Formulations / compositions containing ibrutinib

Abstract

To provide stable formulations / compositions comprising Ibrutinib.SOLUTION: Provided is a stable pharmaceutical formulation comprising: (i) Ibrutinib that is a compound with the structure of compound (I), or a pharmaceutically acceptable salt / solvate thereof, and a suspending agent, optionally in the presence of a pharmaceutically acceptable carrier (e.g., aqueous carrier); and (ii) one or more preservatives being benzyl alcohol, and optionally one or more other pharmaceutically acceptable excipients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a Bruton's tyrosine kinase (BTK) inhibitor, particularly a formulation of ibrutinib. The present invention relates to a process for preparing such formulations / compositions containing ibrutinib and This also relates to methods of using these formulations / compositions in the treatment of hematological malignancies. [Background technology]

[0002] Ibrutinib is classified as 1-[(3R)-3-[4-amino-3-(4-pheno Xyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-yl] It is an organic small molecule having prop-2-en-1-one. This is an international patent application. This is explained in many previously published documents, including Pamphlet No. 2008 / 039218 (Example 1b). It has been revealed and is listed as an irreversible inhibitor of Btk.

[0003] Ibrutinib plays a role in targeting B-cell malignancies. Ibrutinib controls It blocks the signals that stimulate malignant B cells to grow and divide uncontrollably. This refers to chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenström macroglobulinemia and various hematological malignancies such as multiple myeloma. Clinical trials are underway for this. In some counties, this is being used for specific diseases. In contrast, regulatory approval has been obtained. For example, this was approved by the U.S. FDA in 2013. In November, treatment for mantle cell lymphoma was initiated, and in February 2014, treatment for chronic lymphocytic leukemia was initiated. Regarding treatment, in January 2015, regarding the treatment of Waldenström macroglobulinemia It has been approved and is marketed under the trademark name Imbruvica(registered trademark).

[0004] The crystalline forms of ibrutinib are disclosed in WO 2013 / 184572 pamphlet. The formulations of ibrutinib are described in documents such as WO 2014 / 004707 pamphlet, WO 2014 / 0336203 pamphlet, WO 2016 / 022942 pamphlet, WO 2016 / 141068 pamphlet, WO 2016 / 164404 pamphlet, WO 2017 / 125423 pamphlet and WO 2017 / 125424 pamphlet. The co-crystals of ibrutinib are also disclosed in, for example, WO 2016 / 160604 pamphlet and WO 2016 / 156127 pamphlet.

[0005] Alternative formulations of ibrutinib are needed and / or desired, particularly in the pediatric population. In the case of pediatric formulations, there are many possible alternative forms that can be pursued. In the case of suspensions, there are many issues such as storage life stability.

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0007] The formulations of the present invention may be reconstituted, i.e., pharmaceutically acceptable carriers ( For example, it may not contain purified water or another preferred carrier as defined herein. Alternatively, a suspension already containing a carrier (e.g., purified water or another suitable carrier as defined herein) It may be a turbidity product. Therefore, in the latter case, (i) Compound 1 suspended in a pharmaceutically acceptable carrier [ka] ibrutinib is a compound having the structure of; (ii) at least one preservative which is benzyl alcohol; Optionally, one or more other pharmaceutically acceptable excipients A pharmaceutical formulation in the form of a suspension containing the above is provided.

[0008] Therefore, the present invention relates to ibrutinib or its pharmaceutically acceptable salts or solvates. A suspension containing various formulations in which benzyl alcohol is the main preservative. Regarding this, the formulation may further contain one or more further pharmaceutically acceptable excipients. The present invention further relates to methods for preparing such pharmaceutical formulations. The present invention relates, for example, to the following. Furthermore, regarding the use of such formulations as pharmaceuticals in the treatment of the diseases described later... The present invention relates to a method for treating a disease in a patient who requires such treatment. This also relates to methods that include administering therapeutically effective amounts of such pharmaceutical formulations to patients.

[0009] In this specification, benzyl alcohol is the main preservative present in the formulation of the present invention. It has been shown that this has the same or similar effectiveness with respect to preservation, and the same or the It has a certain stability profile and / or forms a cocrystal with the active ingredient (ibrutinib). Those skilled in the art can include suitable equivalents of benzyl alcohol that achieve the same effect. Therefore, it is understood. All of the above is understood in the tests used in the Experiments section later in this specification. It can be tested. For example, sufficient preservation can be tested using the PET (preservative effectiveness test) described herein. If tested as described in ), and for example the following organism is used, after 28 days It can result in a decrease of more than 4 log: A. brasiliensis (A. brasiliensis) ensis), C. albicans, P. aeruginosa (P. E. aeruginosa), S. aureus and / or E. coli (E. .coli) (For example, at the initial concentration of the organism as shown in the experimental section below) Stability can be tested as described in the tests in the experimental section. (Stability tests for 1 month, 2 months, and 6 months under specific conditions). Cocrystal formation is also confirmed. This can be tested by observing under the conditions described in the experimental section below in the detailed manual. Cut.

