Oral pharmaceutical composition and method for producing the same

Abstract

For orally administering pharmacoactive ingredients having a pH-dependent solubility profile, The present invention provides a pharmaceutical composition that can achieve excellent absorption efficiency regardless of the pH inside the chemical tube. [Solution] A pharmacoactive ingredient having a pH-dependent solubility profile and an inorganic or organic acid An oral pharmaceutical composition comprising a hydrophilic polymer.

Description

[Technical Field]

[0001] The present invention relates to an oral pharmaceutical composition for administering a pharmaceutically active ingredient having a pH-dependent solubility profile, and a method for producing the same. [Background technology]

[0002] Pharmaceutical compositions for orally administering pharmaceutically active ingredients preferably exhibit certain solubility characteristics to achieve stable absorption of the pharmaceutically active ingredient by the target gastrointestinal tract. However, the pH within the gastrointestinal tract is not constant, and the pH in the stomach, in particular, varies greatly between individuals, and even within the same individual, it fluctuates significantly depending on conditions such as physical condition and diet. Therefore, especially in the case of pharmaceutically active ingredients with a pH-dependent solubility profile, it is extremely difficult to administer them orally and ensure stable absorption.

[0003] An example of a pharmacoactive ingredient with such a pH-dependent solubility profile is ART-001 (compound name: ceravelisib), a compound currently under development by the applicant. The chemical formula of ART-001 is shown below. ART-001 is currently undergoing clinical trials as a pharmacoactive ingredient that shows therapeutic effects on diseases such as vascular malformations.

[0004] [ka]

[0005] ART-001 has been reported to exhibit a pH-dependent solubility profile, showing high solubility in acidic solutions but extremely low solubility in neutral to basic solutions (Non-Patent Literature 1). In a previous Phase I clinical trial in patients with advanced solid tumors, ART-001 showed high variability in pharmacokinetics and limited therapeutic efficacy (Non-Patent Literature 2). ART-001 also showed significant variability in pharmacokinetic studies in healthy adults (Non-Patent Literature 1). Furthermore, in the same study, co-administration of a proton pump inhibitor (lansoprazole) suppressed gastric acid secretion and adjusted gastric pH to neutral, resulting in a significant decrease in ART-001 absorption. These findings suggest that fluctuations in gastric pH significantly affect the solubility and absorption of ART-001 in the gastrointestinal tract. In addition, pH-dependent solubility and variability in pharmacokinetics in clinical trials have also been confirmed for alperisib, which has a similar mechanism of action to ART-001 (Non-Patent Literature 3, 4). Thus, for poorly soluble pharmacoactive ingredients with pH-dependent solubility profiles, the development of formulations that are stably absorbed regardless of gastric pH is desired for maintaining stable pharmacokinetics and achieving therapeutic effects. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Clinical Pharmacology in Drug Development, 2019, Vol.8, No.5, pp.637-646 [Non-Patent Document 2] Clinical Cancer Research, 2017, Vol.23, No.17, pp.5218-5224 [Non-Patent Document 3] FDA / CENTER FOR DRUG EVALUATION AND RESEARCH, APPLICATION NUMBER: 212526Orig1s000 PRODUCT QUALITY REVIEW(S) (Approval Date: May 24, 2019) [Non-Patent Document 4] FDA / CENTER FOR DRUG EVALUATION AND RESEARCH, APPLICATION NUMBER: 212526Orig1s000 MULTI-DISCIPLINE REVIEW [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present invention has been made in view of the above problems, and aims to provide a pharmaceutical composition for orally administering a pharmacoactive ingredient having a pH-dependent solubility profile, which can achieve excellent absorption efficiency regardless of the pH in the gastrointestinal tract. [Means for solving the problem]

[0008] As a result of diligent research, the inventors discovered that by formulating a pharmaceutical active ingredient having such a pH-dependent solubility profile together with an inorganic or organic acid and a hydrophilic polymer, a pharmaceutical composition capable of achieving excellent absorption efficiency regardless of the pH of the gastrointestinal tract can be obtained, thus completing the present invention.

[0009] In other words, the purpose of this invention relates, for example, to the following: [Item 1] An oral pharmaceutical composition comprising a pharmaceutically active ingredient having a pH-dependent solubility profile, an inorganic or organic acid, and a hydrophilic polymer. [Item 2] The oral pharmaceutical composition according to Item 1, wherein the pharmaceutically active ingredient is an aromatic compound having a π-conjugated system. [Item 3] The oral pharmaceutical composition according to item 1 or 2, wherein the pharmaceutically active ingredient is a compound having a structure represented by the following general formula I. [ka] (In the formula, Ring A represents a 5-16 member monocyclic or condensed dicyclic or tricyclic aromatic hydrocarbon group or aromatic heterocyclic group, which may have one or more substituents. Ring B represents a 5-12 member monocyclic or condensed bicyclic aromatic hydrocarbon group or aromatic heterocyclic group, which may have one or more substituents. L represents a divalent or trivalent linking group which may have one or more substituents. p represents an integer of 0 or 1. q represents an integer of 1 or 2, r represents an integer of 1 or 2. [Item 4] An oral pharmaceutical composition according to any one of items 1 to 3, wherein the pharmaceutically active ingredient is one or more compounds selected from ART-001 (cerabelisib), alpelisib, afatinib, gefitinib, bosutinib, alectinib, palbociclib, taselicib, and copanlicib. [Item 5] An oral pharmaceutical composition according to any one of items 1 to 4, wherein the ratio of the solubility of the pharmaceutically active ingredient at pH 6 to the solubility at pH 2.5 is 50% or less, or 30% or less, or 20% or less, or 10% or less, or 5% or less. [Item 6] An oral pharmaceutical composition according to any one of items 1 to 5, wherein the inorganic or organic acid is one or more acids selected from phosphoric acid, hydrochloric acid, citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, aspartic acid, lactic acid, acetic acid, glutamic acid, and adipic acid. [Item 7] An oral pharmaceutical composition according to any one of items 1 to 6, wherein the hydrophilic polymer is one or more polymers selected from polyvinyl alcohol, povidone, hypromellose, copolividone, hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycol-graft copolymer, hypromellose phthalate, and hypromellose acetate succinate. [Item 8] The oral pharmaceutical composition according to any one of Items 1 to 7, wherein the content rate of the pharmaceutically active ingredient is 2% by mass or more, or 5% by mass or more, or 10% by mass or more, or 15% by mass or more, and further 40% by mass or less, or 35% by mass or less, or 30% by mass or less, or 25% by mass or less. [Item 9] The oral pharmaceutical composition according to any one of Items 1 to 8, wherein the content ratio of the inorganic or organic acid to 1 part by mass of the pharmaceutically active ingredient is in the range of 0.1 part by mass or more, or 0.3 part by mass or more, or 0.5 part by mass or more, and further 10 parts by mass or less, or 7.5 parts by mass or less, or 5 parts by mass or less. [Item 10] The oral pharmaceutical composition according to any one of Items 1 to 9, wherein the content ratio of the hydrophilic polymer to 1 part by mass of the pharmaceutically active ingredient is in the range of 0.02 part by mass or more, or 0.05 part by mass or more, or 0.1 part by mass or more, and further 5 parts by mass or less, or 3 parts by mass or less, or 2 parts by mass or less. [Item 11] The oral pharmaceutical composition according to any one of Items 1 to 10, which is a dry syrup preparation. [Item 12] A method for producing the oral pharmaceutical composition according to any one of Items 1 to 11, which includes wet granulating and drying a mixture containing a pharmaceutically active ingredient, an inorganic or organic acid, and a hydrophilic polymer. [Item 13] The oral pharmaceutical composition produced by the method according to Item 12. [Effect of the Invention]

