention, the denaturation temperature corresponds to the temperature at which half of the drug loses its activity. Generally, the denaturation temperature is preferably above 50° C.

[0057] In another particular embodiment, the molecular weight of the drug is greater than 10 kDa, preferably greater than 14 kDa. In another embodiment, the molecular weight of the drug is greater than 15 kDa.

[0058] In certain embodiments, the drug is selected from the protein with molecular weight of more than 10 kDa, such as lysozyme.In another specific embodiment, the drug is selected from the protein with molecular weight of more than 50 kDa, preferably more than 100 kDa, such as antibody.In another specific embodiment, the drug is selected from the enzyme with molecular weight of more than 30 kDa, preferably more than 50 kDa, such as lipase.In another specific embodiment, the drug is selected from the hormone with molecular weight of more than 9 kDa, such as insulin or parathyroid hormone.In another specific embodiment, the drug is the growth hormone with molecular weight of more than 20 kDa.In another specific embodiment, the drug is the hormone with molecular weight of more than 30 kDa, such as erythropoietin.

[0059] Drug Delivery Composition It is an object of the present invention to provide novel drug delivery compositions that allow for the release of drugs incorporated therein, preferably at a controlled rate.

[0060] In certain embodiments, the drug delivery composition is a pharmaceutical composition. Such a pharmaceutical composition may be in the form of a tablet, a gel, a coating, a particle, or a microbead.

[0061] It is also an object of the present invention to provide a novel drug delivery device that allows the release of a drug contained in the delivery device, preferably at a controlled rate. Thus, the composition of the present invention can be advantageously used to form a drug delivery device, more particularly a medical device.

[0062] Such medical devices may be in the form of implants, films, stents, leaflets, valves, coils, scaffolds, dressings, rods, patches, fibers, sutures, screws, bone plates or implants, bone cements and prostheses.

[0063] In certain embodiments, the drug delivery composition comprises: 51 to 99.98% by weight of a polymer-based matrix, 0.01 to 49% by weight of a drug, and 0.01 to 30% by weight of polymer-degrading enzyme Includes.

[0064] In certain embodiments, the drug delivery composition comprises: 50 to 99.98% by weight of a polymer-based matrix, 0.01 to 49.99% by weight of a drug, and 0.01 to 30% by weight of polymer-degrading enzyme Includes.

[0065] In a preferred embodiment, the drug delivery composition comprises: 60 to 99.98% by weight of a polymer-based matrix, 0.01 to 39.99% by weight of a drug, and 0.01 to 20% by weight of polymer-degrading enzyme Includes.

[0066] In a preferred embodiment, the drug delivery composition comprises: 60 to 99.98% by weight of a polymer-based matrix, 0.01 to 39% by weight of a drug, and 0.01 to 20% by weight of polymer-degrading enzyme Includes.

[0067] For example, a drug delivery composition may comprise 90% by weight of a polymer-based matrix, 5% by weight of a drug, and 5% by weight of a polymer-degrading enzyme.

[0068] Alternatively, the drug delivery composition comprises 85% by weight of a polymer-based matrix, 10% by weight of a drug, and 5% by weight of a polymer-degrading enzyme.

[0069] Alternatively, the drug delivery composition comprises 80% by weight of a polymer-based matrix, 5% by weight of a drug, and 15% by weight of a polymer-degrading enzyme.

[0070] Alternatively, the drug delivery composition comprises 80% by weight of a polymer-based matrix, 10% by weight of a drug, and 10% by weight of a polymer-degrading enzyme.

[0071] Alternatively, the drug delivery composition comprises 70% by weight of a polymer base matrix, 20% by weight of a drug, and 10% by weight of a polymer-degrading enzyme.

[0072] Alternatively, the drug delivery composition comprises 60% by weight of a polymer base matrix, 30% by weight of a drug, and 10% by weight of a polymer-degrading enzyme.

[0073] In certain embodiments, the polymer base matrix is ​​composed of PLA, the polymer-degrading enzyme is a PLA depolymerase, such as proteinase K or a serine protease, and the drug is selected from a bone regenerating enzyme, an anti-inflammatory drug (e.g., ibuprofen), an analgesic drug (e.g., paracetamol, morphine), an anti-diabetic drug (e.g., insulin), a hormone (e.g., progesterone), a cytokine, a monoclonal antibody, an antigen, a contraceptive, an anti-tumor drug, and an anti-infective drug.

[0074] In certain embodiments, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLA-based matrix, a drug selected from pharmaceutical compounds useful for managing alcohol or opioid addiction, preferably naltrexone, and a PLA-degrading enzyme, preferably a serine protease. In certain embodiments, the drug delivery composition comprises 74.99-99.98 wt% PLA-based matrix, 0.01-15 wt% naltrexone, and 0.01-15 wt% PLA-degrading enzyme (e.g., serine protease). In another specific embodiment, the drug delivery composition comprises 51-80 wt% PLA-based matrix, 19.99-48.99 wt% naltrexone, and 0.01-20 wt% PLA-degrading enzyme (e.g., serine protease). In certain embodiments, the drug delivery composition comprises 87±10 wt% PLA (molecular weight (Mw) 180,000 g / mol), 8±10 wt% naltrexone hydrochloride, and 5±10 wt% Savinase® formulation, based on the total weight of the drug delivery composition.

