Solid Dosage Form

Abstract

The present invention provides improved pharmaceutical formulations of active pharmaceutical ingredients such as dengue virus replication inhibitors, and processes for preparing said pharmaceutical formulations. [Solution] A pharmaceutical formulation is provided comprising a) a pharmaceutical active ingredient and b1) methacrylic acid copolymer or b2) cellulose derivative, wherein the pharmaceutical active ingredient is a dengue virus replication inhibitor.

Description

[Technical Field]

[0001] Field of Invention This invention relates to a pharmaceutical active ingredient and a methacrylate copolymer and hydroxypropylmethylcellulose. Pharmaceutical preparations containing lurose or a combination thereof, and solid dosage forms containing said pharmaceutical preparations The present invention also relates to the process of preparing such pharmaceutical formulations, and to diseases, syndromes, conditions, or relating to the use of such pharmaceutical preparations for the prevention or treatment of disorders.

[0002] Background of the Invention Flaviviruses transmitted by mosquitoes or ticks can cause diseases such as encephalitis and hemorrhagic fever in humans. It causes life-threatening infectious diseases. Flavivirus dengue (dengue virus) is different Four closely related serotypes are known. International Publication No. 2016 / 180696 This is a pharmaceutical active ingredient that exhibits high potency activity against all four serotypes of the dengue virus. It is disclosed.

[0003] Many active pharmaceutical ingredients (APIs) are hydrophobic and These properties, such as instability, pose challenges in providing suitable pharmaceutical formulations.

[0004] Medical drugs such as dengue virus replication inhibitors, as described in International Publication No. 2016 / 180696 There is a need for pharmaceutical formulations with improved active ingredients.

[0005] Summary of the Invention The present invention relates to a pharmaceutical formulation, a) Active pharmaceutical ingredient (API), b1) Methacrylic acid copolymer, b2) Cellulose derivatives, e.g., methylcellulose (MC), ethylcellulose (EC) ), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) , carboxymethylcellulose (CMC), sodium carboxymethylcellulose (N It contains aCMC or hydroxypropyl methylcellulose (HPMC), The API targets pharmaceutical formulations that are dengue virus replication inhibitors.

[0006] Embodiments of the present invention are described herein, wherein the API is a dengue virus replication inhibitor. This includes pharmaceutical preparations.

[0007] The present invention also provides solid dosage forms, including the pharmaceutical formulations described herein.

[0008] In embodiments where the API is a dengue virus replication inhibitor, the present invention relates to diseases, syndromes. In subjects including mammals and / or humans, the condition or disorder is due to dengue virus infection. and a method for treating or preventing the disease, syndrome, condition, or disorder, as specified in this specification. This document provides a method for using the pharmaceutical preparations and solid dosage forms described in the book.

[0009] In certain embodiments, the present invention relates to a person infected with dengue virus, or a dengue virus. Inhibits dengue virus replication in mammals and / or humans at risk of dengue infection. This focuses on methods for achieving this.

[0010] The present invention also relates to the preparation of pharmaceuticals prepared for the treatment or prevention of dengue virus infection. This applies to the use of such pharmaceutical preparations and / or solid dosage forms.

[0011] The present invention also provides for such pharmaceutical formulations and / or solid dosage forms for use as pharmaceuticals. The subject is the treatment or prevention of dengue virus infection. In another embodiment, the present invention relates to the treatment or prevention of dengue virus infection. The present invention is directed to the pharmaceutical formulation and / or solid dosage form described herein for use in

[0012] In one specific embodiment, the present invention relates to dengue virus in mammals and / or humans The present invention is directed to the pharmaceutical formulation and / or solid dosage form described herein for use in inhibiting viral replica tion.

[0013] The present invention also provides a process for preparing the pharmaceutical formulation described herein, comprising: a) dissolving an API in a solvent to form a solution; b) mixing a methacrylic acid copolymer or hypromellose or a combination thereof with the solution formed in step a), thereby obtaining a mixture; , c) spray-drying the mixture to obtain a solid dispersion; d) optionally blending the solid dispersion with at least one pharmaceutically acceptable excipient ; and the process provides the pharmaceutical formulation described herein.

[0014] The present invention also provides a process for preparing the solid dosage form described herein, comprising: a) dissolving an API in a solvent to form a solution; b) mixing a methacrylic acid copolymer or hypromellose or a combination thereof with the solution formed in step a), thereby obtaining a mixture; , c) spray-drying the mixture to obtain a solid dispersion; d) optionally blending the solid dispersion with at least one pharmaceutically acceptable excipient ; e) compressing the blend into a tablet; This specification provides a process for providing the pharmaceutical formulations described herein.

[0015] In certain embodiments, the present invention relates to pharmaceutical formulations or solid dosage forms described herein. A process for preparing a pharmaceutical active ingredient, wherein the active ingredient is a methacrylate copolymer or cell When combined with a rose derivative (e.g., hydroxypropyl methylcellulose), it can be used in pharmaceutical manufacturing. The present invention provides a process that includes forming a drug or a solid dosage form. [Brief explanation of the drawing]

[0016] The summary of the invention and the embodiments for carrying out the invention described below should be read in conjunction with the attached drawings. This is further understood. For the purpose of illustrating the present invention, exemplary embodiments of the present invention are shown in the drawings. However, the present invention is not limited to the specific disclosures in the drawings. [Figure 1] This plot shows the percentage of dissolved API against incubation time for the solid dispersions of Concepts 1-7 prepared in Example 1. This plot shows the two-phase dissolution profile in Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF). [Figure 2] This plot shows the percentage of dissolved API against incubation time for the solid dispersions of Concept 8-2 prepared in Example 1. This plot shows the two-phase dissolution profile in simulated gastric juice (SGF) and simulated fasting intestinal fluid (FaSSIF). [Figure 3A]Figure 3A plots the percentage of dissolved API against incubation time and Figure 3B plots the weight (in mg) of dissolved API against incubation time for the solid dispersion prepared in Example 5B. These plots show the two-phase dissolution profile in simulated gastric juice (SGF - left of the vertical dotted line) and simulated fasting intestinal fluid (FaSSIF - right of the vertical dotted line). [Figure 3B] Figure 3A plots the percentage of dissolved API against incubation time and Figure 3B plots the weight (in mg) of dissolved API against incubation time for the solid dispersion prepared in Example 5B. These plots show the two-phase dissolution profile in simulated gastric juice (SGF - left of the vertical dotted line) and simulated fasting intestinal fluid (FaSSIF - right of the vertical dotted line). [Figure 4] This plot shows the percentage of dissolved API against incubation time for the solid dispersion prepared in Example 5B. This plot shows the two-phase dissolution profile in simulated gastric juice (SGF - left of the vertical dotted line) and simulated intestinal fluid (FeSSIF - right of the vertical dotted line).

[0017] Detailed description of the invention This disclosure is based on the following description, including the following glossary and concluding examples. This can be understood more completely. Also, for clarity, in this specification, in the context of different embodiments Certain features of the pharmaceutical formulations and methods described herein are combined in a single manner. It is also understood that they may be provided together. Conversely, for the sake of brevity, they may be explained in the context of a single aspect. The various features of the pharmaceutical formulations and methods of this disclosure can be obtained separately or in any partial combination. It may be offered.

[0018] Some of the quantitative expressions used herein are not modified by the term "approximately". Regardless of whether the term "about" is explicitly used or not, as indicated herein All quantities that are shown refer to their actual values, and such shown Based on ordinary skill in the art, including approximate values ​​obtained through experimentation and / or measurement conditions. It can also refer to an approximate value of the shown value that can be reasonably inferred from that. It is understood that the terms “about” or “approximately” as used herein refer to numerical values. Or, when referring to a range, it implies some degree of variability within that value or range, for example, the stated value or within 10% (i.e., ±10%) or 5% (i.e., ±5%) of the stated range limit. or within 2.5% (i.e., ±2.5%) is acceptable.

[0019] Throughout this specification and in the claims, the terms "comprise" and "cont" are used. The term "ain)" and its variations, such as "comprising" and "comprising" "es)" means "including but not limited to", It is not intended (and will not) exclude other components.

[0020] Numerical ranges specified by endpoints include all integers and, where appropriate, are encompassed within that range. Includes rational numbers (e.g., 1-5, if referring to the number of elements, includes 1, 2, 3, 4). For example, when referring to measured values, 1.5, 2, 2.75, and 3.80 can also be included. The enumeration of endpoints also includes the endpoint values ​​themselves (for example, 1.0 to 5.0 is 1.0 and 5). (Including both .0). Any numerical range listed herein includes all that are contained within it. It is intended to include a subrange.

[0021] All references listed in this specification are incorporated in their entirety by reference. In particular, All teachings of references specifically mentioned in the specification are incorporated by reference.

[0022] Throughout this specification, any reference to “one embodiment” or “a particular embodiment” refers to an embodiment. The specific features, structures, or properties described in conjunction with the present invention are included in at least one embodiment of the present invention. This means that in various places throughout this specification, "in one embodiment" The appearance of the phrase "in one embodiment" or "in one embodiment" does not necessarily mean that all instances refer to the same embodiment. It is not necessarily the case, but it may refer to the same embodiment. Furthermore, its specific features, structure or The characteristics are apparent to those skilled in the art from this disclosure in one or more embodiments. They can be combined in any suitable way. Furthermore, several methods described herein This embodiment includes some features included in other embodiments, but does not include other features, and is based on the same industry. As may be understood by the author, combinations of features of different embodiments are within the scope of the present invention. A certain intention is intended to form different embodiments.

[0023] Regarding pharmaceutical use, APIs such as salts of the compound of formula (I) disclosed herein. The cocrystals or salts of refer to non-toxic, "pharmaceutically acceptable salts." This refers to a regulatory body of the federal or state government, or a corresponding agency in a country other than the United States. Does this mean approved or eligible for approval, or more specifically, animals? It is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in humans. This could mean that it is being done.

[0024] However, other salts may be APIs such as the compound of formula (I) or their pharmaceutically acceptable salt forms. It may also be useful in the preparation of the appropriate pharmaceutically for APIs such as compounds of formula (I). Acceptable salts include, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, when the solution of the compound is removed. pharmaceutically acceptable substances such as succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Examples include acid addition salts that can be formed by mixing with a solution of an acid. Furthermore, formula (I) When an API such as a compound has an acidic moiety, the appropriate pharmaceutically acceptable salt thereof is Examples include alkali metal salts (sodium or potassium salts), calcium salts, or magnesium salts. Suitable organic ligands such as alkaline earth metal salts like ammonium salts and quaternary ammonium salts One could also list the salts that are formed. Therefore, a typical pharmaceutically acceptable salt is vinegar. Salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, bistartrates, ho Salts, bromides, calcium EDTA, cansylates, carbonates, chlorides, clavulanic acid Salt, citrate, dihydrochloride, edetate, edisylate, estrate, esylate, f Marates, gluceptates, glucons, glutamates, glycolyl arsanilates Hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphth Eth, iodide, isothionate, lactate, lactobionate, laurate, apple Salts, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl Sulfates, mucinates, napsylates, nitrates, N-methylglucamine ammonium salts, Leate, pamonate (embonate), palmitate, pantothenate, phosphate / Diphosphate, polygalacturonate, salicylate, stearate, sulfate, basic Acetates, succinates, tannates, tartrates, theoclates, tosylates, triethio Examples include zide and valerate.

[0025] Typical acids and bases that can be used in the preparation of pharmaceutically acceptable salts include acetic acid, 2, 2-Dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L- Aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)- Camphor acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ca Primic acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate , ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfone Acids, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, horse urine Acids, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, male Inic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfone Acids, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy -2-Naphthoic acid, Nicotinic acid, Nitric acid, Oleic acid, Orotic acid, Oxalic acid, Palmitic acid Pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, ceba Succinic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate Acids, including p-toluenesulfonic acid and undecylenic acid, as well as ammonia, L- Arginine, Benetamine, Benzatine, Calcium Hydroxide, Choline, Deanol, Dietary Acid Nolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine N, ethylenediamine, N-methyl-glucamine, hydravamin, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, pipera Zin, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide Examples include bases containing triethanolamine, tromethamine, and zinc hydroxide.

[0026] If the API of a compound such as formula (I) has at least one chiral center, the result is These can exist as enantiomers. The compound has two or more chiral centers. If present, they may also exist as diastereomers. All mixtures of the compounds are understood to be included within the scope of the present invention. Furthermore, several of the compounds The tsuka can exist in polymorphic form and is therefore intended to be included in the present invention. In addition, Some compounds can form solvates (i.e., hydrates) with water or solvates with organic solvents. Some of these solvates are also intended to be included within the scope of the present invention. Those skilled in the art will recognize that the term "compound" as used herein refers to the solvate of the compound of formula (I). They will understand that it includes.

[0027] A process for preparing APIs such as the compound of formula (I) yields a mixture of stereoisomers. If these isomers occur, they can be separated by conventional techniques such as preparative chromatography. The compound may be prepared as a racemic mixture, or the individual enantiomers may be prepared as a racemic mixture. The compounds can also be prepared by either nantioselective synthesis or decomposition. For example, (-)-di-p-toluyl-d-tartaric acid and / or (+)-di-p-toluyl After forming a salt with optically active acids such as l-tartaric acid, fractional crystallization is performed to reconstitute the free base. By using standard techniques such as generating diastereomer pairs, they can be transformed The compound can be divided into enantiomers, which are the components of the compound. After forming an ester or amide of Mer, chromatographic separation is performed to identify the chiral auxiliary group. It can also be divided by removing the chiral stationary phase or It is also possible to partition the data using a sochiral column.

[0028] In one embodiment of the pharmaceutical formulation of the present invention, the API is a compound of formula (I), and the compound A thing is a thing that contains, consists of, and / or is essentially a thing that includes the (+)-enantiomer. It is a compound, and the compound substantially does not contain (-)-isomers. In this context, Qualitatively absent means that the (-)-isomer calculated by the following formula is less than approximately 25% by weight, preferably. Less than approximately 10% by weight, more preferably less than approximately 5% by weight, and even more preferably less than approximately 2% by weight. This means less than half, and more preferably less than about 1% by weight.

[0029]

number

[0030] In another embodiment of the pharmaceutical formulation of the present invention, the API is a compound of formula (I), and the chemical Compounds are compounds that include (-)-enantiomers, consist of them, and essentially consist of them. It is a substance, and the compound in question does not substantially contain (+)-isomers. In this context, substantially "Not included" means that the (+)-isomer calculated by the following formula is less than approximately 25% by weight, preferably approximately Less than 10% by weight, more preferably less than about 5% by weight, even more preferably less than about 2% by weight, And more preferably, it means less than about 1% by weight.

[0031]

number

[0032] In any process for preparing compounds of various embodiments of the present invention, related It is necessary and / or desirable to protect any sensitive or reactive group in the molecule. This can happen. This is related to Protective Groups in Organic C hemistry,Second Edition,JFWMcOmie,Ple num Press, 1973, TWGreene & PGMWuts,P rotective Groups in Organic Synthesis,Jo hn Wiley & Sons, 1991, and TW Greene & PG M.Wuts,Protective Groups in Organic Synt hesis,Third Edition,John Wiley & Sons,19 This can be achieved by conventional protecting group means, such as those described in 99. Protecting groups are At a later, more favorable stage, it can be removed using methods well known in the relevant art. ru.

[0033] Unless otherwise specified, the terms "wt%" and "weight percent" refer to the weight of a pharmaceutical product. Used interchangeably to refer to the concentration of an ingredient (e.g., excipient or active pharmaceutical ingredient) relative to a given amount. It will be done.

[0034] The term "room temperature" (RT) refers to a range of approximately 15°C to 30°C, especially around 20°C. This refers to a temperature of approximately 30°C. Preferably, the room temperature is approximately 25°C.

[0035] The average molecular weight may refer to, for example, the number-average molecular weight or the weight-average molecular weight. For example, it can be measured using gel permeation chromatography or mass spectrometry.

[0036] The term "subject" refers to an animal being treated, observed, or tested, preferably a pediatrician. This refers to dairy animals, most preferably humans.

[0037] The terms "active compound," "active ingredient," and "pharmaceutical active ingredient" are interchangeable in this specification. It is used in a specific way.

[0038] The term "therapeutic effective dose" refers to a decrease or inhibition of enzyme or protein activity, or This includes improving symptoms, alleviating the condition, slowing or delaying the progression of the disease, or preventing the disease. In the tissue systems, animals, or humans that researchers, veterinarians, physicians, or other clinicians seek to obtain This refers to the amount of an active compound or drug that induces a biological or medical response.

[0039] In embodiments where the API is a dengue virus replication inhibitor, the term "therapeutic effective dose" is used The term refers to the condition of a subject caused by the dengue virus when administered to that subject. , or to alleviate, inhibit, prevent, and / or improve at least partially a disorder or disease This can refer to the effective amount of the formulation of the present invention.

[0040] As used herein, the term "dengue virus" refers to a species of the Flaviviridae family. This refers to true-stranded positive-strand RNA viruses. Flavivirus dengue is different but closely related. Four serotypes, the so-called DENV-1, -2, -3, and -4, are known. Mosquitoes or damselflies Flaviviruses transmitted by this virus can cause life-threatening illnesses in humans, such as encephalitis and hemorrhagic fever. It causes a smegma infection.

[0041] As used herein, the term "dengue virus replication inhibitor" refers to dengue virus At least one of the conditions, symptoms, disorders, and / or diseases caused by Russ This refers to drugs that inhibit or reduce one of the effects.

[0042] As used herein, unless otherwise noted, “impact” or “affected” The term refers to a disease, syndrome, condition, or disorder affected by the inhibition of dengue virus replication. (When referring to harm), one or more of the above diseases, syndromes, conditions, or disorders. This includes reducing the symptoms or the frequency and / or severity of the onset of symptoms, and / Or one or more symptoms of the above-mentioned diseases, syndromes, conditions, or disorders. This includes preventing the onset of the condition.

[0043] When used herein, it is intended to "treat" any disease, condition, syndrome, or disorder. The terms "treatment" or "treatment" are all based on actual facts. In terms of treatment methods, the goal is to improve a disease, condition, syndrome, or disorder (i.e., the disease or its clinical (This refers to delaying, suppressing, or reducing the onset of at least one of the bedsickness symptoms.) In another mechanism, “to treat,” “to treat,” or “treatment” means patient At least one physical parameter that may not be recognizable by This refers to alleviating or improving lameter. In further embodiments, it means "to treat" or "to cure". "To treat" or "to treat" refers to physical (e.g., stabilization of recognizable symptoms) and physiological treatments. In relation to (for example, stabilization of physical parameters), or both, disease, condition, symptom It refers to adjusting a symptom or disorder. In yet another embodiment, it means "to treat" or "to cure". "To treat" or "treatment" means the onset, onset, or progression of a disease, condition, syndrome, or disorder. This refers to preventing or delaying an action.