[0010] According to one aspect of the oral composition of the present invention, when a pharmaceutically active ingredient having a pH-dependent dissolution profile is orally administered, it is possible to achieve excellent absorption efficiency regardless of the pH in the digestive tract. Further, according to one aspect of the oral composition of the present invention, it is possible to obtain stable pharmacokinetics with reduced variation among individuals as compared with the case of administration using conventional dosage forms such as capsules and tablets. [Brief Description of the Drawings]

[0011] [Figure 1] It is a graph showing the change in the plasma concentration of ART-001 when the dry syrup preparation of ART-001 (the pharmaceutical composition of the present invention) is administered once to healthy adults. Mean value ± standard deviation. [Figure 2] This graph shows the plasma concentration profile of ART-001 after repeated administration of the ART-001 dry syrup formulation (the pharmaceutical composition of the present invention) to healthy adults for 7 days. From day 2 to day 6 of administration, blood samples were collected only 24 hours after the previous day's administration. Mean ± standard deviation. [Modes for carrying out the invention]

[0012] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the embodiments described below, and can be implemented in any form without departing from the spirit of the invention. Furthermore, any combination of two or more of the various embodiments described below will also be included in the scope of the present invention, unless there is a clear contradiction in their definitions or context.

[0013] [Oral pharmaceutical composition] One aspect of the present invention relates to a pharmaceutical composition for orally administering a pharmaceutically active ingredient having a pH-dependent solubility profile (referred to as "the pharmaceutical composition of the present invention" as appropriate). The pharmaceutical composition of the present invention contains, in addition to the pharmaceutically active ingredient having such a pH-dependent solubility profile, an inorganic or organic acid and a hydrophilic polymer.

[0014] According to the pharmaceutical composition of the present invention having such a composition, when a pharmacoactive ingredient having a pH-dependent solubility profile is administered orally, it is possible to achieve excellent absorption efficiency regardless of the gastrointestinal pH. In fact, according to the inventors' studies, when the pharmaceutical composition of the present invention was used to administer a pharmacoactive ingredient having a pH-dependent solubility profile, it was shown in animal administration studies to achieve excellent absorption efficiency regardless of the gastrointestinal pH, as shown in the examples below (see Example [3. Evaluation of ART-001 Dry Syrup Formulation]). Furthermore, in human administration studies, it was shown that stable pharmacokinetics with reduced inter-individual variability could be obtained compared to administration using conventional capsules or tablets (References: Juric et al., Clin. Cancer Res., (2017), 23

[17] :5015-5023, Patel et al., Clin. Pharmacol. Drug Dev., (2019), 8[5]:637-646) (see Example [4. Examination of Blood Pharmacokinetics of ART-001 Dry Syrup Formulation]). The tight and stable pharmacokinetics obtained from such dry syrup formulations facilitate dose selection to obtain the blood exposure expected to be effective, while also making it possible to avoid side effects associated with high exposure levels.

[0015] • Pharmaceutical active ingredients with pH-dependent solubility profiles: The pharmaceutical composition of the present invention contains a pharmaceutical active ingredient having a pH-dependent solubility profile.

[0016] In this disclosure, "pharmaceutical active ingredient" means an ingredient contained in a pharmaceutical product that exerts physiological activity related to a desired indication. The indications and physiological activities of the pharmaceutical active ingredient in this disclosure are not limited, but examples include pharmaceutical active ingredients that exert their pharmacological effects when administered orally to a subject and absorbed in the gastrointestinal tract (e.g., in the stomach).

[0017] In this disclosure, "pH-dependent solubility profile" means that solubility varies depending on pH. Unless otherwise stated, in this disclosure, "solubility profile" and "solubility" mean solubility in an aqueous medium. In this disclosure, "aqueous medium" means water or various aqueous solutions. Aqueous digestive fluids (e.g., saliva, gastric juice, etc.) and aqueous body fluids other than digestive fluids (blood, lymph, tissue fluid, ascites, etc.) are also included in aqueous mediums.

[0018] In one embodiment, the pharmaceutically active ingredients having a pH-dependent solubility profile in this disclosure are, but are not limited to, compounds that exhibit high solubility under acidic pH conditions, decrease in solubility as the pH increases, and show almost no solubility under neutral to alkaline pH conditions. More specifically, when comparing the solubility of the pharmaceutically active ingredient in an aqueous solvent at around room temperature (e.g., 30°C), the ratio of solubility under neutral pH conditions (e.g., pH 6) to solubility under acidic pH conditions (e.g., pH 2.5) is usually 50% or less, and among them, compounds with a ratio of 30% or less, or 20% or less, or 10% or less, and especially 5% or less. Consequently, examples of pharmaceutically active ingredients in the pharmaceutical composition of the present invention include compounds having a basic nitrogen-containing heterocycle, and compounds having a basic functional group, such as an unsubstituted or substituted amino group.

