Pharmaceutical kit for parenteral combination therapy

Abstract

The present invention relates to a parenteral co-administration pharmaceutical kit, which provides applications for using anti-inflammatory drugs to improve the bioavailability of co-administered drugs, prevent, reduce or treat inflammatory responses caused by co-administered parenteral drug carriers, or modulate the degradation of co-administered parenteral drug carriers. [Solution] The present invention relates to a parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug carrier, which can be used for the prevention, reduction, or treatment of inflammatory responses in the target population by the drug carrier contained in the second formulation, or for the purpose of regulating the degradation of the parenteral drug carrier contained in the second formulation, or for the purpose of increasing the bioavailability of the second drug contained in the second formulation.

Description

Technical Field

[0001] The present invention relates to a parenteral co-administration pharmaceutical kit, which uses an anti-inflammatory drug to improve the bioavailability of the co-administered drug, prevent, reduce or treat an inflammatory reaction caused by a parenteral drug delivery carrier for co-administration, or regulate the degradation of the parenteral drug delivery carrier for co-administration, and provides a use thereof.

Background Art

[0002] There is an actual situation where a large number of co-administration drugs that administer two or more drugs in various ways have been developed for various reasons such as increasing the efficacy of drugs, reducing side effects, or convenience of administration.

[0003] In addition, a drug delivery system (DDS) is used for the purpose of maximizing the therapeutic effect of drugs and minimizing side effects on the human body. The drug delivery carrier includes from a simple formulation with a drug to a highly functional dosage form, and is applied to patients through various routes of the human body such as oral, injection, transdermal, mucosal, transplantation, etc. In particular, for drugs that must be taken for a long time for the treatment of diseases, in order to improve the convenience of taking drugs by patients and improve the therapeutic effect, the development of various types of parenteral drug preparations loaded with drugs is actively carried out.

[0004] However, in the case of such dosage forms, since a substance that does not exist in the living body is used as a drug delivery carrier and a technique in which the target drug is loaded and the therapeutic agent is released in the body for a long time is applied, the drug delivery carrier may also induce undesirable reactions as an in vitro foreign substance in the administration target, such as an immune reaction or an inflammatory reaction.

[0005] Such an inflammatory reaction is continuously maintained until the parenteral drug delivery carrier loaded with the target drug is completely decomposed in the body, and is highly likely to progress from acute inflammation to chronic inflammation. Therefore, there is an actual need for an anti-inflammatory preparation or kit for preventing, reducing or treating the occurrence of inflammation in the administration target by the drug delivery carrier.

[0006] On the other hand, in long-acting drug formulations, excessive or inappropriate drug release can prevent the achievement of the target drug release profile, potentially leading to side effects or failure to achieve the expected drug efficacy.

[0007] Furthermore, when attempting to release a drug continuously over a long period, a large quantity of the drug must be introduced into the drug delivery system to achieve sufficient efficacy over the target period. If the bioavailability of the drug contained in the formulation is low, an excessively large amount of drug delivery system administration is required to achieve long-term effective pharmacological effects. However, administering large quantities of drug delivery systems into the body may not be possible via subcutaneous injection, making it difficult for patients to administer the drug themselves (self-administration), or it may require injections at multiple sites, leading to problems such as very high pain and inflammatory reactions at the injection sites. [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention relates to a parenteral co-administration pharmaceutical kit, which utilizes an anti-inflammatory drug to improve the bioavailability of a co-administered drug, prevent, reduce or treat an inflammatory response caused by a co-administered parenteral drug carrier, or modulate the degradation of a co-administered parenteral drug carrier.

[0009] One example of the present invention is to provide a parenteral combination drug pharmaceutical kit or its applications for preventing, reducing, or treating inflammatory responses induced by parenterally administered drug carriers using anti-inflammatory drugs.

[0010] Another example of the present invention is to provide a parenteral combination drug pharmaceutically kit or its use for regulating the degradation rate of parenteral drug carriers administered concomitantly using an anti-inflammatory drug.

[0011] Another example of the present invention is the provision of a parenteral combination drug pharmaceutically kit or its applications that utilize anti-inflammatory drugs to increase the bioavailability of concomitantly administered drugs.

[0012] Another example of the present invention relates to a parenteral formulation or kit that additionally includes a local anesthetic component in addition to the parenteral combination drug pharmaceutically kit described above. [Means for solving the problem]

[0013] An example of the present invention is a parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system. The first formulation comprises an anti-inflammatory drug, or an anti-inflammatory drug supported on a first parenteral drug carrier, and the second formulation comprises a second parenteral drug carrier and a second drug different from the drug in the first formulation, and the first formulation is for preventing, reducing, or treating a target inflammatory response by the parenteral drug carrier of the second formulation. The present invention relates to a parenteral combination drug pharmacologic kit or its use.

[0014] An example of the present invention is a parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system. The present invention relates to a parenteral combination drug pharmacochemical kit in which the first formulation comprises an anti-inflammatory drug, or an anti-inflammatory drug supported on a first parenteral drug carrier, the second formulation comprises a second parenteral drug carrier and a second drug different from the drug in the first formulation, and the first formulation is for regulating the degradation of the parenteral drug carrier contained in the second formulation.

[0015] An example of the present invention relates to a parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug carrier, wherein the first formulation contains an anti-inflammatory first drug or an anti-inflammatory first drug supported on a first parenteral drug carrier, and the second formulation contains a second parenteral drug carrier and a second drug different from the drug in the first formulation, and the first formulation is intended to increase the bioavailability of the second drug contained in the second formulation.

[0016] The first and second formulations included in the parenteral combination drug pharmacochemical kit may be administered simultaneously or at different times. The parenteral combination drug pharmacochemical kit may contain the first and second formulations in the form of a mixed formulation or individual formulations.

[0017] The parenteral combination drug pharmacologic kit according to the present invention may include a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system.

[0018] The first drug contained in the first formulation may be an anti-inflammatory drug, and the first drug is different from the second drug contained in the second formulation. Furthermore, the first drug may be provided without a separate drug delivery system, or carried together with the drug delivery system of the second formulation, or individually carried on the first parenteral drug delivery system.

[0019] For example, if the first drug included in the pharmaceutical kit is provided without a separate drug delivery system, it may be provided together with the first drug in the form of a mixed formulation of a second formulation containing a second parenteral drug delivery system and the second drug, or the first drug may be provided separately at a different time from the second formulation. Specifically, if the second formulation is a microparticle, the first drug may be provided together with the second drug in a form supported on a single microparticle.

[0020] Alternatively, the first drug contained in the pharmaceutical kit may be provided in a form supported on a separate first drug delivery body, and the first drug delivery body may be the same as or different from the second drug delivery body. Specifically, if the first formulation contains the first drug supported on a first parenteral drug delivery body, it may be provided in the form of a mixed formulation with the second formulation or as separate formulations, and can be administered to subjects who require it simultaneously or at different times.

[0021] Another example of the present invention is that the AUC of the anti-inflammatory drug released from the first anti-inflammatory formulation above the minimum effective blood concentration may be 1 / 2, 1 / 3, 1 / 5, or 1 / 10 of the total AUC of the effective daily dose of the drug, or it may be 50%, 33%, 20%, or 10% or less based on 100% of the total AUC of the effective daily dose of the drug. For example, when the first anti-inflammatory formulation containing dexamethasone is administered to a human body and the blood drug concentration is 1 ng / ml or more, the AUC may be 1 / 2 or less, preferably 1 / 3 or less, more preferably 1 / 5 or less, and most preferably 1 / 10 or less, compared to the total AUC when an oral formulation of 6 mg / dose is administered.

[0022] In a specific example, the anti-inflammatory drug released from the first anti-inflammatory formulation may be released in such a way that its plasma concentration is 1.0 ng / mL or less. In this case, preferred examples of the anti-inflammatory drug may be dexamethasone or its derivatives or pharmaceutically salts thereof.

[0023] According to one example of the present invention, the first drug (anti-inflammatory drug) contained in the first formulation may sometimes induce side effects if its blood concentration is excessively high in the sustained-release formulation. For example, if the anti-inflammatory drug is a glucocorticoid, sometimes high plasma concentrations (administering 1 mg / kg / day for 2-3 weeks) may lead to systemic side effects, and it is preferable to have a plasma concentration lower than the concentration at the local administration site.

[0024] As another example of the present invention, in the blood concentration curve over time after administration of the anti-inflammatory drug released from the anti-inflammatory first preparation, the AUC above the minimum blood concentration that induces side effects throughout the body must be minimized, specifically, it is 1 / 10 or less, 1 / 20 or less, 1 / 30 or less, or 1 / 40 or less of the AUC at a single administration of the same dose of the drug, or based on 100% of the AUC at a single administration of the same dose of the drug, it may be 10% or less, 5% or less, 3.3% or less, or 2.5% or less.

[0025] For example, when an anti-inflammatory first preparation containing dexamethasone or dexamethasone acetate is subcutaneously administered to rats, the AUC when the blood drug concentration is 2 ng / ml or more is 1 / 10 or less, preferably 1 / 20 or less, more preferably 1 / 30 or less, and most preferably 1 / 40 or less when compared with the AUC at subcutaneous administration of the same dose of dexamethasone or dexamethasone acetate.

[0026] In a specific example, the anti-inflammatory drug released from the anti-inflammatory first preparation may be released so that the plasma concentration of the anti-inflammatory drug is 2.0 ng / mL or less. In this case, preferred examples of the anti-inflammatory drug may be dexamethasone or its derivatives or their pharmaceutical salts.

[0027] In this specification, "drug delivery body", "drug delivery system", "drug carrier" or "drug carrier" can be used interchangeably with each other and means a delivery body from which a pharmaceutically active ingredient can be released upon administration in vivo. The drug delivery bodies applicable to the present invention are intended to include all parenteral delivery bodies of drugs such as microspheres, liposomes, micelles, depots, or hydrogels. The hydrogel includes injectable gels. The drug delivery body can be used as a carrier for delivering a drug to a living body and can be a biocompatible substance, and preferably, it may be a biodegradable substance for drug release. For example, the material of the drug delivery body includes, but is not limited to, biodegradable polymers and biodegradable lipids.

[0028] The drug delivery systems applicable to the present invention can use biocompatible substances, including but not limited to, for example, biodegradable polymers, biodegradable lipids, and the like.

[0029] More specifically, the type of biodegradable polymer is not particularly limited, but polyester is preferably used. Examples of biodegradable polymers include polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), which is a copolymer of lactide and glycoside, polydioxanone, polycaprolactone (PCL), polylactide-co-glycolide-co-caprolactone (PLGC), and polylactide-co-hydroxymethylglycolide. Glycolide (PLGMGA), polyalkyl carbonate, polytrimethylene carbonate (PTMC), polylactide-co-trimethylene carbonate (PLTMC), polyhydroxybutyric acid (PHB), polyhydroxybutyrate-co-hydroxyvalerate (PHBV), polyorthoester, polyanhydride, polyanhydride-co-imide, polypropylene fumarate, pseudopolyamino acidsIt is preferable to use one or more polymers, preferably two or more polymers, selected from the group consisting of polymers selected from the group consisting of polyaminoacid, polyalkylcyanoacrylate, polyphosphazene, polyphosphoester, polysaccharide, and poly(butylene succinate lactide) (PBSLA), two or more simple mixtures, copolymers of the polymer and polyethylene glycol (Polyethylenglycol, PEG), and polymer-sugar complexes in which the polymer or copolymer is bonded to a sugar. In a specific embodiment, in the production method according to the present invention, poly(lactide-co-glycolide) and / or polylactide polymers can be used as biodegradable polymers.

[0030] In this specification, if the first formulation comprises an anti-inflammatory drug and a first drug delivery body, the drug delivery bodies of the first formulation and the second formulation may be the same or different in terms of material, size, dosage form, etc., for example, they may be the same dosage form. For example, the first drug delivery body and the second drug delivery body may each be microspheres having diverse materials and / or sizes.

[0031] The drug delivery body of the first formulation is referred to herein as the first parenteral drug delivery body, and there are no special limitations as long as it satisfies the desired anti-inflammatory drug release properties. The first drug delivery body contained in the anti-inflammatory formulation is preferable if it has low pro-inflammatory properties and / or low content.

[0032] The drug delivery bodies contained in the second formulation may be, but are not limited to, drug delivery bodies used to deliver drugs used for the prevention, improvement, or treatment of disease, and may be causes of inflammation, such as biodegradable polymers and biodegradable lipids.

[0033] Microparticles include microparticles or nanoparticles and are usually manufactured using biodegradable polymers. For example, if the first drug delivery system is a microparticle, it may have an average particle size of, for example, 10 to 100 micrometers. The second drug delivery system may also be a microparticle, specifically a microparticle having an average particle size of 10 to 100 micrometers.

[0034] A specific example of the present invention includes an anti-inflammatory first formulation comprising an anti-inflammatory drug and a first parenteral drug carrier, and a second formulation comprising a second parenteral drug carrier. The first parenteral drug delivery system and the second parenteral drug delivery system comprise a biodegradable substance, wherein the second parenteral drug delivery system is an inflammatory drug delivery system that induces inflammation in a subject. The first anti-inflammatory formulation relates to a parenteral anti-inflammatory kit for preventing, reducing, or treating an inflammatory response in a subject caused by the drug delivery system of the second formulation. The second formulation may further comprise a pharmaceutically active ingredient that is different from the anti-inflammatory drug of the first formulation.

[0035] Furthermore, the first and second anti-inflammatory formulations may be included in a mixed formulation or as separate formulations, or they may be administered at different times or simultaneously.

[0036] The first and second formulations are defined as follows: the solid content of the first formulation may be 0.002 to 20 parts by weight, based on the solid content of the second formulation being 100 parts by weight; specifically, it may be 0.002 to 15 parts by weight, 0.002 to 10 parts by weight, etc., and the second formulation may or may not contain a drug.

[0037] When the first and second formulations are provided as a mixed formulation, the anti-inflammatory drug may be present in an amount of 0.001 to 5.0 w / w% of the mixed formulation's solid content, specifically in amounts of 0.001 to 5.0 w / w%, 0.001 to 4.0 w / w%, 0.001 to 3.0 w / w%, 0.001 to 2.0 w / w%, or 0.001 to 1.0 w / w%.

[0038] If the first and second formulations are provided as a mixed formulation, the first drug delivery body may be present in an amount of 0.002 to 20% by weight, based on 100% by weight of the solid content of the mixed formulation.

[0039] If a parenteral combination drug pharmaceutically kit according to an example of the present invention is for preventing, reducing, or treating an inflammatory response in a target by the parenteral drug carrier of the second formulation, the kit may include an anti-inflammatory drug as the first drug, or an anti-inflammatory first formulation containing an anti-inflammatory drug and a first parenteral drug carrier, and a second formulation in which a second drug different from the anti-inflammatory drug of the first formulation is carried on the second parenteral drug carrier. In this case, the anti-inflammatory first drug contained in the anti-inflammatory first formulation may be released for the same period as the administration interval of the second formulation, or for a portion of the administration interval of the second formulation, to achieve anti-inflammatory efficacy.

[0040] Another example is that the anti-inflammatory drug contained in the first anti-inflammatory formulation may be released at a relatively uniform concentration during the release period, or at a relatively high concentration during an initial or late period, depending on the characteristics required by the second formulation, for example, during an initial period of 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less of the total dosing interval of the second formulation. Another example is that the anti-inflammatory drug contained in the first anti-inflammatory formulation may be released at a concentration proportional to the remaining amount of the parenteral second drug carrier contained in the second formulation. Specifically, based on the 100% by weight content of the second drug carrier contained in the second formulation at the start of administration or before administration, the drug release amount of the first formulation may be released in a gradually decreasing amount in accordance with the relative content (by weight) of the second drug carrier remaining at the administration site.

[0041] Furthermore, if the anti-inflammatory drug contained in the first formulation induces an increase in the target blood glucose level depending on its blood concentration, the upper limit of the anti-inflammatory drug release can be set as the concentration at which the level of increase in blood glucose level becomes an acceptable level, and the lower limit of the anti-inflammatory drug release can be set as the amount effective in preventing, improving, or treating the inflammatory response by the second drug carrier contained in the second formulation. Within the range of the combination of the above upper and lower limits, the range of the anti-inflammatory drug release can be appropriately set.

[0042] In the present invention, the terms “individual” or “subject” include mammals, particularly humans, and the administration plan, administration interval, dosage, etc., can be easily set, changed, or adjusted by the elements mentioned above.

[0043] The present invention involves using an anti-inflammatory first formulation containing an anti-inflammatory drug together with a second formulation containing a drug effective for the prevention, alleviation, or treatment of a disease. This reduces the inflammatory response mediated by the drug carrier of the second formulation at the administration site from the initial inflammatory stage, suppressing progression to chronic inflammation and reducing side effects such as edema, erythema, and tissue hardening at the administration site. This improves patient resistance and satisfaction, and the therapeutic effect can be expected to be improved by administering the parenteral formulation containing the therapeutic agent as a single or repeated dose over the period required for treatment.