[0044] As used herein, the terms “prevent,” “prevent,” and “preventing” This refers to a given state, disease, or symptom in a subject who is not diseased but is at risk of developing a disease. To reduce the risk of acquiring or developing such a condition, disease, or disease symptoms. This refers to reducing or inhibiting recurrence. For example, such subjects are high-risk groups, or if They were in a high-risk group, had the disease, or were in close proximity to someone with the disease. There is a possibility that they were there.

[0045] As used herein, “excipient” refers to an inactive component in a pharmaceutical preparation. Examples include diluents, wetting agents (e.g., surfactants), binders, lubricants, and disintegrants. Some examples include:

[0046] As used herein, “disintegrant” or “tablet decomposer” means hydrating a pharmaceutical preparation, It is an excipient that helps disperse tablets. An example of a disintegrant is croscarmellose sodium. Crospovidone (i.e., cross-linked polyvinyl N-pyrrolidone), sodium starch glycolate Examples include lium, or any combination thereof.

[0047] When used herein, “diluent” or “filler” means adding bulk to a pharmaceutical formulation. These are excipients. Examples of diluents include lactose, sorbitol, cellulose, and phosphoric acid. Calcium, starch, sugars (e.g., mannitol, sucrose, etc.) or any of these. One possible combination is...

[0048] When used herein, “wetting agent” or “surfactant” means enhanced solubility and / or an excipient that imparts wetting properties to a pharmaceutical preparation. An example of a wetting agent is sodium lauryl sulfate. Thorium (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 2 0 sorbitan monooleate (i.e., polysorbate 20) (e.g., Tween (trademark) ) or Tween20), Soluplus (registered trademark), or any combination thereof The voice can be raised.

[0049] As used herein, “binder” means an enhanced cohesive force or tensile strength (e.g., It is an excipient that imparts hardness to pharmaceutical preparations. An example of a binder is dicalcium phosphate. , sucrose, corn starch, microcrystalline cellulose, and modified cellulose Examples include hydroxymethylcellulose.

[0050] As used herein, “lubricant” refers to an additive that imparts enhanced flow properties to a pharmaceutical formulation. It is a modifier. Examples of lubricants include colloidal silica and / or talc.

[0051] As used herein, “colorant” is an excipient that imparts a desired color to a pharmaceutical formulation. Examples of colorants include commercially available pigments, such as FD&C Blue #1 Aluminum -Ki, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide Examples include , and / or combinations thereof. Other colorants include FD&C Gre Examples of commercially available pigments include en#3.

[0052] As used herein, “lubricant” means an additive to a pharmaceutical formulation that is compressed into a tablet. It is a formant. The lubricant is used for compressing granules into tablets and for discharging pharmaceutical tablets from the die press. It helps. Examples of lubricants include magnesium stearate and stearic acid (stearing Examples include hydrogenated oil, sodium stearyl fumarate, or any combination thereof. It can be done.

[0053] The following describes preferred features and embodiments of the pharmaceutical formulation, use, and process of the present invention. Each description and embodiment of the present invention as defined herein is not explicitly shown to be otherwise. Unless otherwise specified, it can be combined with any other description and / or embodiment. In particular, Any feature that indicates a desirable or advantageous characteristic, any other feature that indicates a favorable or advantageous characteristic It may be combined with a symbol (singular or plural) or a description. In this regard, the present invention particularly states that Any one of the following numbered embodiments and models, or the following numbered One or more of the described aspects and embodiments, and any other descriptions and / or implementations It is captured by any combination of state.

[0054] 1. A pharmaceutical preparation, a) Active pharmaceutical ingredient (API), b1) Methacrylic acid copolymer, b2) Cellulose derivatives, e.g., methylcellulose (MC), ethylcellulose (EC) ), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) , carboxymethylcellulose (CMC), sodium carboxymethylcellulose (N aCMC) or hydroxypropyl methylcellulose (HPMC), or a combination thereof A pharmaceutical formulation containing a combination of [unclear] and [unclear]. Preferably, the cellulose derivative is HPMC. API is a dengue virus replication inhibitor. 2. A pharmaceutical preparation as described in Description 1, wherein the pharmaceutical preparation is a solid dosage form. 3. The ratio of API to methacrylic acid copolymer is preferably 4:1 w / w to 1:9 w / w. 3.9:1w / w~1:8w / w, preferably 3.8:1w / w~1.7w / w, 3.7 :1w / w~1:6w / w, preferably 3:6:1w / w~1:5w / w, preferably 3 0.5:1w / w~1:4.5w / w, preferably 3:1w / w~1:4w / w, preferably The ratio is 2.5:1w / w to 1:3.5w / w, preferably 2:1w / w to 1:3w / w, preferred Alternatively, 2.5:1w / w to 1:2.5w / w, preferably 2:1w / w to 1:2w / w. Preferably in a ratio of 1.5:1w / w to 1:1.5w / w, or any ratio as referred to herein. A ratio that lies between two ratios, or between any two ratios referred to herein. A pharmaceutical preparation described in description 1 or 2, which is present in the preparation within or in part of the specified range. 4. APIs and cellulose derivatives (e.g., hydroxypropyl methylcellulose) , 4:1w / w~1:5w / w, preferably 3.5:1w / w~1:4.5w / w, preferred Alternatively, 3:1w / w to 1:4w / w, preferably 2.5:1w / w to 1:3.5w / w. Preferably 2:1w / w to 1:3w / w, preferably 2.5:1w / w to 1:2.5w / w, preferably 2:1w / w to 1:2w / w, preferably 1.5:1w / w to 1:1.5 In the ratio of w / w, or in the ratio that falls between any two ratios referred to herein, or as described herein A range or partial range of ratios between any two ratios mentioned in the details, present in the formulation. A pharmaceutical preparation as described in description 1 or 2. 5. Methacrylic acid copolymer is a copolymer of acrylic acid and / or methacrylic acid / ester. Remar, for example, Eudragit (registered trademark) L-100, Eudragit (registered trademark (Trademark) E-100, Eudragit (Registered Trademark) L-100-55, or any mixture thereof Products sold under the Eudragit® brand name, including but not limited to hybrids. A pharmaceutical preparation containing a compound, as described in any one of items 1 to 4. 6. Methacrylic acid copolymer is a copolymer of methacrylic acid and methyl methacrylate. Selected from the group comprising copolymers of tacrylic acid and ethyl acrylate, and any mixture thereof. A pharmaceutical preparation described in any one of the following descriptions (1-5). 7. Methacrylic acid copolymer is a copolymer of methacrylic acid and methyl methacrylate. or a pharmaceutical preparation described in any one of the items 1 to 6. 8. The molar ratio of methacrylic acid to methyl methacrylate in the copolymer is 0.5:2 to 0. The ratio is 6:1.5, preferably 0.8:1.3 to 1.2:1, and more preferably about 1:1. The pharmaceutical preparation described in Description 7. 9. Methacrylic acid copolymer is poly(methacrylate-co-methyl methacrylate)1 :1 (EUDRAGIT(registered trademark) L100), as described in any one of descriptions 1 to 8. A listed pharmaceutical preparation. 10. The cellulose derivative was found to be 3-5000 m in a 2 wt% solution in H2O at 25°C. Hydroxypropyl methylcellulose having a viscosity in the range of Pa·s, e.g., HPMC E5, HPMC E6, HPMC E15, HPMC E50, HPMC K3, HPM C K4M, HPMC-AS, and mixtures thereof, as described in any one of descriptions 1 to 9. A listed pharmaceutical preparation. 11. The cellulose derivative is found to be 3-500 mP in a 2 wt% solution in H2O at 25°C. Hydroxypropyl methylcellulose having a viscosity in the range of as, for example, HPMC E 5. HPMC E6, HPMC E15, HPMC E50, and mixtures thereof. , a pharmaceutical preparation described in any one of the items 1 to 10. 12. Cellulose derivatives are found in a 2 wt% solution in H2O at 25°C at a pressure of 3-50 mPa. A pharmaceutical preparation according to any one of descriptions 1 to 11, having a viscosity in the range of .s. Preferably The cellulose derivatives in question are HPMC E5, HPMC E6, HPMC E15, HP Hydroxypropyl methylcellulose selected from MC E50 and mixtures thereof. That is the case. 13. The formulation shall make up to 50% by weight, preferably up to 40% by weight, of the total weight of the formulation. Preferably up to 30% by weight, most preferably up to 25% by weight, and even more preferably 20% by weight. A pharmaceutical preparation as described in any one of descriptions 1 to 12, containing weight percent of the API. 14. The formulation shall be 0.1% to 50% by weight, preferably 1% by weight, relative to the total weight of the formulation. ~40% by weight, more preferably 2.5% to 30% by weight, most preferably 5% to 2% by weight A pharmaceutical preparation according to any one of descriptions 1 to 13, comprising 5% by weight of the API. 15. The formulation contains disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, lubricants, osmotic agents, One or more pharmaceutically acceptable substances selected from colorants, plasticizers, and coatings. A pharmaceutical preparation according to any one of descriptions 1 to 14, further comprising the excipient. 16. The preparation further comprises one or more excipients, and the preparation contains, in proportion to the total weight of the preparation. One or two of up to 80% by weight, preferably up to 70% by weight, preferably up to 60% by weight The formulation contains the above excipients and / or the formulation is at least 10% by weight of the total weight of the formulation. Preferably at least 20% by weight, preferably at least 30% by weight, one or more of these. A pharmaceutical preparation as described in any one of descriptions 1 to 15, including the above excipients. 17. The formulation further comprises one or more diluents, and the formulation, in proportion to the total weight of the formulation It comprises a diluent in an amount of up to 95% by weight, preferably up to 80% by weight, preferably up to 75% by weight. , and / or the formulation contains at least 5% by weight, preferably at least, of the total weight of the formulation. The diluent also comprises 10% by weight, preferably at least 15% by weight, of any of descriptions 1 to 16. A pharmaceutical preparation as described in item 1. 18. The formulation further contains one or more disintegrants, and the formulation contains, in proportion to the total weight of the formulation Up to 30% by weight, preferably up to 20% by weight, preferably up to 15% by weight, preferably the maximum The formulation contains a disintegrant of 10% by weight, and / or the formulation contains at least 1% by weight of the total weight of the formulation. Weight %, preferably at least 2.5% by weight, preferably at least 5% by weight, preferably A pharmaceutical preparation according to any one of descriptions 1 to 17, comprising at least 8% by weight of a disintegrant. 19. The formulation further comprises one or more binders, and the formulation contains, in proportion to the total weight of the formulation Up to 50% by weight, preferably up to 45% by weight, preferably up to 40% by weight, more preferably It contains up to 35% by weight of a binder, and / or the formulation contains less than 35% by weight of the total weight of the formulation. Also 5% by weight, preferably at least 10% by weight, preferably at least 15% by weight, more Preferably containing at least 20% by weight, most preferably 25% by weight, of the binder, as described in 1~ A pharmaceutical preparation as described in any one of item 18. 20. The formulation further comprises one or more lubricants, and the formulation contains, in proportion to the total weight of the formulation It contains a maximum of 5.5% by weight, preferably a maximum of 3.5% by weight, preferably a maximum of 2% by weight of lubricant. and / or the formulation contains at least 0.5% by weight, preferably a small amount, relative to the total weight of the formulation. Contains at least 1% by weight, preferably at least 1.5% by weight, of the lubricants described in descriptions 1 to 19. A pharmaceutical preparation as described in any one of the items. 21. The formulation further comprises one or more wetting agents, and the formulation contains, in proportion to the total weight of the formulation It contains a maximum of 5.5% by weight, preferably a maximum of 3.5% by weight, preferably a maximum of 2% by weight, of a wetting agent. and / or the formulation contains at least 0.5% by weight, preferably a small amount, relative to the total weight of the formulation. Contains at least 1% by weight, preferably at least 1.5% by weight, of a wetting agent, as described in descriptions 1 to 20. A pharmaceutical preparation as described in any one of the items. 22. The formulation further comprises one or more lubricants, and the formulation contains the most of the total weight of the formulation. It contains a lubricant of up to 10% by weight, preferably up to 8% by weight, preferably up to 5% by weight, and / Alternatively, the formulation may be at least 0.1% by weight, preferably at least 1% by weight, relative to the total weight of the formulation. A lubricant comprising, preferably at least 2% by weight, as described in any one of descriptions 1 to 21. A listed pharmaceutical preparation. 23. The formulation comprises one or more granules that form the granular inner phase of the formulation, and the granular outer phase of the formulation. A pharmaceutical product according to any one of descriptions 1 to 22, comprising one or more excipients that form Agent. 24. The formulation is at least 15% by weight and at least 20% by weight of the pharmaceutical formulation. The medical device described in description 23, comprising at least 28% by weight and at least 34% by weight of a granular inner phase. Drug preparations. 25. The formulation may be up to 99% by weight, up to 93% by weight, and up to 85% by weight relative to the weight of the pharmaceutical formulation. Weight%, up to 80wt%, up to 74wt%, up to 73wt%, up to 67wt%, up to 63wt The medical device described in description 23 or 24, containing a granular inner phase of % by weight, up to 60% by weight, or up to 53% by weight. Drug preparations. 26. The preparation contains a granular internal phase, and the granular internal phase is 1% to 70% by weight relative to the total weight of the pharmaceutical preparation. Weight%, 2% to 60% by weight, 3% to 55% by weight, 4% to 50% by weight, 5% by weight %~45% by weight, preferably 5%~40% by weight, preferably 10%~35% by weight Preferably containing 15% to 30% by weight of API, in any one of descriptions 23 to 25 The pharmaceutical preparation described. 27. The preparation contains a granular internal phase, and the granular internal phase is 5% to 60% by weight of the total weight of the pharmaceutical preparation. Metabacterial % by weight, preferably 8% to 50% by weight, preferably 15% to 45% by weight A lylic acid copolymer or hydroxypropyl methylcellulose or a mixture thereof, A pharmaceutical preparation described in any one of items 23 to 26. 28. The preparation contains a granular internal phase, and the granular internal phase is 5% to 60% by weight of the total weight of the pharmaceutical preparation. Weight %, preferably 10% to 60% by weight, preferably 10% to 50% by weight, preferred Or, a filler containing 15% to 50% by weight, as described in any one of descriptions 23 to 27. Pharmaceutical preparations. 29. The preparation contains a granular internal phase, and the granular internal phase is 1% to 10% by weight relative to the total weight of the pharmaceutical preparation. A disintegrant in a weight of %, preferably 1% to 9% by weight, preferably 1.7% to 8% by weight A pharmaceutical preparation including any one of the items described in items 23 to 28. 30. The formulation contains a granular internal phase, and the granular internal phase is 0.1% by weight of the total weight of the pharmaceutical formulation. 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight A pharmaceutical preparation containing a lubricant in a quantity of % as described in any one of items 23 to 29. 31. The preparation contains a granular internal phase, and the granular internal phase is 0.1% by weight of the total weight of the pharmaceutical preparation. 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4.5% by weight A pharmaceutical preparation containing a certain percentage of a surfactant, as described in any one of descriptions 23 to 30. 32. The preparation contains a granular internal phase, and the granular internal phase is 0.1% by weight of the total weight of the pharmaceutical preparation. 3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight A pharmaceutical preparation according to any one of descriptions 23 to 31, comprising a lubricant in a quantity of %. 33. The preparation contains a granular inner phase, and the granular inner phase constitutes (i) 5% by weight of the total weight of the pharmaceutical preparation. ~45% by weight, preferably 5% to 40% by weight, preferably 10% to 35% by weight, Preferably 15% to 30% by weight of API and (ii) 5 times the total weight of the pharmaceutical formulation Amount % to 60% by weight, preferably 8% to 50% by weight, preferably 15% to 45% by weight % methacrylate copolymer or hydroxypropyl methylcellulose or a mixture thereof (iii) The substance and 5% to 60% by weight, preferably 10% by weight, relative to the total weight of the pharmaceutical preparation. %~60% by weight, preferably 10%~50% by weight, preferably 15%~50% by weight (iv) 1% to 10% by weight, preferably 1% by weight, relative to the total weight of the pharmaceutical preparation. (v) the total weight of the pharmaceutical preparation, comprising (v) a disintegrant in an amount of % to 9% by weight, preferably 1.7% to 8% by weight, and 0.1% to 5% by weight, preferably 0.2% to 4.7% by weight, (i) 0.5% to 4.5% by weight of a lubricant and (vi) 0.1% by weight relative to the total weight of the pharmaceutical preparation Amount % to 5% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 4% by weight 0.5% by weight of surfactant and (vii) 0.1% to 3% by weight relative to the total weight of the pharmaceutical preparation %, preferably 0.2% by weight to 2.7% by weight, preferably 0.5% by weight to 2.5% by weight A pharmaceutical preparation according to any one of descriptions 23 to 32, comprising a lubricant. 34. The pharmaceutical preparation shall be at least 5% by weight and at least 7% by weight of the total weight of the pharmaceutical preparation. %, at least 10% by weight, at least 15% by weight, at least 20% by weight, at least A granular outer phase comprising 28% by weight and at least 34% by weight, according to any one of descriptions 23 to 33. The pharmaceutical preparation described. 35. The pharmaceutical preparation may be up to 74% by weight, up to 73% by weight, of the total weight of the pharmaceutical preparation. Granular outer phase of up to 67% by weight, up to 63% by weight, up to 53% by weight, and up to 40% by weight A pharmaceutical preparation, including any one of the items in descriptions 23 to 34. 36. The preparation contains a granular outer phase, and the granular outer phase is 0.1% by weight of the total weight of the pharmaceutical preparation. 5.0% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% to 3% by weight. A pharmaceutical preparation according to any one of descriptions 23 to 35, comprising 5% by weight of a disintegrant. 37. The preparation contains a granular outer phase, and the granular outer phase is 0.1% by weight of the total weight of the pharmaceutical preparation. 3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight A pharmaceutical preparation according to any one of descriptions 23 to 36, comprising a lubricant in a quantity of %. 38. The preparation contains a granular outer phase, and the granular outer phase is 0.1% by weight of the total weight of the pharmaceutical preparation. 55wt%, 0.2wt%~50wt%, 0.3wt%~45wt%, 0.4wt%~4 0wt%, 0.5wt%~35wt%, 0.6wt%~30wt%, 0.7wt%~25 Weight%, 0.8wt%~20wt%, 1wt%~15wt%, 1.3wt%~12wt% , 2~10, 2.5wt%~9wt%, 3wt%~8wt%, 4wt%~7wt%, 5wt A pharmaceutical preparation according to any one of descriptions 23 to 37, comprising a filler in an amount of % to 6% by weight. 39. The preparation contains a granular outer phase, and the granular outer phase is (a) 0.1 times the total weight of the pharmaceutical preparation. Amount % to 5.0% by weight, preferably 0.2% to 4.7% by weight, preferably 0.5% by weight (b) the total weight of the pharmaceutical preparation, comprising a disintegrant in an amount of ~3.5% by weight, more preferably 1% to 3% by weight. 0.1% to 3% by weight, preferably 0.2% to 2.7% by weight, relative to the amount. (c) 0.5% to 2.5% by weight of lubricant and 1% by weight relative to the total weight of the pharmaceutical formulation ~15% by weight, preferably 1.3% by weight to 12% by weight, preferably 2.5% by weight to 8% by weight A filler in any one of descriptions 23 to 38, comprising %, more preferably 3 to 5% by weight The pharmaceutical preparation described. 40. API is a compound of formula (I),

