CN113508114B - Oral pharmaceutical composition with azetidine derivative as active ingredient, preparation method and application thereof - Google Patents

Oral pharmaceutical composition with azetidine derivative as active ingredient, preparation method and application thereof Download PDF

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Publication number
CN113508114B
CN113508114B CN202080007400.9A CN202080007400A CN113508114B CN 113508114 B CN113508114 B CN 113508114B CN 202080007400 A CN202080007400 A CN 202080007400A CN 113508114 B CN113508114 B CN 113508114B
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China
Prior art keywords
pharmaceutical composition
active ingredient
oral pharmaceutical
present application
dissolution
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CN202080007400.9A
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Chinese (zh)
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CN113508114A (en
Inventor
李岩
蔡孟锬
王梦馨
宋宏梅
蔡家强
赵曦
周丹
赵栋
吴灵静
舒路川
闫海霞
唐超
王英
薛彤彤
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Relates to an oral pharmaceutical composition taking azetidine derivatives as active ingredients, a preparation method and application thereof. The preparation process of the oral pharmaceutical composition is simple, convenient and stable, the API content and the mixing uniformity of intermediate materials are good, and the obtained finished product of the preparation has fast dissolution and stable quality, and is suitable for industrial scale-up production.

Description

Oral pharmaceutical composition with azetidine derivative as active ingredient, preparation method and application thereof
Technical Field
The present application relates to oral pharmaceutical compositions comprising azetidine derivatives as active ingredients, and methods of preparation and use thereof.
Background
JAK is an intracellular non-receptor tyrosine protein kinase belonging to the family of protein kinases. In mammals, the JAK family has four members in total: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). JAKs play a critical role in cytokine signaling, downstream substrates of JAK family kinases include Signal Transduction and Activator of Transcription (STAT) proteins. Interactions between JAK and STAT play an important role in cytokine receptor signaling pathways, and are widely involved in processes such as cell proliferation, differentiation, apoptosis, inflammation, and the like. Activation of the JAK/STAT pathway promotes the development of a variety of diseases, including various solid tumors, lymphomas, leukemias, and inflammatory diseases.
The Chinese patent application 201680059396.4 discloses novel azetidine derivatives which are small molecular medicines capable of being orally administered, can selectively target and inhibit key node JAK1 and JAK2 kinase in the disease process of rheumatoid arthritis (Rheumatoid Arthritis, RA) and block phosphorylation of a downstream transcription factor STAT, finally lead to signal transmission interruption of a key link JAK/STAT signal shaft in the disease process of the rheumatoid arthritis, lead to incapability of transmitting cytokine signals to a cell nucleus for regulation and transcription, play roles in reducing release of inflammatory factors, inhibiting abnormal proliferation of immune cells and the like, which are beneficial to improving the disease process of the rheumatoid arthritis, achieve the aim of improving the pathological process and play a remarkable therapeutic role.
Through comprehensive preclinical drug effect, drug generation and toxicology researches, the azetidine derivatives have obvious treatment effect on a rat collagen-induced arthritis (CIA) model, and can reach the exposure level and the equivalent drug effect equivalent to the same-target drug Baricitinib with the dosage of 10mg/kg at the dosage of 3 mg/kg. In addition, the azetidine derivatives have good drug generation property, systemic drugs mainly exist in original forms, repeated administration does not have accumulation phenomenon, no obvious combination with erythrocytes, wide in-vivo distribution, mainly excreted by feces, and no CYP enzyme inhibition effect. The toxicity research result is similar to toxicity reported in the on-market co-target drug Baricitinib literature, and the toxicity effect can be recovered or has a recovery trend, and repeated administration does not accumulate. In view of the above, the azetidine derivatives have wide application prospect and high clinical development value for clinical treatment of rheumatoid arthritis.
Chinese patent application 201680059396.4 discloses oral pharmaceutical compositions of such azetidine derivatives. However, the preparation process of the compositions is complex, and has a plurality of influencing factors, so that the process repeatability is poor, and the industrial scale-up production is not facilitated. Therefore, there is a need in the clinic to provide a novel method for providing an oral pharmaceutical composition containing such novel azetidine derivatives with excellent dissolution properties, and a stable and simple preparation process, and an oral pharmaceutical composition prepared thereby with excellent dissolution properties.
Summary of The Invention
It is an object of the present application to provide a process for the preparation of an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula I, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
wherein:
R 1 selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Aralkyl, C (O) R 10 And S (O) 2 R 11 ；
R 2 And R is 3 Each independently selected from H, CN, halogen and C 1-6 An alkyl group;
R 4 and R is 5 Each independently selected from H, halogen, and CN;
x is selected from N and CR 6 ；
Y is selected from N and CR 9 ；
Z is selected from N and CR 7 ；
W is selected from N and CR 8 ；
R 6 、R 7 、R 8 And R is 9 Each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C (O) NR 12 R 13 ；
R 10 And R is 11 Each independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Aralkyl and NR 12 R 13 ；
R 12 And R is 13 Each independently selected from H and C 1-6 An alkyl group;
wherein each of the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups is optionally substituted with 1, 2 or 3 groups independently selected from halogen, CN and C 1-4 The substituent of the alkyl group is substituted,
the method comprises the following steps:
i) The active ingredient was crushed to the following particle size ranges:
D v (90) 1-500 mu m;
D v (50) 1-100 mu m;
D v (10) 0.1-10 mu m;
d4, 3 is 1-50 mu m; and/or
D3, 2 is 1-5 mu m; and
ii) mixing the active ingredient with the carrier, sieving with a 40-60 mesh sieve and mixing again.