[0044] The present invention provides a dosage form that allows inflammation to be suppressed only at the site where the parenteral anti-inflammatory preparation is administered, without side effects from systemic exposure of the anti-inflammatory drug. This is achieved by having a first preparation containing an anti-inflammatory drug at a low concentration sufficient to exert local anti-inflammatory efficacy at the site where inflammation is induced when administered together with the drug, and by continuously maintaining the release of the anti-inflammatory drug until all the drug transporters contained in the second preparation are degraded.

[0045] In this specification, the first anti-inflammatory formulation may contain only an anti-inflammatory drug or may contain an anti-inflammatory drug and a first drug carrier. If the first anti-inflammatory formulation contains an anti-inflammatory drug and a first drug carrier, the anti-inflammatory drug may constitute about 1% to about 90% by weight, about 2% to about 90% by weight, about 5% to about 90% by weight, 10% to about 90% by weight, or about 10% to about 80% by weight, based on 100% by weight of the first drug carrier contained in the first formulation.

[0046] In this specification, when the first drug is carried together with the second drug on a single drug carrier, such as a microparticle, the amount of the first drug contained therein may be about 0.001% by weight, 0.005% by weight, 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.2% by weight, 0.5% by weight, 1% by weight, or 5% by weight of the total drug carrier.

[0047] In this specification, “active ingredient,” “active drug,” “active ingredient,” “active formulation,” “drug,” and “therapeutic formulation” refer to any substance that is interchangeable and used herein to prevent, alleviate, or treat a disease of interest.

[0048] In the present invention, the anti-inflammatory drug contained in the first anti-inflammatory formulation includes, but is not limited to, steroid formulations, compounds, or drugs that, when administered in a pharmaceutically effective amount, prevent, reduce, or treat inflammation, modulate the degradation of drug carriers of the second formulation used in combination, or increase the bioavailability of the second drug used in combination.

[0049] More specifically, the anti-inflammatory drug means a drug that prevents, reduces, or treats an inflammatory response to a target disease, which occurs when a parenteral drug delivery system for delivering a drug for preventing, reducing, or treating the target disease is administered to the target. For example, it may be a drug that prevents, reduces, or treats an inflammatory response that occurs locally at the administration site by a drug delivery system for parenteral delivery of an active ingredient for preventing, reducing, or treating the target disease.

[0050] While non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal analgesics, commonly used in inflammation treatment, can be used to manage inflammation that has already occurred, steroidal anti-inflammatory drugs are preferable because they exert a stronger anti-inflammatory effect even in small amounts, especially when administered together with a therapeutic sustained-release formulation.

[0051] However, in the case of steroidal anti-inflammatory drugs, high plasma drug levels typically lead to systemic side effects such as hypertension, hyperglycemia, osteoporosis, cataracts, glaucoma, and gastric ulcers, as well as tolerance and loss of efficacy with long-term use. Due to these systemic exposure side effects, long-term use of sustained-release injectable formulations containing the therapeutic agent is impossible when administered using existing steroid dosage forms such as oral or intravenous injection, as it induces systemic exposure until the drug is broken down in the body.

[0052] Anti-inflammatory agents include, for example, nonsteroidal anti-inflammatory drugs (NSAIDs), which include, but are not limited to, aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. As an example, anti-inflammatory agents include combinations of two or more NSAIDs.

[0053] For more details, nonsteroidal anti-inflammatory drugs include aceclofenac, acemetacin, aluminoprofen, amfenac, apazone, aspirin, bromfenac, bufexamac, celecoxib, and choline salicylate. salicylate, cinnoxicam, clonixin, dexibuprofen, dexketoprofen, diclofenac, diflunisal, emorfazone, etodolac, etoricoxib, ethenzamide, felbinac, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, imidazole salicylate salicylate, indomethacin, isopropylantipyrine, ketoprofen, ketorolac, lornoxicam, loxoprofen, meclofenamate, meloxicam, mefenamic acid(acid), morniflumate, nabumetone, naproxen, nehopam, nimesulide, oxaprozin, oxyphenbutazone, pelubiprofen, phenylbutazone, piroxicam, pranoprofen, proglumetacin, rofecoxib, salsalate, salicylate, sulindac, talniflumate, tenoxicam, tiaprofenic acid, tolfenamic acid This includes, but is not limited to, tolmetin, valdecoxib, zaltoprofen, and their pharmaceutically acceptable salts.

[0054] Anti-inflammatory agents include drugs that, when administered in prophylactic or therapeutically effective doses, prevent, reduce, or treat inflammation, and may specifically include "steroidal anti-inflammatory agents," "corticoids," or "corticosteroids," and "glucocorticoids." Anti-inflammatory agents may also include combinations of two or more steroidal anti-inflammatory agents.

[0055] Steroidal anti-inflammatory agents that can be used in the present invention include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, crocortol, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoxymethasone, and dexamethasone. Tazone, dexamethasone acetate, dexamethasone phosphate, diflorasone, diflucortrone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortrone, fluorometholone, fluperolone acetate Fluprednisolone acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol acetate This includes, but is not limited to, etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and any derivatives thereof.

[0056] The aforementioned corticosteroids include beclomethasone dipropionate, betamethasone, budesonide, deflazacort, dexamethasone, dexamethasone acetate, dexamethasone phosphate, difluprednate, epinephrine, fludrocortisone, and fluocinolone acetonide. This includes acetonides, fluocortin, fluorometholone, fluticasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and pharmaceutically acceptable salts thereof.

[0057] The second drug, which is the active ingredient contained in the second formulation as described herein, may be, for example, a drug that delivers an active ingredient parenterally for the prevention, mitigation, or treatment of the target disease or condition. The active ingredient that may be contained in the second formulation may differ from the anti-inflammatory drug of the first anti-inflammatory formulation and may be an active ingredient for the prevention, mitigation, or treatment of the target disease or condition.

[0058] Specifically, the types of active ingredients that may be included in the second formulation are not particularly limited, but include, for example: dementia treatments; Parkinson's disease treatments; anticancer drugs; antipsychotic drugs such as anxiolytics, antidepressants, tranquilizers, and psychotropic drugs; cardiovascular drugs such as hyperlipidemia treatments, hypertension treatments, hypotension treatments, antithrombotic drugs, vasodilators, and antiarrhythmic drugs; epilepsy treatments; gastrointestinal treatments such as anti-ulcer drugs; rheumatic drugs; antispasmodics; tuberculosis treatments; muscle relaxants; osteoporosis treatments; erectile dysfunction treatments; hemostatic agents; hormones such as sex hormones; diabetes treatments; antibiotics; antifungal drugs; antiviral drugs; antipyretic, analgesic, and anti-inflammatory drugs; autonomic nervous system regulators; diuretics; antidiuretics; analgesics; antihistamines; antiparasitic drugs; anti-anemia drugs; anti-asthma drugs; anticonvulsants; detoxification agents; anti-migraine drugs; antiemetics; and anti-Parkinson's disease drugs. Drugs; antiepileptic drugs; antiplatelet drugs; cough and expectorant drugs; bronchodilators; cardiac drugs; immunomodulators; protein drugs; gene drugs; and mixtures thereof can be selected, preferably from the group consisting of dementia treatments, Parkinson's disease treatments, anticancer drugs, antipsychotic drugs, hyperlipidemia treatments, hypertension treatments, epilepsy treatments, gastrointestinal treatments, rheumatic drugs, antispasmodics, tuberculosis treatments, muscle relaxants, antiarrhythmic drugs, osteoporosis treatments, erectile dysfunction treatments, hemostatic agents, antiviral drugs, hormones, antibiotics, diabetes treatments, antifungal drugs, antithrombotic drugs, antipyretic, analgesic, and anti-inflammatory drugs and mixtures thereof.

[0059] Furthermore, the active ingredient that can be included in the second formulation may be a small molecule compound, protein, antibody, synthetic compound, nucleic acid molecule, or peptide. The nucleic acid molecule may be one or more selected from the group consisting of DNA, RNA, microRNA (miRNA), small RNA (smRNA), small interfering RNA (siRNA), piRNA (piRNA), small nucleolar RNA (snoRNA), tRNA-derived small RNA (tsRNA), small rDNA-derived RNA (srRNA), micronuclear RNA (U-RNA), and long noncoding RNA (lncRNA).

[0060] Of the types of drugs mentioned above, there are no particular limitations, but preferably donepezil, memantine, rivastigmine, entecavir, lamivudine, rotigotine, ropinirole, buprenorphine, fentanyl, nimodipine, granisetron, cytarabine, carmustine, tamsoycin, pharmacoxib, testosterone, estradiol, risperidone, paliperidone, olanzapine, aripiprazole, gothicone The following can be selected: relin, leuprolide, triptorelin, buserelin, napalerin, deslorerin, octreotide, pasireotide, lanreotide, valpretide, exenatide, liraglutide, lixisenatide, semaglutide, 5-α-reductase inhibitors (e.g., finasteride, dutasteride), tirzepatide, dulaglutide, insulin glargine, insulin degludec, insulin icodec, cagrilintide and salts thereof, and mixtures of two or more of these.

[0061] A pharmaceutical kit for parenteral co-administration according to an example of the present invention may further contain a local anesthetic component in addition to the anti-inflammatory first formulation and / or the second formulation. The local anesthetic component can be used as is with the first formulation, the second formulation, or a mixed formulation of the first and second formulations, or it can be used on a suitable separate drug delivery system.

[0062] Another example of the present invention relates to a parenteral combination drug administration pharmaceutical kit for regulating the degradation of parenteral drug carriers of an anti-inflammatory drug and a second formulation used in combination therewith, specifically comprising an anti-inflammatory drug first, or a first formulation comprising an anti-inflammatory drug first and a first parenteral drug carrier, and a second formulation comprising a parenteral drug carrier second, wherein the first parenteral drug carrier and the second parenteral drug carrier comprise biodegradable polymers. The first formulation or the drug contained in the first formulation modulates the degradation rate of the second parenteral drug delivery system, and relates to a parenteral concomitant administration pharmaceutical kit, parenteral formulation, or kit.

[0063] The second formulation may further contain a pharmaceutically active ingredient different from the anti-inflammatory drug of the first formulation, and the description of the second formulation is as described above.

[0064] The first formulation, or the anti-inflammatory drug contained in the first formulation, can regulate the rate of degradation of the second parenteral drug delivery system, thereby regulating the rate of drug release contained in the second formulation. Regulating the rate of degradation of the second parenteral drug delivery system may preferably involve reducing the rate of degradation of the second parenteral drug delivery system to extend the drug release period.

[0065] The anti-inflammatory drug contained in the first formulation is as described above, and may, but is not limited to, dexamethasone free base, dexamethasone acetate, or dexamethasone phosphate.

[0066] Furthermore, in a parenteral co-administration pharmaceutical kit for adjusting the degradation rate of the second parenteral drug delivery system, the first and second formulations may be included as a mixed formulation or individual formulations, or they may be administered at different times or simultaneously.

[0067] The first and second formulations may contain 0.002 to 20 parts by weight of solids in the first formulation, based on a solids content of 100 parts by weight of the second formulation, and the second formulation may or may not contain a drug.

[0068] When the first and second formulations are provided as a mixed formulation, the anti-inflammatory drug may be contained in an amount of 0.001 to 5.0 w / w% of the weight, based on 100% by weight of the solid content of the mixed formulation.

[0069] In this specification, if the first formulation comprises an anti-inflammatory drug and a first drug carrier, and the second formulation comprises an anti-inflammatory drug and a second drug carrier, and the first and second formulations are provided as a mixed formulation, the first drug carrier may be present in an amount of 0.002 to 20 w / w% of weight, based on 100% by weight of the solids content of the mixed formulation.

[0070] An example of a parenteral pharmaceutical kit according to the present invention may include a first formulation containing a first drug and a first parenteral drug carrier, and a second formulation containing a pharmaceutically active ingredient and a second parenteral drug carrier, which is different from the first drug in the first formulation. In this case, the first drug contained in the first formulation may be released during the same period as the administration interval of the second formulation, or during a portion of the administration interval of the second formulation, to achieve the desired efficacy. Another example is that the first drug contained in the first formulation may be released uniformly at a constant concentration during the release period, or it may be released at relatively high or low concentrations at certain times, for example, during an initial period of 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less of the total administration interval of the second formulation, depending on the characteristics required by the second formulation, thus having non-uniform release characteristics. In another example, the first drug contained in the first formulation may be released at a concentration proportional to the remaining amount of the parenteral drug delivery system in the second formulation. Specifically, based on the 100% by weight content of the second drug delivery system contained in the second formulation at the start of administration or before administration, the drug released from the first formulation may be released in a content that gradually decreases in accordance with the relative content (by weight) of the second drug delivery system remaining at the administration site.

[0071] Furthermore, if the anti-inflammatory drug contained in the first formulation induces an increase in the target blood glucose level depending on its blood concentration, the upper limit of the anti-inflammatory drug release can be set as the concentration at which the increase in blood glucose level becomes an acceptable level, and the lower limit of the anti-inflammatory drug release can be set as the amount effective in preventing, improving, or treating the inflammatory response by the second drug carrier contained in the second formulation. Within the range of the combination of the above upper and lower limits, the range of the anti-inflammatory drug release can be appropriately set.

[0072] Furthermore, the material, dosage form, and characteristics of the drug delivery body are as described above, and the active ingredients that can be included in the second formulation are also as described above.

[0073] An example of the present invention relates to a parenteral combination drug administration pharmaceutical kit or formulation comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug carrier, wherein the first formulation contains an anti-inflammatory first drug or an anti-inflammatory first drug supported on a first parenteral drug carrier, the second formulation contains a second parenteral drug carrier and a second drug different from the drug in the first formulation, and the first formulation is intended to increase the bioavailability of the second drug contained in the second formulation.

[0074] In the present invention, the first formulation, which includes an anti-inflammatory drug or an anti-inflammatory drug supported on a first parenteral drug carrier, is a regulator or enhancer of the bioavailability of the second drug.

[0075] In this specification, the term "bioavailability" refers to the portion of a drug dose that reaches the systemic circulation unchanged and is one of the main pharmacokinetic properties of a drug. When a drug is administered intravenously, its bioavailability is 100%. When a drug is administered via a different route (e.g., orally), its bioavailability is generally reduced and can vary from patient to patient. Bioavailability is an important pharmacokinetic variable to consider when calculating doses for non-intravenous routes of administration.

[0076] The parenteral combination drug pharmacologic kit of the present invention requires a smaller drug dose compared to a mono-dosage form of the second formulation without the first formulation containing the first drug, and can improve the pharmacokinetic profile and efficacy of the second drug.

[0077] The improved bioavailability according to the present invention allows drugs previously used for intramuscular injection to be changed to a subcutaneous injection dosage form, or to be formulated with a reduced drug content. In other words, toxicity-related side effects can be reduced with fewer doses or lower dosages. Generally, the pharmacokinetics and / or pharmacodynamics of subcutaneous therapy are improved and have advantages over current intramuscular injections. For example, subcutaneous injections can be administered by the patient or a family member and can be performed at home or anywhere. The improved bioavailability according to the present invention has advantages such as changing the route of administration of a second formulation, reducing the dosage, and / or reducing the frequency of administration. Furthermore, the improved bioavailability allows for a reduction in the effective amount of drug or the drug content loaded into a unit formulation, changing the route of administration from intramuscular injection to a subcutaneous injection, reducing the frequency of administration, and improving patient drug adaptation.

[0078] The term "effective dose" refers to the amount of a therapeutic compound that is effective in achieving the desired therapeutic or preventive outcome during the required period of administration. The "therapeutic effective dose" of a therapeutic compound can vary depending on factors such as the individual's disease state, age, sex, and weight, and the drug's ability to induce the desired response in the individual.

[0079] As a specific example, the applications of increasing, improving, or enhancing the bioavailability of the second drug according to the present invention include an increase in Cmax and / or AUC. For example, a combination therapy pharmaceutical kit containing the first and second drugs means an increase in the Cmax and / or AUC of the second drug compared to a single dosage form of the second drug without the first drug. More specifically, compared to a single dosage form of the second drug, a combination therapy pharmaceutical kit containing the first drug and the second drug in the same dosage form as the single dosage form may have a Cmax of 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 2.0 times or more, and / or an AUC of 120% or more, 130% or more, 150% or more, 200% or more, 250% or more, or 300% or more.

[0080] The material, dosage form, and properties of the drug delivery body are as described above, and the active ingredients that can be included in the second formulation are also as described above. Furthermore, the application of the present invention for improving bioavailability is to improve the bioavailability of the second drug contained in the second formulation described above. Specific examples of the second drug include, but are not limited to, donepezil, rivastigmine, semaglutide, leuprolide, octreotide, and finasteride.