[0019] The type of pharmaceutically active ingredient in the pharmaceutical composition of the present invention is not limited as long as it has a pH-dependent solubility profile, but examples include pharmaceutically active ingredients that can form a stable crystalline structure. Examples of such pharmaceutically active ingredients include aromatic compounds that have a π-conjugated system and can undergo π-π stacking. In this disclosure, "π-π stacking" refers to the phenomenon in which two or more aromatic compound molecules are stacked on a plane and stabilized by π-π interactions. Aromatic compounds that can undergo π-π stacking can generally form a stable crystalline structure and have low solubility in aqueous media. Consequently, by applying the present invention to such aromatic compounds, a significant improvement in the solubility profile can be obtained.

[0020] According to one embodiment, examples of pharmacoactive ingredients in the pharmaceutical composition of the present invention include aromatic compounds having a large π-conjugated system, such as compounds having a condensed aromatic ring and / or multiple linked aromatic rings. Such compounds are prone to π-π stacking, which in turn leads to crystallization and deterioration of solubility, thus the effect of improving the solubility profile by applying the pharmaceutical composition of the present invention becomes more pronounced. Such pharmacoactive ingredients are not limited, but examples include compounds having a structure represented by the following general formula I.

[0021] [ka]

[0022] In general formula I, ring A represents a 5-16 member monocyclic or fused dicyclic or tricyclic aromatic hydrocarbon group or aromatic heterocyclic group, which may have one or more substituents.

[0023] In general formula I, ring B represents a 5-12 member monocyclic or condensed bicyclic aromatic hydrocarbon group or aromatic heterocyclic group, which may have one or more substituents.

[0024] In general formula I, if ring A and / or ring B are aromatic hydrocarbon groups, the aromatic hydrocarbon groups are not limited to these, but include groups selected from the following group (the following are the names of monovalent groups. When r is 2, ring A is a divalent group obtained by removing one more hydrogen atom from the following monovalent group). (Monocyclic) phenyl group. (Condensed bicyclic) indenyl group, naphthyl group, azulenyl group. (Condensed tricyclic) anthracenyl group, phenanthonacenyl group, fluorenyl group.

[0025] In general formula I, if ring A and / or ring B are aromatic heterocyclic groups, these aromatic heterocyclic groups contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur atoms. The types of aromatic heterocyclic groups are not limited to these, but include groups selected from the following group (the following are the names of monovalent groups. When n is 2, ring A becomes a divalent group obtained by removing one more hydrogen atom from the following monovalent group).

[0026] (Monocyclic) pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, furanyl group, thiophenyl group, oxazolyl group, isoxazolyl group, thiazolyl group, oxadiazolyl group, thiadiazolyl group, pyridinyl group, pyridadinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, pyranyl group. (Condensed bicyclic) indenyl group, indolyl group, isoindolyl group, indollidinyl group, indazolyl group, benzimidazolyl group, azaindolyl group, azaindazolyl group, pyrazolopyrimidinyl group, purinyl group, benzofuranyl group, isobenzofuranyl group, benzothiophenyl group, benzooxazolyl group, benzothiazolyl group, benzoisoxazolyl group, benzoisothiazolyl group, quinolinyl group, isoquinolinyl group, quinolidinyl group, quinoxalinyl group, phthalazinyl group, quinazolinyl group, naphthylidinyl group, pyridopyrimidinyl group, pyridopyrazinyl group, benzopyranyl group. (Condensed tricyclic) carbazolyl group, dibenzofuranyl group, acridinyl group, phenazinyl group, phenoxazinyl group, phenothiazinyl group, phenoxathiinyl group.

[0027] In general formula I, L represents a divalent or trivalent linking group which may have one or more substituents. Specifically, when q is 1, L is a divalent linking group, and when q is 2, L is a trivalent linking group. The type of linking group is not particularly limited, but it is preferably a group that can be conjugated with ring A and / or ring B.

[0028] In general formula I, examples of L linking groups are not limited to these, but include groups selected from the following group.

[0029] A divalent or trivalent group obtained by removing one or two more hydrogen atoms from an alkyl group (methyl group, ethyl group, propyl group (n-propyl group, isopropyl group), butyl group (n-butyl group, sec-butyl group, isobutyl group, tert-butyl group), pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group), alkenyl group, or alkynyl group. The number of carbon atoms in the group is not particularly limited, but is usually 1 to 10, preferably 1 to 7, and more preferably 1 to 5. • Carbonyl group. • Azo group, diazo group, divalent or trivalent group obtained by removing one or two more hydrogen atoms from an (primary, secondary, or tertiary) amino group, amide group. Sulfide group, sulfinyl group, sulfonyl group. • Oxy group, dioxy group.

[0030] Furthermore, groups formed by linking any two or more of the aforementioned linking groups in any order (for example, alkoxy groups, alkenyloxy groups, carboxyl groups, sulfinyloxy groups, sulfonyloxy groups, and carbonylamino groups) are also included as examples of linking groups. Furthermore, the connection positions between the aforementioned linking group and rings A and B are not particularly limited and are arbitrary.

[0031] In general formula I, p is an integer of 0 or 1. When p is 0, ring A and ring B are connected by a simple bond.

[0032] In general formula I, q is an integer of 1 or 2. When q is 2, the multiple rings B may be identical or distinct from one another.

[0033] In general formula I, r is an integer of 1 or 2. When r is 2, the multiple B, L, p, and q may be the same as or different from each other.

[0034] In general formula I, substituents that may be present on the aromatic hydrocarbon groups or aromatic heterocyclic groups of rings A and B, and substituents that may be present on the linking group L, are not limited to these but include groups selected from the following group.