[0010] The present invention shall be interpreted in relation to the attached embodiments, all of which form part of this disclosure. This can be more easily understood by referring to the documentation. The present invention is described herein. This is not limited to the specific products, methods, conditions, or parameters shown and / or indicated. Rather, the technical terms used herein are merely to illustrate specific embodiments as examples. The purpose is not to limit any claimed invention. Please understand. Similarly, unless otherwise specified, possible mechanisms or modes of operation or improvements Any explanation regarding the reasons is for illustrative purposes only, and the present invention as herein does not provide such explanations. The accuracy or inaccuracy of the proposed mechanism or mode of operation or the reasons for improvement is constrained by the accuracy or inaccuracy of the proposed mechanism or mode of operation or the reasons for improvement. This does not mean that the descriptions are accurate. Throughout this specification, the descriptions are not accurate in relation to the characteristics of the formulations described herein. It is recognized that this relates to both the manufacturing process and the method of use.

[0011] Where ibrutinib is referred to herein, it refers to Compound 1 above or, for example, as described later herein. The pharmaceutically acceptable salt or solvate thereof is mentioned. Furthermore, ibrucin B (or a pharmaceutically acceptable salt or solvate thereof) is the active ingredient in the formulation of the present invention. And it is present in a therapeutically effective amount. For example, in one embodiment, the formulation is intended for the pediatric population. In some cases, 70 mg of the active ingredient ibrutinib may be present in the formulation (however, ibrutinib (For example, if it is in salt form, a larger mass may exist). However, in one embodiment In this aspect of the present invention, the form of ibrutinib used is not a salt or a solvate. It is in a free form.

[0012] In one embodiment, ibrutinib of the formulation of the present invention is used in its unsalted form. In another embodiment For example, ibrutinib used in the formulation of the present invention is used in the international publication of an international patent application. This is crystal morphology A, described and prepared in pamphlet No. 2013 / 184572.

[0013] In the formulation of the present invention, the active pharmaceutical ingredient ibrutinib (or its salt / solvate) is therapeutic. It may be present in a therapeutically effective amount. The formulation of the present invention comprises a suspension, in this case The suspension contains as much ibrutinib as can be tolerated in the presence of a pharmaceutically acceptable carrier (or Preferably contains its salt / solvate. In one embodiment, a pharmaceutically acceptable carrier (If present) it is an aqueous solution, and in certain embodiments this is water, for example, purified water or sterilized water. It is bacterial water. However, the carrier is water (e.g., tap water, purified water or sterile water), ethanol Glycerol, propylene glycol, glycerol, polyethylene glycol, etc., or these Any combination of these may be selected; for example, in one embodiment, the carrier is up to 90% It contains water, and the remainder is one of the other aforementioned carriers such as ethanol, in another embodiment The carrier then contains at least 90% water (and up to 10% of the remainder being other carriers as described above). (including one or more of the above). In a further embodiment, the amount of ibrutinib is 1 w / v% to 20 w / v%. For example, it may be present in an amount of about 2 w / v% to 15 w / v%, and in one embodiment, this is approximately It can exist in amounts ranging from 3 w / v% to 10 w / v%, for example, about 7 w / v%, and this is a suspension. When relating to formulations, the carrier (e.g., purified water) is intended to be within a w / v ratio. If this relates to a formulation (e.g., powder) that is for reconstitution, the w / v ratio is Consider the amount of carrier (or liquid such as water) that is intended to be added (or will be added). To be added. Therefore, in one embodiment, ibrutinib (or its salt / solvate) is about It is present in amounts ranging from 20 mg / ml to 150 mg / ml, and in further embodiments, approximately 30 mg / ml. ~100 mg / ml, approximately 60 mg / ml to 80 mg / ml, for example, about 70 mg / ml It exists.