[0075] Thus, in certain embodiments, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLA-based matrix, a nonsteroidal anti-inflammatory drug, preferably ibuprofen, and a PLA-degrading enzyme, preferably a serine protease. In certain embodiments, the drug delivery composition comprises 70-99.98 wt% PLA-based matrix, 0.01-20 wt% ibuprofen, and 0.01-10 wt% PLA-degrading enzyme (e.g., serine protease). In another specific embodiment, the drug delivery composition comprises 51-90 wt% PLA-based matrix, 9.99-48.99 wt% ibuprofen, and 0.01-20 wt% PLA-degrading enzyme (e.g., serine protease). In certain embodiments, the drug delivery composition comprises 80±10% by weight PLA (molecular weight (Mw) 180,000 g / mol), 10±10% by weight S-ibuprofen, and 10±10% by weight Savinase® formulation.

[0076] Thus, in certain embodiments, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLA-based matrix, a hormone, preferably estradiol, and a PLA-degrading enzyme, preferably a serine protease. In certain embodiments, the drug delivery composition comprises 85-99.98 wt% PLA-based matrix, 0.01-10 wt% estradiol, and 0.01-10 wt% PLA-degrading enzyme (e.g., serine protease). In another specific embodiment, the drug delivery composition comprises 51-90 wt% PLA-based matrix, 9.99-48.99 wt% estradiol, and 0.01-20 wt% PLA-degrading enzyme (e.g., serine protease). In certain embodiments, the drug delivery composition comprises 90±10 wt% PLA (Mw 180,000 g / mol), 5±5 wt% estradiol, and 5±5 wt% Savinase® formulation, based on the total weight of the drug delivery composition.

[0077] Thus, in certain embodiments, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLA-based matrix, a drug selected from a protein, preferably lysozyme, and a PLA-degrading enzyme, preferably a serine protease. In certain embodiments, the drug delivery composition comprises 70-99.98 wt% PLA-based matrix, 0.01-20 wt% lysozyme, and 0.01-10 wt% PLA-degrading enzyme (e.g., serine protease). In another specific embodiment, the drug delivery composition comprises 50-99.98 wt% PLA-based matrix, 0.01-49.99 wt% lysozyme, and 0.01-10 wt% PLA-degrading enzyme (e.g., serine protease).

[0078] In certain embodiments, the drug is incorporated into a polymer carrier, preferably PCL, and introduced in the form of a masterbatch. Accordingly, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLA-based matrix, a protein, preferably lysozyme, incorporated into the PCL, and a PLA-degrading enzyme, preferably a serine protease. In certain embodiments, the drug delivery composition comprises 50-99.97 wt% PLA-based matrix, 0.01-20 wt% lysozyme, 0.01-20 wt% PCL, and 0.01-10 wt% PLA-degrading enzyme (e.g., a serine protease). In certain embodiments, the drug delivery composition comprises 70±10 wt% PLA (Mw 180,000 g / mol), 10±10 wt% PCL, 10±10 wt% lysozyme, and 10±10 wt% Savinase® formulation, based on the total weight of the drug delivery composition. Thus, in certain embodiments, the present invention relates to a drug delivery composition, e.g., a drug delivery device, comprising a PLGA-based matrix or a PLA / PGA-based matrix, a drug, and a PGLA-degrading enzyme, PLA-degrading enzyme, or PGA-degrading enzyme, or a mixture thereof. In certain embodiments, the drug delivery composition comprises 70 to 99.98% by weight of a PLGA-based matrix or a PLA / PGA-based matrix, 0.01 to 20% by weight of a drug, and 0.01 to 10% by weight of a PGLA-degrading enzyme, PLA-degrading enzyme, or PGA-degrading enzyme, or a mixture thereof. In another specific embodiment, the drug delivery composition comprises 50 to 99.98% by weight of a PLGA-based matrix or a PLA / PGA-based matrix, 0.01 to 49.99% by weight of a drug, and 0.01 to 10% by weight of a PGLA-degrading enzyme, PLA-degrading enzyme, or PGA-degrading enzyme, or a mixture thereof.

[0079] In another specific embodiment, the polymer-based matrix is ​​composed of PCL, the polymer-degrading enzyme is lipase PS, and the drug is selected from bone-regenerating enzymes, anti-inflammatory drugs (e.g., ibuprofen), analgesics (e.g., paracetamol, morphine), antidiabetic drugs (e.g., insulin), hormones (e.g., progesterone), cytokines, monoclonal antibodies, antigens, contraceptives, antitumor drugs, and antiinfective drugs. Accordingly, the present invention relates to a drug delivery composition comprising 70-99.98 wt% PCL-based matrix, 0.01-20 wt% enzyme, such as lysozyme, and 0.01-10 wt% PCL-degrading enzyme. In another specific embodiment, the drug delivery composition comprises 50-99.98 wt% PCL-based matrix, 0.01-49.99 wt% lysozyme, and 0.01-10 wt% PCL-degrading enzyme.