In some embodiments, the present application provides a method of preparing an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, further comprising:
iii) Filling into capsules or tabletting.
It is another object of the present application to provide an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula I as shown above, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, wherein the dissolution of the oral pharmaceutical composition measured in 900ml of disodium hydrogen phosphate/citric acid buffer at pH 3.0 according to the basket method of chinese pharmacopoeia (2015) at a speed of 75rpm at a temperature of 37 ℃ is: at least 80% by weight of the active ingredient dissolves in 30 minutes; preferably, at least 88% by weight of the active ingredient is dissolved in 45 minutes and at least 93% by weight of the active ingredient is dissolved in 60 minutes.
In some embodiments, the present application provides an oral pharmaceutical composition that is a capsule or tablet.
In some embodiments, the present application provides an oral pharmaceutical composition prepared by the methods of the present application.
It is another object of the present application to provide the use of the oral pharmaceutical composition of the present application in the manufacture of a medicament for treating JAK-associated diseases. The JAK-associated disease is preferably selected from inflammatory diseases, autoimmune diseases or cancers, more preferably rheumatoid arthritis.
It is another object of the present application to provide a method of treating JAK-associated diseases comprising administering to a subject in need thereof an oral pharmaceutical composition of the present application.
It is another object of the present application to provide an oral pharmaceutical composition of the present application for use in the treatment of JAK-associated diseases.
Detailed Description
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present application.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "alkyl" is defined to include saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, the alkyl group has 1To 6, for example 1 to 4 carbon atoms. For example, as used herein, the term "C 1-6 Alkyl "refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (e.g., CF) 3 、C 2 F 5 、CHF 2 、CH 2 F、CH 2 CF 3 、CH 2 Cl or-CH 2 CH 2 CF 3 Etc.). The term "C 1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "alkoxy" refers to a linear, branched or cyclic saturated monovalent hydrocarbon radical of the formula-O-alkyl, wherein the term "alkyl" is as defined above or as "cycloalkyl" as defined below, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentoxy, isopentoxy or n-hexoxy, or isomers thereof.
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclic [ 1.1.1:1:]amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 Cycloalkyl "refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo [ 1.1.1)]Pentyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.
As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) selected from C (=o), O, S, S (=o), S (=o) 2 And NR a Wherein R is a heteroatom-containing group a Represents a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 An alkyl group; the heterocycloalkyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. In particular, 3-10 membered heterocyclyl groups are groups having 3-10 carbon atoms and heteroatoms in the ring such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-14 Aryl "means an aromatic group containing 6 to 14 carbon atoms such as phenyl or naphthyl. Aryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom (which may be the same or different, such as oxygen, nitrogen or sulfur) and which may additionally be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and the benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives.
The term "aralkyl" preferably denotes an aryl substituted alkyl group, wherein the aryl and the alkyl are as defined herein. Typically, the aryl group may have from 6 to 14 carbon atoms, and the alkyl group may have from 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" refers to being optionally substituted with a particular group, radical or moiety.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The compounds of the present application may also comprise one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1 H、 2 H (D or deuterium) and 3 h (T or tritium); c may be in any isotopic form, including 12 C、 13 C and C 14 C, performing operation; o may be in any isotopic form, including 16 O and 18 o, etc.
The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, it may result in racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the present application may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the present application may exist in free form for use in therapy, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. According to the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs, which, upon administration to a patient in need thereof, are capable of providing the compounds of the present application or metabolites or residues thereof, directly or indirectly.
Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts thereof.
Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethionate, lactate, methylsulfate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, tannate and xinofoate (xinofoate).
Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.
For a review of suitable salts see Stahl, wermpuh, "Handbook of Pharmaceutical Salts: properties, selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.
The compounds of the present application may exist in the form of a hydrate or solvate, wherein the compounds of the present application comprise a polar solvent as a structural element of the compound lattice, such as, in particular, water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Also included within the scope of the present application are metabolites of the compounds of the present application, i.e., compounds that form in vivo upon administration of a drug.
Prodrugs of the present application may be produced, for example, by replacing the appropriate functional groups present in the compounds of formula I with certain groups known to those skilled in the art, for example the "pro-groups" described in Design of Prodrugs of h.bundegaard (Elsevier, 1985).