[0081] A specific example of the present invention relates to a parenteral co-administration pharmaceutical kit that uses an anti-inflammatory drug in the first formulation to improve the bioavailability of a co-administered drug (the drug in the second formulation).

[0082] Parenteral formulations, such as microgranular formulations, are known to support drugs with biodegradable polymers for long-term drug release. However, drugs encapsulated in microgranular cells have low bioavailability, and large quantities of microgranular cells must be administered to exhibit long-term effective pharmacological effects. However, administering large quantities of microgranular cells into the body presents problems such as difficulty in subcutaneous injection, making it difficult for patients to administer them directly (self-administration), and also resulting in very high pain and inflammatory reactions at the injection site. Therefore, this invention relates to a parenteral combination administration pharmaceutical kit comprising a second formulation containing a drug or a pharmaceutically acceptable salt thereof and a biodegradable polymer, which improves the bioavailability of the drug and exhibits stable drug release characteristics over a long period, and the first formulation.

[0083] More specifically, an example of the present invention relates to a parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug or a pharmaceutically acceptable salt thereof and a parenteral drug carrier as the second drug, wherein the first formulation contains an anti-inflammatory first drug or an anti-inflammatory first drug supported on a first parenteral drug carrier, and the second formulation contains a second parenteral drug carrier and the drug or a pharmaceutically acceptable salt thereof as the drug of the second formulation, and the first formulation is for increasing or improving the bioavailability of the drug contained in the second formulation. In the present invention, the first formulation containing an anti-inflammatory first drug or an anti-inflammatory first drug supported on a first parenteral drug carrier is a regulator or enhancer of the bioavailability of the second drug.

[0084] If the first drug included in the pharmaceutical kit is provided without a separate drug delivery system, the first drug may be provided in the form of a mixed formulation of a second formulation containing a second parenteral drug delivery system and the second drug, or the first drug may be provided separately at a different time from the second formulation. Specifically, if the second formulation is a microparticle, the first drug may be provided in a form supported on a single microparticle together with the second drug.

[0085] Alternatively, the first drug contained in the pharmaceutical kit may be provided in a form supported on a separate first drug delivery body, which may be the same as or different from the second drug delivery body. Specifically, if the first formulation contains the first drug supported on a first parenteral drug delivery body, it may be provided in the form of a mixed formulation with the second formulation or as separate formulations, and may be administered to subjects requiring it simultaneously or at different times.

[0086] In the example described above, the descriptions of the first formulation, the first drug contained in the first formulation, the first parenteral drug carrier that may be contained in the first formulation, and / or the second parenteral drug carrier contained in the second formulation are as described above. Furthermore, the descriptions of bioavailability, modifiers or enhancers of the bioavailability of the second drug, etc., are as described above.

[0087] The parenteral combination drug pharmacologic kit according to the present invention can also be administered parenterally, for example, by subcutaneous injection. The second formulation may consist of a drug portion and a solvent portion used to suspend the drug, and may be in the form of a double-chamber syringe containing the drug portion in one chamber and the solvent portion in the other chamber, or a pre-filled syringe in which the drug portion is suspended in the solvent portion. When configured in this pre-filled syringe form in which the drug portion is suspended in the solvent portion, the solvent portion used may be an injectable oil containing medium-chain oil, mineral oil, etc.

[0088] An example of a drug administered concomitantly with the aforementioned kit may be an active ingredient contained in the second formulation described above, and can be specifically selected from the group consisting of semaglutide, donepezil, rivastigmine, finasteride, octreotide, leuprolide, deslorerin, entecavir, salts and derivatives thereof, and mixtures of two or more thereof.

[0089] For example, a pharmaceutically acceptable salt of semaglutide may be a sodium salt, nitrate, benzoate, hydroxynaphthoate, napadisylate, or pamoate of semaglutide. The pharmaceutically acceptable salt may be leuprolide acetate, the salt of tonepezil may be donepezil hydrochloride, and the pharmaceutically acceptable salt of rivastigmine may be rivastigmine tartrate, rivastigmine pamoate, other octreotide acetates, deslorerin acetate, etc.

[0090] The anti-inflammatory drug of the first formulation included in the kit may be the active ingredient included in the first formulation described above, and can be specifically selected from the group consisting of dexamethasone, meloxicam, ketorolac, salts thereof, derivatives, and mixtures of two or more thereof. In particular, dexamethasone and its derivatives include, but are not limited to, dexamethasone, dexamethasone acetate, and dexamethasone phosphate.

[0091] A parenteral combination drug pharmaceutically kit containing a second drug and / or a pharmaceutically acceptable salt thereof, according to a specific example of the present invention, can contain a high content of the second drug relative to its particle size, and has the advantage of minimizing potential patient pain and inflammatory responses during administration, as it allows for a reduction in the unit dose while exhibiting high bioavailability and long-lasting effects in the body.

[0092] The parenteral co-administration pharmaceutical kit containing the second drug and / or a pharmaceutically acceptable salt thereof has a higher drug content compared to the microgranule content, while suppressing the initial excessive release of the drug that could lead to fatal side effects, and exhibits high bioavailability, allowing it to sufficiently exert its therapeutic effect over the desired period to improve, prevent, or treat the disease.

[0093] Furthermore, the improvement in the bioavailability of the second drug according to the present invention is excellent in terms of maintaining drug concentration based on the drug administration interval, as it can maintain an effective drug concentration even near the end of the unit administration period. For example, if the second drug is leuprolide, the improvement in bioavailability according to the present invention can resolve the inflammation problem caused by the administration of the second formulation, and can particularly improve the side effect of a rapid increase in testosterone levels (surge) that occurs when the drug concentration decreases over a certain period around the end of the unit administration period, that is, around the start of the next dose.

[0094] As a specific example, the applications of increasing, improving, or enhancing the bioavailability of the second drug according to the present invention include an increase in Cmax and / or AUC. For example, a combination therapy pharmaceutical kit containing the first and second drugs means an increase in the Cmax and / or AUC of the second drug compared to a single dosage form of the second drug without the first drug. More specifically, compared to a single dosage form of the second drug, a combination therapy pharmaceutical kit containing the same second and first drugs as the single dosage form may have a Cmax of 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 2.0 times or more, and / or an AUC of 120% or more, 130% or more, 150% or more, 200% or more, 250% or more, or 300% or more.

[0095] More specifically, when the second drug is semaglutide, it is useful for the prevention or treatment of diabetes, specifically type 2 diabetes, preservation of β-cell function, hypertension, hyperlipidemia, obesity, non-alcoholic fatty liver disease, or degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease. In a parenteral co-administration pharmaceutical kit containing the semaglutide and / or a pharmaceutically acceptable salt thereof, the content of the second drug may be 5% or more by weight, 8% or more by weight, 9% or more by weight, 9.5% or more by weight, or 10% or more by weight, for example, 5 to 20% by weight. In addition, in a parenteral co-administration pharmaceutical kit, the unit dose of the second preparation (e.g., microparticles containing biocompatible polymers) containing the semaglutide and / or a pharmaceutically acceptable salt thereof and a parenteral drug carrier may be 10 to 800 mg.

[0096] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, a derivative thereof, or a salt thereof, and the drug of the second formulation is semaglutide or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, semaglutide (free base), in a parenteral combination administration pharmaceutical kit containing all of the first and second formulations may be in the range of 0.0001:1 to 1:1. Preferably, it may be in the range of 0.004:1 to 0.2:1. More preferably, it may be in the range of 0.001:1 to 0.05:1.

[0097] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, a derivative thereof, or a salt thereof, and the drug of the second formulation is donepezil or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, donepezil (free base), in a parenteral combination administration pharmaceutical kit containing all of the first and second formulations may be in the range of 0.00003:1 to 0.02:1. Preferably, it may be in the range of 0.00006:1 to 0.001:1. More preferably, it may be in the range of 0.0001:1 to 0.005:1.

[0098] If the second drug is donepezil, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 25-75% by weight or 27-75% by weight, based on 100% by weight of the entire second formulation containing the second drug and the second parenteral drug carrier. In addition, the unit dose of the second formulation (e.g., microparticles containing biocompatible polymers) containing donepezil and / or a pharmaceutically acceptable salt thereof and a parenteral drug carrier in the parenteral co-administration pharmaceutical kit may be 50-1,200 mg.

[0099] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, its derivatives or salts thereof, and the drug of the second formulation is rivastigmine or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, rivastigmine (free base), in a parenteral co-administration pharmaceutical kit containing all of the first and second formulations may be in the range of 0.0005:1 to 0.2:1. Preferably, it may be in the range of 0.0001:1 to 0.1:1. More preferably, it may be in the range of 0.00015:1 to 0.05:1.

[0100] If the second drug is rivastigmine, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 15-45% or 20-40% by weight, based on 100% by weight of the entire second preparation containing the second drug and the second parenteral drug carrier. In addition, the unit dose of the second preparation (e.g., microparticles containing biocompatible polymers) containing rivastigmine and / or a pharmaceutically acceptable salt thereof and a parenteral drug carrier in the parenteral co-administration pharmaceutical kit may be 20-900 mg.

[0101] If the second drug is finasteride, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 20-75% by weight or 30-70% by weight, based on 100% by weight of the entire second preparation containing the second drug and the second parenteral drug carrier. In addition, the unit dose of the second preparation (e.g., microparticles containing biocompatible polymers) containing finasteride and / or a pharmaceutically acceptable salt thereof and the parenteral drug carrier in the parenteral co-administration pharmaceutical kit may be 15-450 mg or 20-300 mg.

[0102] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, a derivative thereof, or a salt thereof, and the drug of the second formulation is finasteride or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, finasteride (free base), in a parenteral combination drug pharmacochemical kit containing both the first and second formulations may be in the range of 0.0003:1 to 0.3:1. Preferably, it may be in the range of 0.0006:1 to 0.15:1. More preferably, it may be in the range of 0.0009:1 to 0.1:1.

[0103] If the second drug is octreotide, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 15-45% by weight or 20-40% by weight, based on 100% by weight of the entire second formulation containing the second drug and the second parenteral drug carrier. In addition, the unit dose of the second formulation (e.g., microparticles containing biocompatible polymers) containing the octreotide and / or a pharmaceutically acceptable salt thereof and the parenteral drug carrier in the parenteral co-administration pharmaceutical kit may be 20-300 mg or 20-600 mg.

[0104] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, a derivative thereof, or a salt thereof, and the drug of the second formulation is octreotide or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, octreotide (free base), in a parenteral combination drug pharmacochemical kit containing both the first and second formulations may be in the range of 0.0003:1 to 0.6:1. Preferably, it may be in the range of 0.0006:1 to 0.3:1. More preferably, it may be in the range of 0.0009:1 to 0.15:1.

[0105] If the second drug is leuprolide, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 5-25% by weight or 10-20% by weight, based on 100% by weight of the entire second formulation containing the second drug and the second parenteral drug delivery system. In addition, the unit dose of the second formulation (e.g., microparticles containing biocompatible polymers) containing leuprolide and / or a pharmaceutically acceptable salt thereof and the parenteral drug delivery system in the parenteral co-administration pharmaceutical kit may be 15-230 mg or 18-225 mg.

[0106] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, its derivatives or salts thereof, and the drug of the second formulation is leuprolide or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, leuprolide (free base), in a parenteral combination drug pharmacochemical kit containing both the first and second formulations may be in the range of 0.0001:1 to 0.6:1. Preferably, it may be in the range of 0.0002:1 to 0.3:1. More preferably, it may be in the range of 0.0003:1 to 0.15:1.

[0107] If the second drug is entecavir, the content of the second drug in the parenteral co-administration pharmaceutical kit may be 15-35% by weight or 20-35% by weight, based on 100% by weight of the entire second formulation containing the second drug and the second parenteral drug carrier. In addition, the unit dose of the second formulation (e.g., microparticles containing biocompatible polymers) containing entecavir and / or a pharmaceutically acceptable salt thereof and a parenteral drug carrier in the parenteral co-administration pharmaceutical kit may be 45-1,200 mg.

[0108] As an example of the present invention, when the anti-inflammatory drug of the first formulation is dexamethasone, a derivative thereof, or a salt thereof, and the drug of the second formulation is entecavir or a salt thereof, the weight ratio of the first drug, dexamethasone (free base), to the second drug, entecavir (free base), in a parenteral combination drug pharmacochemical kit containing both the first and second formulations may be in the range of 0.00015:1 to 0.2:1. Preferably, it may be in the range of 0.0003:1 to 0.1:1. More preferably, it may be in the range of 0.0006:1 to 0.05:1.

[0109] In one example according to the present invention, if the first drug delivery system contained in the first anti-inflammatory formulation is a microparticle, or the second drug delivery system contained in the second formulation is a microparticle, it can be manufactured using, but is not limited to, methods for producing microparticles known to the art, such as solvent extraction and evaporation or spray drying. Preferably, the dexamethasone sustained-release microparticles according to the present invention can be manufactured, for example, using the O / W method, W / O / W method, or S / O / W method.

[0110] When the first formulation according to the present invention is a microsphere containing an anti-inflammatory drug, the method for producing it can be carried out by the S / O / W method, and specifically includes the steps of (a1) homogeneously dispersing an anti-inflammatory drug, such as dexamethasone particles, in a solution in which a biocompatible polymer is dissolved to produce a dispersed phase; (b1) adding the dispersed phase produced in step (a1) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion; (c1) extracting and evaporating an organic solvent from the dispersed phase in the emulsion state produced in step (b1) in the continuous phase to form microspheres; and (d1) recovering the microspheres from the continuous phase in step (c1) to produce sustained-release microspheres containing dexamethasone.

[0111] When the first formulation according to the present invention is a microparticle containing an anti-inflammatory drug, it can be carried out by the W / O / W method, and specifically includes the steps of (a2) preparing a W1 phase by dissolving an anti-inflammatory drug, such as dexamethasone, in distilled water, preparing an oil phase by dissolving a biocompatible polymer in a water-insoluble organic solvent, and homogeneously dispersing the W1 phase in the oil phase to produce a dispersed phase which is a primary emulsion; (b2) adding the dispersed phase produced in step (a2) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion; (c2) extracting and evaporating the organic solvent from the dispersed phase in the emulsion state produced in step (b) in the continuous phase to form microparticles; and (d2) recovering the microparticles from the continuous phase in step (c2) to produce sustained-release microparticles containing dexamethasone.

[0112] The method for producing dexamethasone sustained-release microspheres according to the present invention can be carried out by the O / W method and specifically includes (a3) ​​the step of dissolving a biocompatible polymer and an anti-inflammatory drug, such as dexamethasone, in an organic solvent to produce a dispersed phase; (b3) the step of adding the dispersed phase produced in step (a3) ​​to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion; (c) the step of extracting and evaporating the organic solvent from the emulsion-like dispersed phase produced in step (b) using a continuous phase to form microspheres; and (d3) the step of recovering the microspheres from the continuous phase in step (c3) to produce sustained-release microspheres containing dexamethasone.

[0113] In the method for producing dexamethasone microparticles according to the present invention, the biocompatible polymer or biodegradable polymer in step (a) above may be a biodegradable polymer having an intrinsic viscosity of 0.16-1.9 dL / g, or 0.10-1.3 dL / g, preferably 0.16 dL / g-0.75 dL / g, taking into consideration factors such as the drug release characteristics and the manufacturing process. The intrinsic viscosity is measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer.

[0114] In one example according to the present invention, if the second drug delivery body contained in the second formulation is a microparticle, it can be manufactured using a method for producing microparticles known to the art, such as solvent extraction and evaporation or spray drying, but is not limited thereto. Preferably, the drug microparticles of the second formulation according to the present invention can be manufactured using, for example, an O / W method, a W / O / W method, or a S / O / W method.

[0115] The method for producing drug microspheres of the second formulation according to the present invention can be carried out by the S / O / W method and specifically includes (a4) the step of homogeneously dispersing drug particles in a solution in which a biocompatible polymer is dissolved to produce a dispersed phase; (b4) the step of adding the dispersed phase produced in step (a4) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion; (c4) the step of extracting and evaporating an organic solvent from the dispersed phase in the emulsion state produced in step (b) using a continuous phase to form microspheres; and (d4) the step of recovering the microspheres from the continuous phase in step (c4) to produce sustained-release microspheres containing the drug of the second formulation.

[0116] The method for producing sustained-release drug microspheres of the second formulation according to the present invention can be carried out by the W / O / W method, and specifically includes the steps of (a5) dissolving a drug in distilled water to prepare a W1 phase, dissolving a biocompatible polymer in a water-insoluble organic solvent to prepare an oil phase, homogeneously dispersing the W1 phase in the oil phase to produce a dispersed phase which is a primary emulsion, (b5) adding the dispersed phase produced in step (a5) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion, (c5) extracting and evaporating the organic solvent from the dispersed phase in the emulsion state produced in step (b5) in the continuous phase to form microspheres, and (d5) recovering the microspheres from the continuous phase in step (c5) to produce sustained-release microspheres containing the drug of the second formulation.