[0080] In another specific embodiment, the polymer base matrix is ​​composed of PGA, the polymer-degrading enzyme is an esterase, and the drug is selected from a bone regenerating enzyme, an anti-inflammatory drug (e.g., ibuprofen), an analgesic drug (e.g., paracetamol, morphine), an antidiabetic drug (e.g., insulin), a hormone (e.g., progesterone), a cytokine, a monoclonal antibody, an antigen, a contraceptive, an anti-tumor drug, and an anti-infective drug.

[0081] Interestingly, the present invention allows for the incorporation of drugs into polymer-based matrices at high concentrations, particularly at concentrations above their solubility threshold in classic solvents used for drug incorporation, such as chloroform or dichloromethane. The solubility threshold is the maximum concentration at which a drug dissolves in a solvent at ambient temperature. In fact, drugs have traditionally been introduced into polymer-based matrices using solvents, which affects the final drug concentration within the polymer-based matrix. The present invention now provides drug delivery compositions with drug concentrations higher than those obtainable by solvent-based methods. For example, the drug / polymer-based matrix ratio can be 0.5 to 2.3, particularly 1. Alternatively, the drug / polymer-based matrix ratio can be 0.05 to 0.7.

[0082] When the polymer-based matrix is ​​partially or completely molten, the drug can be introduced into the polymer-based matrix in a solid form (e.g., powder) or liquid form. Furthermore, according to the present invention, it is possible to incorporate an aqueous composition containing water and a water-soluble drug. This is particularly suitable for producing a drug delivery composition containing a drug that is not soluble in a classical solvent but is soluble in water. According to the present invention, the aqueous composition can be incorporated into the polymer-based matrix in a completely or partially molten state, for example, during the extrusion process.

[0083] (Method of manufacturing drug delivery composition) The present invention also relates to a method for producing a drug delivery composition comprising a polymer base matrix, a drug, and a polymer-degrading enzyme, the method comprising incorporating the drug and the enzyme into the polymer base matrix during heat treatment of the polymer at a temperature T at which the polymer is partially or completely molten. Preferably, the drug and the enzyme are incorporated at a temperature T of 50° C. to 200° C., preferably 60° C. to 180° C., more preferably 70° C. to 160° C. The temperature T can be adjusted by those skilled in the art depending on the polymer and / or drug and / or enzyme of the drug delivery composition.

[0084] In certain embodiments, the drug and enzyme are preferably incorporated simultaneously at a temperature T that is above the glass transition temperature (Tg) of the polymer, and preferably at or above the melting temperature of the polymer.

[0085] In another embodiment, the drug and enzyme are incorporated sequentially.

[0086] For example, the enzyme is preferably incorporated first at a temperature T above the glass transition temperature (Tg) of the polymer, preferably at or above the melting temperature of the polymer, and the drug is then incorporated, preferably at a temperature T between the glass transition temperature (Tg) and the melting temperature of the polymer.

[0087] Alternatively, the drug is incorporated first, preferably at a temperature T above the glass transition temperature (Tg) of the polymer, and preferably at or above the melting temperature of the polymer, and the enzyme is incorporated second, preferably at a temperature T between the glass transition temperature (Tg) and the melting temperature of the polymer.

[0088] Advantageously, the thermal treatment is selected from extrusion, internal mixing, co-mixing, injection molding, thermoforming, rotational molding, compression, calendering, ironing, coating, layering, stretching, pultrusion, extrusion blow molding, extrusion expansion, compression granulation and 3D printing (e.g. fused deposition modeling, selective laser sintering or binder jetting), preferably extrusion and 3D printing. Depending on the selected thermal treatment, the polymer base matrix can be melted together with both the enzyme and the drug and formed into the desired shape.

[0089] In a preferred embodiment, the heat treatment is extrusion, advantageously carried out in an extruder, for example the extruder may be a multi-screw extruder, preferably a twin-screw extruder, more preferably a co-rotating twin-screw extruder.

[0090] In a preferred embodiment, the residence time of the enzyme and / or drug in the extruder is 5 seconds to 3 minutes, preferably less than 2 minutes, more preferably less than 1 minute. When the polymer base matrix contains a polymer with a melting temperature of less than 180°C, the residence time of the mixture in the extruder is preferably less than 2 minutes. The residence time depends on the production method and the polymer base matrix, and can be easily adjusted by those skilled in the art.

[0091] Both the enzyme and the drug can be introduced into the extruder in a solid form, such as a powder, or in a liquid form, such as a liquid formulation. Advantageously, the enzyme and / or the drug are introduced at a later stage of the heat treatment, more specifically, when the polymer base matrix is ​​partially or completely molten. This reduces exposure to high temperatures. Preferably, the residence time of both the enzyme and the drug in the extruder is half or less than the residence time of the polymer base matrix.