As used herein, the term "content uniformity" refers to the degree to which the content of each tablet(s) of a small or single dose solid formulation, semi-solid formulation, and heterogeneous liquid formulation meets the indicated weight.
As used herein, the term "particle size" refers to the size of the particle, wherein D v (50) Representing the median particle size of the distribution, i.e. 50% of the particles are smaller than the size and 50% of the particles are larger than the size. D (D) v (10) Representing 10% of all particles having a particle size less than the stated size. Similarly, D v (90) Representing a particle size of 90% of all particles smaller than said size. D4, 3]Refers to the volume weighted average particle size. D [3,2 ]]Refers to the surface area weighted average particle size.
As used herein, the term "comminution" refers to an operation of comminuting large-sized solid matter to a suitable degree by mechanical force or air flow, which includes dry comminution, wet comminution, cryogenic comminution, and ultra-fine comminution. The pulverizing equipment includes mortar, universal pulverizer, ball mill and jet mill.
As used herein, the term "sieving" refers to the crushing of particles or powders, etc., to meet the needs of preparing a formulation, while having a mixing action to ensure uniformity of the components. The sieving equipment comprises a shaking sieve, a vibrating sieve, a rotating sieve and a drum sieve.
As used herein, the term "gradient mixing" refers to mixing the active ingredient with a quantity of adjuvant (single adjuvant or a pre-mixture of multiple adjuvants) to obtain a first mixture, then adding the adjuvant (single adjuvant or a pre-mixture of multiple adjuvants) in a weight ratio (e.g., 4 times, 5 times, 6 times, etc.) to the obtained first mixture and mixing to obtain a second mixture, and continuing the addition of adjuvant according to the same method until the adjuvant is added in its entirety.
Oral pharmaceutical composition
According to one aspect of the present application, there is provided an oral pharmaceutical composition comprising an azetidine derivative active ingredient and at least one pharmaceutically acceptable carrier. The oral pharmaceutical composition has excellent dissolution property and stability, and the preparation process is stable and simple, and various indexes meet the requirements of Chinese pharmacopoeia and meet the requirements of clinical and commercial use.
< active ingredient >
The active ingredient contained in the oral pharmaceutical composition is a compound of the formula I, pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
wherein:
R 1 selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Aralkyl, C (O) R 10 And S (O) 2 R 11 ；
R 2 And R is 3 Each independently selected from H, CN, halogen and C 1-6 An alkyl group;
R 4 and R is 5 Each independently selected from H, halogen, and CN;
x is selected from N and CR 6 ；
Y is selected from N and CR 9 ；
Z is selected from N and CR 7 ；
W is selected from N and CR 8 ；
R 6 、R 7 、R 8 And R is 9 Each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy and C (O) NR 12 R 13 ；
R 10 And R is 11 Each independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Aralkyl and NR 12 R 13 ；
R 12 And R is 13 Each independently selected from H and C 1-6 An alkyl group;
wherein each of the above alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups is optionally substituted with 1, 2 or 3 groups independently selected from halogen, CN and C 1-4 The substituent of the alkyl group is substituted.
According to some embodiments of the present application, R 1 Selected from C (O) R 10 And S (O) 2 R 11 。
According to some embodiments of the present application, R 2 And R is 3 Each independently selected from H, CN, F and methyl.
According to some embodiments of the present application, R 4 And R is 5 Each independently selected from H, F, cl and CN.
According to some embodiments of the present application, X is CR 6 。
According to some embodiments of the present application, X, Y, Z or W are each independently selected from N and CH. Preferably, X is CH and Y, Z or W are each independently selected from N and CH.
According to some embodiments of the present application, R 6 、R 7 、R 8 And R is 9 Each independently selected from H, F, cl, CN, methyl, ethyl, methoxy and C (O) NH 2 。
According to some embodiments of the present application, R 10 And R is 11 Each independently selected from methyl, ethyl, N-propyl, isopropyl, cyclopropyl, N-butyl, isobutyl, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl and N (CH) 3 ) 2 Wherein each of the foregoing groups is optionally substituted with 1, 2 or 3 substituents independently selected from F, CN and methyl.
According to some embodiments of the present application, R 12 And R is 13 Each independently selected from H, methyl and ethyl.
The present application encompasses compounds of formula I resulting from any combination of the above preferred groups.
According to some embodiments of the present application, the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula II, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
wherein each group and substituent is as defined above for formula I.
According to some embodiments of the present application, the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula III, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
Wherein:
one of W or ZIs N; or W is CR 8 Z is CR 7 And R is 2 、R 4 、R 5 And R is 8 And not H at the same time.
According to some embodiments of the present application, the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula IV, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
wherein:
R 1 selected from C (O) R 10 And S (O) 2 R 11 ；
R 10 And R is 11 Each independently selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Aralkyl and NR 12 R 13 Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted with 1, 2 or 3 groups independently selected from halogen, CN and C 1-4 The substituent of the alkyl group is substituted.
According to some embodiments of the present application, the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula V, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
wherein each group and substituent is as defined above for formula I.