[0117] The method for producing drug microparticles of the second formulation according to the present invention can be carried out by the O / W method and specifically includes (a6) the step of dissolving a biocompatible polymer and a drug in an organic solvent to produce a dispersed phase, (b6) the step of adding the dispersed phase produced in step (a6) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion, (c6) the step of extracting and evaporating the organic solvent from the emulsion-like dispersed phase produced in step (b6) in the continuous phase to form microparticles, and (d6) the step of recovering the microparticles from the continuous phase in step (c6) to produce sustained-release microparticles containing a drug.

[0118] Furthermore, in one example according to the present invention, if the first drug of the first formulation and the second drug of the second formulation are both supported on a single drug transporter, specifically on the second drug transporter, and the second drug transporter is a microbulb, then the method for producing the microbulb can also be the microbulb production method for the first formulation or the microbulb production method for the second formulation.

[0119] In one example according to the present invention, when a mixed formulation of a second drug containing a second parenteral drug delivery system and a first anti-inflammatory drug is in the form of microspheres, it is manufactured in substantially the same manner as the second drug delivery system, except that the first anti-inflammatory drug is included in the dispersed phase along with the second drug during the dispersed phase manufacturing stage. In a specific example, a dispersed phase was prepared by dissolving leuprolide acetate, the second drug, and dexamethasone acetate, the first drug, in dichloromethane and methyl alcohol. This was added to a continuous phase containing a surfactant to produce microspheres containing leuprolide and dexamethasone acetate, which were then freeze-dried.

[0120] In more detail, the method for producing microspheres according to the present invention includes the step of adding the dispersed phase produced in step (a) to an aqueous solution phase (continuous phase) containing a surfactant to produce an emulsion.

[0121] In the drug granule production method according to the present invention, the biocompatible polymer or biodegradable polymer in step (a) above may be a biodegradable polymer having an intrinsic viscosity of 0.16-1.9 dL / g, or 0.10-1.3 dL / g, preferably 0.16 dL / g-0.75 dL / g, taking into consideration factors such as the drug release characteristics and the manufacturing process. The intrinsic viscosity is measured at a concentration of 0.1% (w / v) in chloroform at 25°C using an Ubbelohde viscometer.

[0122] In step (b) above, the amount of surfactant in the continuous phase containing the surfactant may be 0.01% to 20% by weight, preferably 0.1% to 5% by weight, based on the total volume of the continuous phase containing the surfactant. If the amount of surfactant is less than 0.01% by weight, droplet-shaped dispersed phases or emulsions may not be formed in the continuous phase, and if the amount of surfactant exceeds 20% by weight, it may be difficult to remove the surfactant after fine particles have been formed in the continuous phase due to the excess surfactant.

[0123] The method for homogeneously mixing the biodegradable polymer solution in which the drug is dispersed and the continuous phase containing the surfactant in step (b) is not particularly limited, but can be carried out using a high-speed stirrer, an in-line mixer, an ultrasonic disperser, a static mixer, a membrane emulsion method, a microfluidic emulsion method, etc. When forming an emulsion using a high-speed stirrer, an in-line mixer, an ultrasonic disperser, or a static mixer, it is difficult to obtain a uniform emulsion, so it is preferable to perform an additional particle size sorting step between steps (c) and (d) described later.

[0124] Sodium chloride can be added to the continuous phase containing the surfactant to prevent the leakage of the drug from the emulsion formed in step (b).

[0125] The present invention provides a method for producing drug microbulbs, comprising: (c) extracting and evaporating an organic solvent from the emulsion-like dispersed phase produced in step (b) using a continuous phase to form microbulbs; and (d) recovering the microbulbs from the continuous phase of step (c) to produce sustained-release microbulbs containing a first drug and / or a second drug.

[0126] In step (c) above, if the emulsion comprising the droplet-form dispersed phase and the continuous phase containing the surfactant is maintained or stirred at a temperature below the boiling point of the organic solvent for a certain period of time, for example, 2 to 48 hours, the organic solvent can be extracted in the continuous phase from the biocompatible polymer solution in which the droplet-form drug is dispersed. Some of the organic solvent extracted in the continuous phase can evaporate from the surface of the emulsion. As the organic solvent is extracted and evaporated from the biocompatible polymer solution in which the droplet-form drug is dispersed, the droplet-form dispersed phase can solidify to form microspheres.

[0127] In step (c) above, the temperature of the continuous phase can be increased for a certain period of time in order to further efficiently remove the organic solvent.

[0128] In step (c) above, ethanol can be added to the continuous phase to further efficiently remove the organic solvent.

[0129] In step (c) above, the temperature of the continuous phase can be further adjusted to modify the surface of the microparticles in order to regulate the initial release of the drug from the sustained-release microparticles. When the temperature of the continuous phase is adjusted by applying heat for this purpose, the lower limit of the temperature range can be set to 30°C or the glass transition temperature of the polymer, and the upper limit can be set to a temperature 30°C higher than the glass transition temperature of the biocompatible polymer (polymer Tg + 30°C), and the temperature can be adjusted within a numerical range that combines the lower and upper limits.

[0130] In step (d) above, the method for recovering the sustained-release microspheres can be carried out using a variety of known techniques, such as filtration or centrifugation.

[0131] Between steps (c) and (d), any remaining surfactant can be removed by filtration and washing, and the fine particles can be recovered by filtration again. The washing step to remove any remaining surfactant can usually be performed using water, and this washing step can be repeated several times.

[0132] The present invention provides a method for producing sustained-release microbulbs containing a drug, in which, after step (d) or after the filtration and washing step, the obtained microbulbs can be dried using a conventional drying method to obtain ultimately dried microbulbs.

[0133] When the first and / or second formulations are in microbulbous dosage form, the same or different polymers may be used, and the weight-average molecular weight of the usable biodegradable polymer is not particularly limited, but its lower limit may be 5,000 or more, preferably 10,000 or more, and its upper limit may be 500,000 or less, preferably 200,000 or less.

[0134] The type of biodegradable polymer is not particularly limited and is as described above. For example, the biodegradable polymer may be one or more selected from the group consisting of polyethylene glycol-poly(lactide-co-glycolide) block copolymer, polyethylene glycol-polylactide block copolymer, polyethylene glycol-polycaprolactone block copolymer, polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide) glycol, polycaprolactone, and mixtures thereof. More specifically, polylactide, poly(lactide-co-glycolide), and polycaprolactone can be used. When poly(lactide-co-glycolide) is used as the biodegradable polymer, the molar ratio of lactic acid to glycolic acid in the copolymer may be 99:1 to 50:50, preferably 50:50, 75:25, or 85:15.

[0135] If the biodegradable polymers include two or more types, the exemplified polymers may be a combination or blend of polymers of different types, or they may be a combination of polymers of the same type having different intrinsic viscosities and / or monomer ratios (for example, a combination or blend of two or more poly(lactide-co-glycolide) having different intrinsic viscosities), or they may be polymers of the same type with different terminal groups (for example, terminal groups being esters or terminal groups being acids).

[0136] Examples of commercially available biodegradable polymers that can be used in this invention include Evonik's Resomer series RG 502H, RG 503H, RG 504H, and RG 502, RG 503, RG 504, RG 653H, RG 752H, RG 752S, 753H, 753S, RG 755S, RG 756S, RG858S, R202H, R203H, R205H, R202S, R203S, R205S, Corbion PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, PDLG 7504A, PDLG 7504, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A, PDLG 5004, PDLG 5010, PL 10, PL 18, PL 24, PL 32, PL 38, PDL Examples include, but are not limited to, 20, PDL 45, PC 02, PC 04, PC 12, PC 17, PC 24, etc., either alone, in combination, or blended. A person skilled in the art can appropriately select the suitable molecular weight of the biodegradable polymer and the blending ratio, taking into consideration the degradation rate of the biodegradable polymer and the resulting drug release rate. In one specific example, Resomer R755S (iv=0.50-0.70 dL / g; manufacturer: Evonik, Germany) or Resomer R752H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) can be used to produce the microparticles according to the present invention. Alternatively, Resomer R 205S (iv=0.55-0.75 dL / g; manufacturer: Evonik, Germany) or Purasorb PDLG 7502A (iv=0.16-0.24 dL / g; manufacturer: Purac, Netherlands) can be used as the specific polymer. [Effects of the Invention]

[0137] The present invention provides parenteral anti-inflammatory formulations for preventing, reducing, or treating inflammatory responses caused by pharmaceutical products administered parenterally into the body, or provides parenteral formulations or kits containing a drug that can regulate the release rate of a formulation containing a parenteral second drug carrier or increase the bioavailability of the second drug. [Brief explanation of the drawing]

[0138] [Figure 1] This graph shows the improvement in the bioavailability of a formulation containing leuprolide, as illustrated by Example 2. [Figure 2] This image shows the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation at the injection site of placebo microglobulins (which do not contain any drug) in experimental animals. The injection site was then stained with HE (hematoxylin-eosin) to check for inflammation. [Figure 3a] These images show the results of subcutaneous injection of drug-free Placebo microglobulins and dexamethasone anti-inflammatory microglobulins into experimental animals. After staining the injection site with HE (hematoxylin·Eosin) to check for inflammation, the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was observed using a light microscope. [Figure 3b] These images show the results of subcutaneous injection of drug-free Placebo microglobulins and dexamethasone anti-inflammatory microglobulins into experimental animals. After staining the injection site with HE (hematoxylin·Eosin) to check for inflammation, the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was observed using a light microscope. [Figure 4a] This is a pharmacokinetic graph showing the drug release pattern over time in the bloodstream after subcutaneous injection of the first formulation, anti-inflammatory microgranules, into experimental animals. [Figure 4b] This is a pharmacokinetic graph showing the drug release pattern over time in the bloodstream after subcutaneous injection of the first formulation, anti-inflammatory microgranules, into experimental animals. [Figure 4c] This is a pharmacokinetic graph showing the drug release pattern over time in the bloodstream after subcutaneous injection of the first formulation, anti-inflammatory microglobulins, into experimental animals. [Figure 5a] This photograph shows the results of subcutaneous injection of drug-free Placebo microglobulins and anti-inflammatory microglobulins into experimental animals. After staining the injection site with HE (hematoxylin·Eosin) to check for inflammation, the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was confirmed using a light microscope. [Figure 5b] This photograph shows the results of subcutaneous injection of drug-free Placebo microglobulins and anti-inflammatory microglobulins into experimental animals. After staining the injection site with HE (hematoxylin·Eosin) to check for inflammation, the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was confirmed using a light microscope. [Figure 6] This image shows the extent of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation observed at the injection site after subcutaneous injection of both leuprolide microglobulins and anti-inflammatory microglobulins into experimental animals, followed by HE (hematoxylin·Eosin) staining of the injection site. [Figure 7] This document presents the results of preparing histopathology slides from experimental groups G15-G20 to confirm the infiltration of inflammatory cells. [Figure 8] This is an indicator of systemic inflammatory response, and the results were obtained by confirming the concentration of TGF-β2 in the blood using the ELISA method. [Figure 9] These are photographs showing residual microglobulins at the injection site after administering placebo microglobulins alone or a combination of placebo microglobulins and anti-inflammatory microglobulins to experimental animals. [Figure 10] This photograph shows residual microglobulins observed at the administration site after administering leuprolide microglobulins alone or a mixture of leuprolide microglobulins and dexamethasone microglobulins to experimental animals. [Figure 11] This graph shows the measured blood concentration of donepezil from experimental animals using LC-MS / MS. [Figure 12] This graph shows the blood rivastigmine concentration measured using LC-MS / MS after collecting blood from experimental animals. [Figure 13] This graph shows the concentration of finasteride microparticles in the blood, measured using LC-MS / MS after blood was collected. [Figure 14] This graph shows the blood semaglutide concentration measured using LC-MS / MS after collecting blood from experimental animals. [Figure 15] This graph shows the blood octreotide concentration measured using LC-MS / MS after collecting blood from experimental animals. [Figure 16] This graph shows the blood leuprolide concentration measured using LC-MS / MS after collecting blood from experimental animals. [Figure 17] This graph shows the changes in blood dexamethasone concentration after administration of dexamethasone base (not encapsulated in microglobules), dexamethasone acetate, and A-10 (microglobules encapsulated with dexamethasone), which were administered concomitantly to confirm the improvement in the bioavailability of semaglutide microglobules in Example 11. [Figure 18] This is an experimental result regarding the minimum blood concentration that induces drug side effects using dexamethasone microparticles and dexamethasone acetate microparticles. [Figure 19] This is an experimental result regarding the minimum blood concentration that induces drug side effects using dexamethasone microparticles and dexamethasone acetate microparticles. [Modes for carrying out the invention]

[0139] The following are preferred embodiments to aid in understanding the present invention. However, these embodiments are merely illustrative of the present invention, and it will be obvious to those skilled in the art that various changes and modifications are possible within the scope of the present invention and the technical concept, and that such variations and modifications fall within the scope of the appended claims.

[0140] Example 1: Production of anti-inflammatory microglobulins

[0141] 1-1: Production of microglobules containing anti-inflammatory drugs For the dispersion phase used to produce microspheres, 1.2 g of the biocompatible polymer Resomer RG 502H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) was mixed with 6.00 g of dichloromethane (manufacturer: JTBaker, USA) and dissolved until clear. Then, 0.8 g of dexamethasone (D50=1.8 μm; manufacturer: Farmabios, Italy) was added to the solution and stirred for at least 5 minutes to ensure thorough dispersion before use.

[0142] For the continuous phase used to produce microspheres, a 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution was used. 1,200 mL of the continuous phase was placed in a preparation vessel, and the dispersed phase was added at a flow rate of 6.0 mL per minute while stirring with a high-speed stirrer (L4RT, Silverson, England) at a speed of 2000 rpm to form an emulsion. After the injection of the dispersed phase was complete, the emulsion was stirred at a speed of 200 rpm while maintaining a temperature of 25°C for 30 minutes. Then, the temperature was raised to 45°C and maintained at that temperature for 3 hours while the organic solvent was evaporated and removed to produce microspheres.

[0143] After the removal of the organic solvent, the temperature of the microparticle suspension was lowered to 25°C, and then the residual polyvinyl alcohol was removed by filtration and repeated washing three times with tertiary distilled water to obtain microparticles. The microparticles obtained at this stage were freeze-dried to recover the final dexamethasone-containing sustained-release microparticles. The anti-inflammatory microparticles produced in this example were named A-1 microparticles.

[0144] Additionally, anti-inflammatory microglobulins A-2, A-3, and A-4 were produced in substantially the same manner as anti-inflammatory microglobulin A-1, except that the conditions described in Table 1 below were differed from those used for producing microglobulins by membrane emulsification without the use of a high-speed stirrer.

[0145] Specifically, anti-inflammatory microgranulocytes A-2 were produced using 3.5g of Resomer R 203H (iv=0.25-0.35 dL / g; manufacturer: Evonik, Germany), anti-inflammatory microgranulocytes A-3 were produced using 3.5g of Purasorb PDL 05 (iv=0.4-0.6 dL / g; manufacturer: Purac, Netherlands), and anti-inflammatory microgranulocytes A-4 were produced using 0.78g of Resomer RG 752H (iv=0.14-0.22 dL / g; manufacturer: Evonik, Germany) and 1.82g of Resomer RG 753H (iv=0.32-0.44 dL / g; manufacturer: Evonik, Germany).

[0146] [Table 1]

[0147] 1-2: Production of microglobules containing anti-inflammatory drugs The dispersed phase was prepared by mixing 0.39 g and 0.91 g of the biocompatible polymers RG 752H (iv 0.14-0.22 dl / g; manufacturer: Evonik, Germany) and RG 753H (iv 0.32-0.44 dl / g; manufacturer: Evonik, Germany), respectively, with 0.70 g of dexamethasone acetate (manufacturer: Pfizer, USA), 6.50 g of dichloromethane (manufacturer: JTBaker, USA), and 4.37 g of benzyl alcohol (manufacturer: Junsei, Japan).

[0148] The dispersed phase was used after being stirred for at least 30 minutes to ensure complete dissolution. The continuous phase was prepared by adding 2.5% (w / v) sodium chloride to a 0.5% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s). 1,500 mL of the continuous phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane, and the prepared dispersed phase was injected simultaneously to produce a microsphere suspension. The microsphere suspension was placed in a preparation container and stirred at 200 rpm, maintaining the container temperature at 25°C. After the injection of the dispersed phase, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 45°C for 3 hours. After the removal of the organic solvent, the temperature of the microsphere suspension was lowered to 25°C.

[0149] Dexamethasone acetate-containing microparticles contained 31.76% by weight, based on a total of 100% by weight of macromolecules and drug, and the microparticle size (D50) was 36.70 μm. The microparticles containing dexamethasone acetate produced in this example were named A-5.