[0092] The enzyme and drug may be formulated in any support known by those skilled in the art. A single formulation containing both the enzyme and drug may be used.

[0093] In certain embodiments, the enzyme and / or drug is incorporated into a polymer carrier, preferably a polymer having a melting temperature of less than 140°C. Preferably, the enzyme and / or drug is introduced in the form of a masterbatch. According to certain embodiments, the masterbatch is preferably prepared by (i) extruding a carrier polymer and (ii) introducing the drug and / or enzyme during the extrusion of the carrier polymer. This allows the masterbatch to be incorporated into a polymer base matrix to obtain a drug delivery composition according to the present invention. This embodiment of the present invention is particularly interesting for more precisely controlling the final dosage and uniformity of the drug in the drug delivery composition / device.

[0094] Preferably, the carrier polymer has a melting temperature of less than 140°C, and is preferably selected from polycaprolactone (PCL), polybutylene succinate adipate (PBSA), polybutylene adipate terephthalate (PBAT), polydioxanone (PDS), polyhydroxyalkanoic acid (PHA), polylactic acid (PLA), polyglycolic acid (PGA), polyethylene glycol (PEG), preferably PEG with a molecular weight of more than 600g / mol, polyethylene oxide (PEO) or copolymer.In certain embodiments, enzyme and / or drug are incorporated into the polymer carrier selected from PCL and introduced in the form of a masterbatch.

[0095] In another particular embodiment, the drug and / or enzyme are formulated in an aqueous solvent, preferably water, before being introduced into the polymer base matrix.

[0096] Another object of the present invention is to provide a medical drug device obtained from a manufacturing method comprising the step of incorporating a drug and an enzyme having polymer-degrading activity into a polymer-based matrix, wherein such step is carried out by heat treatment of the polymer at a temperature T at which the polymer is in a partially or completely molten state. [Example]

[0097] Example 1 Drug delivery composition of the present invention containing ibuprofen, PLA and PLA-degrading enzyme

[0098] The drug delivery composition of the present invention was prepared by dissolving 80% by weight of a micronized polymer of polylactic acid (Ingeo, available from NatureWorks) based on the total weight of the drug delivery composition. TM The polymer was prepared by mixing Biopolymer 4043D (molecular weight (MW) 180,000 g / mol), 10% by weight of S-ibuprofen powder (Sigma-Aldrich reference 375160) and 10% by weight of a powdered Savinase® formulation. Savinase® is an enzyme from Novozymes known to have the ability to degrade PLA (Degradation of Polylactide by Commercial Proteases; Y. Oda, A. Yonetsu, T. Urakami and K. Tonomura; 2000).

[0099] A powdered Savinase® formulation was obtained as follows: A liquid formulation was obtained by ultrafiltration and diafiltration of commercially available Savinase® 16L (diafiltration factor approximately 100) through a 3.5 Kd membrane to obtain a concentrated liquid composition and remove some polyols present in the commercial solution. Gum arabic (INSTANT GUM AA-NEXIRA) was added, and the resulting composition was then dried by lyophilization to obtain a solid composition containing approximately 33 wt. % enzyme, 15.7 wt. % gum arabic, 0.5 wt. % water, and 50.8 wt. % polyols (glycerol, propylene glycol) and other additives, based on the total weight of the solid composition.

[0100] The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) to incorporate the ibuprofen and Savinase® into the PLA. A control composition without Savinase® was also prepared. The twin-screw extruder was used at 80 rpm while the composition was manually filled.

[0101] A drug delivery composition of the present invention was produced by extruding a mixture consisting of 4.0 g of PLA, 0.5 g of S-ibuprofen, and 0.5 g of a solid composition containing Savinase® at 155° C. A control composition without Savinase® contained 4.5 g of PLA and 0.5 g of S-ibuprofen.

[0102] The degradation of PLA and release of ibuprofen were analyzed by UHPLC for titration of lactic acid and ibuprofen using the following method: The compositions were cut into small pieces with pliers. Approximately 100 mg of these compositions were introduced into dialysis tubing cellulose membrane (14,000 Da cutoff, Sigma-Aldrich) with 3 mL of 0.1 M Tris-HCl buffer, pH 8. The dialysis tubing was then introduced into 50 mL of 0.1 M Tris-HCl buffer, pH 8, and incubated at 37°C for several days. Samples were taken at various time points during the degradation of the compositions.

[0103] (UHPLC method used for lactic acid titration) An Ultimate 3000 HPLC system (Thermofisher Scientific) equipped with a Shodex RI-101 Analytical refractive index detector and a Phenomenex RFQ-Fast Acid H+ (8%), 7.8 x 100 mm, 8 μm column was used. The column temperature was controlled at 60 °C. The mobile phase was 5 mM HSO4, and the flow rate was 0.75 mL / min. Lactic acid (LA) powder was accurately weighed and dissolved in water to obtain a 10 g / L solution. Serial dilutions with water were performed to obtain LA concentrations ranging from 0.5 to 5 g / L. The prepared standard solution was injected (20 μL) under the same conditions as the sample. The peak area of ​​the lactic acid concentration was calculated. The LA concentration was regressed against the peak area and used to estimate the amount of LA released from the polymer.