[0055] [ka] The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is ,below: A compound in which R1 is H, R2 is F, and R3 is either H or CH3. A compound in which R1 is H, CH3, or F, R2 is OCH3, and R3 is H. A compound in which R1 is H, R2 is OCH3, and R3 is CH3. A compound in which R1 is CH3, R2 is F, and R3 is H. A compound in which R1 is CF3 or OCF3, R2 is H, and R3 is H. A compound in which R1 is OCF3, R2 is OCH3, and R3 is H, A compound in which R1 is OCF3, R2 is H, and R3 is CH3. A pharmaceutical preparation described in any one of descriptions 1 to 39, selected from the group. 41. The compound of formula (I)

[0056] [ka] or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, as described. The pharmaceutical preparation described in item 40. 42. A solid dosage form containing a pharmaceutical preparation described in any one of items 1 to 41. 43. A solid dosage form as described in description 42, wherein the dosage form is an oral dosage form. 44. A solid dosage form as described in description 42 or 43, wherein the dosage form is a tablet. 45. The formulation contains 0.5 to 1000 mg of API, preferably 1 to 900 mg of API. Preferably 2 to 800 mg of API, preferably 3 to 700 mg of API, preferably 4 ~600 mg of API, preferably 5~500 mg of API, preferably 6~400 mg API, preferably 7-300 mg of API, preferably 8-200 mg of API, The formulation contains 9 to 100 mg of API, preferably 10 to 50 mg of API, as described in 42. A solid dosage form as described in any one of items ~44. 46. ​​The preparation contains at least 0.1 mg, at least 5 mg, at least 10 mg, and less At least 20 mg, at least 50 mg, at least 100 mg, at least 200 mg, At least 300 mg, at least 400 mg, at least 500 mg or at least 1 It contains 000 mg of API, preferably the API is

[0057] [ka] or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, as described. A solid dosage form as described in any one of items 42 to 45. 47. A method for treating or preventing dengue virus infection, the treatment or prevention For those requiring it, administer the pharmaceutical preparation described in any one of the descriptions of the therapeutically effective doses from 1 to 41. To do so, or to the subject who requires treatment or prevention, a description of the effective therapeutic dose 42-46 A method comprising administering a solid dosage form as described in any one of the items. 48. Description 1 for preparing medicines for the treatment or prevention of dengue virus infection Use of any one of the pharmaceutical preparations described in item 41. 49. Description 4 for preparing medicines for the treatment or prevention of dengue virus infection Use of any one of the solid dosage forms described in items 2 to 46. 50. A pharmaceutical preparation described in any one of items 1 to 41, for use as a drug. 51. A solid dosage form described in any one of items 42 to 46, for use as a pharmaceutical agent. 52. Description 1 for use in methods for treating or preventing dengue virus infection. A pharmaceutical preparation described in any one of the items ~41. 53. Description 4 for use in methods for treating or preventing dengue virus infection. A solid dosage form as described in any one of items 2 to 46. 54. A process for preparing a pharmaceutical preparation according to any one of claims 1 to 41. That is, a) A step of dissolving the API in a solvent to form a solution, b) Methacrylic acid copolymer or hydroxypropyl methylcellulose or the same The combination is mixed with the solution formed in step a) to obtain a mixture. , c) A step of spray-drying the mixture to obtain a solid dispersion, d) Optionally, the solid dispersion is mixed with at least one pharmaceutically acceptable excipient. The process of adding, A process for providing a pharmaceutical preparation as described in any one of the descriptions 1 to 41. 55. The API is a compound of formula (I),

[0058] [ka] The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is , A compound in which R1 is H, R2 is F, and R3 is either H or CH3. A compound in which R1 is H, CH3, or F, R2 is OCH3, and R3 is H. A compound in which R1 is H, R2 is OCH3, and R3 is CH3. A compound in which R1 is CH3, R2 is F, and R3 is H. A compound in which R1 is CF3 or OCF3, R2 is H, and R3 is H. A compound in which R1 is OCF3, R2 is OCH3, and R3 is H, A compound in which R1 is OCF3, R2 is H, and R3 is CH3. A process described in 54 is selected from the group. 56. The API is

[0059] [ka] or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, as described. The process described in any one of items 54-55. 57. The active ingredient of the pharmaceutical is a methacrylate copolymer or a cellulose derivative (e.g., hyd To form pharmaceutical formulations or solid dosage forms in combination with roxypropylmethylcellulose. A pharmaceutical preparation described in any one of descriptions 1 to 41, or any one of descriptions 42 to 46. The process for preparing the solid dosage forms described in the section.

[0060] Pharmaceutical preparations The present invention also relates to a pharmaceutical formulation, a) A dengue virus replication inhibitor (API), b1) Methacrylic acid copolymer, b2) Cellulose derivatives, e.g., methylcellulose (MC), ethylcellulose (EC) ), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) , carboxymethylcellulose (CMC), sodium carboxymethylcellulose (N aCMC) or hydroxypropyl methylcellulose (HPMC), or a combination thereof We provide pharmaceutical formulations that include combinations of [unclear].

[0061] In some embodiments, the cellulose derivative is HPMC.

[0062] In some embodiments, the pharmaceutical formulation according to the present invention is a dengue virus replication inhibitor. It comprises a certain API and at least one methacrylic acid copolymer.

[0063] As used herein, the term “methacrylate copolymer” is preferably an acrylate copolymer. Copolymers of lylic acid and / or methacrylic acid / esters (e.g., trade name Eudragi) This refers to compounds sold under the registered trademark t. Eudragit is an example. For example, Evonik Healthcare & Nutrition GmbH (Es It is commercially available from Sen (Germany).

[0064] Various types of methacrylate copolymers can be used, including poly(meth Co-methyl methacrylate acrylic acid) 1:1 (Eudragit(registered trademark) L-10 0, Eudragit(registered trademark) L12.5, etc.), poly(co-methyl methacrylate) Methacrylate) 1:2 (e.g., Eudragit® S-100, Eudr agit(registered trademark) S12,5, Eudragit(registered trademark) FS30D), Poly( Coethyl acrylate methacrylate) 1:1 (e.g., Eudragit®) L30D55, Eudragit (registered trademark) L100-55), poly(ethyl acrylate) Co-methyl methacrylate-co-trimethylammonium ethyl methacrylate Chloride) 1:2:0.1 (Eudragit(registered trademark) RS30D, etc.), Poly(E Tyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate Chloride) 1:2:0.2 (Eudragit(registered trademark) RL30D, etc.), Poly(A Ethyl acrylate co-methyl methacrylate) 2:1 (Eudragit(registered trademark) NM) (30D or Eudragit NE 30D, etc.), Dimethylaminoethyl Methacrylate Catio, based on butyl methacrylate and methyl methacrylate in a 2:1:1 ratio Non-polymer (Eudragit® E-100), and combinations thereof It includes se.

[0065] In some embodiments, the methacrylic acid copolymer is composed of methacrylic acid and methacrylic acid Copolymers with methyl acid, copolymers of methacrylic acid and ethyl acrylate, and the Selected from the group including mixtures of the following.

[0066] In some embodiments, the methacrylic acid copolymer is composed of methacrylic acid and methacrylic acid It is a copolymer with methyl acid. Preferably, methacrylic acid vs. methacrylic acid in the copolymer. The molar ratio of methyl acid is 0.5:2 to 2:0.5, preferably 0.8:1 to 1.2:1 (example). For example, 1:1.

[0067] In some embodiments, the methacrylic acid copolymer is poly(methacrylic acid-co -Methyl methacrylate) 1:1 (EUDRAGIT(registered trademark) L100, CAS number: (25086-15-1)

[0068] In some embodiments, the pharmaceutical formulation according to the present invention is a dengue virus replication inhibitor. It contains a certain API and hydroxypropyl methylcellulose.

[0069] In some embodiments, the pharmaceutical formulation according to the present invention includes a crystallization rate inhibitor. The term "crystallization rate inhibitor" refers to a formulation that inhibits the crystallization of APIs when administered to the target. This refers to excipients added to pharmaceutical formulations for the purpose of crystallization, such as polymer excipients. When the crystalline form is significantly lower compared to the amorphous / dissolved state, the bioavailability of the API It can be used to improve quality. Crystallization rate inhibitors are crystallization inhibitors or stabilizers. It can be called that.

[0070] In one embodiment, the crystallization rate inhibitor is polyvinylpyrrolidone. done, PVP), polyvinylpyrrolidone-vinyl acetate copolymer -vinyl acetate copolymer, PVPVA), poly(meth)acrylate polymer (e.g., (methacrylate-methyl methacrylate copolymer), cyclodextrin or cyclodextrin String derivatives (e.g., (2-hydroxypropyl)-β-cyclodextrin (2-hyd roxypropyl)-β-cyclodextrin, HPBCD), hydroxypropylcellulose, hydroxypropylcellulose Roxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose (hy Hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate Tate succinate (hydroxypropyl methylcellulose acetate succinate, HPMCA) S) Polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft Polymers, poly(vinyl alcohol), poloxamers (e.g., poloxamer 188, 3) 38, or 407), and any combination thereof.

[0071] In one embodiment, the crystallization rate inhibitor is hydroxypropylmethylcellulose (H PMC), Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) ), polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer Remer, polyvinylpyrrolidone (PVP), and polyvinylpyrrolidone-vinyl acetate copolymer A rimer (PVPVA), and combinations thereof, are selected. In further embodiments... Furthermore, the crystallization rate inhibitors are hydroxypropyl methylcellulose (HPMC) and poly Selected from vinylpyrrolidone-vinyl acetate copolymer (PVPVA). PVPVA is , a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (PVPV A64) This is possible.

[0072] The name and abbreviation for polyvinylpyrrolidone-vinyl acetate copolymer is PVPVA. PVP-Vac-copolymer and poly(1-vinylpyrrolidone-co-vinyl acetate) These are some examples, but are not limited to them.

[0073] A copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4 (PVPVA 64) The names and abbreviations for this drug include copolividone, copovidum, and copovidone. However, it is not limited to these. An example of commercially available PVPVA64 is Kollidon (registered trademark). (Mark) VA64, Kollidon (registered trademark) VA64 Fine, Luviskol These are VA64 (registered trademark) and Plasdone S-630 (registered trademark).

[0074] Polyvinylpyrrolidone is known by the names and abbreviations PVP, povidone, and crospovidone. Examples include, but are not limited to, crospovidone, vinylpyrrolidone crosslinking. It is a homopolymer. An example of a commercially available PVP is Plasdone(registered trademark) K-12. ru.

[0075] Hydroxypropyl methylcellulose, also known as hypromellose (HPMC), Some of the hydroxyl groups are replaced with methyl groups to form a methyl ether moiety, and the others hydroxypropyl group or methoxypropyl group is substituted for hydroxypropyl ether It is anhydrous glucose that forms a hydroxypropyl ether moiety.

[0076] Hydroxypropyl methylcellulose polymer (HPMC) is a Dow Chemical product. al Co. sells the product name Methocel (registered trademark), and Shin Etsu also sells it. We offer a variety of viscosity grades from several suppliers, including those under the product name Metrolose (registered trademark). Available at [website / platform name]. An example of a low viscosity polymer is Methocel E5®. Methocel E6 (registered trademark), Methocel E-15LV (registered trademark), Methocel E50LV (registered trademark), Methocel K100LV (registered trademark) These are (standard) and Methocel F50LV (registered trademark), and their 2 wt% aqueous solutions are At 25℃, the pressures are approximately 5mPas, 6mPas, 15mPas, 50mPas, and 100mPas respectively. It has viscosities of mPas and 50 mPas. An example of a medium viscosity HPMC is Methocel. These are E4M (registered trademark) and Methocel K4M, and their 2 wt% aqueous solutions are 2 It has a viscosity of 4,000 mPas at 5°C. An example of a high-viscosity HPMC is Methocel. These are K15M (registered trademark) and Methocel K100M (registered trademark), and these A 2 wt% aqueous solution has viscosities of 15,000 mPas and 100,000 mPas at 25°C. do.

[0077] In some embodiments, hydroxypropyl methylcellulose, for example, HPMC, is used. E5, HPMC E6, HPMC E15, HPMC E50, HPMC K4M, H PMC K15M, HPMC-AS, and mixtures thereof are 2% by weight in H2O at 25°C. In solution, it has a viscosity in the range of 3 to 5000 mPa·s. In some embodiments, For example, hydroxypropyl methylcellulose, such as HPMC E5, HPMC E6, H PMC E15, HPMC E50, and mixtures thereof are 2 by weight in H2O at 25°C. In a % solution, it has a viscosity in the range of 3 to 500 mPa·s. In some embodiments, For example, hydroxypropyl methylcellulose, such as HPMC E5, HPMC E6, H PMC E15, HPMC E50, and mixtures thereof are 2 by weight in H2O at 25°C. In a % solution, it has a viscosity in the range of 3 to 50 mPa·s.

[0078] In one embodiment, the present invention is a pharmaceutical formulation, a) defined herein as above A compound of formula (I), preferably

[0079] [ka] or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, The active pharmaceutical ingredient (API) is a virus replication inhibitor, b1) Methacrylic acid copolymer, b2) Cellulose derivatives, for example, methylcellulose (MC), ethylcellulose (E C), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) ), carboxymethylcellulose (CMC), sodium carboxymethylcellulose ( NaCMC or hydroxypropyl methylcellulose (HPMC), or the same The present invention provides a pharmaceutical formulation containing a combination of [a specific compound]. Preferably, the cellulose derivative is HPM It is C.

[0080] The pharmaceutical formulation of the present invention contains, in a maximum of 50% by weight and a maximum of 40% by weight, based on the total weight of the formulation. May contain at most 35% by weight, at most 30% by weight, or at most 25% by weight of API. The pharmaceutical formulation comprises, based on the total weight of the formulation, at least 0.1% by weight, at least 0.5% by weight, at least 1% by weight, at least 5% by weight, at least 10% by weight, at least 15% by weight , at least 17% by weight, or at least 20% by weight of API. The pharmaceutical formulation , based on the total weight of the formulation, may comprise 0.1% by weight to 45% by weight, 0.5% by weight to 40% by weight, 1% by weight % to 40% by weight, 5% by weight to 35% by weight, or 10% by weight to 35% by weight of API .

[0081] The pharmaceutical formulation of the present invention contains 0.1 mg to 3000 mg of API, 1 mg to 2000 mg of A PI, 5 mg to 1500 mg of API, 5 mg to 1000 mg of API, 10 mg to 50 0 mg of API, 15 mg to 400 mg of API, 20 mg to 350 mg of API, or any specific amount or range of API subsumed therein. A therapeutically effective amount of the API varies depending on the disease, syndrome, condition and disorder to be prevented or treated.

[0082] The pharmaceutical formulation of the present invention comprises: 20 mg to 6000 mg of methacrylic acid copolymer, 30 mg to 4000 mg of methacrylic acid copolymer, 40 mg to 2000 mg of methacrylic acid copolymer, 50 mg to 15 00 mg of methacrylic acid copolymer, 60 mg to 1000 mg of methacrylic acid copolymer , 70 mg to 1000 mg of methacrylic acid copolymer, 80 mg to 600 mg of methacrylic acid copolymer, or any specific amount or range subsumed therein, or 20 mg to 6000 mg of hydroxypropyl methylcellulose, 30 mg to 4000 mg of hydroxypropyl methylcellulose, 40 mg to 2000 mg of hydroxypropyl Hydroxypropyl methylcellulose, 50mg to 1500mg , 60mg~1000mg of hydroxypropyl methylcellulose, 70mg~1000 mg of hydroxypropyl methylcellulose, 80 mg to 600 mg of hydroxypropyl This may include methylcellulose, or any specific amount or range contained therein. .

[0083] The pharmaceutical formulation of the present invention may further contain one or more diluents, and the formulation is 20 ml Diluent of g to 7500 mg, preferably 30 mg to 6500 mg, preferably 40 mg to 4500 mg, preferably 50 mg to 2500 mg, preferably 60 mg to 2000 mg Preferably 80 mg to 1000 mg, preferably 90 mg to 550 mg, or more Includes any specific amount or range of diluents.

[0084] The pharmaceutical formulation of the present invention may further contain one or more surfactants, and the formulation is 0 0.5 mg to 300 mg of surfactant, preferably 0.6 mg to 250 mg, preferably 0 0.8mg to 200mg, preferably 1mg to 150mg, preferably 1.2mg to 100mg mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg, or containing these. Contains any specific amount or range of surfactant.

[0085] The pharmaceutical formulation of the present invention may further contain one or more disintegrants, and the formulation may be 3 mg ~900 mg of disintegrant, preferably 4 mg to 850 mg, preferably 5 mg to 600 mg Preferably 6 mg to 500 mg, preferably 7 mg to 400 mg, preferably 7.5 mg g to 200 mg, preferably 8 mg to 100 mg, or any specific amount contained therein. Or it may contain a disintegrant of a certain range.