[0035] Halogen atoms, hydroxyl groups, carboxyl groups, nitro groups, cyano groups, thiol groups, sulfinic acid groups, sulfonic acid groups, amino groups, amide groups, imino groups, imide groups.

[0036] Hydrocarbon group, hydrocarbon oxy group, hydrocarbon carbonyl group (acyl group), hydrocarbon oxycarbonyl group, hydrocarbon carbonyloxy group, hydrocarbon substituted amino group, hydrocarbon substituted aminocarbonyl group, hydrocarbon carbonyl substituted amino group, hydrocarbon substituted thiol group, hydrocarbon sulfonyl group, hydrocarbon oxysulfonyl group, hydrocarbon sulfonyloxy group.

[0037] Here, the "hydrocarbon" group may be aliphatic or aromatic, or a combination thereof. Aliphatic hydrocarbons may be linear or cyclic, or a combination thereof. Linear hydrocarbons may be linear or branched. Cyclic hydrocarbons may be monocyclic or bicyclic, and in the case of bicyclics, they may be fused, bridged, or spirocyclic, or a combination thereof. Furthermore, the "hydrocarbon" group may be saturated or unsaturated; in other words, it may contain one or more carbon-carbon double bonds. That is, the "hydrocarbon" group is a concept that includes alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, aryl groups, etc. The number of carbon atoms in the "hydrocarbon" group is not particularly limited, but in the case of linear hydrocarbon groups, it is usually 1 to 20, preferably 1 to 15, and more preferably 1 to 12, and in the case of cyclic hydrocarbon groups, it is usually 3 to 20, preferably 4 to 15, and more preferably 5 to 12. Unless otherwise specified, one or more hydrogen atoms of the "hydrocarbon" group may be substituted with any substituent, and one or more carbon atoms of the hydrocarbon may be replaced with any heteroatom depending on its valency. The type of heteroatom is not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, and silicon atoms.

[0038] Heterocyclic group, heterocyclic oxy group, heterocyclic carbonyl group, heterocyclic oxycarbonyl group, heterocyclic carbonyloxy group, heterocyclic amino group, heterocyclic aminocarbonyl group, heterocyclic carbonyl-substituted amino group, heterocyclic-substituted thiol group, heterocyclic sulfonyl group, heterocyclic oxysulfonyl group, heterocyclic sulfonyloxy group.

[0039] Here, the "heterocyclic" group may be saturated or unsaturated; in other words, it may contain one or more carbon-carbon double bonds. If unsaturated, it may or may not have aromatic properties. Furthermore, the "heterocyclic" group may be monocyclic or bicyclic, and if bicyclic, it may be fused, bridged, or spirocyclic. The number of ring constituent atoms of the "heterocyclic" group is not particularly limited, but is usually 3 or more, or 4 or more, or 5 or more, and is also usually 20 or less, or 15 or less, or 12 or less. The type of heteroatoms contained in the "heterocyclic" group is not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, and silicon atoms. The number of heteroatoms is also not particularly limited, but is usually 1 to 8, preferably 1 to 5, and more preferably 1 to 3. If the "heterocyclic" group contains two or more heteroatoms, these heteroatoms may be identical or different.

[0040] Furthermore, any of the substituents mentioned above, insofar as their valence and physicochemical properties permit, a functional group in which one or more substituents are further substituted with one or more of the substituents mentioned above is also included in the definition of "substituent" in this invention. The number of substituents on a functional group is not particularly limited, as long as their valence and physicochemical properties permit. Also, if multiple substituents exist, these substituents may be identical or different.

[0041] In general formula I, if the aromatic hydrocarbon group or aromatic heterocyclic group of ring A and / or ring B has substituents, the number of substituents may be one or two or more. If the aromatic hydrocarbon group or aromatic heterocyclic group of ring A and / or ring B has two or more substituents, these substituents may be identical or different.

[0042] In general formula I, if the aromatic hydrocarbon group or aromatic heterocyclic group of ring A and / or ring B has substituents, two or more of these substituents may bond to each other to form a ring that condenses with ring A and / or ring B.

[0043] According to one embodiment, the pharmaceutically active ingredient in the pharmaceutical composition of the present invention is selected from the compounds listed in Table 1 below.

[0044] [Table 1-1]

[0045] [Table 1-2]

[0046] According to one embodiment, the pharmaceutically active ingredient in the pharmaceutical composition of the present invention is selected from ceravelicib, alpelicib, afatinib, gefitinib, bosutinib, alectinib, palbociclib, taselicib, and copanlicib.

[0047] According to one embodiment, the pharmaceutically active ingredient in the pharmaceutical composition of the present invention is cerabelisib or alpelisib.

[0048] Furthermore, the pharmaceutical composition of the present invention may contain any one of these pharmaceutically active ingredients alone, or it may contain two or more in any combination and ratio.

[0049] In one embodiment, the pharmaceutically active ingredient in the pharmaceutical composition of the present invention does not maintain a stable crystalline structure within the pharmaceutical composition of the present invention, but is partially amorphous. In a more preferred embodiment, even if such pharmaceutically active ingredient is an aromatic compound capable of π-π stacking, such aromatic compound does not undergo π-π stacking in the pharmaceutical composition of the present invention, and each molecule exists in a separated state. A method for incorporating the pharmaceutically active ingredient in an amorphous state into the formulation will be described later.

[0050] The content of the pharmaceutically active ingredient in the pharmaceutical composition of the present invention may be appropriately selected according to various conditions such as the type of pharmaceutically active ingredient, indication, dosage form, and route of administration. In one embodiment, the content of the pharmaceutically active ingredient in the pharmaceutical composition of the present invention may be, for example, 2% by mass or more, 5% by mass or more, 10% by mass or more, or 15% by mass or more, or 40% by mass or less, 35% by mass or less, 30% by mass or less, or 25% by mass or less.

[0051] Furthermore, the pharmaceutical composition of the present invention may, without departing from the spirit of the present invention, contain, in addition to the pharmaceutically active ingredient having a pH-dependent solubility profile, one or more additional pharmaceutically active ingredients that do not have a pH-dependent solubility profile.