[0150] Additionally, anti-inflammatory microgranulocytes A-6, A-7, A-8, A-9, and A-10 were manufactured in substantially the same manner as anti-inflammatory microgranulocyte A-5, except that the dispersed phase was manufactured and used under the conditions described in Table 2 below.

[0151] For the production of anti-inflammatory microgranules A-6, the dispersed phase was prepared by mixing 1.60 g of the biocompatible polymer Purasorb PDLG 5002A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands) and 0.40 g of dexamethasone acetate (manufacturer: Pfizer, USA) with 4.00 g of dichloromethane (manufacturer: JTBaker, USA) and 2.50 g of benzyl alcohol (manufacturer: Junsei, Japan). For the production of anti-inflammatory microgranules A-7, the dispersed phase was prepared by mixing 0.32 g and 1.28 g of the biocompatible polymers Purasorb PDLG 7502A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands) and Purasorb PDL 04A (iv 0.35-0.45 dl / g; manufacturer: Purac, Netherlands), respectively, with 0.40 g of dexamethasone acetate (manufacturer: Pfizer, USA), 4.00 g of dichloromethane (manufacturer: JTBaker, USA), and 2.50 g of benzyl alcohol (manufacturer: Junsei, Japan). For the production of anti-inflammatory microgranules A-8, the dispersed phase was prepared by mixing 0.54 g and 1.26 g of the biocompatible polymers Purasorb PDL 02A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands) and RG 755S (iv 0.50-0.70 dl / g; manufacturer: Evonik, Germany), respectively, with 0.20 g of dexamethasone acetate (manufacturer: Pfizer, USA), 4.50 g of dichloromethane (manufacturer: JTBaker, USA), and 1.25 g of benzyl alcohol (manufacturer: Junsei, Japan).

[0152] For the production of anti-inflammatory microgranules A-9, the dispersed phase was prepared by mixing 1.40 g of the biocompatible polymer R 203H (iv 0.25-0.35 dl / g; manufacturer: Evonik, Germany), 0.60 g of dexamethasone acetate (manufacturer: Pfizer, USA), 3.50 g of dichloromethane (manufacturer: JTBaker, USA), and 3.74 g of benzyl alcohol (manufacturer: Junsei, Japan).

[0153] For the production of anti-inflammatory microgranulocytes A-10, the dispersed phase was prepared by mixing 0.88g, 0.18g, and 0.41g of the biocompatible polymers Purasorb PDLG 7502A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands), RG 752H (iv 0.14-0.22 dl / g; manufacturer: Evonik, Germany), and RG 753H (iv 0.32-0.44 dl / g; manufacturer: Evonik, Germany), respectively, with 0.54g of dexamethasone acetate (manufacturer: Pfizer, USA), 5.13g of dichloromethane (manufacturer: JTBaker, USA), 0.73g of dimethyl sulfoxide (manufacturer: JTBaker, USA), and 1.97g of benzyl alcohol (manufacturer: Junsei, Japan).

[0154] [Table 2]

[0155] [Table 3]

[0156] 1-3: Production of microglobules containing anti-inflammatory drugs The dispersed phase was prepared by mixing 0.45 g each of the biocompatible polymers RG 752H (iv 0.14-0.22 dl / g; manufacturer: Evonik, Germany) and RG 753H (iv 0.32-0.44 dl / g; manufacturer: Evonik, Germany), and 0.10 g of meloxicam (manufacturer: Swati, India) with 4.50 g of dichloromethane (manufacturer: JTBaker, USA) and 1.20 g of dimethyl sulfoxide (manufacturer: JTBaker, USA).

[0157] The dispersed phase was used after being stirred for at least 30 minutes to ensure complete dissolution. The continuous phase was prepared by adding 2.5% (w / v) sodium chloride to a 0.5% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s). 2,000 mL of the continuous phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane, and the prepared dispersed phase was injected simultaneously to produce a granular suspension. The granular suspension was placed in a preparation container and stirred at a speed of 200 rpm, maintaining the temperature of the preparation container at 25°C. After the injection of the dispersed phase was complete, the organic solvent was removed while maintaining the temperature of the granular suspension at 45°C for 3 hours. After the removal of the organic solvent was complete, the temperature of the granular suspension was lowered to 25°C.

[0158] The meloxicam-containing microspheres had a meloxicam content of 9.82% by weight, based on a total of 100% by weight of polymer and drug, and the microsphere size (D50) was 60.24 μm. The meloxicam-containing microspheres produced in this example were named A-11.

[0159] 1-4: Production of microglobules containing anti-inflammatory drugs The dispersed phase was prepared by mixing 0.40 g each of the biocompatible polymers RG 752H (iv 0.14-0.22 dl / g; manufacturer: Evonik, Germany) and RG 753H (iv 0.32-0.44 dl / g; manufacturer: Evonik, Germany), and 0.10 g of ketorolak (manufacturer: Dr. Reddy's Laboratories, India) with 4.00 g of dichloromethane (manufacturer: JTBaker, USA) and 0.60 g of dimethyl sulfoxide (manufacturer: JTBaker, USA). The continuous phase and granules were prepared in substantially the same manner as the meloxicam-containing granules preparation method described in 1-3 above, to produce ketorolak-containing granules.

[0160] The ketorolac-containing microspheres had a content of 12.30% by weight, based on a total of 100% by weight of polymer and drug, and the microsphere size (D50) was 52.28 μm. The ketorolac-containing microspheres produced in this example were named A-12.

[0161] Example 2. Production of inflammatory microglobulins

[0162] 2-1: Production of Placebo microspheres For the production of microspheres, the dispersed phase was prepared by dissolving 10 g of the biocompatible polymer Resomer RG502H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) in 90 g of dichloromethane (manufacturer: JTBaker, USA) until clear.

[0163] A 0.1% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was mixed with 2.5% (w / v) sodium chloride and used as a continuous phase. 9,000 mL of this continuous phase was connected to an emulsifier equipped with a 10 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the membrane emulsifier and the preparation container was maintained at 25°C. After the injection of the dispersed phase was complete, the emulsion was stirred at a speed of 200 rpm while maintaining the temperature at 25°C for 30 minutes, and then the temperature was raised to 45°C and maintained at that temperature for 3 hours while the organic solvent was evaporated and removed.

[0164] After the organic solvent was removed, the temperature of the microsphere suspension was lowered to 25°C, and then the residual polyvinyl alcohol was removed by filtration and repeated washing three times with tertiary distilled water to obtain microspheres with an average particle size of 20 μm.

[0165] For the production of microspheres, the dispersed phase was prepared by dissolving 30 g of the biocompatible polymer Resomer RG502H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) in 120 g of dichloromethane (manufacturer: JTBaker, USA) until clear. For the continuous phase, an aqueous solution of 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used. 12,000 mL of the continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 20 μm, and simultaneously the prepared dispersed phase was injected to produce microspheres. The production of the microsphere emulsion, evaporation and removal of the organic solvent, and washing were carried out substantially in the same manner as for the microspheres with an average particle size of 20 μm, to obtain microspheres with an average particle size of 30 μm.

[0166] For the production of microspheres, the dispersed phase was prepared by dissolving 10 g of the biocompatible polymer Resomer RG502H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) in 18.57 g of dichloromethane (manufacturer: JTBaker, USA) until clear. For the continuous phase, an aqueous solution of 0.5% (w / v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used. 2,786 mL of the continuous phase was connected to an emulsifier equipped with a porous membrane with a diameter of 40 μm, and simultaneously the prepared dispersed phase was injected to produce microspheres. The production of the microsphere emulsion, evaporation and removal of the organic solvent, and washing were carried out substantially in the same manner as for the microspheres with an average particle size of 20 μm, to obtain microspheres with an average particle size of 60 μm.

[0167] Biodegradable polymer microparticles with an average particle size of 20, 30, or 60 μm were produced using the method described above, and the inflammation-inducing Placebo microparticles produced in this example were named B-1.

[0168] The average particle size analysis of the aforementioned microparticles was performed using a laser diffraction particle size analyzer. 50 mg of the composition was mixed with 1 mL of ultrapure water and mixed in a vortex mixer for 20 seconds, then dispersed in an ultrasonic generator for 1 minute. The dispersion was placed in a particle size analyzer (Microtrac Bluewave, Japan) and measured for 20 seconds. The particle size corresponding to 50% of the volume in the particle size distribution curve represents the average particle size (Median Diameter) and is expressed as D50 or D(v, 0.5). As a result of the particle size measurement, the measured D50 values ​​for 20 μm, 30 μm, and 60 μm microspheres were 21.02 μm, 35.56 μm, and 56.49 μm, respectively.

[0169] 2-2: Production of donepezil microglobules The dispersed phase used in the production of donepezil granules was prepared as follows: The dispersed phase contained 580.1 g of the biocompatible polymer PLA (Resomer R 203H i.v=0.25-0.35 dl / g; manufactured by Evonik, Germany / Resomer R 205S, iv=0.55-0.75 dL / g; manufactured by Evonik, Germany) and was prepared by mixing 396.1 g of donepezil base (manufactured by Neuland Laboratories, India) with 3,156.2 g of dichloromethane (manufactured by JTBaker, USA). The dispersed phase was stirred for at least 30 minutes to ensure complete dissolution before use.

[0170] A 1% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used as the continuous phase. The continuous phase for the dispersed phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane, and at the same time, the prepared dispersed phase was injected into the emulsifier to produce a microsphere suspension. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm, maintaining the temperature of the preparation container at 25°C. After the injection of the dispersed phase was complete, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 47.5°C for 4 hours. After the removal of the organic solvent was complete, the temperature of the microsphere suspension was lowered to 20°C.

[0171] The donepezil-containing microglobules had a drug content of 31.3% by weight, based on a total of 100% by weight of polymer and drug, and the microglobule size (D50) was 74.47 μm. The donepezil microglobules produced in this example were named B-2.

[0172] 2-3: Production of rivastigmine microspheres The dispersed phase consists of 2.00 g of the biocompatible polymer Resomer RG 653H (IV=0.32-0.44 dL / g; manufacturer: Evonik, Germany) and Resomer R 4.00 g of 203H (IV = 0.25-0.35 dL / g; manufacturer: Evonik, Germany), 2.70 g of rivastigmine (manufacturer: Hwail Pharmaceutical, South Korea), and 2.09 g of pamoic acid (manufacturer: Amitychem, China) were mixed with 30.00 g of dichloromethane (manufacturer: JTBaker, USA) and thoroughly dissolved until clear. The biodegradable polymer was used in a 653H:203H (1:2 weight ratio) ratio.

[0173] A 0.5% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used as the continuous phase. 4,500 mL of the continuous phase was connected to an emulsifier equipped with a 30 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the membrane emulsifier and the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 45°C for 3 hours. After the removal of the organic solvent, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0174] The rivastigmine microspheres described above had a drug content of 21.24% by weight, based on a total of 100% by weight of polymer and drug, and a microsphere size (D50) of 49.02 μm. The rivastigmine microspheres produced in this example were named B-3.

[0175] 2-4: Production of finasteride microglobules The dispersed phase consisted of 0.60 g of the biocompatible polymer Purasorb PDL 02A (IV = 0.16-0.24 dL / g; manufacturer: Purac, Netherlands) and 0.40 g of finasteride (manufacturer: Aurobindo Pharma, India), which were mixed with 5.40 g of dichloromethane (manufacturer: JTBaker, USA) and thoroughly dissolved until the solution became clear.

[0176] A 0.5% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used as the continuous phase. 1,500 mL of the continuous phase was connected to an emulsifier equipped with a 20 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the membrane emulsifier and the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 40°C for 3 hours. After the removal of the organic solvent, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0177] The finasteride microparticles described above had a drug content of 42.6% by weight, based on a total of 100% by weight of polymer and drug, a drug encapsulation rate of 106.5%, and a microparticle size (D50) of 40.43 μm. The finasteride microparticles produced in this example were named B-4.

[0178] 2-5: Production of semaglutide microspheres The dispersed phase consisted of 0.9 g of Purasorb PDLG 7504A (iv 0.38-0.48 dl / g, Purac, Netherlands) as a biocompatible polymer and 0.1 g of semaglutide (manufacturer: Chengdu, China) as a drug, which were thoroughly dissolved in 17.14 g of dichloromethane (manufacturer: JTBaker, USA) and 3.42 g of glacial acetic acid (manufacturer: Daejeong, South Korea) until the solution became clear.

[0179] A 0.1% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used as the continuous phase. 2.0 L of the continuous phase was connected to an emulsifier equipped with a 40 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 300 rpm. The temperature of the membrane emulsifier and the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 40°C for 3 hours. After the removal of the organic solvent, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0180] The semaglutide-containing microspheres had a drug content of 9.10% by weight, based on a total of 100% by weight of polymer and drug, and a microsphere size (D50) of 41.77 μm. The semaglutide microspheres produced in this example were named B-5.

[0181] 2-6: Manufacturing of semaglutide microglobules (GB-7001-717 dosage form (additional dosage form)) The dispersed phase consisted of 1.85 g of Resomer RG 503H (IV=0.32-0.44 dL / g; manufacturer: Evonik, Germany) and 3.70 g of Resomer RG 653H (IV=0.32-0.44 dL / g; manufacturer: Evonik, Germany) as biocompatible polymers, and 0.45 g of semaglutide (manufacturer: Chengdu, China) as a drug, which were thoroughly dissolved in 48.6 g of dichloromethane (manufacturer: JTBaker, USA) and 25.2 g of glacial acetic acid (manufacturer: Daejeong, South Korea) until the solution became clear.

[0182] The continuous phase and the production of microspheres were carried out in substantially the same manner as the method for producing semaglutide-containing microspheres described in 2-5 above, and the semaglutide-containing microspheres were produced and freeze-dried.

[0183] The semaglutide-containing microspheres had a drug content of 6.92% by weight, based on a total of 100% by weight of polymer and drug, and a microsphere size (D50) of 36.20 μm. The semaglutide microspheres produced in this example were named B-6.

[0184] 2-7: Production of octreotide microspheres The dispersed phase consists of 0.65 g of the biocompatible polymer Purasorb PDLG 7504A (iv 0.38-0.48 dl / g, Purac, Netherlands), 0.30 g of octreotide acetate (manufacturer: Zhejiang Peptites Biotech Co., Ltd, China), and pamoic acid (manufacturer: Amitychem, China or 0.05g of Kyeongbo Pharmaceutical (South Korea) was mixed with 5.80g of dichloromethane (manufacturer: JTBaker, USA) and 1.90g of dimethyl sulfoxide (manufacturer: Samchun Chemical, South Korea) and dissolved until the solution was visibly clear.

[0185] As the continuous phase solution, a 0.1% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used with the addition of 2.5% (w / v) sodium chloride. 2 L of the continuous phase was connected to an emulsifier equipped with a 10 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the membrane emulsifier and the preparation container was maintained at 25°C. After the injection of the dispersed phase was completed, the organic solvent was removed while maintaining the temperature of the microsphere suspension at 40°C for 3 hours. After the removal of the organic solvent, the temperature of the microsphere suspension was lowered to 25°C. The microsphere suspension was repeatedly washed with ultrapure water to remove residual polyvinyl alcohol, and the microspheres were freeze-dried.

[0186] The octreotide-containing microspheres had a drug content of 21.75% by weight, based on a total of 100% by weight of polymer and drug, and a microsphere size (D50) of 30.59 μm. The microspheres produced in this example were named B-7.

[0187] 2-8. Production of leuprolide microglobules The dispersed phase consisted of 3.6 g of the biocompatible polymer Purasorb PDLG 7502A (iv 0.16-0.24 dl / g, Purac, Netherlands) and 0.444 g of leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt, Ltd., India), mixed with 6.0 g of dichloromethane (manufacturer: JTBaker, USA) and 1.722 g of methyl alcohol (manufacturer: Tedia Company, USA), dissolved until the solution was visibly clear.

[0188] A 1.0% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) was used as the continuous phase solution. 2.5 L of the continuous phase was connected to an emulsifier equipped with a 20 μm diameter porous membrane, and simultaneously, the prepared dispersed phase was injected to produce microspheres. The microsphere suspension was placed in a preparation container and stirred at a speed of 200 rpm. The temperature of the membrane emulsifier, preparation container, and microsphere suspension was maintained at 15°C. After the injection of the dispersed phase was completed, the mixture was stirred for 3 hours, and then the organic solvent was removed by exchanging it twice with 5 L of continuous phase containing 0.5% (w / v) polyvinyl alcohol with 10% ethyl alcohol (manufacturer: Samchun Chemical, South Korea). After the removal of the organic solvent, the microsphere suspension was repeatedly washed with ultrapure water to remove any remaining polyvinyl alcohol, and the microspheres were freeze-dried.