[0086] The pharmaceutical formulation of the present invention may further contain one or more lubricants, and the formulation may contain 1 mg or more 400 mg of lubricant, preferably 2 mg to 350 mg, preferably 3 mg to 300 mg, The recommended dosage is 4 mg to 200 mg, preferably 5 mg to 100 mg, preferably 6 mg to 50 mg. mg, preferably 8.5 mg to 35 mg, or any specific amount contained therein Contains a range of lubricants.

[0087] The pharmaceutical formulation of the present invention may further contain one or more lubricants, and the formulation is 0.5 mg to 200 mg of lubricant, preferably 1 mg to 150 mg, preferably 3 mg to 100 mg mg, preferably 4 mg to 90 mg, preferably 7 mg to 90 mg, preferably 8 mg to 80 mg, preferably 10 mg to 50 mg, or any specific amount contained therein It includes a range of lubricants.

[0088] The pharmaceutical formulation of the present invention is as follows: Up to 60% by weight, up to 50% by weight, up to 45% by weight, and up to the total weight of the formulation. A large amount of 40% by weight, or up to 35% by weight, of methacrylic acid copolymer, Up to 60% by weight, up to 50% by weight, up to 45% by weight, and up to the total weight of the formulation. Contains 40% by weight, or up to 35% by weight, of hydroxypropyl methylcellulose. It is visible.

[0089] The pharmaceutical formulation of the present invention is as follows: At least 0.2% by weight, at least 1% by weight, and at least 5% of the total weight of the formulation. % by weight, at least 10% by weight, or at least 20% by weight of methacrylic acid copolyme r, or based on the total weight of the preparation, at least 0.2% by weight, at least 1% by weight, at least 5 % by weight, at least 10% by weight, or at least 20% by weight of hydroxypropyl me thylcellulose.

[0090] The pharmaceutical preparation may comprise: 0.2% by weight to 60% by weight, 1% by weight to 50% by weight, or 5% by weight to 40% by weight of methacrylic acid copolymer, or 0.2% by weight to 60% by weight, 1% by weight to 50% by weight, or 5% by weight to 40% by weight of hydroxypropyl methylcellulose, based on the total weight of the preparation.

[0091] In some embodiments, the API and the methacrylic acid copolymer are present in a 4:1 w / w ratio, 3.8:1 w / w ratio, 3.5:1 w / w ratio, 3.3:1 w / w ratio, 3:1 w / w ratio, 2.8:1 w / w ratio, 2.5:1 w / w ratio, 2.3:1 w / w ratio, 2:1 w / w ratio, 1.8:1 w / w ratio, 1.5:1 w / w ratio, 1:5 w / w ratio, 1:4 .8 w / w ratio, 1:4.5 w / w ratio, 1:4.3 w / w ratio, 1:4 w / w ratio, 1 :3.8 w / w ratio, 1:3.5 w / w ratio, 1:3.3 w / w ratio, 1:3 w / w ratio , 1:2.8 w / w ratio, 1:2.5 w / w ratio, 1:2.3 w / w ratio, 1:2 w / w ratio, 1:1.5 w / w ratio, or 1:1.2 w / w ratio, or a ratio included between any two ratios mentione d herein, or a ratio range or subrange between any two ratios mentione d herein, present in the pharmaceutical preparation of the present invention.

[0092] In some embodiments, API and hydroxypropyl methylcellulose are 4 :1w / w ratio, 3.8:1w / w ratio, 3.5:1w / w ratio, 3.3:1w / w ratio , a ratio of 3:1 w / w, a ratio of 2.8:1 w / w, a ratio of 2.5:1 w / w, a ratio of 2.3:1 w / w The ratio of , the ratio of 2:1 w / w, the ratio of 1.8:1 w / w, the ratio of 1.5:1 w / w, the ratio of 1:5 w / w The ratio of 1:4.8w / w, the ratio of 1:4.5w / w, the ratio of 1:4.3w / w, the ratio of 1:4w / w ratio, 1:3.8w / w ratio, 1:3.5w / w ratio, 1:3.3w / w ratio, 1: Ratios of 3 w / w, 1:2.8 w / w, 1:2.5 w / w, 1:2.3 w / w In a ratio of 1:2 w / w, a ratio of 1:1.5 w / w, or a ratio of 1:1.2 w / w, or as per the original instructions. A ratio that falls between any two ratios mentioned in the Specified Reference, or any ratio mentioned herein The present compound is present in the pharmaceutical formulation of the present invention within a range or partial range of ratios between two ratios.

[0093] The pharmaceutical formulations of the present invention are one or more pharmaceutically permitted as described in detail herein. It may further contain pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include disintegrants, binders, Examples include diluents, lubricants, stabilizers, osmotic agents, colorants, plasticizers, and coatings. , but not limited to these. Further preferred pharmaceutically acceptable excipients and their properties are discussed in Handbo. ok of Pharmaceutical Excipients,Edited b y RC Rowe, PJ Sheskey & PJ Weller, 6th edition ( Published by Pharmaceutical Press, a division of the Royal Society of Pharmacists. ) can be found in.

[0094] Diluent / Filler In the present invention, useful diluents (or fillers) include microcrystalline cellulose (for example, A Vicel(R) PH 102, Avicel(R) PH 101, CEO Ceolus UF, Ceolus KG, or Ceolus PH), silicified microcrystalline cellulose Sucrose, lactose, sorbitol, cellulose, calcium phosphate, starch (for example, part Partially or fully gelatinized corn starch), sugar or lactose (for example) Examples include mannitol, sucrose, etc., or any combination thereof. Examples of crystalline cellulose include microcrystalline cellulose with a particle size of 100 μm (for example, A The commercially available Avicel (registered trademark) series, such as vicel (registered trademark) PH102, Examples include commercially available CEO in UF, KG, or PH grade as microcrystalline cellulose. lus is another example. Other examples of diluents include commercially available Prosolv® silicone. Series (for example, Prosolv® SMCC50 and SMCC HD90), etc. Examples include silicified microcrystalline cellulose. Suitable lactose for the present invention is lacto Examples include sulfate hydrate. The amount of diluent relative to the total weight of the pharmaceutical preparation is 5% to 95% by weight. %, 20wt%~80wt%, 25wt%~50wt%, 30wt%~48wt%, 30 It can be between 52% by weight, 35% by weight, 52% by weight, or 40% by weight, 50% by weight. For example, the diluent in a pharmaceutical preparation may be 5% to 95% by weight relative to the weight of the pharmaceutical preparation, or 20% by weight. Amount%~80wt%, 25wt%~50wt%, 30wt%~48wt%, 30wt%~5 2% by weight, 35% to 52% by weight, 30% to 45% by weight, or 32.5% to 4% by weight 5% by weight of microcrystalline cellulose, silicified microcrystalline cellulose, and partially or completely alpha It may contain a combined (or total) concentration of ionized corn starch.

[0095] Disintegrant Disintegrants promote the dispersion of pharmaceutical formulations. A non-limiting list of disintegrants useful in this invention is available. Examples include croscarmellose (e.g., croscarmellose sodium), crospor Vidone, sodium starch glycolate (e.g., sodium starch glycolate) Examples of disintegrants include croscarmellose. Sodium cellulose (e.g., Ac-Di-Sol®) and starch glycol Sodium acid is an example. The pharmaceutical formulation of the present invention contains 1% by weight of the pharmaceutical formulation. 10% by weight, 5% to 9% by weight, 6% to 8% by weight, 6.5% to 7.5% by weight, 6.75% by weight to 7.25% by weight, 3% by weight to 7% by weight, 1% by weight to 7% by weight, or 1. A combined (or total) concentration of one or more disintegrants ranging from 2% to 8.2% by weight. It may include. In some embodiments, the pharmaceutical formulation is double the weight of the pharmaceutical formulation. Amount % to 8% by weight (for example, 2.5% to 7.5% by weight), preferably 3% to 6% by weight It contains, more preferably, 4% to 5% by weight of a disintegrant (e.g., crospovidone).

[0096] Binder The binder is mixed with the diluent and the active pharmaceutical ingredient to form the active pharmaceutical ingredient. It may contain agents used in preparing the granules. The present invention is not limited to any useful binders. Typical examples include polyvinylpyrrolidone, sugars, and modified cellulose (e.g., hydroxypropyl cellulose). Hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), and Examples include hydroxyethylcellulose (HEC), and any combination thereof. Other examples of binders include polyvinylpyrrolidone (PVP). Examples include low viscosity polymers and HPC-SL. PVP is a polymer composition It can be characterized by the "K value," a useful measure of viscosity. PVP is Povi done(registered trademark)K12, Povidone(registered trademark)K17, Povidone (Registered Trademark) K25, Povidone (Registered Trademark) K30, Povidone (Registered Trademark) It can be marketed under the trade names K60 and Povidone® K90 (for example) (Tokyo Chemical Industries, Ltd.). A specific example of PVP is soluble spray-dried PVP. Another example is PVP with an average molecular weight of 3,000-4,000, for example, 4, Povidone® K12, which has an average molecular weight of 000, is an example. It can be used in either a wet or dry state. The pharmaceutical formulation of the present invention is a medical 0.1% to 50% by weight, 0.5% to 43% by weight, and 2% by weight relative to the weight of the drug formulation. ~45wt%, 5wt%~40wt%, 10wt%~35wt%, 15wt%~30wt A combination (or total) of one or more binders in an amount of %, 20% to 25% by weight. It may contain in a concentration. In some embodiments, the pharmaceutical formulation contains 0 of the pharmaceutical formulation by weight. 0.5% by weight to 2% by weight (for example, 1.5% by weight to 2.0% by weight or 1.75% by weight to 2% by weight). It contains 25% by weight of a binder (e.g., hydroxypropyl methylcellulose).

[0097] Lubricant Lubricants function, for example, to improve the compression and discharge of pharmaceutical formulations from dipresses. In this invention, a non-limiting example of a useful lubricant is magnesium stearate. Stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, complete Examples include glyceryl behenate and any combination thereof. One example is lubricant. The agent contains sodium stearyl fumarate. In another example, the lubricant contains stearate. Contains magnesium. The pharmaceutical formulation of the present invention contains 0.1% to 10% by weight of the pharmaceutical formulation. Weight%, 0.5% to 6% by weight, 0.8% to 3.5% by weight, 1% to 3% by weight, 1.5% to 5.5% by weight, 2% to 4% by weight, or 0.25% to 5.25% by weight It may contain a concentration of % of one or more lubricants combined (or in total). In this embodiment, the pharmaceutical formulation contains 0.5% to 5.5% by weight, preferably 1% by weight. It contains 2.5% by weight of a lubricant (e.g., magnesium stearate).

[0098] Humectants / surfactants One or more wetting agents can be used in the pharmaceutical formulation of the present invention. Suitable wetting agents generally enhance the solubility of pharmaceutical formulations. Examples of wetting agents include nonionic surfactants. Examples include surfactants such as action agents and anionic surfactants. Non-exclusive examples of surfactants include sodium lauryl sulfate (SLS) and polyoxyethylene. Lensorbitan fatty acids (e.g., polysorbate 20 (e.g., TWEEN20 (trademark)) )), sorbitan fatty acid ester (e.g., Spans®), dodecylbenzase Sodium sulfonate (SDBS), sodium dioctyl sulfosuccinate (docucine) (Dioxycholic acid), sodium deoxycholic acid (DOSS), sorbitan molybdenum Nostearate, sorbitan tristearate, N-lauroyl sarcosinate sodium, Sodium oleate, sodium myristate, sodium stearate, palmitin Sodium acid, Gelucire 44 / 14, Ethylenediaminetetraacetic acid (EDTA), Vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate ( TPGS), lecithin, MW677~692, monosodium glutamate monohydrate, ra Brasol, PEG-8 Caprylic / Capric Glyceride, Transktol, Dietary Acid Lenglycol monoethyl ether, Solutol HS-15, Soluplus ( (Registered trademark), polyethylene glycol / hydroxystearate, taurocholic acid, poly Copolymers of oxypropylene and polyoxyethylene (e.g., pluronic( (Registered Trademarks) L61, pluronic(registered trademark) F68, pluronic(registered trademark) F108 and Pluronic (registered trademark) F127, etc. Poloxamer, saturated polyglycolated glycerin, is also known and commercially available as a standard. Examples include gelucirs (registered trademark) and any combination thereof. Examples include the anionic surfactant sodium lauryl sulfate, and nonionic One example is a copolymer of the surfactant polyoxypropylene and polyoxyethylene. An example of a copolymer of polyoxypropylene and polyoxyethylene is a copolymer with a molecular weight of 1 It contains 800 g / mol of polyoxypropylene and 80% polyoxyethylene. Examples of poloxamers include poloxamers such as poloxamer 188. The pharmaceutical formulations of the Ming Dynasty contain 0.25% to 10% by weight of the pharmaceutical formulation, and 0.25% by weight. %~5.75% by weight, 0.5%~5% by weight, 1%~3% by weight, or 1.5% by weight It may contain one or more wetting agents combined (or in total) in a concentration of ~2% by weight. In some embodiments, the pharmaceutical formulation contains 0.25% to 5% by weight (for example, 0.3%). It contains 5% to 4.5% by weight of a wetting agent (e.g., sodium lauryl sulfate).

[0099] lubricant Lubricants enhance the flow properties of the formulation during processing into the final drug product form. Non-limiting examples of such lubricants include silicon dioxide (e.g., colloidal fumed silica). Examples of lubricants include colloidal anhydrous silica and / or talc. Examples include id-shaped fumed silica (e.g., Aerosil® 200). The pharmaceutical formulation of the present invention contains 0.1% to 10% by weight, preferably, relative to the weight of the pharmaceutical formulation. 1% to 8% by weight, preferably 2% to 7.5% by weight, preferably 3% to 5% by weight It may contain a % concentration of one or more lubricants combined (or in total). In this embodiment, the pharmaceutical formulation contains 0.10% to 5% by weight relative to the weight of the pharmaceutical formulation. For example, it contains a lubricant in an amount of 0.75% to 3.25% by weight. In other embodiments, Pharmaceutical preparations contain 0.10% to 2% by weight (for example, 0.75% by weight) of the pharmaceutical preparation's weight. It contains fumed silica in an amount of % to 1.5% by weight.

[0100] The tablet dosage form may further include a coating. A preferred coating is a film-forming polymer. For example, cellulose derivatives (HPC (hydroxypropylcellulose), HPMC) (Hydroxypropoxymethylcellulose), MC (Methylcellulose), HPMCAS (e.g., hydroxypropoxymethylcellulose acetate succinate), dextrin N, starch, opdary (registered trademark), natural rubber, e.g., gum arabic, xanthan gum alginates, polyvinyl alcohols, polymethacrylates, and their derivatives, for example These include Eudragit (registered trademark), and these are used in various conventional methods in the pharmaceutical field. For example, it can be applied to tablets as a solution or suspension by means of film coating, etc. . In addition to any existing film-forming polymer, one or more auxiliary agents (e.g., Hydrophilizers, plasticizers, surfactants, dyes, and, for example, titanium dioxide. Coatings that may contain any white pigment are typically applied as a solution / suspension. .

[0101] In some embodiments, the pharmaceutical formulation according to the present invention comprises multiple particles forming the granular internal phase of the formulation. It comprises several granules and one or more excipients that form the outer phase of the granules of the formulation. Preferably The pharmaceutical preparation includes a tablet, and the tablet includes an inner granular phase and an outer granular phase.

[0102] As used herein, the term “granular interior phase” means together with and / or within the granules. This refers to the components of the formulation located in [the specified location]. As used herein, the term "granular outer phase" refers to granules. This refers to the components of the preparation located on the outside.

[0103] In some embodiments, the granular internal phase of the pharmaceutical formulation according to the present invention comprises the active pharmaceutical ingredient and , methacrylate copolymer, or cellulose derivative (methylcellulose (MC), ethyl Cellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose Rose (HPC), carboxymethylcellulose (CMC), carboxymethylcellulose Sodium (NaCMC) or hydroxypropylmethylcellulose (HPMC) Includes one or a combination of the following (etc.). In some embodiments, the present invention The granular phase of the pharmaceutical preparation consists of the active pharmaceutical ingredient and a methacrylate copolymer or hydroxyl Propylmethylcellulose (HPMC) and one or more excipients This includes combinations of those.

[0104] In some embodiments, the pharmaceutical formulation is at least 15% of the total weight of the pharmaceutical formulation. By weight %, at least 20% by weight, at least 25% by weight, at least 28% by weight, less 30% by weight, at least 34% by weight, at least 40% by weight, at least 45% by weight , at least 50% by weight, at least 55% by weight, at least 60% by weight, at least 6 It contains 5% by weight of the granular inner phase. In some embodiments, the pharmaceutical formulation is the total weight of the pharmaceutical formulation. Up to 99% by weight, up to 95% by weight, up to 93% by weight, up to 90% by weight relative to the quantity , up to 85% by weight, up to 80% by weight, up to 75% by weight, up to 74% by weight, up to 73% by weight, up to 70% by weight, up to 67% by weight, up to 63% by weight, up to 60% by weight It contains a granular inner phase of up to 53% by weight.

[0105] In some embodiments, the pharmaceutical formulation is preferably 1 in weight relative to the total weight of the pharmaceutical formulation. Weight % to 70% by weight, preferably 2% to 69% by weight, preferably 3% to 68% by weight %, preferably 4% by weight to 67% by weight, preferably 5% by weight to 66% by weight, preferably 6% by weight Weight % to 65% by weight, preferably 10% to 64% by weight, preferably 15% to 60% by weight Weight %, preferably 20% to 55% by weight, preferably 25% to 50% by weight, preferred The granular inner phase contains 30% to 45% by weight, preferably 35% to 40% by weight of API. Includes.

[0106] In some embodiments, the pharmaceutical formulation is 5% to 6% by weight of the total weight of the pharmaceutical formulation. 0% by weight, preferably 7% to 55% by weight, preferably 8% to 50% by weight, preferred The methacrylate copolymer is 17% to 45% by weight, preferably 15% to 45% by weight. or hydroxypropyl methylcellulose, or a combination thereof, granular inner phase Includes.

[0107] In some embodiments, the pharmaceutical formulation is 5% to 6% by weight of the total weight of the pharmaceutical formulation. 0% by weight, preferably 10% to 60% by weight, preferably 12% to 60% by weight, preferred The filler comprises approximately 15% to 50% by weight, preferably 18% to 45% by weight. It contains a granular internal phase.