According to some embodiments of the present application, the active ingredient contained in the oral pharmaceutical composition of the present application is a compound of formula VI, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof,
Wherein each group and substituent is as defined above for formula I.
According to some embodiments of the present application, the active ingredient is a compound selected from the group consisting of the following, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof:
/>
according to some embodiments of the present application, the active ingredients are the following compounds:
the above active ingredients, their preparation and use are described in the applicant's filed chinese patent application No. 201680059396.4. The above-mentioned chinese patent application is incorporated herein by reference in its entirety.
According to some embodiments of the present application, the amount of the active ingredient is 0.01 to 30% by weight, preferably 0.05 to 10% by weight, preferably 0.1 to 30% by weight, more preferably 0.5 to 10% by weight of the oral pharmaceutical composition.
According to some embodiments of the present application, the oral pharmaceutical composition of the present application comprises 0.1-10mg, preferably 0.1-5mg, preferably 1-10mg, more preferably 1-5mg of said active ingredient.
According to some embodiments of the present application, the oral pharmaceutical compositions of the present application may further comprise one or more additional therapeutic or prophylactic agents, including, but not limited to: chemotherapeutic or antiproliferative agents, anti-inflammatory agents, immunomodulators or immunosuppressants, neurotrophic factors, agents for treating cardiovascular diseases, agents for treating destructive bone disorders, agents for treating liver diseases, antiviral agents, agents for treating hematological diseases, agents for treating diabetes or agents for treating immunodeficiency diseases. In particular, the one or more additional therapeutic or prophylactic agents are selected from the group consisting of efolizumab, mycophenolate sodium, etanercept, methotrexate, and the like.
< pharmaceutically acceptable Carrier >
Pharmaceutically acceptable carriers for use in the oral pharmaceutical compositions of the present application include, but are not limited to, fillers, disintegrants, lubricants, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The filler includes, but is not limited to, one or more of the following: mannitol, microcrystalline cellulose, starch, pregelatinized starch, lactose, monocalcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, and the like. Preferably, the filler is mannitol, microcrystalline cellulose or lactose. More preferably, the filler is microcrystalline cellulose. According to some embodiments of the present application, the filler is present in an amount of 1 to 99.99%, preferably 20 to 99.99%, more preferably 70 to 99.99% by weight of the oral pharmaceutical composition. When the filler is microcrystalline cellulose, the weight ratio of microcrystalline cellulose to the active ingredient used in the oral pharmaceutical compositions of the present application is from 20:1 to 1300:1, preferably from 20:1 to 200:1, more preferably from 25:1 to 150:1.
The disintegrants include, but are not limited to, one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hypromellose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and the like. Preferably, the disintegrant is croscarmellose sodium. According to some embodiments of the present application, the amount of disintegrant is 0 to 20%, preferably 0 to 10% by weight of the oral pharmaceutical composition. When the filler is microcrystalline cellulose, the oral pharmaceutical composition of the present application may not include a disintegrant.
The lubricant includes, but is not limited to, one or more of the following: stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, talc, polyethylene glycol, sodium stearyl fumarate, silica and the like. Preferably, the lubricant is magnesium stearate, sodium stearyl fumarate or silica. According to some embodiments of the present application, the lubricant is present in an amount of 0 to 10%, preferably 0 to 5% by weight of the oral pharmaceutical composition.
According to some embodiments of the present application, the oral pharmaceutical composition of the present application comprises an active ingredient as described above and microcrystalline cellulose, wherein the weight ratio of microcrystalline cellulose to said active ingredient is 20:1 to 1300:1, preferably 20:1 to 200:1, more preferably 25:1 to 150:1. In particular, the oral pharmaceutical composition of the present application comprises 0.01 to 30% by weight, preferably 0.05 to 10% by weight of the active ingredient as described above and 1 to 99.99%, preferably 20 to 99.99%, more preferably 70 to 99.99% of microcrystalline cellulose, wherein the weight ratio of microcrystalline cellulose to said active ingredient is 20:1 to 1300:1, preferably 20:1 to 200:1, preferably 25:1 to 150:1, more preferably 60:1 to 140:1.
< dosage form >
Dosage forms of the oral pharmaceutical compositions of the present application include, but are not limited to, tablets, capsules, troches, hard candies, powders, granules, solutions, aromatic water agents, spirits, suspensions, elixirs, syrups, and the like.
According to some embodiments of the present application, the oral pharmaceutical composition of the present application is a capsule. The capsule shell of the capsule is gelatin empty capsule, hydroxypropyl methylcellulose empty capsule and the like, preferably gelatin empty capsule.
According to some embodiments of the present application, the oral pharmaceutical composition of the present application is a tablet, preferably a coated tablet, more preferably a gastric-soluble coated tablet, such as a gastric-soluble film coated tablet.