[0189] The leuprolide-containing microparticles had a drug content of 10.07% by weight, based on a total of 100% by weight of polymer and drug, and the microparticle size (D50) was 32.42 μm. The microparticles produced in this example were named B-8.

[0190] 2-9: Production of microparticles containing leuprolide and dexamethasone acetate The dispersed phase consisted of 3.594 g of the biocompatible polymer Purasorb PDLG 7502A (iv 0.16-0.24 dl / g, Purac, Netherlands), 0.448 g of leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt, Ltd., India), and 0.0064 g of dexamethasone acetate, which were mixed with 6.0 g of dichloromethane (manufacturer: JTBaker, USA) and 1.739 g of methyl alcohol (manufacturer: Tedia Company, USA) until the mixture became visibly clear.

[0191] The continuous phase and the production of microparticles were carried out in substantially the same manner as the method for producing leuprolide-containing microparticles described in 2-8 above, to produce microparticles containing leuprolide and dexamethasone acetate, which were then freeze-dried. The drug microparticles produced in this example were named B-9.

[0192] 2-10: Production of microparticles containing leuprolide and dexamethasone base The dispersed phase consists of 3.587 g of the biocompatible polymer Purasorb PDLG 7502A (iv 0.16-0.24 dl / g, Purac, Netherlands) and leuprolide acetate (manufacturer: Polypeptide Laboratories Pvt). 0.448 g of (JTBaker Ltd., India) and 0.0128 g of dexamethasone base were mixed with 6.0 g of dichloromethane (manufacturer: JTBaker, USA) and 1.739 g of methyl alcohol (manufacturer: Tedia Company, USA) and dissolved until the mixture was visibly clear.

[0193] The continuous phase and the production of microparticles were carried out in substantially the same manner as the method for producing leuprolide-containing microparticles described in 2-8 above, to produce microparticles containing leuprolide and dexamethasone free base, which were then freeze-dried. The drug microparticles produced in this example were named B-10.

[0194] The properties of the microspheres produced in Examples 2-8, 2-9, and 2-10 are shown in Table 4.

[0195] [Table 4]

[0196] The improvement in the bioavailability of the microglobulins produced in Examples 2-8, 2-9, and 2-10 is shown in Table 5 and Figure 1.

[0197] [Table 5]

[0198] As shown in Table 5 above, leuprolide microgravities containing dexamethasone have a higher bioavailability (AUC) than leuprolide microgravities without dexamethasone. 0-28 Using 100 as the baseline, the bioavailability (AUC) of leuprolid 0-28 When dexamethasone acetate is used together, the rate is 147%, and when dexamethasone free base is used together, it improves to 167%.

[0199] 2-11: Production of deslorerin microglobules The dispersed phase was prepared by mixing 8.57 g and 31.43 g of the biocompatible polymers Purasorb PDLG 7502A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands) and Purasorb PDL 04A (iv 0.35-0.45 dl / g; manufacturer: Purac, Netherlands) in a weight ratio of 21:79, with 10.00 g of deslorerline acetate (manufacturer: Chengdu, China), 150.20 g of dichloromethane (manufacturer: JTBaker, USA), and 93.96 g of N-methyl-2-pyrrolidone (manufacturer: Ashland, India). The dispersed phase was stirred for at least 30 minutes to ensure complete dissolution before use.

[0200] A continuous phase was prepared using a 2.0% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s). A high-speed stirrer (Verso UHS, Silverson, England) was operated sequentially at 1,700 and 1,400 rpm, while the prepared dispersed and continuous phases were injected into an emulsifier to produce a granular suspension. The granular suspension was placed in a preparation container and stirred at 200 rpm, maintaining the container temperature at 25°C. After the injection of the dispersed phase, the organic solvent was removed while maintaining the temperature of the granular suspension at 45°C for 3 hours. After the removal of the organic solvent, the temperature of the granular suspension was lowered to 25°C, and the granular suspension was repeatedly washed with ultrapure water to remove residual polyvinyl alcohol. The granular particles were then freeze-dried.

[0201] The deslorerin-containing microspheres described above had a deslorerin content of 13.52% by weight, based on a total of 100% by weight of polymer and drug, and the microsphere size (D50) was 50.84 μm. The deslorerin-containing microspheres produced in this example were named B-11.

[0202] 2-12: Preparation of microparticles containing deslorerin and dexamethasone base The dispersed phase was prepared by mixing 0.93 g and 3.41 g of the biocompatible polymers Purasorb PDLG 7502A (iv 0.16-0.24 dl / g; manufacturer: Purac, Netherlands) and Purasorb PDL 04A (iv 0.35-0.45 dl / g; manufacturer: Purac, Netherlands) in a weight ratio of 21:79, with 1.04 g of deslorerline acetate (manufacturer: Chengdu, China) and 0.023 g of dexamethasone base (manufacturer: Pfizer, USA), along with 16.29 g of dichloromethane (manufacturer: JTBaker, USA) and 10.19 g of N-methyl-2-pyrrolidone (manufacturer: Ashland, India).

[0203] The continuous phase and the production of microbulbs were carried out in substantially the same manner as the method for producing deslorerin-containing microbulbs described in 2-11 above, to produce microbulbs containing deslorerin and a dexamethasone base, which were then freeze-dried.

[0204] The deslorerin and dexamethasone-based microparticles contained 13.25% by weight of deslorerin and 0.16% by weight of dexamethasone-based, based on 100% by weight of the total amount of polymer and drug, and the microparticle size (D50) was 43.28 μm. The deslorerin and dexamethasone-based microparticles produced in this example were named B-12.

[0205] 2-13: Production of entecavir microglobules The dispersed phase for the production of entecavir microspheres is a biocompatible polymer called Resomer RG858S (iv=1.3-1.7 dL / g; manufacturer: Evonik, Germany) and 502H (iv=0.16-0.24 dL / g; manufacturer: Evonik, Germany) were dissolved in 0.53 g and 0.23 g of each in a 70:30 weight ratio, along with 0.25 g of entecavir (manufacturer: Kyeongbo Pharmaceutical, South Korea), in 3.60 g of dichloromethane (manufacturer: JTBaker, USA) and 5.39 g of dimethyl sulfoxide, respectively. The mixtures were then mixed and stirred thoroughly until they became transparent to the naked eye before use.

[0206] For the production of microspheres, a continuous phase was prepared by adding 2.5 wt% NaCl to a 0.5% (w / v) aqueous solution of polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s). 800 mL of the continuous phase was placed in a preparation vessel, and the dispersed phase was added at a flow rate of 10.0 mL per minute while stirring with a high-speed stirrer (L4RT, Silverson, England) at 3000 rpm to form an emulsion. After the emulsion had been injected, the temperature was raised to 45°C while stirring at 200 rpm, and maintained for 2 hours to remove the organic solvent. Subsequently, the temperature of the microsphere suspension was cooled to 25°C, and the residual polyvinyl alcohol was removed by filtration and repeated washing with tertiary distilled water to obtain microspheres. The obtained microspheres were freeze-dried to recover sustained-release microspheres containing entecavir.

[0207] The entecavir-containing microglobulins had a drug content of 22.50% by weight, based on a total of 100% by weight of macromolecules and drug, and a microglobulin size (D50) of 63.63 μm. The anti-inflammatory microglobulins produced in this example were named B-13 microglobulins.

[0208] Example 3: Confirmation of the inflammation-inducing properties of microgranulocytes We used rats to experiment with whether administering microgranules induced inflammation in animals. Drug-free placebo microgranules with average particle sizes of 20 μm and 60 μm, prepared in Example 2-1, were used as the inflammatory agent.

[0209] The animal experiment was conducted in accordance with the regulations of the Animal Experiment Ethics Committee. Specifically, five-week-old male SD (Sprague-Dawly) rats were purchased, purified for one week, and then divided into two groups of four rats each. Placebo microglobules with average particle sizes of 20 μm and 60 μm, prepared in Example 2-1, were subcutaneously injected into the dorsal subcutaneous tissue of the rats at a dose of 120 mg / head. On the third and eighth days after administration, two rats from each group were sacrificially killed, and the injection sites were excised to examine the difference in the degree of inflammation induced by the administered microglobule size between the acute and chronic inflammation phases.

[0210] To observe the degree of inflammation induction, the excised administration site was fixed and embedded in neutral formalin. After preparing a paraffin block, it was sectioned to a thickness of 4-5 μm and stained with HE (hematoxylin·Eosin). The degree of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was then examined using a light microscope, and the resulting images are shown in Figure 2.

[0211] In Table 6 below, the degree of inflammatory cell infiltration was determined by selecting five arbitrary fields on stained histopathology slides using a light microscope at 400x magnification to check for inflammatory cell infiltration. If the number was ≤5 (or less), it was classified as "grade 0"; if it was between 6 and 20, as "grade 1"; if it was between 21 and 50, as "grade 2"; and if it exceeded 50, as "grade 3". Table 6 shows the average values ​​for each group. Furthermore, the formation of fibrous connective tissue is indicated by the total number of developing animals in each group.

[0212] [Table 6]

[0213] As shown in the photograph in Figure 2, no angiogenesis was observed in any of the groups administered 20 μm and 60 μm size placebo microglobules at the administration site on day 3, which is the acute inflammation induction phase, or on day 8, which is the chronic inflammation phase.

[0214] At the administration site on day 3, which is the acute inflammation induction phase, infiltration of inflammatory cells was observed in all groups administered 20 μm and 60 μm placebo microgranules, and weak fibrous tissue formation was observed in the group administered 20 μm placebo microgranules. At the administration site on day 8, which is the chronic inflammation phase, similar infiltration of inflammatory cells and fibrous tissue formation were observed in all animals administered 20 μm and 60 μm placebos at the administration site. Considering these results, inflammation induction by microgranule introduction was confirmed upon single subcutaneous administration of 20 μm and 60 μm placebo microgranules.

[0215] Example 4: Efficacy study with concomitant administration of anti-inflammatory microglobulins Dexamethasone microparticles (A-1) containing 36.8% by weight of dexamethasone as a free base, manufactured in Example 1-1, were mixed with 120 mg of 20 μm-sized placebo microparticles and 60 μm-sized placebo microparticles manufactured in Example 2-1 at doses of 0.94 mg (based on active ingredient content of 0.35 mg) or 0.23 mg (based on active ingredient content of 0.087 mg), respectively, to prepare mixed formulations.

[0216] The mixed formulation was administered subcutaneously to the dorsal side of SD rats in a manner substantially similar to that of Example 3, and two rats from each experimental group were sacrificially killed on the 3rd and 8th days after administration. The administration sites of the sacrificial rats were excised, and histopathological slides were prepared to test the anti-inflammatory efficacy of dexamethasone administration and the dosage administered during the acute and chronic inflammatory stages.

[0217] The experimental results are shown in Figures 3a and 3b, and the degree of inflammatory cell infiltration and fibrous tissue formation at the administration site were evaluated in essentially the same manner as in Example 2, as shown in Table 7 below.

[0218] [Table 7]

[0219] As shown in the photographs in Figures 3a and 3b, no angiogenesis was observed in any of the experimental groups in which placebo microparticles with average particle sizes of 20 μm and 60 μm produced in Example 2-1 and dexamethasone anti-inflammatory microparticles produced in Example 1-1 were subcutaneously injected together at the injection sites on day 3 post-administration (acute inflammation induction phase) and day 8 post-administration (chronic inflammation phase).

[0220] The experimental results showed that in experimental groups G4-1 to G4-4, which were administered a mixed formulation of placebo microgranules and dexamethasone microgranules, inflammatory cell infiltration at the administration site on day 3 post-administration (the acute inflammation induction phase) was reduced in all groups compared to G3-1 to G3-2, which were administered only placebo microgranules. Furthermore, in G4-1 and G4-2, which were administered a mixed formulation containing a high dose of dexamethasone microgranules (0.94 mg / head, 0.35 mg / head as dexamethasone free base), the reduction in cell infiltration was greater than in G4-3 and G4-4, which were administered a mixed formulation containing a low dose of dexamethasone microgranules (0.23 mg / head, 0.087 mg / head as dexamethasone free base). No fibrous tissue formation was observed in any of the experimental groups on day 3 post-administration (the acute inflammation induction phase).

[0221] In the experimental results described above, in experimental groups G4-1 to G4-4, which were administered a mixed formulation of placebo microgranules and dexamethasone microgranules, inflammatory cell infiltration at the administration site did not occur in G4-1 on day 8 post-administration, which is the chronic inflammation induction stage. It occurred in G4-2 to G4-4, but was less than in G3-1 and G3-2, which were administered only placebo microgranules. On day 8 post-administration, which is the chronic inflammation induction stage, fibrous tissue formation with an average grade of 0.5 was observed only in the G4-4 group.

[0222] Based on these results, we were able to confirm that when dexamethasone microglobulins were administered in combination, the degree of inflammation was suppressed compared to when only placebo microglobulins, which were used as inflammation-inducing microglobulins, were administered.

[0223] Example 5. Characteristics of the drug release profile of anti-inflammatory microglobulins Pharmacokinetic evaluations were performed on the anti-inflammatory microparticles A-2, A-3, and A-4 of Example 1 using 9-week-old SD (Sprague-Dawly) rats. The anti-inflammatory microparticles A-2, A-3, and A-4 injectable formulations of Example 1 were measured at 0.06 mg / head, suspended in 0.3 mL of dispersion solvent, and then subcutaneously injected into the SD rats. 0.25-0.5 mL of blood was collected at predetermined time intervals, and the serum dexamethasone concentration was measured using LC-MS / MS. The measurement results are shown in Figures 4a-4c.

[0224] As shown in Figures 4a to 4c, we confirmed that dexamethasone release occurs up to 168 days for A-2 anti-inflammatory microgravities, up to 84 days for A-3 anti-inflammatory microgravities, and up to 42 days for A-4 anti-inflammatory microgravities. The Cmax for A-2 anti-inflammatory microgravities was 0.5 ng / mL, for A-3 anti-inflammatory microgravities it was 0.9 ng / mL, and for A-4 anti-inflammatory microgravities it was 0.7 ng / mL, all of which were less than 1 ng / mL. In particular, we confirmed that A-2 and A-3 anti-inflammatory microgravities exhibited a gradual release pattern. From these results, we confirmed that all A-2, A-3, and A-4 microgravities are formulations that gradually release dexamethasone.

[0225] Example 6. Efficacy test of anti-inflammatory microglobulins 30 μm placebo microglobulins (B-1) prepared in Example 2-1 were used as pro-inflammatory microglobulins. Pro-inflammatory microglobulins were prepared either alone (G6-1) or as a mixed formulation with dexamethasone microglobulins (G6-2 to G6-5) in a manner substantially similar to that of Example 3, and administered subcutaneously to the dorsal side of SD rats at doses of 120 mg / head or 240 mg / head.

[0226] To confirm whether the anti-inflammatory effect of dexamethasone is maintained until almost all of the administered placebo microglobulins are biodegraded, we added day 33 after administration of placebo microglobulins, in addition to the inflammation confirmation points of 3 and 8 days after administration in Example 3.

[0227] Dexamethasone microglobulins, administered as a mixed formulation with the aforementioned pro-inflammatory microglobulins, were administered at doses of 0.22 mg / head (based on active ingredient content of 0.08 mg / head), 0.82 mg / head (based on active ingredient content of 0.3 mg / head), or 1.63 mg / head (based on active ingredient content of 0.6 mg / head). The specific experimental groups were G6-1 to G6-5, as shown in Table 8 below. Each experimental group contained a total of 13 animals, with 5 animals allocated to the day 3 experiment, 4 to the day 8 experiment, and 4 to the day 33 experiment, respectively.

[0228] In the table below, the dosage of pro-inflammatory microglobulins is based on the amount of microglobulins in mg / head, while the dosage of anti-inflammatory microglobulins is based on the amount of dexamethasone, the active ingredient, in mg / head.

[0229] [Table 8]

[0230] At each confirmation point, histopathology slides were prepared using the same method as in Example 3 to confirm inflammatory cell infiltration, angiogenesis, and fibrous tissue formation. Furthermore, collagen deposition at the administration site was confirmed through collagen staining of the histopathology slides. Photographs of the stained specimens are shown in Figures 5a and 5b.

[0231] The degree of inflammatory cell infiltration and fibrous tissue formation at the aforementioned administration site were evaluated in substantially the same manner as in Example 3, and are shown in Table 9 below.

[0232] [Table 9]

[0233] As shown in the analysis results in Table 9 above, in the G6-1 group, which was administered only 120 mg / head of 30 μm placebo, an average grade 3 infiltration of inflammatory cells was observed on day 3 after administration when acute inflammation occurred, and an average grade 3 infiltration of inflammatory cells, neovascularization, and fibrous tissue formation were observed in all animals on day 8 when chronic inflammation occurred.