[0104] (UHPLC method used for ibuprofen titration) An Ultimate 3000 HPLC system (Thermofisher Scientific) equipped with a diode array detector (DAD-3000(RS)) and a Phenomenex Kinetex EVO C18 LC column (100 x 2.1 mm, 2.6 μm, 100 Å pore size) were used. The column temperature was controlled at 50 °C. The mobile phase was a mixture of 38% acetonitrile and 62% 20 mM KHPO4 buffer (pH 3, phosphate) at a flow rate of 0.75 mL / min. S-ibuprofen powder was accurately weighed and dissolved in the mobile phase to obtain a 400 μg / mL solution. Serial dilutions were performed with the mobile phase to obtain concentrations ranging from 23 to 400 μg / mL. The prepared standard solution was injected (20 μL) under the same conditions as the samples. The peak areas of the ibuprofen concentrations were calculated. The peak areas were then regressed against the ibuprofen concentration to estimate the amount of ibuprofen released from the polymer composition. The HPLC peak of the released ibuprofen was the same as that of the unextruded ibuprofen, indicating that the ibuprofen was not degraded during extrusion.

[0105] The results are shown in Figure 1. PLA degradation is expressed as a percentage of the total lactic acid present in the PLA of the composition, and ibuprofen release is expressed as a percentage of the total ibuprofen embedded in the composition.

[0106] The results showed that PLA was degraded only when PLA-degrading enzyme was added to the composition, indicating that PLA-degrading enzyme maintained its PLA-degrading activity in the drug delivery composition of the present invention. The results also showed that ibuprofen was not degraded by extrusion. Due to the degradation of PLA by PLA-degrading enzyme, ibuprofen was released regularly without enzymatic degradation. Approximately 30% of ibuprofen (i.e., 0.15 g) was released over 6 days, corresponding to a daily dose of 25 mg. In the control composition without Savinase®, PLA was not degraded and ibuprofen was not significantly released.

[0107] The rate of PLA degradation can be adjusted by the enzyme concentration, which then controls the rate of drug release.

[0108] Example 2 Drug Delivery Composition of the Present Invention Comprising Naltrexone, PLA, and PLA-Degrading Enzyme

[0109] The drug delivery composition of the present invention was prepared by dissolving 87% by weight of a micronized polymer of polylactic acid (Ingeo, available from NatureWorks) based on the total weight of the drug delivery composition. TM A PLA composition was prepared by blending Biopolymer 4043D (molecular weight (Mw) 180,000 g / mol), 8 wt. % naltrexone hydrochloride powder (Sigma-Adrich), and 5 wt. % Savinase® powder (prepared in Example 1). The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) to simultaneously incorporate naltrexone and Savinase® into the PLA. A control composition without Savinase® was also prepared. The twin-screw extruder was used at 80 rpm and 168°C while the composition was manually filled.

[0110] The weights (in g) of each component of the drug delivery composition and the control composition are summarized in Table 1. [Table 1]

[0111] The degradation of the compositions was analyzed by the degradation of PLA and the release of naltrexone.

[0112] The compositions were cut into small pieces with pliers. Approximately 100 mg of these compositions were placed in a dialysis tube cellulose membrane (14,000 Da cutoff, Sigma-Aldrich) with 3 mL of 0.1 M Tris-HCl buffer, pH 8. The dialysis tube was then placed in 50 mL of 0.1 M Tris-HCl buffer, pH 8, and incubated at 37°C for several days. Samples were taken at various time points during the degradation of the compositions.

[0113] The degradation of PLA and release of naltrexone was analyzed by UHPLC by titration of lactic acid (as described in Example 1) and naltrexone (using the method below).

[0114] (UHPLC method used for naltrexone titration) An Ultimate 3000 HPLC system (Thermofisher Scientific) equipped with a diode array detector (DAD-3000(RS)) and a Phenomenex Kinetex EVO C18 LC column, 100 x 2.1 mm, 2.6 μm, 100 Å pore size, was used. The column temperature was controlled at 30 °C. The mobile phase was a gradient of 20 mM ammonium bicarbonate pH 9 / acetonitrile (95 / 5 to 35 / 65% over 5 min) at a flow rate of 0.75 mL / min. Naltrexone hydrochloride powder was accurately weighed and dissolved in water to obtain a 450 μg / mL solution. Serial dilutions with water were performed to obtain concentrations ranging from 7 to 450 μg / mL. The prepared standard solution was injected under the same conditions as the samples. The peak areas of the naltrexone concentrations were calculated. Regression of the peak areas against the naltrexone concentrations was used to estimate the amount of naltrexone released from the polymer. The HPLC peak of the released naltrexone was the same as that of unextruded naltrexone, indicating that the naltrexone was not degraded during extrusion.