< dissolution Pattern >
According to some embodiments of the present application, the dissolution rate of the oral pharmaceutical composition, measured in 900ml of disodium hydrogen phosphate/citric acid buffer at pH 3.0 according to the basket method of the chinese pharmacopoeia (2015 edition) at a rotation speed of 75rpm and a temperature of 37 ℃, is: at least 80% by weight of the active ingredient dissolves out within 30 minutes. Preferably, at least 88% by weight of the active ingredient is dissolved in 45 minutes and at least 93% by weight of the active ingredient is dissolved in 60 minutes.
According to some embodiments of the present application, the dissolution rate of the oral pharmaceutical composition, measured in 900ml of disodium hydrogen phosphate/citric acid buffer at pH 3.0 according to the basket method of the chinese pharmacopoeia (2015 edition) at a rotation speed of 75rpm and a temperature of 37 ℃, is:
30-80% by weight of the active ingredient dissolves out within 5 minutes,
at least 55% by weight of the active ingredient dissolves in 10 minutes,
at least 60% by weight of the active ingredient dissolves in 15 minutes,
at least 80% by weight of the active ingredient dissolves out within 30 minutes,
at least 88% by weight of the active ingredient dissolves in 45 minutes,
at least 93% by weight of the active ingredient dissolves out in 60 minutes.
Preparation method
According to another aspect of the present application, there is provided a method of preparing an oral pharmaceutical composition of the present application, comprising:
i) The active ingredient was crushed to the following particle size ranges:
D v (90) 1 to 500. Mu.m, preferably 1 to 100. Mu.m;
D v (50) 1 to 100. Mu.m, preferably 1 to 20. Mu.m;
D v (10) 01 to 10. Mu.m, preferably 0.1 to 5. Mu.m;
d4, 31 is 1-50 μm, preferably 1-30 μm; and/or
D3, 21 is 1-10 μm, preferably 1-5 μm; and
ii) mixing the active ingredient with the carrier, sieving with a 40-60 mesh sieve and mixing again.
According to some embodiments of the present application, the method further comprises:
iii) Filling into capsules or tabletting.
According to some embodiments of the present application, step ii) in the method is: the active ingredient is mixed with the carrier in gradient, screened through a 40-60 mesh sieve and mixed again.
According to some embodiments of the present application, the preparation methods provided herein are used to prepare small-sized (e.g., 0.1-5mg, 0.5mg, 1-5mg active ingredient-containing) oral pharmaceutical compositions.
Compared with the prior art, the preparation method provided by the application has the advantages of simple and stable process, good API content and mixing uniformity of intermediate materials in the preparation process, quick dissolution of the obtained preparation finished product, stable quality and suitability for industrial scale-up production.
Pharmaceutical use and method of treatment
According to yet another aspect of the present application there is provided the use of an oral pharmaceutical composition of the present application in the manufacture of a medicament for the treatment of a JAK-associated disease.
According to yet another aspect of the present application, there is provided a method of treating a JAK-associated disease comprising administering to a subject in need thereof an oral pharmaceutical composition of the present application.
According to yet another aspect of the present application, there is provided an oral pharmaceutical composition of the present application for use in the treatment of JAK-associated diseases.
According to some embodiments of the present application, the JAK-associated disease is selected from, but is not limited to, diseases of the immune system (such as organ transplant rejection), autoimmune diseases (such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis), allergic disorders (such as asthma, food allergy, atopic dermatitis and rhinitis), skin diseases (such as psoriasis, atopic dermatitis, rash), solid and hematological malignancies (such as prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, leukemia, lymphoma, multiple myeloma), myeloproliferative disorders (including erythrocytosis, idiopathic thrombocytosis, chronic idiopathic myelofibrosis, bone marrow outgrowth with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, eosinophilic syndrome and systemic cytopathy), in particular inflammatory diseases, autoimmune diseases, and cancer, more particularly hypertrophic arthritis.
In some embodiments, the present application also provides the use of the oral pharmaceutical compositions of the present application for simultaneous, separate and sequential use in combination with another therapeutic or prophylactic agent (e.g., as described above).
The dosage of the active ingredient contained in the oral pharmaceutical compositions of the present application is administered in a range of about 0.0001 to about 50mg/kg body weight/day, for example about 0.01 to about 10mg/kg body weight/day (single or divided administration). The precise dosage required to treat a patient is determined by the physician based on the stage and severity of the disease and the specific needs and response of the individual patient.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such disorder or condition, or one or more symptoms of such disorder or condition to which such term applies.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in this application include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Examples
In order to make the objects and technical solutions of the present application more clear, the present application is further described below in conjunction with specific embodiments. It should be understood that these examples are illustrative only of the present application and are not intended to limit the scope of the present application. Moreover, the specific experimental methods not mentioned in the following examples were carried out according to conventional experimental methods.
Example 1: basic prescription formulation and dissolution determination
Capsules were prepared according to the formulation shown in tables 1-1 and examined for dissolution of capsules in different pH media.