[0052] • Inorganic or organic acids: The pharmaceutical composition of the present invention contains an inorganic or organic acid. In this disclosure, "inorganic or organic acid" means a proton (H + This refers to inorganic or organic compounds (so-called Brønsted acids) that can provide ) to the active pharmaceutical component. Although not bound by theory, it is presumed that in the pharmaceutical composition of the present invention, the presence of such an acid interposed between the molecules of the active pharmaceutical component stabilizes its solubility profile regardless of pH.

[0053] In one embodiment, the acid in the pharmaceutical composition of the present invention is, but is not limited, an acid with an acid dissociation constant (pKa value) of, for example, 4.2 or less, 3.1 or less, or 2.2 or less. In this disclosure, unless otherwise specified, the acid dissociation constant (pKa value) refers to the acid dissociation constant in water, and in the case of a polyvalent acid, it refers to the acid dissociation constant (so-called pKa1 value) relating to the dissociation reaction in which one hydrogen ion is released. Acids with an acid dissociation constant (pKa value) of less than or equal to the above upper limit facilitate the protonation of basic pharmaceutically active ingredients and solubilize pharmaceutically active ingredients having a pH-dependent solubility profile.

[0054] According to one embodiment, the acid in the pharmaceutical composition of the present invention is an acid whose molecular mass is within a predetermined range. Specifically, the molecular mass of the acid is not limited, but is usually between 30 and 200.

[0055] Specific examples of acids in the pharmaceutical composition of the present invention are not limited, but according to one embodiment, examples include phosphoric acid, hydrochloric acid, citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, aspartic acid, lactic acid, acetic acid, glutamic acid, and adipic acid. According to one embodiment, specific examples of acids include phosphoric acid, hydrochloric acid, citric acid, malic acid, and tartaric acid. According to one embodiment, specific examples of acids in the pharmaceutical composition of the present invention include phosphoric acid, citric acid, and tartaric acid. The pharmaceutical composition of the present invention may contain any one of these acids alone, or may contain two or more in any combination and ratio.

[0056] According to one embodiment, the acid in the pharmaceutical composition of the present invention is a compound having two or more acidic functional groups. Examples of compounds having two or more acidic functional groups include, but are not limited to, compounds having two or more hydroxyl groups (e.g., phosphoric acid), compounds having two or more carboxyl groups (e.g., citric acid, malic acid, tartaric acid), and compounds having one or more hydroxyl groups and one or more carboxyl groups (e.g., lactic acid).

[0057] In one embodiment, the acid content in the pharmaceutical composition of the present invention is not limited, but is, for example, 5% by mass or more, 10% by mass or more, or 15% by mass or more, and also, for example, 50% by mass or less, 45% by mass or less, or 40% by mass or less. In another embodiment, the mass ratio of inorganic or organic acid to pharmaceutically active ingredient in the pharmaceutical composition of the present invention is, for example, 0.1 parts by mass or more, 0.3 parts by mass or more, or 0.5 parts by mass or more of inorganic or organic acid per 1 part by mass of pharmaceutically active ingredient, and also, for example, 10 parts by mass or less, 7.5 parts by mass or less, or 5 parts by mass or less of inorganic or organic acid.

[0058] Furthermore, the pharmaceutical composition of the present invention may contain, without departing from the spirit of the present invention, one or more inorganic or organic acids in unit value in addition to inorganic or organic acids.

[0059] • Hydrophilic polymer: The pharmaceutical composition of the present invention contains a hydrophilic polymer. Although not bound by theory, it is presumed that in the pharmaceutical composition of the present invention, in addition to the acid, such a hydrophilic polymer intervenes between the molecules of the pharmaceutical active ingredient, preventing its re-aggregation and crystallization, thereby stabilizing its dissolution profile regardless of pH.

[0060] In this disclosure, "hydrophilic polymer" means a polymer that is soluble in water at room temperature. Specifically, it means a polymer whose 1-10% aqueous solution has a viscosity of 1 mPa·s or more under 20°C and normal pressure conditions.

[0061] According to one embodiment, the hydrophilic polymer in the pharmaceutical composition of the present invention is not limited to those having hydrophilic substituents such as carboxyl groups, hydroxyl groups, sulfo groups, and amide groups. Such a hydrophilic polymer can prevent the re-aggregation and crystallization of the pharmacoactive ingredient through hydrophobic interactions between molecules, thereby contributing to the stabilization of its dissolution profile.

[0062] Specific examples of hydrophilic polymers in the pharmaceutical composition of the present invention are not limited, but according to one embodiment, examples include polyvinyl alcohol, povidone, hypromellose, copolividone, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol-graft copolymer, hypromellose phthalate, and hypromellose acetate succinate. According to a specific embodiment, specific examples of hydrophilic polymers in the pharmaceutical composition of the present invention include polyvinyl alcohol, povidone, hypromellose, hydroxypropyl cellulose, etc. The pharmaceutical composition of the present invention may contain any one of these hydrophilic polymers alone, or may contain two or more in any combination and ratio.

[0063] In one embodiment, the content of the hydrophilic polymer in the pharmaceutical composition of the present invention is not limited, but is, for example, 1% by mass or more, 2% by mass or more, or 3% by mass or more, and also, for example, 15% by mass or less, 12.5% ​​by mass or less, or 10% by mass or less. In another embodiment, the mass ratio of the hydrophilic polymer to the pharmaceutical active ingredient is, for example, usually 0.02 parts by mass or more, 0.05 parts by mass or more, or 0.1 parts by mass or more of the hydrophilic polymer per 1 part by mass of the pharmaceutical active ingredient, and also usually 5 parts by mass or less, 3 parts by mass or less, or 2 parts by mass or less of the hydrophilic polymer.

[0064] Furthermore, the pharmaceutical composition of the present invention may contain, without departing from the spirit of the present invention, one or more inorganic or organic acids in unit value in addition to inorganic or organic acids.