[0115] The results are shown in Figure 2. PLA degradation is expressed as a percentage of the total lactic acid present in the PLA of the composition, and naltrexone released is expressed as a percentage of the total naltrexone embedded in the composition.

[0116] The results showed that PLA degraded only when PLA-degrading enzyme was added to the composition, indicating that PLA-degrading enzyme maintained its PLA-degrading activity in the drug delivery composition of the present invention. The results also showed that naltrexone was not degraded by extrusion. Due to the degradation of PLA by PLA-degrading enzyme, naltrexone was released regularly without enzymatic degradation. Approximately 54% of naltrexone (i.e., 0.22 g) was released for 11 days, corresponding to a daily dose of 20 mg. In the control composition without Savinase®, PLA was not degraded and naltrexone was not significantly released.

[0117] The rate of PLA degradation can be adjusted by the enzyme concentration, which then controls the rate of drug release.

[0118] Example 3 Drug delivery composition of the present invention containing estradiol, PLA and PLA-degrading enzyme

[0119] The drug delivery composition of the present invention was prepared by mixing 90% by weight of a micronized polymer of polylactic acid (Ingeo, available from NatureWorks) based on the total weight of the drug delivery composition. TM A PLA composition was prepared by blending Biopolymer 4043D (MW 180,000 g / mol), 5 wt. % estradiol powder (Sigma-Adrich), and 5 wt. % Savinase® powder (prepared in Example 1). The blend was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) to incorporate the estradiol and Savinase® into the PLA. A control composition without Savinase® was also prepared. The twin-screw extruder was used at 80 rpm and 165°C while the composition was manually filled.

[0120] The weights (in g) of each component of the drug delivery composition and the control composition are summarized in Table 2. [Table 2]

[0121] The degradation of the compositions was analyzed, resulting in the degradation of PLA and the release of estradiol.

[0122] The compositions were cut into small pieces with pliers. Approximately 50 mg of these compositions were placed in a dialysis tube cellulose membrane (14,000 Da cutoff, Sigma-Aldrich) with 3 mL of 0.1 M Tris-HCl buffer, pH 8. The dialysis tube was then placed in 50 mL of 0.1 M Tris-HCl buffer, pH 8, and incubated at 37°C for several days. Due to the low solubility of estradiol (approximately 3.6 mg / L), the same number of vials as sampling points were prepared. For each sampling point, a vial was used. 1 mL was withdrawn and titrated for lactate, and the remaining sample was diluted with 52 mL of acetonitrile. Further dilutions were applied if necessary.

[0123] The degradation of PLA and release of estradiol was analyzed by UHPLC via titration of lactic acid (as described in Example 1) and estradiol (using the method below).

[0124] (UHPLC method used for estradiol titration) An Ultimate 3000 HPLC system (Thermofisher Scientific) equipped with a diode array detector (DAD-3000(RS)) and a Phenomenex Kinetex EVO C18 LC column, 100 x 2.1 mm, 2.6 μm, 100 Å pore size, was used. The column temperature was controlled at 30 °C. The mobile phase was a gradient of 20 mM ammonium bicarbonate pH 9 / acetonitrile (85 / 15 to 35 / 65% over 5 min) at a flow rate of 0.75 mL / min. Estradiol powder was accurately weighed and dissolved in 80% acetonitrile to obtain a 110 μg / mL solution. Serial dilutions with water were performed to obtain concentrations ranging from 0.3 to 11 μg / mL. The prepared standard solutions were injected under the same conditions as the samples. The peak areas of the estradiol concentrations were calculated. Regression of the peak areas against the estradiol concentrations was used to estimate the amount of estradiol released from the polymer. The HPLC peak of the released estradiol was the same as that of unextruded estradiol, indicating that the estradiol was not degraded during extrusion.

[0125] The results are shown in Figure 3. PLA degradation is expressed as a percentage of the total lactic acid present in the PLA of the composition, and estradiol release is expressed as a percentage of the total estradiol embedded in the composition.

[0126] The results show that in the drug delivery composition of the present invention, estradiol is released after the PLA polymer is degraded by Savinase®. In the control composition without Savinase®, PLA was not degraded and estradiol was not released.

[0127] The results showed that PLA was degraded only when PLA-degrading enzyme was added to the composition, indicating that PLA-degrading enzyme maintained its PLA-degrading activity in the drug delivery composition of the present invention. The results also showed that estradiol was not degraded by extrusion. Due to the degradation of PLA by PLA-degrading enzyme, estradiol was released regularly without enzymatic degradation. Approximately 53% of estradiol was released for 20 days, which corresponds to a daily dose of 70 μg when considering a 50 mg drug delivery composition. In the control composition without Savinase®, PLA was not degraded and estradiol was not significantly released.