[0014] Where the ratio w / v is stated herein, and the quantity is in units of mg / ml (or equivalent as specified herein), When expressed in mg / ml (as commonly used), the volume is such that the formulation of the present invention is a suspension. In some cases, it is understood to include a carrier (e.g., purified water), and the formulation of the present invention is for reconstitution. If it is a powder (for example), the w / v ratio and mg / ml are the values ​​of the intended addition (and It includes a carrier (or a liquid such as water) which will be added. In these cases, the carrier or drug A scientifically acceptable carrier can also be called a diluent. The carrier may be water, and in the case of a suspension, It is preferable to use purified water (otherwise the shelf life may be affected), Also, for example, in the case of a reconstitution powder, this could be purified water, but drinking water (for example, tap water) ) That is also possible.

[0015] In this specification, at least one preservative, which is benzyl alcohol, is present in the formulation of the present invention. It is shown that it exists in [location]. Therefore, for example, one or more selected from the list below. Other preservatives may exist. However, in one embodiment, the preservative of the formulation of the present invention is , containing more than 25% (by weight), for example more than 50% benzyl alcohol, and in this case However, the ingredients include other preservatives besides benzyl alcohol, such as the other preservatives listed below. It may further contain other preservatives (however, the total weight percentage of other preservatives may be 75% or 50% as needed). (The percentage shall not exceed 70%). In one embodiment, the preservative in the formulation of the present invention is more than 70% ben A benzyl alcohol, for example, containing more than 90% benzyl alcohol, and in one embodiment, a preservative. It essentially consists of benzyl alcohol (i.e., the preservative in the formulation of the present invention is 99%) It is more than or approximately 100% benzyl alcohol, and other preservatives are present in less than 1% or more of the original amount. (Qualitatively absent). This is because, as explained below, the presence of benzyl alcohol is otherwise This is because it is unexpectedly advantageous compared to other preservatives. This is because the suspension has proper stability. It is extremely important for this purpose, and achieving this remains a challenge. However, However, using benzyl alcohol as a preservative may have the following benefits: (i) Shelf life of the formulation of the present invention; (ii) Stability of the formulation (e.g., physical stability) ) and its bactericidal activity (for example, measured by PET (preservative efficacy test)); (iii) )By-products, such as precipitates or particles in the formulation / suspension (e.g., ibrutinib particles) Undesirable co-crystals and other visible defects may occur in the suspension due to improper dispersion. Reduced formation of visible impurities or spots. These visible impurities or spots are aggregates. It is a sign of formation, and therefore a sign of instability.

[0016] As described herein, the formulation of the present invention comprises benzyl alcohol plus one or more Contains other preservatives as listed above (however, in one embodiment, the preservative is exclusively benzyl alcohol) In this regard, preservatives include antimicrobial agents, antioxidants, free radical scavengers, oxygen absorbers and / or It may contain one or more chelating agents. For example, antibacterial agents and antioxidants include benzoic acid, parabens. (e.g., methyl or ethylparaben), butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), chlorbutol, gallate, hydroxybenzo Zoate, EDTA, phenol, chlorocresol, metacresol, benzethonine chloride Um, myristyl-γ-picolinium chloride, phenylmercury acetate, thimerosal, sol The group consisting of bic acid and propionic acid may be selected (propylene glycol is also mentioned). (May be possible). Free radical scavenging agents include BHA, BHT, vitamin E and ascorbic acid Examples include luminate and mixtures thereof. Examples of oxygen scavengers include sodium ascorbate. Thorium, sodium sulfite, L-cysteine, acetylcysteine, methionine, thio Glycerol, acetone, sodium bisulfite, isoascorbic acid, hydroxypropyl Cyclodextrins are one example. Sodium citrate and sodium chloride are examples of chelating agents. Examples include EDTA and malic acid. Other preservatives that may be mentioned include acetic acid (for example). Examples include substances that can act as antioxidants or chelating agents. In one embodiment, other The preservative is not an oxygen scavenger, and in a further embodiment, the other preservative is an antimicrobial and / or acid fastener. It is a purifying agent. In one embodiment of the present invention, the formulation of the present invention is a purifying agent other than benzyl alcohol. It does not contain preservatives.