[0108] In some embodiments, the pharmaceutical formulation is 1% by weight to 1% by weight of the total weight of the pharmaceutical formulation. 0% by weight, preferably 1% to 9% by weight, preferably 1.7% to 8% by weight, preferred The granules contain 1.6% to 7.5% by weight, preferably 2% to 5% by weight, of a disintegrant. Includes the Interior.

[0109] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~5% by weight, preferably 0.2% by weight to 4.7% by weight, preferably 0.5% by weight to 4.5% by weight Lubricant in weight %, preferably 0.8% to 4% by weight, preferably 1% to 3.5% by weight It contains a granular inner phase, which includes a granular inner phase.

[0110] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~5% by weight, preferably 0.2% by weight to 4.7% by weight, preferably 0.5% by weight to 4.5% by weight Weight percent, preferably 0.6% to 4.5% by weight, preferably 0.8% to 4.0% by weight The granular inner phase contains a surfactant in an amount of %, preferably 1% to 3.5% by weight.

[0111] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight The material contains a granular internal phase comprising a lubricant in an amount of weight %, preferably 0.7% to 2% by weight.

[0112] In some embodiments, the pharmaceutical formulation is at least 5 times the total weight of the pharmaceutical formulation. Quantity %, at least 7% by weight, at least 10% by weight, at least 15% by weight, at 20% by weight, at least 25% by weight, at least 28% by weight, at least 30% by weight, small It contains at least 34% by weight, and at least 35% by weight, of the granular outer phase. In some embodiments, Furthermore, the pharmaceutical preparation can be up to 75% by weight, up to 74% by weight, and up to the total weight of the pharmaceutical preparation. Large: 73% by weight, Maximum: 70% by weight, Maximum: 67% by weight, Maximum: 63% by weight, Maximum: 65% by weight Weight %, up to 60% by weight, up to 55% by weight, up to 53% by weight, up to 40% by weight It contains a granular outer phase. In some embodiments, the pharmaceutical formulation is, relative to the total weight of the pharmaceutical formulation At least 15% by weight to a maximum of 75% by weight, at least 25% by weight to a maximum of 70% by weight, At least 30% by weight to a maximum of 65% by weight, at least 35% by weight to a maximum of 60% by weight, It contains at least 35% to a maximum of 70% by weight of granular outer phase.

[0113] In some embodiments, the pharmaceutical formulation is at least 15% of the total weight of the pharmaceutical formulation. By weight %, at least 20% by weight, at least 25% by weight, at least 28% by weight, less Each contains 30% by weight, at least 34% by weight, and at least 35% by weight of granular internal phase. In several embodiments, the pharmaceutical formulation is up to 99% by weight of the total weight of the pharmaceutical formulation. Large: 93% by weight, Maximum: 85% by weight, Maximum: 80% by weight, Maximum: 75% by weight, Maximum: 74% by weight Weight %, up to 73% by weight, up to 70% by weight, up to 67% by weight, up to 65% by weight, Granular internal phase of up to 63% by weight, up to 60% by weight, up to 55% by weight, and up to 53% by weight. Includes. In some embodiments, the pharmaceutical formulation is at least the total weight of the pharmaceutical formulation. Also 15% to a maximum of 75% by weight, at least 25% to a maximum of 70% by weight, and at least 30% to a maximum of 65% by weight, at least 35% to a maximum of 60% by weight, and at least It also contains 35% to a maximum of 70% by weight of granular internal phase.

[0114] In some embodiments, the pharmaceutical formulation is (i) 5% to 45% by weight, 10% to 40% by weight, relative to the total weight of the pharmaceutical preparation. APIs of 15% to 35% by weight, (ii) 5% to 60% by weight, 10% to 50% by weight relative to the total weight of the pharmaceutical preparation , 15% to 55% by weight of methacrylate copolymer or hydroxypropylmethyl Cellulose or combinations thereof (iii) 5% to 60% by weight and 10% to 50% by weight relative to the total weight of the pharmaceutical preparation %, 15% to 40% by weight of filler (e.g., mannitol, microcrystalline cellulose), (iv) 1% to 10% by weight, 1.5% to 9% by weight relative to the total weight of the pharmaceutical preparation , 1.5% to 8% by weight of a disintegrant (e.g., croscarmellose sodium), (v) 0.1% to 5% by weight, 0.2% to 4.5% by weight relative to the total weight of the pharmaceutical preparation A lubricant in an amount of %, 0.5% to 4% by weight (e.g., colloidal fumed silica), (vi) 0.1% to 5% by weight, 0.2% to 4.5% by weight relative to the total weight of the pharmaceutical preparation A surfactant (e.g., sodium lauryl sulfate) in weight %, 0.5% to 4% by weight, and Beauty (vii) 0.1% to 3% by weight, 0.2% to 2% by weight, relative to the total weight of the pharmaceutical preparation. 5% by weight, 0.5% to 2% by weight of lubricant (e.g., magnesium stearate) It contains a granular inner phase, which includes a granular inner phase.

[0115] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~5.0% by weight, preferably 0.2% by weight ~ 4.7% by weight, preferably 0.5% by weight ~ 4 0.5% by weight, preferably 1% to 3.5% by weight, preferably 1.5% to 3% by weight It contains a granular outer phase that includes a disintegrant.

[0116] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~3% by weight, preferably 0.2% to 2.7% by weight, preferably 0.5% to 2.5% by weight The granular outer phase contains a lubricant in an amount of weight %, preferably 0.8% to 2% by weight.

[0117] In some embodiments, the pharmaceutical formulation is 0.1% by weight relative to the total weight of the pharmaceutical formulation. ~55wt%, 0.2wt%~50wt%, 0.3wt%~45wt%, 0.4wt%~ 40wt%, 0.5wt%~35wt%, 0.6wt%~30wt%, 0.7wt%~2 5% by weight, 0.8% to 20% by weight, 1% to 15% by weight, 1.3% to 12% by weight %, 2wt%~10wt%, 2.5wt%~9wt%, 3wt%~8wt%, 4wt%~ The granular outer phase contains 7% by weight and 5% to 6% by weight of filler.

[0118] In some embodiments, the pharmaceutical formulation is (a) 0.1% to 5.0% by weight, 0.2% to 4% by weight relative to the total weight of the pharmaceutical preparation. 5% by weight, 0.5% to 3% by weight of a disintegrant (e.g., croscarmellose sodium) , (b) 0.1% to 3% by weight, 0.2% to 2.5% by weight relative to the total weight of the pharmaceutical preparation A lubricant (e.g., magnesium stearate) in an amount of % or 0.5% to 2% by weight, and Beauty (c) 1% to 15% by weight, 1.5% to 10% by weight relative to the total weight of the pharmaceutical preparation , or 2% to 8% by weight of a filler (e.g., hydroxypropyl methylcellulose) It contains a granular outer phase, including a granular outer phase.

[0119] In some embodiments, the pharmaceutical formulation of the present invention comprises an inner granular phase and an outer granular phase, The agent contains granular internal phase of 50 mg to 17,000 mg, preferably 80 mg to 10,000 mg. The amount is 100 mg to 5000 mg, preferably 120 mg to 3000 mg, preferably 150 mg to 2500 mg, preferably 200 mg to 2000 mg, preferably 250 mg g to 1200 mg, or any specific amount or range of the granular inner phase contained therein. .

[0120] In some embodiments, the pharmaceutical formulation of the present invention comprises an inner granular phase and an outer granular phase, The agent is a granular outer phase of 4 mg to 1500 mg, preferably 6 mg to 1000 mg, preferably 8 mg to 500 mg, preferably 10 mg to 300 mg, preferably 15 mg to 250 mg g, preferably 20 mg to 200 mg, preferably 30 mg to 100 mg, or more Includes any specific amount or range of granular outer phase.

[0121] In some embodiments, the pharmaceutical formulation is 1 mg to 2000 mg, preferably 5 mg ~1500mg, preferably 5mg~1000mg, preferably 10mg~500mg, Preferably 15 mg to 400 mg, preferably 20 mg to 350 mg of API, or The granular inner phase includes any specific amount or range of API contained therein.

[0122] In some embodiments, the pharmaceutical formulation is 20 mg to 6000 mg, preferably 30 mg mg to 4000 mg, preferably 40 mg to 2000 mg, preferably 70 mg to 100 mg 0 mg of methacrylate copolymer or hydroxypropyl methylcellulose or so This includes one of these combinations, or any specific quantity or range contained therein. It contains a granular internal phase.

[0123] In some embodiments, the pharmaceutical formulation is 10 mg to 6500 mg, preferably 12 mg mg to 5000 mg, preferably 15 mg to 4000 mg, preferably 15 mg to 200 mg 0 mg, preferably 18 mg to 1000 mg, preferably 18 mg to 500 mg of diluent / fillers, or any specific amount or range of diluents / fillers contained therein, It contains a granular internal phase.

[0124] In some embodiments, the pharmaceutical formulation is 0.5 mg to 300 mg, preferably 0. 6 mg to 250 mg, preferably 0.8 mg to 200 mg, preferably 1 mg to 150 mg g, preferably 1.2 mg to 100 mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg of surfactant, or any specific amount or range contained therein It contains a granular internal phase which includes a surfactant.

[0125] In some embodiments, the pharmaceutical formulation is 2 mg to 720 mg, preferably 4 mg to 650 mg, preferably 5 mg to 400 mg, preferably 6 mg to 300 mg, preferably The dosage is 7 mg to 200 mg, preferably 7.5 mg to 100 mg, preferably 8 mg to 60 mg. g of disintegrant, or any specific amount or range of disintegrant contained therein, within granules Includes phase.

[0126] In some embodiments, the pharmaceutical formulation is 1 mg to 400 mg, preferably 2 mg to 350 mg, preferably 3 mg to 300 mg, preferably 4 mg to 200 mg, preferably The dosage is 5 mg to 100 mg, preferably 6 mg to 50 mg, preferably 8.5 mg to 35 mg. A granular inner phase comprising a lubricant, or any specific amount or range of a lubricant contained therein. nothing.

[0127] In some embodiments, the pharmaceutical formulation is 0.3 mg to 90 mg, preferably 0.5 mg mg to 70 mg, preferably 0.6 mg to 50 mg, preferably 0.7 mg to 25 mg, Preferably 0.8 mg to 10 mg of lubricant, or any specific amount contained therein It contains a granular internal phase which includes a range of lubricants.

[0128] In some embodiments, the pharmaceutical formulation is (i) 1 mg to 2000 mg, preferably 5 mg to 1500 mg, preferably 5 mg to 1000 mg, preferably 10 mg to 500 mg, preferably 15 mg to 400 mg, The API is 20mg to 350mg. (ii) 20 mg to 6000 mg, preferably 30 mg to 4000 mg, preferably 4 0 mg to 2000 mg, preferably 70 mg to 1000 mg, of methacrylate copolymer. or hydroxypropyl methylcellulose or one of the combinations thereof, (iii) 10 mg to 6500 mg, preferably 12 mg to 5000 mg, preferably 15mg to 4000mg, preferably 15mg to 2000mg, preferably 18mg to 1 000 mg, preferably 18 mg to 500 mg of diluent / filler (e.g., mannitol) (microcrystalline cellulose), (iv) 2 mg to 720 mg, preferably 4 mg to 650 mg, preferably 5 mg to 4 00 mg, preferably 6 mg to 300 mg, preferably 7 mg to 200 mg, preferably 7.5 mg to 100 mg, preferably 8 mg to 60 mg of a disintegrant (e.g., croscarmellose) (Sodium cellulose), (v) 1 mg to 400 mg, preferably 2 mg to 350 mg, preferably 3 mg to 30 0 mg, preferably 4 mg to 200 mg, preferably 5 mg to 100 mg, preferably 6 mg to 50 mg, preferably 8.5 mg to 35 mg of lubricant (e.g., colloidal fume) (Dosilica), (vi) 0.5 mg to 300 mg, preferably 0.6 mg to 250 mg, preferably 0 0.8mg to 200mg, preferably 1mg to 150mg, preferably 1.2mg to 100mg mg, preferably 1.5 mg to 80 mg, preferably 2 mg to 30 mg of surfactant (e.g.) For example, sodium lauryl sulfate, and (vii) 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 0. 6 mg to 50 mg, preferably 0.7 mg to 25 mg, preferably 0.8 mg to 10 mg Lubricants (e.g., magnesium stearate) It contains a granular inner phase, which includes a granular inner phase.

[0129] In some embodiments, the pharmaceutical formulation is 0.6 mg to 180 mg, preferably 1 mg. g to 100 mg, preferably 2 mg to 80 mg, preferably 3 mg to 50 mg, preferably It contains a granular outer phase with 5 mg to 20 mg of a disintegrant.

[0130] In some embodiments, the pharmaceutical formulation is 3.5 mg to 1100 mg, preferably 5 mg to 500 mg, preferably 10 mg to 250 mg, preferably 15 mg to 100 mg The granular outer phase preferably contains 25 mg to 90 mg of diluent / filler.

[0131] In some embodiments, the pharmaceutical formulation is 0.3 mg to 90 mg, preferably 0.5 mg mg to 70 mg, preferably 1 mg to 50 mg, preferably 1.5 mg to 20 mg, preferred Alternatively, it contains a granular outer phase containing 2 mg to 10 mg of lubricant.

[0132] In some embodiments, the pharmaceutical formulation is (a) 0.6 mg to 180 mg, preferably 1 mg to 100 mg, preferably 2 mg to 80 mg, preferably 3 mg to 50 mg, preferably 5 mg to 20 mg of disintegrant (e.g.) (For example, croscarmellose sodium), (b) 0.3 mg to 90 mg, preferably 0.5 mg to 70 mg, preferably 1 mg to 50 mg, preferably 1.5 mg to 20 mg, preferably 2 mg to 10 mg of lubricant (e.g. For example, magnesium stearate, and (c) 3.5 mg to 1100 mg, preferably 5 mg to 500 mg, preferably 10 mg g to 250 mg, preferably 15 mg to 100 mg, preferably 25 mg to 90 mg Diluent / filler (e.g., hydroxypropyl methylcellulose) It contains a granular outer phase, including a granular outer phase.

[0133] Those skilled in the art will know that a suitable pharmaceutically acceptable excipient is compatible with other excipients and has medicinal properties. It is easily recognizable that the active ingredient is selected so as not to bind to it or cause its decomposition. Let it be recognized.

[0134] None of the above descriptions relating to the components of the pharmaceutical formulations are any other aspects or embodiments of the present invention It will be understood that this can be applied to all of these situations.

[0135] Active ingredients in pharmaceuticals Appropriate active pharmaceutical ingredients (APIs) can restore, modify, or alter physiological functions. or for the purpose of performing medical diagnosis, exerting pharmacological, immunological, or metabolic effects. These include analgesics and anti-inflammatory drugs, antiarrhythmic drugs, antibacterial agents and Antiparasitic agents, anticoagulants, antidepressants, antidiabetic drugs, antiepileptic drugs, antifungal agents, antihistamines Antihypertensive drugs, antimuscarinic drugs, antineoplastic agents and antimetabolites, antimigraine drugs, antiparkinsonian drugs Antipsychotics, hypnotics and sedatives, antistroke drugs, cough suppressants, antivirals, β-adrenergic Electron receptor blockers, cardiac inotropic agents, corticosteroids, disinfectants, diuretics, enzymes, essential oils, stomach Intestinal drugs, lipid regulators, local anesthetics, opioid analgesics, parasympathetic stimulants and antidementia drugs, Examples include sex hormones, stimulants, and vasodilators.

[0136] The present invention relates to a pharmaceutical formulation, a) API and, b1) Methacrylic acid copolymer, b2) Cellulose derivatives, for example, methylcellulose (MC), ethylcellulose (E C), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) ), carboxymethylcellulose (CMC), sodium carboxymethylcellulose ( NaCMC or hydroxypropyl methylcellulose (HPMC), or the same combinations, including, API provides a pharmaceutical formulation that is a dengue virus replication inhibitor.

[0137] In particular, APIs exist in an amorphous or soluble state (i.e., molecular dispersion) within pharmaceutical formulations.

[0138] In one embodiment, the API is a dengue virus replication inhibitor. Embodiments of the present invention This refers to a pharmaceutical preparation described herein, wherein the API is a compound of formula (I),

[0139] [ka] The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is , A compound in which R1 is H, R2 is F, and R3 is either H or CH3. A compound in which R1 is H, CH3, or F, R2 is OCH3, and R3 is H. A compound in which R1 is H, R2 is OCH3, and R3 is CH3. A compound in which R1 is CH3, R2 is F, and R3 is H. A compound in which R1 is CF3 or OCF3, R2 is H, and R3 is H. A compound in which R1 is OCF3, R2 is OCH3, and R3 is H, A compound in which R1 is OCF3, R2 is H, and R3 is CH3. Includes pharmaceutical preparations selected from the group.

[0140] An additional embodiment of the present invention is a pharmaceutical formulation described herein, wherein the API is as follows: A compound of formula (I) selected from the group,

[0141] [ka]

[0142] [ka] or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs, pharmaceuticals Includes formulations.

[0143] In particular, APIs are compounds of formula (I), or their enantiomers, diastereomers, or This is a pharmaceutically acceptable salt form.

[0144] In particular, APIs are compounds of formula (I) in an amorphous or dissolved state (i.e., molecular dispersion), These are its enantiomers, diastereomers, or pharmaceutically acceptable salt forms.

[0145] In particular, when used as a starting material in the process for preparing the pharmaceutical formulations described herein The API used is the compound of formula (I), or its enantiomer, diastereomer, or solvent. A mediator or a pharmaceutically acceptable salt form, which is the final pharmaceutical formulation as defined herein. Alternatively, the API in the solid dosage form is a compound of formula (I) or its equivalent in amorphous or dissolved form. This is a nantiomer, diastereomer, or pharmaceutically acceptable salt form.

[0146] In one preferred embodiment, the compound of formula (I) is

[0147] [ka] Compound (a), or its stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs. It is the body.

[0148] The API is in the form of compound (a) or its solvate or pharmaceutically acceptable salt. The API may be compound (a) or a pharmaceutically acceptable salt form thereof. For example, it may be a compound (a) in a solvated form as a monohydrate. Preferably, the API is Compound (a) is used. Preferably, the API is the (S)-enantiomer of compound (a). There is. Preferably, the API is compound (a) in an anhydrous form. Preferably, the API is amorphous. Compound (a) is in an amorphous form. Preferably, the API is in an amorphous or dissolved state. The substance (a) or a pharmaceutically acceptable salt form thereof. Preferably, the API is in amorphous form. Alternatively, the compound (a) is in a dissolved state. Preferably, the API is the compound (a) in an amorphous form. It is the (S)-enantiomer of compound (a) in its anhydrous form. S)- It is an enantiomer.