TABLE 1-1 formulation and composition of the base prescription
The preparation process comprises the following steps: (1) grinding and sieving the raw materials; (2) weighing the raw materials and auxiliary materials in the prescription amount, and mixing for 10min; (3) sieving the mixed materials once by a 60-mesh sieve; (4) mixing the materials again for 10min; (5) filling the capsule.
The dissolution measurement method is the basket method of Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, the volume of the medium is 900ml, and the dissolution investigation results under the conditions of hydrochloric acid solution with pH of 1.0, disodium hydrogen phosphate/citric acid buffer with pH of 3.0 and sodium acetate/acetic acid buffer with pH of 4.5 are shown in tables 1-2.
TABLE 1-2 dissolution results of the base recipe in different pH Medium
The results show that the dissolution rate of the API in the formulation decreases significantly with increasing pH. The dissolution medium with pH of 3.0 has certain distinguishing force for different prescriptions, the dissolution rate can reach more than 90% within 60min, and the RSD (relative standard deviation) (%) is 5.12.
Example 2: investigation of the disintegrant usage
And taking the croscarmellose sodium as a disintegrating agent, and researching the influence of the dosage of the disintegrating agent on the dissolution behavior of the preparation. The recipe composition is shown in Table 2-1.
TABLE 2-1 prescription composition with and without disintegrant
The preparation process of prescription 2-1 and prescription 2-2 is the same as that of prescription 1 in example 1. The dissolution measurement method is the basket method of Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, the dissolution medium is 900ml of disodium hydrogen phosphate/citric acid buffer solution with pH of 3.0, and the dissolution investigation result is shown in Table 2-2.
TABLE 2-2 dissolution of disintegrant-containing and disintegrant-free formulations
The result shows that the addition of the disintegrating agent has no obvious effect on the dissolution of the preparation, the dissolution rate is more than 90% in 60min, and the RSD (%) is less than 5.13%.
Example 3: examination of filler types
Lactose, pregelatinized starch and microcrystalline cellulose were selected as fillers to examine the dissolution behavior of the formulation. The specific prescription composition is shown in Table 3-1.
TABLE 3-1 prescription composition containing different fillers
The preparation process comprises the following steps: (1) the raw materials are subjected to jet milling treatment; (2) weighing the raw materials with the prescription amount, adding the auxiliary materials in three times, mixing for 5min after the first two times of adding, and mixing for 10min after the last time of adding; (3) sieving the materials once by a 50-mesh sieve; (4) mixing again for 10min; (5) filling the capsule.
The dissolution measurement method is basket method in Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, and the dissolution medium is 900ml of disodium hydrogen phosphate/citric acid buffer solution with pH of 3.0. The results of the examination are shown in Table 3-2.
TABLE 3-2 dissolution results for formulations containing different fillers
The result shows that when lactose or microcrystalline cellulose is used as a filler, the dissolution rate is high, more than 85% of the solution is dissolved in 30min, and RSD (%) is less than 5%; the dissolution rate can reach more than 93% in 60min, and the RSD (%) is less than 5%. When pregelatinized starch is used as filler, the dissolution rate is slow, 60nin still cannot reach 80% dissolution, and RSD (%) is greater than 5%.
Example 4: examination of the amount of filler (microcrystalline cellulose)
Prescriptions containing microcrystalline cellulose with different dosages are prepared, and proper capsule shell types are selected according to the total content, and the influence of the dosage of the filler (microcrystalline cellulose) on dissolution is examined. The specific prescription composition is shown in Table 4-1.
TABLE 4-1 prescription composition of different filler (microcrystalline cellulose) amounts
The preparation process comprises the following steps: (1) sieving the raw materials with 80 mesh sieve once; (2) weighing the raw materials and auxiliary materials in the prescription amount, and mixing for 10min; (3) sieving the mixed materials once by a 60-mesh sieve; (4) mixing again for 10min; (5) filling the capsule.
The dissolution measurement method is basket method in Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, and the dissolution medium is 900ml of disodium hydrogen phosphate/citric acid buffer solution with pH of 3.0. The results are shown in Table 4-2.
TABLE 4-2 dissolution results for formulations containing different amounts of fillers
The results show that prescription 4-2 dissolves faster at 5min, prescription 4-1 dissolves faster after 15min, and prescription 4-1 dissolves in smaller batch differences (RSD < 7%) with better dissolution effect.
Example 5: investigation of particle size of crude drug
Capsules were prepared according to the formulation shown in Table 5-1, and the effect of the particle size distribution of the drug substance on dissolution of the preparation was examined.
TABLE 5-1 formulation 5 amounts of ingredients
The preparation process comprises the following steps: (1) pulverizing the crude drug to different particle sizes by optional method (such as grinding, sieving, mechanical pulverizing or jet milling, etc.), and the particle size information is shown in Table 5-2; (2) gradient mixing of raw materials and auxiliary materials; (3) sieving with 50 mesh sieve for one time; (4) mixing again; (5) filling the capsule. Four batches of products with different particle sizes of the raw materials are obtained and are respectively represented by a prescription 5-1 (sieving), a prescription 5-2 (air flow crushing), a prescription 5-3 (air flow crushing) and a prescription 5-4 (air flow crushing).