[0065] Other ingredients: The pharmaceutical composition of the present invention may further contain other components. Specific examples of these other components, though not limited to them, include excipients such as mannitol, erythritol, powdered reduced maltose syrup, crystalline cellulose, and corn starch; disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate, partially pregelatinized starch, carmellose calcium, and low-substituted hydroxypropyl cellulose; sweeteners such as sucralose, aspartame, acesulfame potassium, sodium saccharin, monoammonium glycyrrhizinate, and thaumatin; and other additives such as fluidizers, colorants, and fragrances. These components can be appropriately selected and used depending on the dosage form of the pharmaceutical composition of the present invention. The pharmaceutical composition of the present invention may contain any one of these components alone, or two or more components in any combination and ratio. For details regarding the components that can be used in the pharmaceutical composition of the present invention, refer to, for example, the descriptions in University of the Sciences in Philadelphia, “Remington: The Science and Practice of Pharmacy, 20th EDITION”, Lippincott Williams & Wilkins, 2000, as appropriate.

[0066] • Dosage form of the formulation: The dosage form of the pharmaceutical composition of the present invention is not limited and can be any orally administered dosage form. Examples include various orally administered dosage forms listed in the Japanese Pharmacopoeia, namely tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc. These dosage forms may be appropriately selected depending on the type of pharmaceutically active ingredient and indication.

[0067] In one embodiment, the pharmaceutical composition of the present invention is in the form of a dry syrup. In this disclosure, "dry syrup" refers to a subcategory of "syrup" as described in the Japanese Pharmacopoeia, meaning a granular or powdered dry solid preparation that can be reconstituted into a syrup by adding water at the time of administration to dissolve or suspend it immediately. Such dry syrup formulations are advantageous in terms of their good shelf life, portability, and ease of administration, especially when formulating pharmaceutical active ingredients (e.g., ART-001, alpelisib, etc.) primarily for administration to children.

[0068] [Method for producing oral pharmaceutical compositions] The method for producing the pharmaceutical composition of the present invention is not limited, and it may be produced by any known method depending on the dosage form. For example, depending on the desired dosage form, the pharmaceutically active ingredient, an inorganic or organic acid, a hydrophilic polymer, and other optionally used components may be mixed using known formulation techniques, and then subjected to appropriate processing such as granulation. For example, in the case of a granular formulation, the raw material mixture may be granulated using known granulation methods such as dry granulation or wet granulation. In the case of tablets, the granulated raw material mixture obtained by known granulation methods may be compressed into tablets, and the resulting tablets may be coated as needed. Alternatively, the raw material mixture may be directly compressed into tablets by a direct tableting method without going through a granulation process.

[0069] In one embodiment, when the pharmaceutical composition of the present invention is in the form of a dry syrup, it can be manufactured by processing the following steps (as appropriate, referred to as "the manufacturing method of the present invention") using a pharmaceutical active ingredient, an inorganic or organic acid, a hydrophilic polymer, and other optionally used ingredients as raw materials. • A step of mixing the above raw materials in any order. • A step of wet granulating the mixture. • A step of drying the wet granules.

[0070] Furthermore, some of the raw material components other than the pharmaceutical active ingredient may be added to the raw material mixture after wet granulation, at the discretion of the user.

[0071] In the manufacturing method of the present invention, by wet granulation of a raw material mixture containing a pharmaceutical active ingredient, aggregation and crystallization of the molecules of the pharmaceutical active ingredient are eliminated, making it possible to have the molecules of the pharmaceutical active ingredient in an amorphous state within the formulation.

[0072] The following describes the wet granulation process in particular. The solvent used during granulation is not particularly limited, and any known solvent can be used. Examples include water, ethanol, methanol, acetone, and dichloromethane. Among these, water and ethanol are particularly suitable from a handling standpoint. One of these solvents may be used alone, or two or more may be used in any combination and ratio. The solvent and each raw material component are mixed and subjected to the granulation process. The granulation method used is also not particularly limited, and any known granulation method can be used. Examples include extrusion granulation, spray drying granulation, fluidized bed granulation, and agitation granulation. In one embodiment, the granulation method is fluidized bed granulation. The wet granulator is also not particularly limited, and any known granulator can be used depending on the solvent and granulation method used. Examples include cylindrical extrusion granulators, rolling fluidized bed granulators, spray drying granulators, fluidized bed granulator dryers, and agitation granulators. According to one embodiment, the granulator is a tumbling fluidized bed granulator, a fluidized bed granulator dryer, etc.

[0073] In addition to the above steps, various steps well known in the pharmaceutical field may be added as needed, such as wet or dry grinding of each raw material component, sieving of each raw material component or raw material mixture, and coating the granules with a predetermined coating material.

[0074] [Method of use for oral pharmaceutical compositions] The pharmaceutical compositions of the present invention are administered orally to a target for the purpose of treating, preventing, or regulating diseases or conditions depending on the type of pharmaceutically active ingredient. The target of administration of the pharmaceutical compositions of the present invention is not particularly limited, but examples include humans, non-human mammals, and other animals. The dosage and frequency of administration of the pharmaceutical compositions of the present invention are also not particularly limited, but may be appropriately adjusted depending on the type and activity of the pharmaceutically active ingredient, the species, age, weight, and condition of the target, etc. Furthermore, two or more pharmaceutical compositions of the present invention, each containing two or more pharmaceutically active ingredients individually, may be administered to the same target simultaneously or consecutively, and a pharmaceutical composition of the present invention containing one pharmaceutically active ingredient and another pharmaceutical composition containing another pharmaceutically active ingredient may be administered to the same target simultaneously or consecutively. In particular, when administering a first pharmaceutically active ingredient having pH-dependent solubility and a second pharmaceutically active ingredient whose solubility is not pH-dependent to the same target, a pharmaceutical composition of the present invention formulated with the first pharmaceutically active ingredient having pH-dependent solubility and a conventional pharmaceutical composition formulated with the second pharmaceutically active ingredient whose solubility is not pH-dependent may be combined and administered to the target simultaneously or consecutively. The pharmaceutical composition administered in combination with the pharmaceutical composition of the present invention may be administered orally, or it may be administered by another route. [Examples]

[0075] The present invention will be described in more detail below with reference to examples, but these examples are merely illustrative examples for convenience, and the present invention is not limited in any sense to these examples.