[0149] In particular, when used as a starting material in the process for preparing the pharmaceutical formulations described herein The API used is compound (a), or its solvated form or pharmaceutically acceptable salt form. On the other hand, APIs in the final pharmaceutical formulation or solid dosage form are amorphous or dissolved compounds. The substance (a) or a pharmaceutically acceptable salt form thereof.

[0150] In particular, when used as a starting material in the process for preparing the pharmaceutical formulations described herein The API used is the compound (a) in solvated form or a pharmaceutically acceptable salt form thereof. On the other hand, APIs in the final pharmaceutical formulation or solid dosage form are in amorphous form or dissolved state (i.e., molecular fractions) Compound (a) of the powder or a pharmaceutically acceptable salt form thereof.

[0151] The compound of formula (I) is described in its entirety in International Publication No. 2016 / 180696 (see reference). It can be synthesized according to the procedure disclosed in the specification (which is incorporated into the specification).

[0152] Any of the above descriptions regarding the active pharmaceutical ingredient may apply to the pharmaceutical preparations and solid dosage forms described herein. Applicable to any embodiment of the process, use, and methods of prevention, treatment, and virus inhibition. It will be understood that this is possible. For example, any mention of dengue virus replication inhibitors. This refers to the compound of formula (I), or its stereoisomers, pharmaceutically acceptable salts, solvates, or cocrystals. Alternatively, it could refer to a polymorph.

[0153] In certain embodiments, the API in the pharmaceutical formulation described herein is compound (a) or These are stereoisomers, pharmaceutically acceptable salts, solvates, or polymorphs. In terms of form, the API in the pharmaceutical formulation described herein is compound (a).

[0154] In certain embodiments, the API in the pharmaceutical formulation described herein is in amorphous or soluble form. It is a dengue virus replication inhibitor in a decontaminated state. In specific embodiments, the following is described herein. APIs in pharmaceutical formulations are compounds (a) in amorphous or soluble form or their pharmaceutically acceptable form. It is in the form of a salt. In certain embodiments, the API in the pharmaceutical formulation described herein is (a) is a compound in an amorphous or dissolved state.

[0155] solid dosage form The present invention also provides solid dosage forms, including the pharmaceutical formulations described herein.

[0156] The dosage form may be an oral dosage form (e.g., a capsule for oral administration). Alternatively, dosage form It may be in an enteral dosage form. Alternatively, the solid dosage form may be a tablet.

[0157] The solid dosage forms (e.g., tablets) described herein are APIs ranging from 0.1 mg to 3000 mg. APIs ranging from 1mg to 2000mg, 5mg to 1000mg, and 10mg to 500mg APIs for 20mg-400mg, 30mg-300mg, 50mg- APIs of 200mg, 70mg-150mg, and 100mg-120mg or may contain any specific amount or range of APIs included therein. The therapeutically effective dose varies depending on the disease, syndrome, condition, and disorder being prevented or treated.

[0158] The solid dosage forms (e.g., tablets) described herein contain 0.5 mg to 1000 mg of API. It may contain. In some embodiments, the solid dosage form is 0.5 mg to 800 mg, for example It may contain 1.0 mg to 600 mg, for example, 2.0 mg to 450 mg, preferably, The API is

[0159] [ka] It is (compound (a)), preferably the (S)-enantiomer of compound (a). The solid dosage form contains at least 2 mg, at least 10 mg, at least 50 mg, and at 100 mg, at least 200 mg, at least 300 mg, at least 400 mg or It may contain at least 500 mg of compound (a).

[0160] In one particular embodiment, the solid dosage form is a tablet, a) API and, b1) Methacrylic acid copolymer, b2) Cellulose derivatives, for example, methylcellulose (MC), ethylcellulose (E C), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) ), carboxymethylcellulose (CMC), sodium carboxymethylcellulose ( NaCMC or hydroxypropyl methylcellulose (HPMC), or the same combinations, including, API is a tablet that acts as a dengue virus replication inhibitor.

[0161] In one particular embodiment, the solid dosage form is a tablet, a) API and, b1) Methacrylic acid copolymer, b2) Hydroxypropyl methylcellulose (HPMC), d) Disintegrants, binders, diluents, lubricants, stabilizers, wetting agents, lubricants, osmotic agents, colorants, etc. One or more pharmaceutically acceptable excipients selected from plasticizers and coatings, and , including, API is a tablet that acts as a dengue virus replication inhibitor.

[0162] In one particular embodiment, the solid dosage form is a tablet containing the pharmaceutical formulation of the present invention.

[0163] In one embodiment, the solid dosage form is a pharmaceutical preparation, and this preparation contains at least 5 mg , at least 15 mg, at least 25 mg, at least 50 mg, at least 55 mg , at least 100 mg, at least 150 mg, at least 200 mg, at least 2 50mg, at least 300mg, at least 350mg, at least 400mg, less It contains at least 450 mg or at least 500 mg of API, preferably the API is

[0164] [ka] This includes pharmaceutical preparations that are either pharmaceutically acceptable salt forms thereof.

[0165] For oral administration, the solid dosage form should contain at least 1.0 mg, at least 0.5 mg, At least 1 mg, at least 5 mg, at least 10 mg, at least 20 mg, less At least 30mg, at least 40mg, at least 50mg, at least 60mg, less At least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, At least 110 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, and less Also 180mg, at least 190mg, at least 200mg, at least 210mg, At least 220 mg, at least 230 mg, at least 240 mg, at least 25 0 mg, at least 260 mg, at least 270 mg, at least 280 mg, less 290 mg each, at least 300 mg, at least 310 mg, at least 320 mg , at least 330 mg, at least 340 mg, at least 350 mg, at least 3 60mg, at least 370mg, at least 380mg, at least 390mg, less At least 400 mg, at least 410 mg, at least 420 mg, at least 430 mg g, at least 440 mg, at least 450 mg, at least 460 mg, at least 470 mg, at least 480 mg, at least 490 mg, and at least 500 mg , at least 510 mg, at least 520 mg, at least 530 mg, at least 5 40mg, at least 550mg, at least 560mg, at least 570mg, less at least 580 mg, at least 590 mg, at least 600 mg, at least 610 mg g, at least 620 mg, at least 630 mg, at least 640 mg, at 650 mg, at least 660 mg, at least 670 mg, at least 680 mg, less At least 690mg, at least 700mg, at least 710mg, at least 720 mg, at least 730 mg, at least 740 mg, at least 750 mg, less than Also 760mg, at least 770mg, at least 780mg, at least 790mg, At least 800 mg, at least 810 mg, at least 820 mg, at least 83 0 mg, at least 840 mg, at least 850 mg, at least 860 mg, less 870 mg each, at least 880 mg, at least 890 mg, at least 900 mg , at least 910 mg, at least 920 mg, at least 930 mg, at least 9 40mg, at least 950mg, at least 960mg, at least 970mg, less at least 980 mg, at least 990 mg, at least 1000 mg, at least 110 0 mg, at least 1200 mg, at least 1210 mg, at least 1220 mg, At least 1230 mg, at least 1240 mg, at least 1250 mg, and at least 1260mg, at least 1270mg, at least 1280mg, at least 129 0 mg, at least 1300 mg, at least 1410 mg, at least 1320 mg, At least 1330mg, at least 1340mg, at least 1350mg, and at least 1360mg, at least 1370mg, at least 1390mg, at least 140 It is provided in the form of tablets containing 0 mg of API, or any value of API included in the above-mentioned values. In particular, the solid dosage form contains 15 mg to 500 mg of API.

[0166] Advantageously, this API or solid dosage form may be administered in a once-daily dose, or 1 The total daily dose may be divided and administered in 2, 3, 4, or 5 doses per day. The daily dose may be maintained unchanged throughout all or part of the treatment or prophylactic period. The daily dose may change during the treatment or prophylactic period, for example, during the treatment or The daily dose may be increased and / or decreased during the prophylactic period. For example, the daily dose may be increased and / or decreased during the first day. , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 days or longer It remains unchanged, and thereafter, over the remainder of the treatment or prophylactic period, it is lower and / or higher. The daily dose may continue. The remaining number of days in the treatment or prophylactic period is 1, 2, 3, 4, 5. , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2 0, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 ,34,35,36,37,38,39,40,41,42,43,44,45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 6 It may be 0 days or more. APIs or solid dosage forms may also be used at least once a week. At least once every two weeks, at least once every three weeks, at least once every four weeks or once a month, At least once every two months, at least once every three months, at least once every four months, at least It may also be administered once every five months, at least once every six months, or at least once a year. API or solid dosage forms are also available in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 6, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 ,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, Administer daily for 53, 54, 55, 56, 57, 58, 59, 60 days or longer. This may be done, and thereafter at least once a week, at least once every two weeks, and at least three weeks. Once every four weeks or once every month, at least once every two months, at least three times Once a month, at least once every four months, at least once every five months, at least once every six months Or, it may be administered at least once a year.

[0167] In a particular embodiment, the API or solid dosage form is used during a first period (e.g., loading phase). ) at the first dose, and at the second dose over a second period (e.g., maintenance phase) It can be administered as follows. The loading phase is as described in this specification (e.g., about 10 mg to about 1 (000mg, approximately 25mg to approximately 800mg, or approximately 50mg to approximately 400mg) This may include administration. The first administration period in the loading phase is the period intended herein (for example) It could be one of the following: approximately 1 to 40 days, approximately 3 to 20 days, or approximately 5 to 10 days. The maintenance phase is performed using the dosages described herein (for example, approximately 10 mg to approximately 1000 mg). This may include administration of either approximately 25 mg to approximately 800 mg, or approximately 50 mg to approximately 400 mg. The second administration period in the maintenance phase is the period intended herein (e.g., about 1 day to It could be one of the following: approximately 60 days, approximately 5 to 45 days, or approximately 10 to 30 days.

[0168] The optimal dose of the administered pharmaceutical preparation can be easily determined, depending on the specific compound used and the method of administration. It varies depending on the formula, the strength of the formulation, and the progression of the disease, syndrome, condition, or disorder. The above dosage is an example of an average case. Needless to say, higher or lower doses are not appropriate. There may be individual cases where the dosage range is effective, and these are also included within the scope of the present invention. Born.

[0169] The present invention also provides a process for preparing the pharmaceutical formulations described herein. Seth, a) A step of dissolving the API in a solvent to form a solution, b) Methacrylic acid copolymer or hydroxypropyl methylcellulose or the same The combination is mixed with the solution formed in step a) to obtain a mixture, for example Then, the mixture is further stirred, c) A step of spray-drying the mixture to obtain a solid dispersion, d) Selectively combine the solid dispersion with one or more pharmaceutically acceptable excipients. The process of adding, This specification provides the solid dosage forms described herein.

[0170] As used herein, the term "solid dispersion" refers to AP in a solid matrix. A dispersion of I, wherein the matrix consists of small molecules, polymers, or combinations thereof. It means something that includes.

[0171] The pharmaceutical formulation according to the present invention comprises a solid dispersion in which the matrix is ​​a polymer, and this polymer Mer is methacrylate copolymer, or methylcellulose (MC), ethylcellulose ( EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HP C), carboxymethylcellulose (CMC), sodium carboxymethylcellulose Cellulose (NaCMC) or hydroxypropyl methylcellulose (HPMC) Cellulose derivatives or combinations thereof are selected. Preferably, the cellulose derivative is It's HPMC.

[0172] The present invention also relates to a process for preparing solid dosage forms described herein, a) A step of dissolving the API in a solvent to form a solution, b) Methacrylic acid copolymer, or methylcellulose (MC), ethylcellulose (E C), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) ), carboxymethylcellulose (CMC), sodium carboxymethylcellulose ( Cellulose derivatives such as NaCMC or hydroxypropylmethylcellulose, These combinations are mixed with the solution formed in step a), thereby obtaining a mixture. Then, a step of optionally further stirring the mixture, c) A step of spray-drying the mixture to obtain a solid dispersion, d) Selectively combine the solid dispersion with one or more pharmaceutically acceptable excipients. The process involves adding, for example, pharmaceutically acceptable excipients include fillers, surfactants, and disintegrants. A process that can be selected from the group including destructors, lubricants, and mixtures thereof, e) The process of compressing the blend into tablets, This specification provides a process for providing the solid dosage forms described herein.

[0173] In some embodiments, the process for preparing the solid dosage forms described herein S is a) A step of dissolving the API in a solvent to form a solution, b) Methacrylic acid copolymer or hydroxypropyl methylcellulose or the same The combination is mixed with the solution formed in step a) to obtain a mixture, and any A step of selectively further stirring the mixture, c) A step of spray-drying the mixture to obtain a solid dispersion, d) The solid dispersion comprises at least one filler, at least one surfactant, and at least The process of blending with another disintegrant, at least one lubricant and at least one lubricant. and, e) The process of granulating the blend, f) The mixture obtained in step e) contains at least one disintegrant, a filler and at least one The process involves blending with two lubricants, g) The process of compressing the blend into tablets, This specification provides the solid dosage forms described herein.

[0174] In some embodiments, the solid dispersion is obtained using hot melt extrusion molding. This can be done. In some embodiments, the process of granulating the blend is performed using a roller compressor. This is done using or by slugging.

[0175] Another aspect of the present invention provides a packaged pharmaceutical formulation, wherein the pharmaceutical formulation is packaged in a blister film. Any formulation described herein (e.g., a tablet) sealed in a blister film This is a formulation holder configured to hold one or more pharmaceutical formulations (e.g., tablets). It includes a layer and a sealing layer configured to cover the retaining layer in order to seal a pharmaceutical formulation within the retaining layer. The sealing layer includes aluminum foil and a desiccant material. When used herein, "dry The term "desiccant material" refers to any hygroscopic substance that is useful as a desiccant. Examples of desiccant materials Examples include silica (e.g., silica gel), activated carbon, calcium sulfate, calcium chloride, Examples include, but are not limited to, zeolite materials.

[0176] In some embodiments, the retaining layer comprises one or more chambers, and each chamber Nba is one or more pharmaceutical formulations (for example, any pharmaceutical formulation described herein). For example, configured to hold one or more tablets, each chamber has a sealing layer It is sealed by a transparent or opaque material (e.g., For example, a transparent or opaque polyethylene material. In some embodiments, a sealing layer It completely overlaps the retaining layer and any chamber provided in the retaining layer.

[0177] An example of a commercially available blister film useful for this invention is one available from Amcor plc. Possible options include Dessiflex Plus and Dessiflex Ultra. In some embodiments, the packaged pharmaceutical formulation is sealed in a blister film. One or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-4, 2 It consists of 10 tablets (or 1 to 10 tablets), and the blister film contains one card. The stability and shelf life of the pharmaceutical formulation of the present invention are determined by a blister pack having a sealing layer lacking a desiccant material. The packaging of pharmaceutical preparations in a film (for example, Aclar 400 blister film) In comparison, the blister film packaging of the present invention, in which the sealing layer contains a desiccant material, This will improve the situation.

[0178] Another aspect of the present invention relates to packaged pharmaceutical preparations such as any packaged pharmaceutical preparation described herein. The kit includes a drug formulation and instructions for administering the packaged drug formulation.

[0179] None of the above considerations regarding solid dosage forms and processes for their preparation are described herein. It is understood that this can be applied to any embodiment of the solid dosage form, process, prevention, and treatment described herein. It will probably happen.

[0180] Methods of prevention, treatment, or inhibition The present invention also provides pharmaceutical formulations and solid dosage forms described herein for use as pharmaceuticals. This invention further encompasses the dengue virus infection in biological in vitro samples or subjects. Prevention of infection, treatment of dengue virus infection, or inhibition of dengue virus replication. This method includes methods for causing harm. This method applies to effective amounts of the pharmaceutical formulations and solid dosage forms described herein. This includes administering it to an in vitro sample or a subject (that requires it). The sample or subject is at risk of dengue virus infection or is infected with dengue virus. They are doing it.

[0181] The pharmaceutical preparations described herein may be administered in any of the aforementioned dosage forms and regimens, or Whenever the use of a pharmaceutical formulation is required by those who need it, it is confirmed in the art. They can be administered in the established dosage forms and regimens.

[0182] The pharmaceutical formulations and dosage forms of the present invention are for the treatment, improvement, and / or treatment of diseases, syndromes, conditions or disorders. In a subject requiring prevention, a method for treating, improving, and / or preventing it It is useful. Such methods are necessary for such treatment, improvement, and / or prevention. A therapeutically effective dose of the formulation or dosage form described in this specification for subjects including animals, mammals, and humans. A drug comprising, and / or essentially comprising, the administration of a drug active ingredient. In embodiments in which a dengue virus replication inhibitor is present, the pharmaceutical formulation and dosage form of the present invention are Diseases, syndromes, and conditions affected by inhibition of dengue virus replication, treatment, remission, and It is useful in methods of infection / prevention.

[0183] A U.K.D. is intended for those who require prevention of dengue virus infection (such as In animals (including mammals and humans) that require protection, a method for preventing it The method involves administering to the subject a therapeutically effective amount of the pharmaceutical preparation or dosage form described herein. It applies to the law.

[0184] One day, the device is intended for individuals who require treatment for dengue virus infection (such treatment In animals (including mammals and humans) that require medical treatment, a method of treating it The method involves administering to the subject a therapeutically effective amount of the pharmaceutical preparation or dosage form described herein. It applies to the law.

[0185] A certain model requires the inhibition of dengue virus replication (and In animals, mammals, and humans (including humans) that require such treatment, a method that inhibits it A law that allows for the administration of a therapeutically effective amount of the pharmaceutical preparation or dosage form described herein to a subject. This includes methods.