TABLE 5-2 information on particle size of crude drug
The dissolution measurement method is basket method in Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, and the medium is 900ml of disodium hydrogen phosphate/citric acid buffer solution with pH of 3.0. The results of the examination are shown in tables 5 to 3.
TABLE 5-3 dissolution results of formulations containing drug substances of different particle sizes
The results show that the particle size of the API has some effect on the dissolution of the formulation. The dissolution rates of the formulations 5-2, 5-3 and 5-4 reach more than 93% in 60min, and RSD (%) are less than 4.02%, which shows that the preparation products have excellent dissolution properties by controlling the particle size of the API within a proper range.
Example 6: research on mixing process
Capsules of 1mg, 2mg and 5mg specifications were prepared according to the formulations shown in Table 6-1, and the content and mixing uniformity of the intermediate materials were examined.
Table 6-1.1 mg, 2mg and 5mg specification capsule formulations
The preparation process comprises the following steps:
(1) Pretreatment of raw materials: taking the raw materials, mechanically crushing, and detecting the particle size, wherein the results are shown in Table 6-2;
(2) Weighing and mixing: weighing the prescription amount of the raw material medicine and microcrystalline cellulose with the dosage being 5 times that of the raw material medicine, placing the raw material medicine and microcrystalline cellulose into a glass bottle, and manually mixing for 5min;
(3) Mixing:
2mg and 1mg specifications: continuously adding 5 times of microcrystalline cellulose into the mixture obtained in the step (2), manually mixing for 5min, and adding the obtained mixture into a three-dimensional motion mixer;
5mg specification: adding the mixed material obtained in the step (2) into a three-dimensional mixer;
(4) Adding all the rest microcrystalline cellulose into the three-dimensional motion mixer, and mixing for 10min to obtain a premixed intermediate material;
(5) Sieving the powder obtained in the step (4) once through a 20-mesh sieve, and sieving the intermediate material;
(6) Adding the mixed material obtained in the step (5) into a three-dimensional motion mixer, and mixing for 10min to obtain a total mixed intermediate material;
(7) And in different mixing stages, taking intermediate samples at different positions for content detection. The results of the mixing uniformity (RSD (%)) of the API content of the intermediate material are shown in tables 6-3.
(8) Filling the capsule: and selecting a 3# gelatin hollow capsule, calculating a theoretical filling amount and a control range according to an intermediate result, and filling the capsule.
TABLE 6-2 API particle size data
TABLE 6-3 mixing uniformity of API contents of intermediate materials
As can be seen from the intermediate detection results of different stages in the mixing process of prescription 6-1 and prescription 6-3, the mixing procedure of mixing, sieving and remixing is beneficial to improving the mixing uniformity, but the process repeatability of adopting a 20-mesh screen is not high.
Example 7: preparation and properties of capsules of different specifications
Capsules of 1mg, 2mg and 5mg were prepared according to the formulations shown in Table 7-1, and stability properties such as properties, impurities, dissolution and content were examined.
Table 7-1.1 mg, 2mg and 5mg specification capsule formulations
The preparation process comprises the following steps:
(1) Pretreatment of raw materials: taking the raw materials, carrying out jet milling, and carrying out particle size detection, wherein the results are shown in Table 7-2;
(2) Weighing and mixing: weighing the raw materials and microcrystalline cellulose with the dosage of 5 times that of the raw materials, placing the raw materials and microcrystalline cellulose into a plastic bag, and manually mixing for 5min;
(3) Gradient mixing:
2mg and 1mg specifications: continuously adding 5 times of microcrystalline cellulose into the mixture obtained in the step (2), manually mixing for 5min, and adding the obtained mixture into a three-dimensional motion mixer;
5mg specification: adding the mixed material obtained in the step (2) into a three-dimensional mixer;
(4) Adding all the rest microcrystalline cellulose into the three-dimensional motion mixer, and mixing for 10min;
(5) Sieving the powder obtained in the step (4) through a 50-mesh sieve once;
(6) Adding the mixed material obtained in the step (5) into a three-dimensional motion mixer, and mixing for 10min;
(7) Intermediate control: the content of intermediate samples at different positions is detected, the average content of API (pharmaceutical active ingredient) of intermediate materials is in the range of 90-110%, the mixing uniformity is required to meet the requirement (RSD (relative standard bat difference) < 3.0%), and the detection results are shown in tables 7-3.
(8) Filling the capsule: and selecting a 3# gelatin hollow capsule, calculating theoretical filling quantity and a control range according to an intermediate result, setting the frequency of a host machine to be 15Hz, and filling the capsule.
TABLE 7-2 API particle size data
TABLE 7-3 API content and blend uniformity for intermediate materials
The results show that the adoption of the mixing-sieving (50 meshes) -remixing process can effectively ensure that the API content of the intermediate material meets the regulation, and the mixing uniformity and the repeatability are better than those of the mixing process of sieving with a 20-mesh sieve; the intermediate material has good powder physical properties and good fluidity, and meets the filling requirement of capsules.