[0076] [1. Investigation of the pH-dependent solubility profile of ART-001] The dissolution profiles of ART-001 under various pH conditions were tested using the following procedure. Specifically, excess amounts of ART-001 were added to 50 mM phosphate buffer (pH 1, 2, 7, and 8), citrate buffer (pH 3, 4, 5, and 6), borate buffer (pH 9), and bicarbonate buffer (pH 10), all of which were adjusted to various pH levels within the range of 1 to 10 using 6 N hydrochloric acid or 10 N sodium hydroxide aqueous solution. The mixture was then stirred at room temperature. Once the dissolution state reached equilibrium, a certain amount of sample was taken, centrifuged at 1000 rpm for 10 minutes, and the supernatant was collected and measured by HPLC. The pH at the start and end of dissolution was also measured and recorded.

[0077] The results are shown in Table 2 below. As is clear from this table, ART-001 exhibits extremely high solubility at room temperature (RT) under low pH conditions (e.g., pH 2.5 or lower) (solubility 312 mcg / mL to approximately 10,000 mcg / mL), while its solubility decreases rapidly as the pH increases, showing almost no solubility under high pH conditions (e.g., pH 6 or higher) (solubility 1.3 mcg / mL: approximately 4% if solubility under low pH conditions is considered 100%). From this, it can be seen that ART-001 has a highly pH-dependent solubility profile.

[0078] [Table 2]

[0079] [2. Preparation of ART-001 dry syrup formulation] A dry syrup formulation of ART-001 was prepared using the following procedure.

[0080] • Formulation A: (1) 270g of D-mannitol (Bussan Food Science Co., Ltd.) that had passed through a 42M sieve and 30g of crystalline cellulose (KG-1000, Asahi Kasei Corporation) were mixed. (2) 75g of phosphoric acid (Kokusan Chemical Co., Ltd.) and 25g of povidone (PLASDONE K-25, ASHLAND) were dissolved in 600g of purified water. (3) 100g of ART-001 (Carbogen Amcis AG) was added to the solution in (2) and dispersed. (4) The mixture from (1) was placed into a fluid bed granulator (FD-MP-01D / SFP type, Powrec Co., Ltd.), and the dispersion from (3) was sprayed onto it to granulate. (5) The granules obtained in (4) above were dried at 60°C. (6) The dried granules obtained in (5) above were sized using a 30M sieve. (7) 0.25 g of the whole granules obtained in (6) above and 0.15 g of citric acid hydrate (Kokusan Chemical Co., Ltd.) were mixed to obtain a target dry syrup formulation corresponding to the pharmaceutical composition of the present invention.

[0081] • Formulation B: (1) 270g of D-mannitol (Bussan Food Science Co., Ltd.) that had passed through a 42M sieve and 30g of crystalline cellulose (KG-1000, Asahi Kasei Corporation) were mixed. (2) 75g of phosphoric acid (Kokusan Chemical Co., Ltd.) and 25g of povidone (PLASDONE K-25, ASHLAND) were dissolved in 600g of purified water. (3) 100g of ART-001 (Carbogen Amcis AG) was added to the solution in (2) and dispersed. (4) The mixture from (1) was placed into a fluid bed granulator (FD-MP-01D / SFP type, Powrec Co., Ltd.), and the dispersion from (3) was sprayed onto it to granulate. (5) The granules obtained in (4) above were dried at 60°C. (6) The dried granules obtained in (5) above were sized using a 30M sieve. (7) 0.25 g of the whole granules obtained in (6) above, 0.0583 g of tartaric acid (L(+)-tartaric acid, Kokusan Chemical Co., Ltd.), and 0.035 g of L-glutamic acid hydrochloride (Fujifilm Wako Pure Chemical Industries, Ltd.) were mixed to obtain a target dry syrup formulation corresponding to the pharmaceutical composition of the present invention.

[0082] • Formulation C: (1) 48 g of crystalline cellulose (KG-1000, Asahi Kasei Corporation) and 32 g of polyvinyl alcohol (partially saponified) (Gosenol EG-05PW, Mitsubishi Chemical Corporation) were mixed. (2) 160g of D-mannitol (Bussan Food Science Co., Ltd.) that had passed through a 42M sieve was mixed with the mixture from (1) above. (3) 120g of phosphoric acid (Taihei Chemical Industry Co., Ltd.) and 40g of povidone (PLASDONE K-25, ASHLAND) were dissolved in 960g of purified water. (4) 160g of ART-001 (Carbogen Amcis AG) was added to the solution from (3) and dispersed. (5) The mixture from (2) above was placed into a fluid bed granulator (FD-MP-01D / SFP type, Powrec Co., Ltd.), and the dispersion from (4) above was sprayed onto it to granulate. (6) The granules obtained in (5) above were dried at 60°C. (7) The dried granules obtained in (6) above were sized using a 30M sieve to obtain a target dry syrup formulation corresponding to the pharmaceutical composition of the present invention.

[0083] [3. Evaluation of ART-001 Dry Syrup Formulation] The dry syrup formulation of ART-001 prepared according to the procedure described above was administered to dogs according to the procedure detailed below, and the pharmacokinetics of ART-001 in the blood were investigated. As a control, a formulation in which ART-001 was suspended in a 0.5% methylcellulose (MC; METOLOSE, SM-100, manufactured by Shin-Etsu Chemical Co., Ltd.) aqueous solution was also prepared, and the pharmacokinetics of ART-001 in the blood were investigated in the same manner when administered to dogs.

[0084] Specifically, six male dogs aged 5-6 years obtained from Kitayama Labes Co., Ltd. were subjected to a total of five administration tests with a drug-free period of more than one week. Thirty minutes before the start of administration of each formulation, in Test 1, pentagastrinn (manufactured by Sigma-Aldrich) was administered intramuscularly to adjust the gastric pH to strongly acidic, and in Tests 2-5, famotidine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was administered intravenously to adjust the gastric pH to neutral to weakly alkaline. Then, immediately before the start of administration of each formulation, the gastric pH of each individual in each group was measured using pH test strips. In Tests 1 and 2, the control ART-001 0.5% MC suspension was administered, and in Tests 3, 4, and 5, ART-001 dry syrup formulations A-C were administered at a dose of 4 mg / kg each. After administration, blood samples were collected sequentially from the cephalic vein of each individual in each group, and the concentration of ART-001 in the plasma (μg / mL) was measured by HPLC. The results are shown in Table 3 below.