[0234] In groups G6-2 to G6-5, which were administered a mixed formulation of 30 μm placebo microocytes (B-1), an inflammation-inducing microgranule, and dexamethasone microgranules, inflammatory cell infiltration was lower in all experimental groups on day 3 after administration, when acute inflammation occurred, compared to G6-1, which was administered only placebo microgranules. The GRADE of inflammatory cell infiltration decreased as the dose of the dexamethasone active component increased, and no angiogenesis or fibrous connective tissue formation was observed.

[0235] On day 8 after administration, when chronic inflammation occurs, all animals in G6-1, which did not receive dexamethasone microglobulins, showed an average grade 3 infiltration of inflammatory cells and the formation of neovascularization and fibrous tissue. However, G6-2, G6-3, and G6-5, which received the mixed formulation, showed lower grade inflammatory cell infiltration, and no inflammatory cell infiltration was observed in G6-4.

[0236] In the G6-5 group, which received 240 mg / head of 30 μm placebo microgranules and 1.63 mg / head of dexamethasone microgranules (based on an active ingredient content of 0.6 mg / head), an average grade 0.8 inflammatory cell infiltration was observed on day 3 post-administration, when acute inflammation occurs. On day 8 post-administration, which is the chronic inflammation induction stage, an average grade 0.5 inflammatory cell infiltration and angiogenesis were observed at the administration site in one individual. All inflammation-related symptoms observed in all treatment groups resolved by day 33.

[0237] Based on these results, we confirmed that when inflammatory microglobulins and dexamethasone microglobulins were administered together, inflammatory cell infiltration and neovascularization were suppressed in both the acute and chronic inflammatory stages compared to the group administered inflammatory microglobulins alone. In particular, we confirmed that the formation of fibrous connective tissue was completely suppressed in the chronic inflammatory stage compared to the group administered dexamethasone microglobulins in combination.

[0238] Example 7. Anti-inflammatory test by combined administration of drug microglobulins and anti-inflammatory microglobulins.

[0239] 7-1: Combination therapy with leuprolide microglobulins and anti-inflammatory microglobulins After confirming that co-administration of dexamethasone microglobulins alleviated inflammation induced by placebo microglobulins without drug-containing cells, this study was conducted to confirm whether dexamethasone microglobulins also exhibit anti-inflammatory effects against inflammation induced by microglobulins containing actual drugs.

[0240] For this experiment, we purchased Leuplin, a commercially available leuprolide microparticle that maintains its efficacy for three months, and named it microparticle B-14. Nine male 9-week-old SD (Sprague-Dawly) rats were divided into three groups of nine rats each. Leuplin was administered subcutaneously once to the back of each rat at a dose of 0.5 mL / head. This experiment is shown as experimental group G7-1 in Table 10 below.

[0241] A mixture of leuprolide microparticles for inflammation induction (2.7 mg / head, based on leuprolide free base content), dexamethasone microparticles (0.23 mg / head, based on active ingredient content of 0.06 mg / head), and dexamethasone microparticles (1.04 mg / head, based on active ingredient content of 0.27 mg / head) was prepared (G7-2 to G7-3), and administered as a single subcutaneous injection to the dorsal side of SD rats at a dose of 0.5 mL / head.

[0242] In this experiment, experimental groups G7-1 to G7-3 were designated in Table 10 below. Each experimental group contained 9 animals, with 3 animals assigned to each group on day 1, week 4, and week 12.

[0243] Three animals from each group were sacrificially killed one day, four weeks, and twelve weeks after administration of the test substance. Tissue from the administration site was then excised, and residual microgranules were identified. These tissues were fixed in 10% neutral buffered formalin solution, embedded in paraffin, and prepared as blocks. These sections were then thinly sliced ​​to a thickness of 4-5 μm and stained with HE (hematoxylin·Eosin) to evaluate the degree of inflammation, including inflammatory cell infiltration, angiogenesis, and fibrous tissue formation. Photographs of the stained specimens are shown in Figure 6.

[0244] Figure 6 shows photographs taken after subcutaneously injecting both leuprolide microglobulins and anti-inflammatory microglobulins into experimental animals. Inflammation at the injection site was stained with HE (hematoxylin·Eosin), and the degree of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was confirmed using a light microscope.

[0245] On day 1 after administering leuprolide microgranules and anti-inflammatory microgranules to each experimental group, the degree of inflammatory cell infiltration and fibrous tissue formation at the administration site were evaluated in substantially the same manner as in Example 2, and the results are shown in Table 10 below. In the table below, the doses of drug microgranules and anti-inflammatory microgranules are based on the active ingredient content in mg / head.

[0246] [Table 10]

[0247] In the G7-1 group, which received leuprolide microgranules at 2.7 mg / head (based on active ingredient content) alone, an average grade 3.3 inflammatory cell infiltration was observed on day 1 post-administration, when acute inflammation was induced, but no angiogenesis or fibrous connective tissue formation was observed.

[0248] In the G7-2 group, which received leuprolide microgranules at 2.7 mg / head (based on active ingredient content) and dexamethasone microgranules at 0.23 mg / head (based on active ingredient content of 0.06 mg / head), an average grade 2 inflammatory cell infiltration was observed on day 1 post-administration, when acute inflammation was induced, but no angiogenesis or fibrous connective tissue formation was observed.

[0249] In the G7-3 group, which received leuprolide microgranules at 2.7 mg / head (based on active ingredient content) and dexamethasone microgranules at 1.04 mg / head (based on active ingredient content of 0.27 mg / head), an average grade 1.3 inflammatory cell infiltration was observed on day 1 post-administration, when acute inflammation was induced, but no angiogenesis or fibrous connective tissue formation was observed.

[0250] 7-2: Combination therapy of placebo-containing microbulbars and dexamethasone-containing microbulbars The 30 μm placebo microparticles prepared in Example 2-1 were used as inflammatory microparticles. These were prepared in substantially the same manner as in Example 3, either as inflammatory microparticles alone (G7-4) or as a mixture of inflammatory microparticles and dexamethasone microparticles (A-1) (G7-5, G7-6, G7-7).

[0251] The experimental formulations prepared as described above were administered to SD rats subcutaneously on the dorsal side at a dose of 120 mg / head for pro-inflammatory microglobulins. Dexamethasone microglobulins (A-1), which were administered in a mixed formulation with the pro-inflammatory microglobulins, were administered at doses of 0.033 mg / head (based on active ingredient content of 0.012 mg / head), 0.164 mg / head (based on active ingredient content of 0.06 mg / head), or 0.82 mg / head (based on active ingredient content of 0.3 mg / head).

[0252] To confirm whether the administered placebo microspheres maintain the anti-inflammatory effect of dexamethasone, the 3rd and 8th days after administration, which are the time points for inflammation confirmation in Example 3, were examined. At each examination time point, histopathological slide specimens of G7-4 to G7-7 were prepared using the same method as in Example 3, and the infiltration of inflammatory cells was examined, and the results are shown in FIG. 7 and Table 11. Specifically, the infiltration of inflammatory cells at the administration site was examined through HE staining of the histopathological slide specimens. The degree of infiltration of inflammatory cells at the administration site was evaluated in substantially the same manner as in the evaluation of Example 3.

[0253] 7-3: Combined use of placebo microspheres and dexamethasone drug Different from using the single preparation of inflammatory induction microspheres (G7-4) or the mixed preparation of dexamethasone microspheres (A-1) in Example 7-2 above, in this experiment, dexamethasone base or dexamethasone acetate not encapsulated in microspheres was mixed with the 30-μm placebo microspheres prepared in Example 2-1 as inflammatory induction microspheres to produce test preparations (G7-8, G7-9).

[0254] Also, as anti-inflammatory drugs, dexamethasone base and dexamethasone acetate not encapsulated in microspheres were each administered at a dosage of 0.06 mg / head based on the active ingredient content (G7-8, G7-9). The detailed information regarding the specific experimental groups (G7-8 and G7-9) was entered in Table 11 below. In the following experiment, the number of animals on the 3rd day in each experimental group was assigned 4 each to G7-8 and G7-9.

[0255] To confirm whether the administered placebo microspheres maintain the anti-inflammatory effect of dexamethasone, the 3rd and 8th days after administration, which are the time points for inflammation confirmation in Example 3, were examined. At each examination time point, histopathological slide specimens of G7-8 and G7-9 were prepared using the same method as in Example 3 to examine the infiltration of inflammatory cells, and the results are shown in FIG. 7 and Table 11.

[0256]

Table 11

[0257] As shown in the analysis results in the table above, in the G7-4 group, which was administered only 120 mg / head of 30 μm placebo microgranules, an average grade 3 infiltration of inflammatory cells was observed on day 3 after administration when acute inflammation occurred, and an average grade 3 infiltration of inflammatory cells was also observed in all animals on day 8 when chronic inflammation occurred.

[0258] In the G7-5 to G7-7 groups, who received a mixed administration of 120 mg / head of 30 μm placebo microparticles and 0.03 mg / head (based on active ingredient content of 0.012 mg / head), 0.16 mg / head (based on active ingredient content of 0.06 mg / head), and 0.82 mg / head (based on active ingredient content of 0.3 mg / head) of dexamethasone microparticles, an average grade of 0.7 to 1.7 inflammatory cell infiltration was observed on day 3 after administration, when acute inflammation occurred, and an average grade of 0.8 to 1.3 inflammatory cell infiltration was observed on day 8, when chronic inflammation occurred. It was confirmed that inflammatory cell infiltration decreased as the amount of dexamethasone increased.

[0259] Furthermore, as an indicator of the inflammatory response at the administration site, CD68 staining, a macrophage (phagocytic cell) marker, was performed at the administration site using antibody staining. The degree of macrophage infiltration at the administration site is shown in Table 12 below. In Table 12, a score of 1 indicates that 5-30% of macrophages were positive in the microscopic image, a score of 2 indicates that 31-60% were positive, and a score of 3 indicates that 60% or more were positive.

[0260] [Table 12]

[0261] On day 3, when the acute inflammatory response appears, the degree of macrophage infiltration was confirmed to be decreased in all groups (G7-5 to G7-9) in the dexamethasone combination therapy group compared to G7-4. On day 8, the macrophage infiltration pattern was confirmed to be decreased in all groups (G7-5 to G7-9) in the dexamethasone combination therapy group compared to G7-4. However, in groups G7-8 and G7-9, which were administered with dexamethasone (without drug carriers), the macrophage infiltration pattern was confirmed to have increased compared to day 3.

[0262] As an indicator of systemic inflammatory response, the concentration of TGF-β2 in the blood was confirmed using the ELISA method, and the blood TGF-β2 concentrations are shown in Figure 8.

[0263] The results of the aforementioned tests, similar to the histopathological data, confirmed that serum TGF-β decreased in all test groups G7-5 to G7-9, which were administered dexamethasone on day 3 when acute inflammation occurred. On day 8, serum TGF-β2 decreased more than in group G7-4, which was administered 30 μm placebo microgranules alone. The mechanism by which dexamethasone reduces TGF-β2 concentration is similar to the mechanism by which it reduces the degree of cell infiltration in the histopathological data. On day 8, the anti-inflammatory effect of dexamethasone was shown to be better in the microgranular formulation compared to dexamethasone not encapsulated in microgranules.

[0264] Example 8: Analysis of the anti-inflammatory effect of the combination formulation

[0265] 8-1: Combination formulations of drug microglobulins and anti-inflammatory microglobulins The degree of inflammation induction in rat animals was examined based on whether or not drug-induced microglobulins and anti-inflammatory microglobulins were administered in combination. The drug-treated microgranulocytes used were donepezil microgranulocytes (B-2), rivastigmine microgranulocytes (B-3), finasteride microgranulocytes (B-4), semaglutide microgranulocytes (B-5), leuprolide microgranulocytes (B-8, B-9), octreotide microgranulocytes (B-7), and deslorerin microgranulocytes (B-11, B-12). Deslorerin microgranulocytes and donepezil microgranulocytes were administered in combination with A-2 anti-inflammatory microgranulocytes, respectively. Rivastigmine microgranulocytes and finasteride microgranulocytes were administered in combination with A-4 anti-inflammatory microgranulocytes, respectively. Octreotide microgranulocytes were administered in combination with A-3 anti-inflammatory microgranulocytes, and semaglutide microgranulocytes and leuprolide microgranulocytes were administered in combination with A-10 anti-inflammatory microgranulocytes, respectively.

[0266] The animal experiments were conducted in accordance with the regulations of the Animal Experiment Ethics Committee. Specifically, six-week-old male SD (Sprague-Dawly) rats were purchased, purified for one week, and then administered to seven-week-old rats. Donepezil microglobulins, rivastigmine microglobulins, and leuprolide microglobulins were administered into the thigh muscle of the right hind leg of the rats, while the other drug microglobulins were administered subcutaneously on the dorsal side of the rats. The dosage, volume of administration solution, and composition of the animal groups are as follows. In Table 13, the drug dosages listed in the front represent the drug dosage of the second formulation, and the drug dosages listed in the back represent the anti-inflammatory drug dosage of the first formulation. Also, in Table 13 below, second-generation microglobulins refer to microglobulins containing the second drug, and first-generation microglobulins refer to microglobulins containing the anti-inflammatory drug of the first formulation.

[0267] [Table 13]

[0268] On the 3rd and 8th days after administration, four animals from each group were sacrificially killed, and the administration sites were excised to examine the difference in the degree of inflammation induced by drug-induced microgranules and by co-administration of anti-inflammatory microgranules in the acute and chronic inflammation phases.

[0269] After the administration site removed for observing the degree of inflammation induction was fixed in neutral formalin and embedded, paraffin blocks were prepared, sliced into sections with a thickness of 4-5 μm, stained with HE (hematoxylin-eosin), and then the degree of infiltration of inflammatory cells, angiogenesis, and fibrous tissue formation was confirmed using an optical microscope.

[0270] The degrees of inflammatory cell infiltration, fibrous tissue formation, and angiogenesis were shown in Table 14 below. Three arbitrary fields were selected at a magnification of 400 times using an optical microscope for the stained tissue pathological slides to confirm the infiltration of inflammatory cells. If the number was ≤ 5 (hereinafter), it was determined as "grade0"; if it was 6-20, it was determined as "grade1"; if it was 21-50, it was determined as "grade2"; if it exceeded 50, it was determined as "grade3". Table 14 was described with the average value of each group. Also, if there was no fibrous tissue formation and angiogenesis, it was determined as "grade0"; if it was weak, it was determined as "grade1"; if it was intermediate, it was determined as "grade2"; if it was strong, it was determined as "grade3"; if it was severe, it was determined as "grade4".

[0271]

Table 14

[0272] On the 3rd day after administration of the drug microspheres, in the groups administered with the test substance compared with the G8-1 control group, significant infiltration of inflammatory cells, angiogenesis, and fibrosis in the subcutaneous or muscle were observed, and there were differences in the degree of inflammatory reaction among the test substances. The inflammatory reaction tended to decrease in the combined administration group of anti-inflammatory microspheres. A similar trend was also shown in the examination on the 8th day after administration. When dexamethasone, an anti-inflammatory agent, was encapsulated with the drug in the second drug carrier, or when dexamethasone was encapsulated in the first drug carrier and then co-administered with the combined microspheres of the second drug carrier, it was similar to reduce the infiltration of inflammatory cells, angiogenesis, and fibrosis.

[0273] 8-2: Combined preparation of drug microspheres and anti-inflammatory drugs The degree of inflammation induction in rats was investigated with and without the combined administration of semaglutide microgranules and meloxicam. Specifically, male 8-week-old SD (Sprague-Dawly) rats were purchased, purified for one week, and then administered subcutaneously to the dorsal side of 9-week-old rats. Semaglutide microgranules (B-6) were administered at 3.6 mg / head, and meloxicam at 1.5 mg / head, in 0.5 mL volumes.

[0274] Three days after administration, one animal from each group was sacrificially killed, and the administration site was excised to check for differences in the degree of inflammation induction in the acute inflammatory stage. The tissue was stained using the HE method of Example 8-1, and the degree of inflammatory cell infiltration, angiogenesis, and fibrous tissue formation was checked using the same criteria.

[0275] Table 15 below shows the degree of inflammatory cell infiltration, fibrous tissue formation, and angiogenesis. We confirmed that meloxicam itself effectively reduces inflammation caused by semaglutide microlocytes.

[0276] [Table 15]

[0277] Example 9. Evaluation of drug release regulation efficacy

[0278] 9-1: Delayed degradation of biodegradable polymers of dexamethasone After administering either 30 μm placebo microparticles alone (G9-1 experimental group) prepared in Example 2-1 or a mixed formulation of placebo microparticles and dexamethasone microparticles (A-1) prepared in Example 1 (G7-5 experimental group) subcutaneously on the dorsal side of SD rats, the degree of placebo microparticle degradation was compared. On the 16th day after administration of placebo microparticles or the mixed formulation of placebo microparticles and dexamethasone microparticles, tissue was excised from the administration site and residual microparticles were examined. The results showed that the degradation of biodegradable microparticles was delayed in the group administered with placebo microparticles and dexamethasone microparticles (A-1) compared to the group treated with placebo microparticles alone. Photographs of the rats obtained from the above experiment are shown in Figure 9.