The dissolution measurement method is basket method in Chinese pharmacopoeia (2015 edition), the rotation speed is 75rpm, the temperature is 37 ℃, and the dissolution medium is 900ml of disodium hydrogen phosphate/citric acid buffer solution with pH of 3.0. The results are shown in tables 7-4.
Table 7-4.1 mg, 2mg and 5mg specification capsules dissolution comparison (n=6)
The results show that the composition can realize in-vitro quick dissolution, the dissolution rate can reach more than 80% in 15min, and the dissolution rate can reach more than 90% in 30min, and has the effects of in-vivo quick dissolution and absorption, so that the efficacy can be better exerted.
Influence factor test results
Influence factor tests were performed with unpackaged formulations and the results are shown in tables 7-5.
Table 7-5.1 mg, 2mg and 5mg Specification Capsule influence factor test results
(1) The dissolution rate was measured by basket method, chinese pharmacopoeia (2015 edition), rotation speed 75rpm, temperature 37℃and dissolution medium 900ml disodium hydrogen phosphate/citric acid buffer solution pH 3.0, and sampling at 30 min.
The results show that the composition of the application has stable properties under the conditions of illumination, high humidity and high temperature without packaging, no obvious change of impurities, and good stability of the preparation, wherein the dissolution rate and the content meet the regulations.
Stability investigation results
The stability was examined using oral solid pharmaceutical high density polyethylene heat sealed gasket bottles as the inner package and the results are shown in tables 7-6.
Tables 7-6.1 mg, 2mg and 5mg Standard Capsule stability test results
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(1) The dissolution rate was measured by basket method, chinese pharmacopoeia (2015 edition), rotation speed 75rpm, temperature 37℃and dissolution medium 900ml disodium hydrogen phosphate/citric acid buffer solution pH 3.0, and sampling at 30 min.
The results show that the composition has stable properties under accelerated, middle and long-term conditions under the condition of taking an oral solid medical high-density polyethylene heat-sealing gasket bottle as an inner package, has no obvious change of impurities, has the dissolution rate and the content which meet the regulations, and has better stability.
In conclusion, the preparation process of the oral pharmaceutical composition is simple, convenient and stable, the API content and the mixing uniformity of intermediate materials are good, and the obtained preparation finished product is fast in dissolution and stable in quality, and is suitable for industrial scale-up production.
The above embodiments are not intended to limit the aspects of the present application in any way. Various modifications of the present application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (14)

1. A method for preparing an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of the formula or a pharmaceutically acceptable salt thereof,
the method comprises the following steps:
i) The active ingredient was crushed to the following particle size ranges:
dv (90) is 1-100 mu m;
dv (50) is 1-20 mu m;
dv (10) is 0.1-5 mu m;
d4, 3 is 1-30 mu m; and/or
D3, 2 is 1-5 mu m; and
ii) mixing the active ingredient with the carrier, sieving with a 40-60 mesh sieve and mixing again; and
iii) Filling capsules or tabletting;
the amount of the active ingredient is 0.01-30% by weight of the pharmaceutical composition, the carrier is a filler, and the filler is lactose or microcrystalline cellulose; the filler accounts for 70-99.99% of the pharmaceutical composition.
2. The method of claim 1, wherein the amount of the active ingredient is 0.05 to 10% by weight of the pharmaceutical composition.
3. The method of claim 1, wherein the amount of the active ingredient is 0.1 to 30% by weight of the pharmaceutical composition.
4. The method of claim 1, wherein the amount of the active ingredient is 0.5 to 10% by weight of the pharmaceutical composition.
5. The method of claim 1, wherein the weight ratio of microcrystalline cellulose to the active ingredient is 20:1 to 200:1.
6. The method of claim 1, wherein the weight ratio of microcrystalline cellulose to the active ingredient is from 25:1 to 150:1.
7. An oral pharmaceutical composition prepared according to the method of any one of claims 1 to 6.
8. The oral pharmaceutical composition of claim 7, wherein the oral pharmaceutical composition comprises 0.1-10mg of the active ingredient.
9. The oral pharmaceutical composition of claim 8, wherein the oral pharmaceutical composition comprises 0.1-5mg of the active ingredient.
10. The oral pharmaceutical composition of claim 8, wherein the oral pharmaceutical composition comprises 1-10mg of the active ingredient.
11. The oral pharmaceutical composition of claim 10, wherein the oral pharmaceutical composition comprises 1-5mg of the active ingredient.
12. Use of an oral pharmaceutical composition according to any one of claims 7-11 for the manufacture of a medicament for the treatment of a JAK-associated disease.
13. The use of claim 12, wherein the JAK-associated disease is selected from an inflammatory disease, an autoimmune disease, or cancer.
14. The use of claim 12, wherein the JAK-associated disease is rheumatoid arthritis.
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