[0128] Example 4 Drug delivery composition of the present invention containing lysozyme, PLA and PLA-degrading enzyme

[0129] Based on the total weight of the masterbatch, 50 wt. % lysozyme and 50 wt. % polycaprolactone (PCL, Capa from Perstorp) were used. TM A masterbatch containing PCL (6500, melting temperature 58-60°C) was prepared by mixing 2.5 g of micronized PCL and 2.5 g of lysozyme powder (Sigma-Aldrich, denaturation temperature 76°C, 14.7 kDa). The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) at 78°C and 80 rpm while being manually filled.

[0130] The drug delivery composition of the present invention was mixed with 1 g of the masterbatch cut into small pieces (approximately 2 mm x 2 mm), 3.5 g (70%) of micronized polymer of polylactic acid (Ingeo, NatureWorks) TM The drug delivery composition was prepared by mixing 0.5 g (10%) of Biopolymer 4043D (Mw 180000 g / mol) and Savinase® powder (see Example 1). The drug delivery composition mixture was then extruded using the same extruder at 80 rpm and 165°C while the composition was manually filled.

[0131] Lysozyme was extracted from the drug delivery composition by liquid-liquid extraction. 50 mg of the drug delivery composition was dissolved in 2.5 mL of dichloromethane. 7.5 mL of chilled 66 mM potassium phosphate buffer, pH 6.24, was then added. The mixture was vortexed vigorously. Samples were kept on ice between each step. After phase separation, the aqueous phase was collected and lysozyme activity was measured using a lysozyme activity kit (Sigma-Aldrich).

[0132] After two extrusions at 78°C and 165°C, the lysozyme embedded in the composition still exhibited activity (results not shown).

[0133] Example 5 Incorporation of high amounts of drugs into polymer-based matrices by extrusion

[0134] Example 5.1 Incorporation of High Amounts of Naltrexone into a Polymer-Based Matrix by Extrusion A composition containing 50% PLGA and 50% naltrexone was prepared by mixing 2.5 g of DL-lactic acid / glycolic acid copolymer (PLGA or PLA / PGA, PURASORB PDLG 5002A from Corbion Purac, with a rubbery plateau) and 2.5 g of naltrexone hydrochloride powder (Sigma-Aldrich). The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) to incorporate naltrexone into the PLGA. The twin-screw extruder was operated at 80 rpm and 100°C while the composition was manually filled.

[0135] The extruded composition is obtained in the form of solid pellets suitable for subsequent processing and / or shaping in an extrusion process to form a drug delivery device.

[0136] The composition was cut into small pieces, and 20% by weight of this composition was mixed with 80% by weight of the same PLGA copolymer (PURASORB PDLG 5002A from Corbion Purac) and extruded at 100°C and 80 rpm using the same extruder as above. The resulting composition was also obtained in the form of solid pellets suitable for molding to form drug delivery devices.

[0137] The results show that it is possible to incorporate approximately 50% of the drug into the polymer composition by extrusion and obtain a composition suitable for subsequent processing or direct molding to form a drug delivery device.

[0138] Example 5.2 Incorporation of high amounts of lysozyme into a polymer-based matrix by extrusion A composition containing 50% PCL and 50% lysozyme was prepared by adding 2.5 g of PCL powder (Perstorp Capa TM The mixture was prepared by mixing 2.5 g of lysozyme powder (Sigma-Aldrich, denaturation temperature 74°C) with 2.5 g of lysozyme powder (Sigma-Aldrich, melting temperature 58-60°C). The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) at 78°C and 80 rpm while the composition was manually filled.

[0139] Lysozyme was extracted from the drug delivery composition by liquid-liquid extraction as described in Example 4, and lysozyme activity was titrated with a lysozyme activity kit (Sigma-Aldrich). The results show that it is possible to incorporate approximately 50% lysozyme into the polymer composition by extrusion, and that such drugs retain 95% activity after extrusion.

[0140] Example 5.3 Incorporation of high amounts of lysozyme into a polymer-based matrix by extrusion A composition containing 50% PLGA and 50% lysozyme was prepared by mixing 2.5 g of PLGA copolymer powder (PURASORB PDLG 5002A from Corbion Purac) and 2.5 g of lysozyme powder (Sigma-Aldrich). The mixture was then extruded using a twin-screw extruder (Thermo Scientific HAAKE Minilab II) at 100 °C and 80 rpm while the composition was manually filled.

[0141] The extruded composition is obtained in the form of solid pellets suitable for subsequent processing and / or shaping in an extrusion process to form a drug delivery device.

[0142] The composition was cut into small pieces, and 20% by weight of this composition was mixed with 80% by weight of another PLGA copolymer (PURASORB PDLG 5010 from Corbion Purac) and extruded at 100°C and 80 rpm using the same extruder as above. The resulting composition was also obtained in the form of solid pellets suitable for molding to form drug delivery devices.

[0143] The results show that it is possible to incorporate approximately 50% protein into a polymer composition by extrusion and obtain a composition suitable for subsequent processing or direct molding to form a drug delivery device.