[0279] 9-2: Delayed degradation of drug microglobulins by dexamethasone In the same manner as in Example 9-1, leuprolide-containing microparticles alone or a mixture of leuprolide microparticles and dexamethasone microparticles (A-1) were administered as a single subcutaneous injection to the dorsal side of SD rats. This experiment was conducted with experimental groups G9-3 to G9-5 in Table 17 below, with each experimental group containing three animals.

[0280] In Table 17 below, the amount of residual microglobulins was analyzed by calculating the area using the open-source software imageJ (version 1.45s, NIH). The area in experimental group G9-3 was set to 1 (indicated by +), and an increase of 1-100% relative to the residual amount in experimental group G9-3 was indicated by ++, and an increase of 101-200% was indicated by +++. Photographs of the rats obtained from the above experiment are shown in Figure 10. Three animals were used in each experimental group used in Table 16 below.

[0281] [Table 16]

[0282] Four weeks after administration of the test substance, rats were sacrificially killed, and tissue from the administration site was excised to examine residual microgranulocytes. The results showed that the amount of residual microgranulocytes was higher in the groups administered with dexamethasone microgranulocytes (G9-4, G9-5) than in the group administered with leuprolide microgranulocytes alone (G9-3). This indicates that the amount of residual microgranulocytes increased with increasing dexamethasone levels. Through these results, it was confirmed that dexamethasone delays the degradation of drug microgranulocytes, and that the release characteristics of drug microgranulocytes can be regulated by utilizing this property.

[0283] Example 10. Improvement of bioavailability (AUC) by co-administration of drug microglobulins and anti-inflammatory microglobulins. For the anti-inflammatory microgranulocytes A-2, A-3, and A-4 produced in Example 1, 9-week-old SD (Sprague-Dawly) rats were used to produce donepezil microgranulocytes (B-2), rivastigmine microgranulocytes (B-3), semaglutide microgranulocytes (B-5) produced in Example 2, and commercially available sandostatin Lar as a 1-month sustained-release octreotide microgranulocyte, which was purchased and named microgranulocyte B-15 for this experiment. Furthermore, as described in Example 7, a pharmacokinetic evaluation study was conducted in combination with commercially available leuprolide microgranulocytes (B-14).

[0284] In the case of donepezil microgranulocytes, 26.04 mg / head (API standard) and anti-inflammatory microgranulocytes A-2 were mixed and administered intramuscularly at a dose of 0.3 mg / head (API standard).

[0285] In the case of rivastigmine microgranules, 8.64 mg / head (API standard) and anti-inflammatory microgranules A-4 were administered intramuscularly as a mixture of 0.03 mg / head (API standard) and 0.01 mg / head (API standard), respectively.

[0286] In the case of finasteride microgranules (B-4), 8.4 mg / head (API standard) and anti-inflammatory microgranules A-4 were mixed and administered subcutaneously at a dose of 0.018 mg / head (API standard).

[0287] In the case of semaglutide microgranules (B-5), 3.6 mg / head (API standard) and anti-inflammatory microgranules A-4 were mixed and administered subcutaneously at a dose of 0.054 mg / head (API standard).

[0288] In the case of semaglutide microgranules (B-5), 3.6 mg / head (API standard) and anti-inflammatory microgranules A-10 were mixed and administered subcutaneously at a dose of 0.054 mg / head (API standard).

[0289] In the case of octreotide microgranules (B-15), 3 mg / head (API standard) and anti-inflammatory microgranules A-4 were mixed and administered intramuscularly at 0.03 mg / head (API standard).

[0290] In the case of leuprolide microgranules (B-14), 4.5 mg / head (API standard) and anti-inflammatory microgranules A-3 were mixed and administered subcutaneously at a dose of 0.072 mg / head (API standard).

[0291] In the case of deslorerin microgranules (B-11), 4.7 mg / head (API standard) and anti-inflammatory microgranules A-2 were mixed and administered subcutaneously at a dose of 0.06 mg / head (API standard).

[0292] 0.25–0.5 mL of blood was collected at predetermined time intervals, and the concentration of drug microparticles in the blood was measured using LC-MS / MS, as shown in the graphs in Figures 11–16.

[0293] Table 17 below shows the dosage of drug microglobulins and anti-inflammatory microglobulins, indicating the amount of active ingredient (mg / head) administered by the microglobulins.

[0294] [Table 17]

[0295] In the case of donepezil microgranulocytes, when administered in combination with anti-inflammatory microgranulocyte A-2 (A-2&B-2), the AUC improved by 277% compared to the monotherapy group, confirming an increase in the drug release mechanism. In the case of rivastigmine microgranulocytes, when administered in combination with anti-inflammatory microgranulocyte A-4 (A-4&B-3), the AUC improved by 26% compared to the monotherapy group.

[0296] In the case of finasteride microgranulocytes, when administered in combination with anti-inflammatory microgranulocyte A-4 (A-4 & B-4), a 461% improvement in AUC was observed compared to the monotherapy group.

[0297] In the case of semaglutide microglobulins, when administered in combination with anti-inflammatory microglobulin A-4 (A-4 & B-5), a 290% improvement in AUC was observed compared to the monotherapy group.

[0298] In the case of octreotide microparticles, we confirmed that when co-administered with anti-inflammatory microparticle A-4 (A-4 & B-15), the AUC improvement was 287% compared to the monotherapy group.

[0299] In the case of leuprolide microgravity cells, when administered in combination with anti-inflammatory microgravity cells A-3 (A-3 & B-14), not only was the AUC improvement increased by 293% compared to the monotherapy group, but the drug release period was also confirmed to increase.

[0300] In the case of deslorerin microlocytes, we confirmed that when administered concomitantly with anti-inflammatory microlocyte A-2 (A-2 & B-11), the AUC improvement was 509% compared to the monotherapy group.

[0301] Based on these results, we confirmed that co-administration of anti-inflammatory microgranulocytes, specifically A-2, A-3, and A-4 microgranulocytes, with drug microgranulocytes improved the bioavailability (AUC) of donepezil, rivastigmine, finasteride, leuprolide, semaglutide, octreotide, and deslorerin.

[0302] Example 11. Improvement of bioavailability (AUC) by co-administration of semaglutide microparticles and anti-inflammatory drugs. Using 9-week-old SD (Sprague-Dawly) rats, we tested the improvement in the bioavailability of semaglutide when it was administered in combination with semaglutide microparticles (B-6) produced in Examples 2-6 and anti-inflammatory microparticles produced in Example 1 (corresponding to G3-G6 and G9 in Table 18 below).

[0303] Furthermore, the aforementioned experiments were conducted by preparing a mixed formulation of semaglutide microparticles (B-6) manufactured in Example 2-6 with dexamethasone base, dexamethasone acetate, or meloxicam, which were not encapsulated in microparticles, and testing the improvement in the bioavailability of semaglutide through co-administration (corresponding to G7, G8, and G12 in the table below).

[0304] In a manner substantially similar to that of Example 9, the mixed formulation was administered to rats, and 0.25–0.5 mL of blood was collected at pre-planned intervals for 28 days. The concentration of semaglutide in the blood was measured using LC-MS / MS. Based on the measured drug concentrations, Cmax and AUC were calculated and shown in the table below. In the table below, the semaglutide microparticles used in G11 and G12 were B-5 produced in Example 2, and the semaglutide microparticles used in G3–G8 were B-6 produced in Example 2.

[0305] The experimental results are shown in Table 18 and Figure 17.

[0306] [Table 18]

[0307] As shown in the table above, when semaglutide microgranulocytes were administered alone without concomitant use of anti-inflammatory microgranulocytes or anti-inflammatory drugs (G3), the AUC was 402.0 (ng*day / mL) / (mg / kg). However, when semaglutide microgranulocytes were administered in combination with microgranulocytes containing dexamethasone acetate (G4, G5, G6), the AUCs were 1423.7, 888.2, and 1606.7 (ng*day / mL) / (mg / kg), respectively. These values ​​were significantly higher than those of G3, when semaglutide microgranulocytes were administered alone, confirming excellent bioavailability.

[0308] Furthermore, even among combination formulations of microgranulocytes containing dexamethasone acetate, it was confirmed that G6, which has a higher content of the active ingredient contained in the anti-inflammatory microgranulocytes, shows higher bioavailability compared to G4, which is administered at 0.054 mg / head of dexamethasone acetate. In addition, even among combination formulations of semaglutide microgranulocytes and microgranulocytes containing dexamethasone acetate, when comparing G4, a 1-month formulation, with G5, a 7-day formulation, it was confirmed that G4, a 1-month formulation, shows a higher AUC despite the same dosage of 0.054 mg / head of dexamethasone acetate.

[0309] Furthermore, while the dosage of the anti-inflammatory drug administered was the same at 0.108 mg / head, experimental group G6, which was a combination formulation of semaglutide microgravities (B-6) and microgravities containing dexamethasone acetate (A-10), showed a significantly improved AUC, confirming that the combination administration of semaglutide microgravities and anti-inflammatory microgravities is more preferable.

[0310] The graph below shows the dexamethasone release patterns of groups G6, G7, and G8. While the release in G7 and G8 was short-lived, the A-10 release in group G6 was maintained at 3 ng / head or less for more than 28 days. The semaglutide AUC of group G6 was approximately twice as high as that of G7 and G8, reaching a concentration of 1606.7 ng*day / mL / mg / kg. This confirms the superior ability of anti-inflammatory microgravities to increase semaglutide AUC, resulting in a low and prolonged dexamethasone release pattern.

[0311] Example 12. Improvement of bioavailability (AUC) by co-administration of deslorerin microparticles and anti-inflammatory drugs. Using 9-week-old SD (Sprague-Dawly) rats, we tested the improvement in the bioavailability of deslorerin when it was administered in combination with deslorerin microparticles B-11 produced in Example 2 and anti-inflammatory microparticles produced in Example 1.

[0312] In a manner substantially similar to that of Example 9, the mixed formulation was administered to rats, and 0.25–0.5 mL of blood was collected at pre-planned intervals for 98 days. The concentration of deslorerin in the blood was measured using LC-MS / MS. Based on the measured drug concentrations, Cmax and AUC were calculated and shown in the table below. A significant improvement in the bioavailability of deslorerin administered in combination with anti-inflammatory microglobulins was confirmed compared to the deslorerin microglobulin monotherapy group. In particular, diverse PK patterns were observed depending on the raw materials of the anti-inflammatory formulation and the type of microglobulins, and all of these showed a significantly improved AUC compared to the deslorerin microglobulin monotherapy group.

[0313] [Table 19]

[0314] Example 13. Confirmation of the toxic concentration of dexamethasone Dexamethasone microparticles corresponding to microparticles A-13 to A-16 and dexamethasone acetate microparticles corresponding to microparticles A-17 to A-22 in Table 20 below were manufactured in substantially the same manner as anti-inflammatory microparticles A-2 (Example 1-1) and A-5 (Example 1-2), respectively, except that the dispersed phase manufacturing conditions and continuous phase usage amounts were different according to the conditions described in Table 20.

[0315] [Table 20]

[0316] The toxic concentration of dexamethasone was confirmed by administering the prepared dexamethasone acetate microparticles or dexamethasone microparticles to 9-week-old SD (Sprague-Dawly) rats. In Experiment A, dexamethasone acetate microparticles were administered subcutaneously to rats at a dose of 0.3 mg / head as the active ingredient, and in Experiment B, dexamethasone microparticles were administered at a dose of 1 mg / head as the active ingredient. 0.25-0.5 mL of blood was collected at pre-planned intervals, and the blood dexamethasone concentration was measured using LC-MS / MS. The rats' body weight was also measured weekly for 28 days, and the rats' body weight and dexamethasone release patterns are shown in Figures 18, 19, and Tables 21 and 22.

[0317] [Table 21]

[0318] [Table 22]

[0319] As can be seen from Figures 18 and 19 and the table above, when the blood concentration of dexamethasone was maintained at approximately 4 ng / mL or higher for 7 days or more, as in Experiment A's A-17, A-18, A-19, A-20, and A-21, rats showed signs of weight loss. In particular, in the high-concentration test of Experiment B, it was confirmed that when the blood concentration of dexamethasone was maintained at 10 ng / mL or higher for 7 days or more, rats lost weight, and when it was maintained at 20 ng / mL or higher for 7 days or more, rats lost weight severely or died. Furthermore, when microgranulocytes were examined in Experiment B's A-16, it was confirmed that when the dexamethasone concentration was maintained at 3 ng / mL, weight loss did not occur, but normal weight gain did not occur. When the blood concentration of dexamethasone was maintained at less than 2 ng / mL, as in Experiment A's A-22 microgranulocyte test group, rats did not lose weight and showed normal weight gain.

Claims

1. A parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system, The first formulation comprises an anti-inflammatory drug, or an anti-inflammatory drug supported on a first parenteral drug carrier. The second formulation comprises a second parenteral drug delivery system and a second drug different from the drug of the first formulation. The first formulation is intended to prevent, reduce, or treat the target inflammatory response mediated by the parenteral drug carrier of the second formulation. Parenteral combination therapy pharmaceutical kit.

2. A parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system, The first formulation comprises an anti-inflammatory drug, or an anti-inflammatory drug supported on a first parenteral drug carrier. The second formulation comprises a second parenteral drug delivery system and a second drug different from the drug of the first formulation. The first formulation is intended to regulate the degradation of parenteral drug carriers contained in the second formulation. Parenteral combination therapy pharmaceutical kit.

3. A parenteral combination drug administration pharmaceutical kit comprising a first formulation containing a first drug and a second formulation containing a second drug and a parenteral drug delivery system, The first formulation comprises an anti-inflammatory drug, or an anti-inflammatory drug supported on a first parenteral drug carrier. The second formulation comprises a second parenteral drug delivery system and a second drug different from the drug of the first formulation. The first formulation is intended to increase the bioavailability of the second drug contained in the second formulation. Parenteral combination therapy pharmaceutical kit.

4. The pharmaceutical kit according to any one of claims 1 to 3, wherein the second parenteral drug delivery body is selected from the group consisting of biodegradable polymers and biodegradable lipids, and induces inflammation in the target.

5. The pharmaceutical kit according to any one of claims 1 to 3, wherein the drug delivery body is a microgranule, liposome, micelle, depot, or hydrogel.

6. The pharmaceutical kit according to any one of claims 1 to 3, wherein the first formulation and the second formulation are administered simultaneously or at different times.

7. The pharmaceutical kit according to any one of claims 1 to 3, wherein the first formulation and the second formulation are provided as a mixed formulation or as individual formulations.

8. The pharmaceutical kit according to any one of claims 1 to 3, wherein the first drug and the second drug are together supported on a second parenteral drug carrier.

9. A pharmaceutical kit according to any one of claims 1 to 3, comprising: a mixed formulation of the first drug; and a second formulation containing the second parenteral drug carrier and the second drug.

10. The pharmaceutical kit according to any one of claims 1 to 3, wherein the first drug and the second drug are each individually supported on parenteral drug carriers made of the same or different materials.

11. A pharmaceutical kit according to any one of claims 1 to 3, comprising a first formulation containing a first drug supported on a first parenteral drug delivery body, and a second formulation containing a second drug supported on a second parenteral drug delivery body.

12. The pharmaceutical kit according to any one of claims 1 to 3, wherein, when the first and second formulations are provided as a mixed formulation, the anti-inflammatory drug is contained in an amount of 0.001 to 5.0 w / w% of the mixed formulation based on 100% by weight of solids content.

13. The pharmaceutical kit according to any one of claims 1 to 3, wherein the first formulation and the second formulation are provided as a mixed formulation, and the first formulation contains an anti-inflammatory first drug supported on a first parenteral drug delivery body, the first parenteral drug delivery body is contained in an amount of 0.002 to 20 w / w% of the solid content of the mixed formulation, based on 100% by weight.

14. The pharmaceutical kit according to any one of claims 1 to 3, wherein the solid content of the first formulation is 0.002 to 20 parts by weight, based on the solid content of 100 parts by weight of the second formulation.

15. The pharmaceutical kit according to claim 1, wherein the AUC of the anti-inflammatory drug is equal to or greater than the minimum effective concentration of the anti-inflammatory drug, and is 10% or less of the AUC of the daily dose formulation.

16. The pharmaceutical kit according to claim 1, wherein the parenteral drug delivery body is delivered by intra-articular, subcutaneous, intradermal, intramuscular, intratumoral, intraocular, intravitreal, or intratympanic administration.

17. The drug delivery body is a microsphere having an average particle size of 10 to 100 micrometers. A pharmaceutical kit according to any one of claims 1 to 3.

18. A pharmaceutical kit comprising a parenteral anti-inflammatory kit according to any one of claims 1 to 3, further comprising a local anesthetic component.

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