[0186] In a particular embodiment, the plasma level of the API is, for example, a therapeutic regimen (for therapeutic use) During the period of (or for prophylactic use), approximately 5 ng / mL to approximately 10,000 ng / mL, approximately 10 ng / mL ~Approx. 8,000ng / mL, approx. 15ng / mL ~ approx. 6,500ng / mL, approx. 20ng / mL ~ approx. 5,000ng / mL, approx. 25ng / mL ~ approx. 4,500ng / mL, approx. 30n g / mL to approximately 3,000 ng / mL, approximately 40 ng / mL to approximately 2,000 ng / mL, if The range is approximately 50 ng / mL to approximately 1,000 ng / mL, or any single value within that range. The 'k' represents a partial range level. In a particular embodiment, the maximum plasma level of the API The maximum values ​​are approximately 10,000 ng / mL, 8,000 ng / mL, and 6,500 ng / mL, maximum approximately 4,500ng / mL, maximum approximately 3,000ng / mL, maximum approximately 2,0 00 ng / mL, a maximum of approximately 1,000 ng / mL, or any single value or portion within that range. It is a range. In a particular embodiment, for example, a treatment regimen (for treatment or prevention) The minimum plasma level of API during this period was at least approximately 5 ng / mL and at least approximately 10 ng / mL. g / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 2 5 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at Approximately 50 ng / mL, or any single value or sub-range within that range. (As referred to herein) The plasma levels obtained are achieved using any of the doses and / or drug regimens described herein. You can obtain it by doing so.

[0187] In another embodiment of the present invention, the pharmaceutical formulation described herein comprises one or two or more It can be used in combination with the other drugs mentioned above, more specifically, with other antiviral agents.

[0188] Modifications to the aforementioned embodiments of the present invention are made while still remaining within the scope of the present invention. It will be understood that this is possible. Each feature disclosed herein is unless otherwise specified. It may be replaced by an alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, each disclosed feature is not a general set of equivalent or similar features. This is just one example of a symptom.

[0189] Method of administration The above compounds and pharmaceutically acceptable formulations are used in humans and other animals for the prevention or treatment of disease. Depending on the severity of the infection, the method of administration may be oral, rectal, cisterna magna, vagina, abdominal cavity, or topical (powder, ointment, or It can be administered as a drop, buccal mucosa, oral spray, or nasal spray.

[0190] While not limited to these, liquid dosage forms for oral administration are pharmaceutically acceptable. Emulsions, microemulsions, solutions, suspensions, syrups, and elixirs Examples include agents. In addition to active compounds, liquid dosage forms are commonly used in the art. Inert diluents, such as water or other solvents, solubilizers and emulsifiers (e.g., ethyl alcohol) Coal, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formaldehyde Mido), oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil) (Oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycerol It may contain fatty acid esters of kohl and sorbitan, and mixtures thereof. In addition to dissolving agents, oral formulations also contain adjuvants (e.g., humectants, emulsifiers, and suspending agents). It may also contain suspending agents, sweeteners, flavoring agents, and fragrances.

[0191] Formulations for rectal or vaginal administration, in particular, contain the compounds described herein in a suitable non-irritating manner. Excipients or carriers (for example, cocoa butter, polyethylene glycol, or (ambient temperature) It is a solid at body temperature, but is liquid at body temperature, and therefore melts and activates in the rectum or vaginal cavity. It is a suppository that can be prepared by mixing it with a suppository wax (which releases a substance).

[0192] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is at least one inert pharmaceutically acceptable Excipients or carriers, such as sodium citrate or dicalcium phosphate, and (a) diluents or bulking agents (e.g., starch, lactose, sucrose, glycerides) (b) Lucose, mannitol, and silicic acid), (b) Binder (e.g., carboxymethyl cellulose) (Rose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia) (c) Humectants (e.g., glycerol), (d) Disintegrants (e.g., agar, calcium carbonate) Potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate (a) a ammonium compound, (e) a solubility retardant (e.g., paraffin), (f) an absorption enhancer (e.g., quaternary ammonium compound). (Ammonium compounds), (g) Wetting agents (e.g., acetyl alcohol and monostearin) (glycerol acid), (h) absorbent (e.g., kaolin and bentonite clay), and ( i) Lubricants (e.g., talc, calcium stearate, magnesium stearate, solid Polyethylene glycol, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0193] Similar types of solid formulations include excipients (e.g., lactose or milk sugar) and high molecular weight polypropylene. As a diluent for soft and hard-filled gelatin capsules using ethylene glycol, etc. It can also be used. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills and granules are coated. and shells, for example, enteric coatings and other well-known coatings in the field of pharmaceutical formulation technology. These can be prepared using coatings. These may optionally contain an opacifying agent. It may also be done in an optional, delayed manner, in a specific part of the gastrointestinal tract, The formulation may release only the active ingredient or preferentially release it. Examples of implantable formulations include polymer materials and waxes. Solid formulations of this type contain excipients (e.g., lactose or milk sugar, and high molecular weight polyethylene). It is also used as a diluent in soft and hard-filled gelatin capsules (such as those used in recalls). It is possible.

[0194] The active compound is also a microcapsule containing one or more excipients, as described above. It can be in a chemical form. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills and granules are coated. and shells, for example, enteric coatings, controlled-release coatings, and techniques for pharmaceutical formulations. It can be prepared using other coatings well known in the field. Such solid In the dosage form, the active compound is combined with at least one inert diluent, such as sucrose or lavone. It can be mixed with lactose or starch. Such dosage forms are conventionally inactivated. Additional substances other than diluents, such as tableting lubricants and other tableting aids, such as stearyl It may also contain magnesium phosphate and microcrystalline cellulose. In the case of capsules, tablets and pills, the agent The form may also include a buffering agent. These may optionally contain an opacifying agent, and also, In a selectively delayed manner, the active ingredient is released only in a specific part of the digestive tract. It may be a formulation that releases or preferentially releases it. Embeddings that can be used Examples of formulations include polymeric substances and waxes.

[0195] Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, This includes creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredients are pharmaceutically acceptable carriers and, if necessary, any required preservatives under sterile conditions. Alternatively, it may be mixed with a buffering agent. Ophthalmic formulations, ear drops, and eye drops are also within the scope of the present invention. Furthermore, the present invention intends to use a transdermal patch, which controls the introduction of compounds into the body. Such a dosage form has the additional advantage of providing controlled delivery. It can be prepared by dissolving or distributing it in. Using an absorption enhancer, the skin It is also possible to increase the flow of crossing compounds. The velocity provides a velocity control film, or The compound can be controlled by dispersing it in a polymer matrix or gel. Cut.

[0196] The formulations described herein may be administered orally, as an inhalation spray, topically, rectally, intranasally, via the buccal mucosa, or vaginally. It can be administered via an implantable reservoir.

[0197] The pharmaceutical preparations described herein include capsules, tablets, pills, aqueous suspensions, or aqueous solutions. However, it may be administered orally in any orally acceptable dosage form, not limited to these. For tablets intended for use, commonly used carriers include lactose and corn methyl phosphate. Examples include, but are not limited to, lubricants such as magnesium stearate. It is also typically added. In relation to oral administration in capsule form, it is a useful diluent. Examples include lactose and dried corn starch. An aqueous suspension is required for oral use. If required, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or colorings may also be added.

[0198] Alternatively, the pharmaceutical formulations described herein may be administered in the form of suppositories for rectal administration. These drugs are solid at room temperature but liquid at rectal temperature, and therefore the rectum It is prepared by mixing it with a suitable non-irritating excipient that dissolves internally and releases the drug. This can be done. Such materials include cocoa butter, beeswax, and polyethylene glycol. These include, but are not limited to, the following:

[0199] The pharmaceutical formulations described herein also have, in particular, targets for prevention and / or treatment of the eyes, skin, or This includes areas or organs that are easily accessible by topical application, including diseases of the lower intestinal tract. In combination, it can be administered topically. Suitable topical formulations are for each of these areas or organs, It is easily prepared. For local application to the lower intestinal tract, use a rectal suppository formulation (see above) or a suitable enema. This can be done using a pharmaceutical formulation. Topical transdermal patches can also be used.

[0200] For topical application, the pharmaceutical formulation contains an active ingredient suspended or dissolved in one or more carriers. It can be formulated into a suitable ointment containing the compound of the present invention. Suitable carriers for topical administration of the compound include mineral oil and liquid Petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropyl This includes, but is not limited to, pyrene compounds, emulsifying waxes, and water. Alternatively, A pharmaceutical preparation is an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. It can be formulated into a suitable lotion or cream containing the following. Suitable carriers include mineral oil, mono Sorbitan stearate, polysorbate 60, cetyl ester wax, cetearyl ester It contains ethanol, 2 octyldodecanol, benzyl alcohol, and water, but these Not limited to this.

[0201] Pharmaceutical preparations can also be administered by intranasal aerosol or inhalation. The formulation is prepared in accordance with well-known techniques in the field of pharmaceutical formulations, and benzyl alcohol A suitable preservative or other suitable preservative, an absorption enhancer to increase bioavailability, Using Luolocarbon and / or other conventional solubilizers or dispersants, physiological saline It can be prepared as a solution.

[0202] The compounds used in the method of the present invention can be formulated as unit dosage forms. The term "dosage form" refers to a physical form that is appropriate as a unit dose for the target to which prevention or treatment is being performed. Each unit refers to an individual unit, and each unit, in some cases, is used in combination with an appropriate drug carrier to achieve the desired therapeutic effect. It contains a predetermined amount of active substance calculated to produce the effect. The unit dosage form is a single daily dose, or multiple doses. A daily dose tailored to one of several options (for example, 1 to 4 times a day, or more times) It is possible. When multiple daily doses are used, the unit dosage form is the same for each dose. It's okay if they're different.

[0203] All possible combinations of the above embodiments are considered to be included within the scope of the present invention. ru.

[0204] Herein, we refer to the following examples illustrating the present invention in a non-limiting manner.

[0205] General synthesis methods Typical compounds used in this invention are described below in the following scheme and examples. It can be synthesized based on the general synthesis methods exemplified therein. The scheme is illustrative. Therefore, the present invention is not limited to the chemical reactions and conditions described in these schemes and examples. It should not be interpreted as being defined. Chemicals similar to the target compounds of these examples The compounds can be prepared according to a similar route. The compounds of this disclosure are as described herein. It is useful as a pharmaceutical product. The various starting materials used in the scheme and examples are commercially available. It can be prepared by a method that is either fully within the scope of the skills of a person skilled in the art. .

[0206] Compound of formula I The synthesis of compounds of general formula I can be carried out as outlined in Scheme 1. -(4-chloro-2-methoxyphenyl)acetic acid(II) is like thionyl chloride, for example. Using a chlorinating agent, the corresponding 2-(4-chloro-2-methoxyphenyl)acetylchloride It can be converted to (III). Acid chloride III and substituted indole of general formula IV The Friedel-Crafts reaction is carried out in a suitable solvent (e.g., CH2Cl2 or 1,2-dichlorochloro). Typically, in ethane, using a Lewis acid reagent (e.g., Et2AlCl or TiCl4), This can be carried out under suitable reaction conditions involving cooling (though not exclusively), and this allows for Obtain 3-acylated indole of general formula V. Add an aluminum compound to the carbonyl portion of the compound of general formula V. The introduction of the aniline moiety at the pha position can be achieved by the following reaction sequence. In a suitable solvent... (For example, THF (tetrahydrofuran)) and reagents (for example, phenyltrimethylammonium V is brominated with mutribromide, and the compound of general formula VI is reacted to produce general formula VI. Next, the compound of general formula VI is typically prepared in a suitable solvent (e.g., CH3CN). For example, triethylamine (TEA) or N,N-diisopropylethylamine (DIPE Using bases such as A), 3-methoxy-5-(methyl-sulfonyl)aniline (VI) It is reacted with (I) to obtain the compound of general formula I as a racemic mixture. Chiral separation is performed, for example, by chiral chromatography, to enantitis of general formula I. Omer A and B can be obtained.

[0207] [ka]

[0208] Scheme 1 In some cases, the intermediate of general formula V by the Friedel-Crafts synthesis approach The synthesis of the body occurs during the Friedel-Crafts reaction step, as outlined in Scheme 2. The presence of a protecting group (PG) on ru-N is beneficial. For this purpose, First, the substituted indole of general formula IV is subjected to a base using a reagent such as tosyl chloride. For example, in the presence of sodium hydride, for example, the N-tosylation intermediate of general formula VIII (P It can be converted to an N-protected intermediate of general formula VIII, such as G=Ts). General formula I The Friedel-Crafts reaction of V-substituted indole and acid chloride III occurs in a suitable solvent. For example, CH2Cl2 or 1,2-dichloroethane, and Lewis acid reagents (e.g., Et2Al) Using Cl or TiCl4, a suitable reaction typically involves (but not exclusively) cooling. This can be carried out under appropriate conditions, thereby enabling the 3-acylated N-protected indole of general formula IX. The following is obtained. Removal of the indole-N protecting group PG from the intermediate of general formula IX is performed on the solvent mixture (e.g. For example, in THF / water, at an appropriate reaction temperature, such as LiOH (in the case of PG=Ts) This can be done using reagents, and the result is a 3-acylated indole of general formula V. .

[0209] [ka]

[0210] Scheme 2 As an alternative approach, the intermediates of general formula V can also be adjusted as outlined in Scheme 3. It can be manufactured. N-Boc-protected substituted indole-3-carbaldehyde of general formula X is For example, in the presence of reagents such as sodium cyanide and sodium bisulfite, appropriate Morpholine in a solvent (for example, a mixture of water and a water-miscible organic solvent (for example, dioxane)) Through this reaction, it can be converted into the corresponding Strecker-type intermediate of general formula XI. 4- Alkylation of compounds of general formula XI with chloro-2-methoxybenzyl chloride is performed on the salt In the presence of a group (e.g., potassium hexamethyldisilazane), a suitable solvent (e.g., dimethyl hydroxypropyl alcohol) is used. This can be achieved in lumamide (DMF), thereby obtaining compounds of general formula XII. This is possible. Compounds of general formula XII can be subjected to appropriate aqueous acidic hydrolysis conditions (for example) When subjected to treatment with an aqueous hydrochloric acid solution at high temperature, an intermediate of general formula V is obtained.

[0211] [ka]

[0212] Scheme 3 The compound of formula (I) is described in its entirety in International Publication No. 2016 / 180696 (see reference). It can be synthesized according to the procedure disclosed in the specification (which is incorporated into the specification). [Examples]

[0213] In the following examples, compound (a), preferably compound (a), is (+)-enantio M is used as an active pharmaceutical ingredient (API). Compound (a) is described in International Publication No. 20 It was synthesized according to the description in Example 9 of Issue 16 / 180696. This was obtained as a white powder.

[0214] [ka]

[0215] reagent

[0216] [Table 1]

[0217] Example 1: Solid dispersion screening The solid dispersion formulation was prepared in a 96-well plate by solvent evaporation (the required amount of AP). Transfer 100 μL of liquid containing I and the additive to each well, and heat the well plate at 70°C. (Then it was transferred to a vacuum furnace with a pressure of less than 2 mbar and left for 1 hour, then cooled to room temperature.) API (amorphous) Both the compound in its qualitative form (a)) and the excipient are mixed with dichloromethane and methanol ( Dissolved in 50 / 50, v / v. Automated liquid processing workstation (Hamilton) The mixture was prepared using Microlab STAR plus. After dispensing, the organic solvent... Amorphous API polymer films were produced by the rapid evaporation of the medium. This was done under reduced pressure and odor Then, evaporate it for 1 hour using a vacuum oven set to 70°C and 200 mbar. This was achieved by [method]. The prepared solid dispersions are shown in Table A. Each contains approximately 100 μg of A The resulting film containing PI (12 copies of each formulation per screening) was cooled. On the other hand, at room temperature, for the first screening, one day, and for the second screening... After maintaining the sample for 3 days, a lysis assay was initiated. A fixed percentage of API (33% by weight) was used. A film was prepared, and the total amount of excipients was 67% by weight. For reference, only APIs were included. Including the film I possess.

[0218] [Table 2] * If

[0219] After film casting, the dissolution study was initiated on the day of the study, and then after 1 week and 2 weeks at 40°C / 75% humidity. Crystallinity was evaluated by polarizing microscope after stabilization for 4 weeks and 14 hours. The date the dissolution test was started, and the following periods of 1 week, 2 weeks, and 4 weeks at 40°C / 75% relative humidity. After stabilization, no crystalline material was detected.

[0220] In vitro, a two-phase (SGF / FaSSIF) miniaturization and dissolution was performed, and the dissolved API was... The quantity was monitored as a function of time. Before starting the dissolution assay, the film was left at room temperature. The results of screening 1 were stored for one day, and the results of screening 2 were stored for three days. By doing so, most of the residual solvent evaporated. The actual dissolution experiment involved sample collection and Hamilton STAR plus liquid processing platform for both sample preparation and processing. The procedure was performed using a film with 96 1 mL glass vials. Before adding to the film, the culture medium was... Preheated to 37°C. 300 μL of preheated SGF (37°C, pH 1.3) was added to the amorphous solids. It was added to the dispersion. After incubation in SGF for 15 minutes, it was added to preheated concentrated FaS. 600 μL of SIF (37°C, pH 10.5) was added to the sample. This concentrated FaS By adding SIF to SGF, a typical FaSSIF culture used in a one-phase dissolution test is formed. A culture medium with a composition similar to that of the soil was obtained. Predetermined time intervals (11, 24, 34, 49, 7 9. After 139 minutes, remove the aliquots from the lysis medium and place them in a 0.45 μm GHP membrane filter. The solution was filtered through a filter. The filtered solution was then quantified using N-methylpyrrolidone (NMP). The solution was diluted to prevent precipitation. The amount of dissolved API was measured using UPLC / UV-Vis. The results were measured by analysis. The experiment was performed twice for each formulation during each screening.

[0221] Figure 1 shows solid dispersions 1-7 in SGF-FaSSIF (concepts 1-7 in Figure 1). The corresponding dissolution profile is shown. For undiluted amorphous API reference, see film. The final emission of approximately 9% of the total amount of API present was measured. All other tests were performed. The solid dispersion exhibits an improved dissolution profile compared to the reference. In the gastric phase, AP I did not dissolve in any of the solid dispersions. For solid dispersion 1, the final reaction of API The output reached 20%.

[0222] The second solubility screening was performed on solid dispersions 8-12 (their compositions are listed in Table B). The above procedure was followed for (the substance). These solid dispersions were prepared as described above.

[0223] [Table 3] * If a This solid dispersion was also tested in the first screening.

[0224] Figure 2 shows the solid dispersions 8-12 in SGF-FaSSIF (concept 8-1 in Figure 2). The dissolution profile (corresponding to 2) is shown. For reference to undiluted amorphous API, see the following. The final emission of approximately 9% of the total amount of API present in the lum was measured. Regarding dispersion 8... For distribution 9, the final emission rate reached 54% of the APIs, while for distribution 9, it reached 28% of the APIs. The final release has been reached.