Claims

1. A drug delivery composition comprising a drug and a polymer-degrading enzyme embedded in a polymer-based matrix, the polymer-based matrix having a molecular weight (Mw) greater than 100,000 g / mol, the polymer-degrading enzyme capable of degrading at least one polymer of the polymer-based matrix, the composition comprising incorporating the drug and the enzyme into the polymer-based matrix during heat treatment at a temperature T at which the polymer is partially or completely molten, wherein the temperature T is between 60°C and 180°C.

2. The composition comprises a drug and a polymer-degrading enzyme embedded in a polymer-based matrix, the composition comprising: 50 to 99.98 wt. % of a polymer base matrix; 0.01 to 49.99% by weight of a drug, and 0.01 to 30% by weight of a polymer-degrading enzyme Including, The drug delivery composition of claim 1.

3. 3. The drug delivery composition of claim 1, wherein the polymer-degrading enzyme is selected from a protease, an esterase, a cutinase, or a lipase.

4. 4. The drug delivery composition of claim 1, wherein the polymer base matrix contains at least one polymer selected from polylactic acid (PLA), polybutylene adipate terephthalate (PBAT), polyhydroxyalkanoic acid (PHA), polyglycolic acid (PGA), polybutylene succinate (PBS), polycaprolactone (PCL), poly(ethylene adipate) (PEA), dextran, gelatin, polybutylene succinate adipate (PBSA), polydioxanone (PDS), polyethylene glycol (PEG), polyethylene oxide (PEO), poly(L-lactic acid) (PLLA), and / or poly(D-lactic acid) (PDLA).

5. 5. The drug delivery composition of claim 1, wherein the polymer base matrix comprises a lactic acid copolymer selected from lactic acid-glycolic acid copolymer (PLA-co-PGA), lactic acid-caprolactone copolymer (PLA-co-PCL), lactic acid-ethylene glycol copolymer (PLA-co-PEG), lactic acid-ethylene oxide copolymer (PLA-co-PEO), or grafted PLA (PLA-g-gelatin).

6. 6. The drug delivery composition of claim 1, wherein the polymer base matrix comprises PLA having a Mw greater than 100,000 g / mol, a Mw greater than 150,000 g / mol, or a Mw greater than 180,000 g / mol.

7. 7. The drug delivery composition of claim 1, wherein the polymer base matrix comprises PLA, the polymer-degrading enzyme comprises a PLA-degrading enzyme, and the drug is selected from a compound useful in managing alcohol or opioid dependence, a nonsteroidal anti-inflammatory drug, a hormone, or a protein.

8. The drug delivery composition of any one of claims 1 to 5, wherein the polymer base matrix comprises polycaprolactone (PCL) and / or the polymer base matrix comprises poly(ethylene adipate) (PEA).

9. The drug delivery composition of claim 8, wherein the polymer base matrix is ​​made of polycaprolactone (PCL), the polymer-degrading enzyme is lipase PS, and the drug is selected from bone regeneration enzymes, anti-inflammatory drugs, analgesics, antidiabetic drugs, hormones, cytokines, monoclonal antibodies, antigens, contraceptives, antitumor drugs, or anti-infective drugs.

10. 9. The drug delivery composition of claim 8, wherein the polymer base matrix is ​​made of poly(ethylene adipate) (PEA), the polymer-degrading enzyme is an esterase, and the drug is selected from bone regenerating enzymes, anti-inflammatory drugs, analgesics, antidiabetic drugs, hormones, cytokines, monoclonal antibodies, antigens, contraceptives, antitumor drugs, or anti-infective drugs.

11. The drug delivery composition of any one of claims 1 to 10, wherein the composition is a pharmaceutical composition selected from a tablet, a gel, a coating, a particle, or a microbead.

12. A drug delivery device comprising the drug delivery composition of any one of claims 1 to 10.

13. 13. The drug delivery device of claim 12, wherein the device is a medical device, preferably selected from an implant, a film, a stent, a leaflet, a valve, a coil, a scaffold, a dressing, a rod, a patch, a fiber, a suture, a screw, a bone plate or implant, a bone cement, or a prosthesis.

14. 1. A method for producing a drug delivery composition comprising a polymer base matrix, a drug, and a polymer-degrading enzyme, wherein the polymer base matrix comprises a molecular weight (Mw) of greater than 100,000 g / mol, the method comprising incorporating the drug and the enzyme into the polymer base matrix during heat treatment at a temperature T at which the polymer is partially or completely molten, wherein the temperature T is between 60°C and 180°C.

15. 15. The method of claim 14, wherein the drug and enzyme are incorporated at a temperature T of 70°C to 160°C.

16. 16. The process of any one of claims 14 or 15, wherein the thermal treatment is selected from extrusion, internal mixing, co-kneading, injection molding, thermoforming, rotational molding, compression, calendering, ironing, coating, layering, stretching, pultrusion, extrusion blow molding, extrusion expansion, compression granulation, or 3D printing.

17. A drug delivery device obtainable by the method according to any one of claims 14 to 16.

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