[0085] In a study in which a 0.5% MC suspension of ART-001 was administered, in Study 1, where the gastric pH was adjusted to be strongly acidic (pH approximately 2), the plasma ART-001 concentration reached approximately 1.4 μg / mL about 0.5 hours after administration, and then gradually decreased. On the other hand, in Study 2, where the gastric pH was adjusted to be neutral to slightly alkaline (pH approximately 8-9), the plasma ART-001 concentration hardly increased after administration. This indicates that gastric pH significantly affects the absorption of ART-001.

[0086] On the other hand, in studies 3-5 in which ART-001 dry syrup formulations A-C were administered, despite the gastric pH being adjusted to neutral to slightly alkaline (pH approximately 8-9), the maximum plasma ART-001 concentration (C) was similar to that in study 1. max ) and area under the blood concentration curve (AUC) up to 24 hours after administration 0-24h This shows that the dry syrup formulation of ART-001, which corresponds to the pharmaceutical composition of the present invention, can achieve the same absorption profile as when the gastric pH is strongly acidic (pH approximately 2), even when the gastric pH is neutral to weakly alkaline (pH approximately 8 to 9).

[0087] [Table 3]

[0088] [4. Examination of the pharmacokinetics of ART-001 dry syrup formulation] The dry syrup formulation of ART-001 (the pharmaceutical composition of the present invention) prepared according to the above procedure was administered to healthy adult males as a single dose or repeatedly, and the subsequent pharmacokinetics of ART-001 in the blood were examined.

[0089] Specifically, in the single-dose study, the ART-001 dry syrup formulation was dissolved in 100 mL of water at doses of 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg of ART-001, and administered orally as a single dose to 6 healthy adult males. Blood samples were collected at various time points from before administration to 48 hours after administration, and the concentration of ART-001 in plasma (ng / mL) was measured by HPLC. In the repeated-dose study, the ART-001 dry syrup formulation was dissolved in 100 mL of water at a dose of 100 mg of ART-001, and administered orally once daily for 7 days to 6 healthy adult males, with blood samples collected at various time points.

[0090] The results of the single-dose study are shown in Figure 1 and Table 4. After administration of the dry syrup formulation, ART-001 was rapidly absorbed, and the peak plasma concentration (C) was reached approximately 1 hour after administration. max After reaching ), it gradually decreased (Figure 1). C of ART-001 max and area under the blood concentration curve (AUC) last ) increased in proportion to the dose of ART-001 (Table 4). The coefficient of variation (%CV), an indicator of plasma concentration variability, was C max AUC of 3-22% last The percentages ranged from 16% to 34%.

[0091] [Table 4]

[0092] The results of the repeated-dose study are shown in Figure 2 and Table 5. On the 5th day of administration of the dry syrup preparation, the trough value of the plasma concentration of ART-001 reached a steady state, and the accumulation rate of ART-001 after 7 days of administration was 2.4-fold in terms of AUC 0-24h (Figure 2, Table 5). Also, the %CV on the 7th day of administration was 19% in terms of C max and 32% in terms of AUC 0-24h , which was equivalent to that on the first day of administration.

[0093] [Table 5]

[0094] From the above results, when the dry syrup preparation corresponding to the pharmaceutical composition of the present invention is used for administration of ART-001, which is an example of a pharmaceutically active ingredient having a pH-dependent dissolution profile, compared with the case of administration using conventional capsules or tablets (References: Juric et al., Clin. Cancer Res., (2017), 23

[17] :5015-5023, Patel et al., Clin. Pharmacol. Drug Dev., (2019), 8[5]:637-646), it was revealed that stable pharmacokinetics with reduced inter-individual variability can be obtained. The tight and stable pharmacokinetics obtained by such a dry syrup preparation facilitate dose selection to obtain a blood exposure for which efficacy is expected and also enable avoidance of side effects due to high exposure. [Industrial Applicability]

[0095] The present invention can be widely applied in the field of pharmaceuticals, particularly for administering various pharmaceutically active ingredients having a pH-dependent dissolution profile, and its utility value is extremely high.

Claims

1. ART-001 (Cerabellicib), an inorganic or organic acid, and a hydrophilic polymer are included in An oral pharmaceutical composition which is a lye syrup preparation, wherein the inorganic or organic acid is phosphoric acid, Hydrochloric acid, citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, asparagus One or more acids selected from nic acid, lactic acid, acetic acid, glutamic acid, and adipic acid. An oral pharmaceutical composition.

2. As an inorganic or organic acid, at least phosphoric acid, citric acid, tartaric acid, and glutamic acid An oral pharmaceutical composition according to claim 1, comprising an acid selected from the above.

3. The hydrophilic polymers are polyvinyl alcohol, povidone, hypromellose, and copolyvidone. Hydroxypropylcellulose, polyvinyl alcohol, polyethylene glycol, Raft copolymer, hypromellose phthalate, and hypromellose acetate The polymer is one or more polymers selected from succinate esters, according to claim 1 or 2. The oral pharmaceutical composition described.

4. Claims 1 to 40% by mass contain ART-001 (cerabelisib). An oral pharmaceutical composition as described in any one of item 3.

5. The content ratio of inorganic or organic acid per 1 part by mass of ART-001 (Ceravelicib) is 0. An oral pharmaceutical composition according to any one of claims 1 to 4, wherein the amount is in the range of 1 to 10 parts by mass.

6. The hydrophilic polymer content is 0.0% per 1 part by mass of ART-001 (Ceravellicib). An oral pharmaceutical composition according to any one of claims 1 to 5, wherein the amount is in the range of 2 to 5 parts by mass.

7. A method for producing an oral pharmaceutical composition according to any one of claims 1 to 6, wherein ART -001 (Cerabellicib), a mixture containing an inorganic or organic acid and a hydrophilic polymer, is wet-processed. A method including granulation and drying.

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