[0225] Example 2: Solubility Screening To screen for a suitable solvent for spray drying, the approximate solubility of the starting material is determined by the surrounding area. The estimation was performed in various organic solvents at ambient temperatures. Approximately 5 mg of each sample (API, Eud) was used in each solvent. A 2 mL glass vial containing ragit L100 and HPMC E5) contains 50 μg Add in increments of L or 100 μL until the solid dissolves or until a total volume of 1 mL is reached. I did. The results are summarized in the table below.

[0226] [Table 4] * This is likely due to the inherent properties of HPMC E5 itself, resulting in a transparent appearance with very few particles. solution. *1 HPMC E5 was added directly to the organic solvent mixture. *2 First, HPMC E5 was dissolved in water, and then an organic solvent was added.

[0227] Equilibrium solubility of MeOH and MeOH / dichloromethane (DCM) (1 / 1, v / v) The levels were measured by UPLC and were 42 mg / mL and 317 mg / mL, respectively.

[0228] Example 3: Spray drying Based on the solvent selection and polymer screening results mentioned in the above section, E Three polymers including udragit L100, HPMC AS, and HPMC E5 Selected as the support material, acetone / EtOH (2:1, v / v) (Eudragit L (Regarding 100) and MeOH / DCM (1:1, v / v) (HPMC E5 and HPM C AS was selected as the solvent system for spray drying.

[0229] Weigh out sufficient amounts of different polymers into appropriate glass bottles, and then weigh out sufficient amounts of selected The solvent was added and dissolved. Then, approximately 25 g of compound (a) (amorphous state) was weighed out. Dissolve in each of the above solutions, and for Eudragit L100, use 14 mg / A clear solution in acetone / EtOH (2:1, v / v) at an API concentration of mL is prepared in HPMC. For E5 and HPMC AS, use MeOH / DCM(1) ​​at an API concentration of 10 mg / mL. Clear solutions were obtained in 1 and v / v solutions. Approximately 35 g of compound (a) was also weighed and acetone was used. Dissolve in a clear solution with an API concentration of 50 mg / mL to prepare amorphous API. We obtained the liquid. Solid dispersion 1 (SD1): API+Eudragit L100 (1:2w / w). Solid dispersion 2 (SD2):API+HPMC E5 (1:2w / w). Solid dispersion 3 (SD2): API+HPMC AS (1:2w / w). Spray drying equipment: Buchi B-290.

[0230] [Table 5]

[0231] Spray-dried dispersions (SDDs) and amorphous API spray-dried powders The mixture was further dried under reduced pressure at a temperature below the Tg of the mixture.

[0232] Example 4: Stability of the solid dispersion (SD): The obtained SD1, SD2, and SD3 powders (i.e., Eudragit L100-based) ASD1, ASD2 (based on HPMC E5), ASD3 (based on HPMC AS) After final processing and drying, the product is weighed directly in the vial, and its physical and chemical stability is assessed. I turned it up.

[0233] Appropriate amounts of each SD product were weighed into 40 mL glass vials (i.e., chemical stability). (For this, 12 mg; for physical stability, 50 mg). Next, the sample vial is gas Seal with a cap and wrap in aluminum foil, and store at 25°C / 60%RH (closed) and 40°C. In a stable chamber at 75%RH (closed), at different time points (2 weeks, 1 month, 2 months, 3 months) It was stored for up to 1 month and 6 months. The chemical stability at each time point and under each condition was examined in three separate tests. The sample was set up, and the physical stability of a single sample was assessed. Compound ( a) Weigh Eudragit L100 and HPMC E5 into 40 mL glass vials. Chemical stability was set up under each condition and at each time point for API and excipient controls. Regarding this, assays and impurities were tested at each time point under each condition to determine physical stability. XRPD, PLM, and mDSC were tested.

[0234] The SD1 powder was placed in a glass bottle under the stress conditions described in the first column of Table 3, as in the example. The stability of SD1, which was fabricated in step 3, was tested.

[0235] [Table 6] "RH": relative humidity, "M": number of months, "N": non-birefringence, "Am": amorphous, "P1" : White, fluffy powder, "P2": White, fluffy powder, some of the powder is via "PLM": Polarizing microscope, which can adhere to the bottom and walls of the tube.

[0236] After being stored in a sealed glass bottle at 25°C and 60% relative humidity for 6 months, a clear chemical reaction occurred. No physical changes were observed. However, compared to the initial total impurities, at 40°C and After 6 months of storage in a sealed glass bottle at 75% relative humidity, an increase in total impurities was observed. Ta.

[0237] Example 5: Stability of Solid Dispersion 2 (SD2): The SD2 powder was placed in a glass bottle under the stress conditions described in the first column of Table 4, as in the example. The stability of SD2, which was produced in step 3, was tested.

[0238] [Table 7] "RH": relative humidity, "M": number of months, "N": non-birefringence, "Am": amorphous, "P3" It is a white powder, and some of the powder may adhere to the bottom and walls of the vial. "PLM": Polarizing microscope.

[0239] Store in a sealed glass bottle for 6 months at 25°C / 60% relative humidity and 40°C / 75% relative humidity. Afterward, no significant chemical or physical changes were observed compared to the initial state.

[0240] Example 5A: Stability of solid dispersion 3 (SD3): The SD3 powder was placed in a glass bottle and carried out under the stress conditions listed in the first column of Table 4A. The stability of the SD3 prepared in Example 3 was tested.

[0241] [Table 8] "RH": relative humidity, "W": week number, "M": month number, "N": non-birefringence, "Am": non Crystalline, "P3": White powder; some powder may adhere to the bottom and walls of the vial. "PLM": Polarizing microscope.

[0242] Compared to the initial state, all impurities have been removed, especially when stored in a sealed glass bottle at 40°C and 75% relative humidity. The amount in the storage area increased (from 0.08% at T0 to approximately 0.2% after 3 months).

[0243] Example 5B: Dissolution test of HPMC E5 solid dispersion Four solid dispersions containing various API / HPMC E5 weight ratios (listed below) are described above. It was prepared as described in Example 3. Solid dispersion 2a (SD2a): API+HPMC E5 (1:1w / w) Solid dispersion 2b (SD2b): API+HPMC E5 (1:2w / w) Solid dispersion 2c (SD2c): API+HPMC E5 (1:3w / w) Solid dispersion 2d (SD2d): API+HPMC E5 (1:4w / w)

[0244] The prepared solid dispersion is subjected to a physiologically based dissolution test using simulated intestinal fluid as a medium (P The tests were conducted under BDT conditions. SD2a, SD2b, SD2c, and SD2d were tested under fasting conditions. The tests were conducted under PBDT conditions. SD2a, SD2b, and SD2d were evaluated under feeding conditions in PBDT. The tests were conducted under the following conditions. Details of the PBDT are shown in Table 4B and Table 4B for fasting and feeding conditions, respectively. Provided to 4B'.

[0245] [Table 9] * simulated gastric juice, ** Intestinal fluid simulating fasting state

[0246]

Table 10

[0247] Figure 3A shows the dissolution percentage of the tested SD powders, and Figure 3B shows the dissolved amount (mg) of the same SD powders. SD2b and SD2c exhibit improved dissolution profiles compared to SD2a and SD2d. The improved dissolution profile, as seen in Figure 4, was also observed for SD2b under PBDT fed conditions.

[0248] Further, dissolution testing of API and polymer in SD2a, SD2b, SD2c and SD2d was performed in SGF-FaSSIF by adding 50 mg of each SD to 150 mL of preheated SGF (pH 1.3). After 15 minutes, 280 mL of preheated 1.5× concentrated FaSS IF (pH 10.3) was added to the SGF (pH 1.3) to obtain FaSSIF (pH 6.5). The samples were stirred at 250 rpm in an incubator at 37°C. Time-dependent analysis was performed by collecting 5 mL aliquots after 5’, 14’, 20’, 25’, 30’, 45’, 60’, 75’, 105’ and 135’ . Undissolved API was separated from the solution by filtration through a Millex LCR 25 mm filter with 0.45 μm PTFE (3 mL was discarded, and 2 mL was used for concentration measurement). To avoid precipitation , the solution was diluted 2-fold with ACN / water 50 / 50 v / v. The API concentration in the solution was measured using UPLC-UV. The concentration of HPMC E5 in the solution was measured using UPLC-RI.

[0249] Example 6: Stability of 10 mg SD1 tablets: Tablets containing SD1 (10 mg strength) were prepared. The composition of the coated formulation is shown in Table 5. It is being done.

[0250] [Table 11]

[0251] The stability of API, SD1 powder, and SD1-containing tablets (10 mg strength) is shown in column 2 of Table 6. Tablets in high-density polyethylene (HDPE) bottles under stress conditions as described above. The test was conducted by adding the substance. The results are shown in Table 6.

[0252] [Table 12] "RH": relative humidity, "W": Week number, "M": Number of months, "Am": Amorphous, "T1": white powder, "T2": White or off-white round tablets

[0253] Example 7: Stability of 10 mg SD2 tablets: Tablets containing SD2 (10 mg strength) were prepared. The composition of the coated formulation is shown in Table 7. It is being done.

[0254] [Table 13]

[0255] The stability of API, SD2, and tablets containing SD2 (10 mg strength) is shown in column 2 of Table 7. The tests were conducted by placing tablets in HDPE bottles under stress conditions as described. The results are shown in Table 7.

[0256] [Table 14] "RH": relative humidity, "W": Week number, "M": Number of months, "Am": Amorphous, "T1": white powder, "T2": White or off-white round tablets

[0257] Example 8: Tablet Manufacturing Manufacturing of solid dispersions SD1 powder and SD2 powder (see Table 8 for formulation details). 1. Methanol (for SD1 powder) or a mixture of methanol and methylene chloride (1 / 1, v Transfer the (for / v, SD2 powder) to a container and stir using a mixer. While stirring, the chemical Substance (a) was added to the solvent. Stirring was continued until compound (a) dissolved. The dried solution was then prepared. It was filtered. 2. Process using Eudragit L100 or hydroxypropyl methylcellulose E5. It was added to solution 1. The mixture was stirred until homogenized. 3. Spray-dry the two mixtures using a suitable spray dryer (PSD-1). The dried product was recovered.

[0258] The obtained powder was dried using a tray oven dryer and then collected.

[0259] [Table 15] a It is removed during processing (by drying).

[0260] Manufacturing of tablets containing SD1 powder (see Table 8 for formulation details). 1. SD1 powder, microcrystalline cellulose, mannitol, croscarmellose sodium, Colloidal silicon dioxide, magnesium stearate, and sodium lauryl sulfate together It was sifted and then blended in a glass blender. 2. The mixture was compressed using a roller compressor WP-120, and the resulting granules were collected. . 3. Sift together croscarmellose sodium and microcrystalline cellulose, and in step 2 The mixture was added to the resulting dried granules and blended in a bottle blender. 4. Add the sieved magnesium stearate and blend the resulting mixture in a bin blender. It was blended with this. 5. The blend was compressed into tablets using an XL 100 Korsch tablet press.

[0261] [Table 16]

[0262] Manufacturing of tablets containing SD2 powder (see Table 9 for formulation details). 1. SD2 powder, microcrystalline cellulose, mannitol, croscarmellose sodium, Colloidal silicon dioxide, magnesium stearate, and sodium lauryl sulfate together It was sifted and then blended in a glass blender. 2. The mixture was compressed using a roller compressor WP-120, and the resulting granules were collected. . 3. Sift together croscarmellose sodium and microcrystalline cellulose, and in step 2 The mixture was added to the resulting dried granules and blended in a bottle blender. 4. Add the sieved magnesium stearate and blend the resulting mixture in a bin blender. It was blended with this. 5. The blend was compressed into tablets using an XL 100 Korsch tablet press.

[0263] [Table 17]

[0264] [Table 18]

[0265] [Table 19]

[0266] Example 9: Pharmacokinetics of tablets after oral administration in fasted dogs. Pharmacokinetic (PK) studies were conducted using tablets 7 and 10 described above. These tablets were administered to patients under fasting conditions. Three male beagle dogs (N=3) were given the drug orally once, twice, or three times. The results are shown in Table 14. .

[0267] [Table 20] Mean ± standard deviation AUC = Area under the plasma concentration-time curve. last = By the final point of plasma levels Calculated AUC, AUC ∞ =Calculated using extrapolation of the plasma profile to infinite time. AUC, C max = Maximum plasma concentration observed, N: Number of animals, T max = Observed The time corresponding to the maximum plasma concentration.

[0268] Example 10: Pharmacokinetics of tablets after oral administration in fasted and fed dogs. Pharmacokinetic (PK) studies were conducted using tablets 9 and 12 described above. Three tablets were administered under fasting conditions. The drug was orally administered to male beagle dogs (N=3) under feeding conditions. The results are shown in Table 15.

[0269] [Table 21] Mean ± standard deviation AUC = Area under the plasma concentration-time curve; AUC last = By the final point of plasma levels Calculated AUC, AUC ∞ =Calculated using extrapolation of the plasma profile to infinite time. AUC, C max = Maximum plasma concentration observed, N: Number of animals, T max = Observed The time corresponding to the maximum plasma concentration.

[0270] Pharmacokinetic data in dogs showed that AUC values ​​were similar in both fasting and feeding conditions. This is clearly shown, indicating that it is not affected by food. Therefore, this formulation is It releases APIs regardless of whether or not the patient has eaten. This is beneficial from the perspective of patient compliance. Therefore, the formulation according to the present invention may have a reduced effect of diet compared to other formulations. .

[0271] Preferred embodiments of the present invention are shown and described herein, but such embodiments are It will be obvious to those skilled in the art that this is presented merely as an example. Many variations, alterations, and substitutions will be conceived without deviating from the original. Even if various substitutes for the embodiments of the present invention described are used when carrying out the present invention, Often, embodiments within the scope of these claims and their equivalents are thereby encompassed. It should be understood that...

Claims

1. It is a pharmaceutical preparation, a) Active ingredients in pharmaceuticals, b1) Methacrylic acid copolymer, or b2) comprising a cellulose derivative, A pharmaceutical preparation in which the aforementioned active ingredient is a dengue virus replication inhibitor.

2. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is a solid preparation.

3. The pharmaceutical active ingredient and the methacrylic acid copolymer or the cellulose derivative, Claim 1 or 2, wherein one of the is present in the formulation in a ratio of 4:1 w / w to 1:5 w / w The pharmaceutical preparations described above.

4. The methacrylic acid copolymer is a copolymer of methacrylic acid and methyl methacrylate. Selected from the group including copolymers of methacrylic acid and ethyl acrylate, and mixtures thereof. A pharmaceutical preparation according to any one of claims 1 to 3.

5. The cellulose derivative, in a 2% by weight solution in H2O at 25°C, has a concentration of 3 to 5000 mP. a. Having a viscosity in the range of s, and HPMC E5, HPMC E6, HPMC E15 Selected from the group including HPMC E50, HPMC K4M and HPMC-AS. A pharmaceutical preparation described in any one of the requests 1 to 3.

6. The formulation is in an amount of up to 40% by weight, preferably up to 30% by weight, relative to the total weight of the formulation. preferably comprising up to 25% by weight of the pharmaceutical active ingredient, any one of claims 1 to 5 The pharmaceutical preparations described above.

7. The aforementioned formulation contains a disintegrant, binder, diluent, lubricant, stabilizer, wetting agent, lubricant, osmotic agent, and One or more pharmaceutically acceptable substances selected from colorants, plasticizers, and coatings. A pharmaceutical preparation according to any one of claims 1 to 6, further comprising an excipient.

8. The formulation comprises a plurality of granules that form the granular inner phase of the formulation, and the granular outer phase of the formulation. A pharmaceutical preparation according to any one of claims 1 to 7, comprising one or more excipients. 。

9. The aforementioned active pharmaceutical ingredient is a compound of formula (I), 【Chemistry 1】 The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is ,below: R １ H is R ２ F is R ３ is H or CH ３ The compound, R １ is H, CH ３ , or F, and R ２ is OCH ３ , and R ３ is H, a compound, R １ H is R ２ ga OCH ３ And R ３ ga CH ３ The compound, R １ ga CH ３ And R ２ F is R ３ A compound in which H R １ ga CF ３ or OCF ３ And R ２ H is R ３ A compound in which H R １ OCF ３ And R ２ ga OCH ３ And R ３ Compounds in which H, and R １ OCF ３ And R ２ H is R ３ ga CH ３ The compound, A pharmaceutical preparation according to any one of claims 1 to 8, selected from the group.

10. The compound of formula (I) is 【Chemistry 2】 or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph, claim Pharmaceutical preparations as described in item 9.

11. A solid dosage form comprising a pharmaceutical preparation according to any one of claims 1 to 10.

12. The formulation contains 0.5 mg to 1000 mg of the active pharmaceutical ingredient, preferably the The formulation contains 1 mg to 1000 mg of the active pharmaceutical ingredient, preferably the formulation contains 2 mg The solid dosage form according to claim 11, comprising g to 500 mg of the pharmaceutical active ingredient.

13. Any one of claims 1 to 10 for use in the treatment or prevention of dengue virus infection Pharmaceutical preparations as described in the section.

14. A process for preparing a pharmaceutical preparation according to any one of claims 1 to 10, a) A step of dissolving the API in a solvent to form a solution, b) The methacrylic acid copolymer or the cellulose derivative formed in (a) The process involves mixing with the solution to obtain a mixture, c) A step of spray-drying the mixture to obtain a solid dispersion, d) Optionally, the solid dispersion is provided with at least one pharmaceutically acceptable excipient. This includes the blending process, A process for providing a pharmaceutical formulation according to any one of claims 1 to 10.

15. The aforementioned active pharmaceutical ingredient is a compound of formula (I), 【Transformation 3】 The stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph of the compound is ,below: R １ H is R ２ F is R ３ is H or CH ３ The compound, R １ H, CH ３ , or F, R ２ ga OCH ３ And R ３ A compound in which H R １ H is R ２ ga OCH ３ And R ３ ga CH ３ The compound, R １ ga CH ３ And R ２ F is R ３ A compound in which H R １ ga CF ３ or OCF ３ And R ２ H is R ３ A compound in which H R １ OCF ３ And R ２ ga OCH ３ And R ３ Compounds in which H, and R １ OCF ３ And R ２ H is R ３ ga CH ３ The compound, The process according to claim 14, selected from the group.

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