[0017] For example, the amount of preservative is 0.1 w / v% to 10 w / v%, for example, about 0.1 w / v% to 5 It can exist in w / v% quantities, and in one embodiment, about 0.5 w / v% to 2 w / v%, for example, about 1 w It may be present in an amount of / v%. Therefore, in one embodiment, the preservative is about 1 mg / ml to 5 It is present in an amount of 0 mg / ml, and in further embodiments, approximately 2 mg / ml to 25 mg / ml, approximately It is present in amounts ranging from 5 mg / ml to 20 mg / ml, for example, in amounts of approximately 10 mg / ml. As such, the formulation of the present invention contains a preservative that is benzyl alcohol, and in one embodiment In this state, this is at least about 0.1 w / v% or at least about 1 mg / ml of benzyl It contains alcohol, and in further embodiments, this is at least about 0.5 w / v% or less It contains at least approximately 5 mg / ml of benzyl alcohol. For example, in this specification, When it is stated that a preservative contains more than 50% benzyl alcohol, this specifically means, If 1 w / v% preservative is present, 0.5 w / v% benzyl alcohol and 0.5 w Interpret / v% as one or more other preservatives (e.g., as described above herein). However However, in one embodiment, the preservative is shown to consist essentially of benzyl alcohol. Therefore, the ranges described above in this specification apply specifically to the amount of benzyl alcohol present. (For example, approximately 0.5 w / v% to 2 w / v% or approximately 5 mg / ml to 20 mg / ml of benzoate) In this embodiment, (alcohol) there are substantially no other preservatives in the formulation of the present invention.

[0018] As shown, the formulation of the present invention may be a suspension. Therefore, in one embodiment, The formulation of the invention comprises a further excipient which is a suspending agent. The suspending agent is for the suspension of particles or Promotes dispersion and / or point deposition or accumulation (or aggregation) of particles in the suspension. ) can be any substance that reduces ). The suspending agent increases viscosity and also provides sufficient surface activity. It can be facilitated (for example, if it is also a wetting agent). In this respect, suspending agents are It may be one or more of the following agents: alginate, cellulose ether, methylcellulose hydroxyethylcellulose, carboxymethylcellulose, carboxymethylcellulose - Sodium, microcrystalline cellulose, acacia, tragacanth, xanthan gum, vent Night, carbomer, carrageenan, powdered cellulose, and gelatin. Other ingredients that may be mentioned. As turbidifying agents, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl Examples include pyrucellulose (HPC), which acts as a suspending and wetting agent. This can be achieved, but in one embodiment the wetting agent is selected from HPMC and / or HPC. Therefore, the suspending agents are not the same.

[0019] In one embodiment, the suspending agent that can be used in the formulation of the present invention is carrageenan, xanthan gum. Xanthan gum (or xanthan gum; for example, produced by the fermentation of carbohydrates by Gram-negative bacteria) Any suitable polysaccharide (or cellulose ether, e.g., typically alkali cellulose) Examples include any suitable cellulose ether produced by etherification of the ether. In this case, the suspending agent is cellulose ether, for example, microcrystalline cellulose and / or carboxyl Sodium methylcellulose (for example, available under the trademark name Avicel®) It is a turbidifier and is suitable for use in suspensions where shelf-life stability is desired. The present invention provides formulations that can be selected from microcrystalline cellulose and / or when sodium carboxymethylcellulose is used as a suspending agent, the optimal The form is preferred, and in one embodiment, for example, the formulation of the present invention is a reconfigurable suspension. It may be a turbidity, or in another embodiment, the formulation may be an already pharmaceutically acceptable carrier (e.g.) For example, it may contain purified water, and in each of these cases, more than each embodiment You will understand that a suitable Avicel® product may exist.

[0020] In some embodiments, the suspending agent is natural starch, pregelatinized starch, sodium Moisten starch, methyl crystalline cellulose, methylcellulose (for example, Methocel( (Registered trademark), croscarmellose, croscarmellose sodium, cross-linked sodium Ruboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose , cross-linked starch, e.g., sodium starch glycolate, cross-linked polymer, e.g., cross A group consisting of povidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, and rubber. Selected from. In one embodiment, starch excessively increases viscosity beyond the desired level. Because it can cause other substances to be added, it is not used as a suspending agent.

[0021] Microcrystalline cellulose that can be used as a suspending agent in the formulation of the present invention is any suitable material It may originate from the source, for example, this is SMCC HD90 (for example, JRS Pharma Silicidized microcrystalline cells such as PROSOLV SMCC (registered trademark) may be available from [source]. It may be lurose (SMCC), or it may be microcrystalline cellulose and carboxymethyl cellulose. A mixture with sodium cellulose (for example, commercially available under the trademark name Avicel®) It is possible that...

[0022] The amount of suspending agent should be 0.1 w / v% to 10 w / v%, for example, about 0.1 w / v% to 5 w / v It can be present in amounts of %, and in one embodiment, about 0.5 w / v% to 2 w / v%, for example, about 1.2 w / It may be present in an amount of v%. Therefore, in one embodiment, the suspending agent is about 1 mg / ml to 5 It is present in an amount of 0 mg / ml, and in further embodiments, it is about 2 mg / ml to 25 mg / ml, about 5 It exists in an amount of mg / ml to 20 mg / ml, for example, about 12 mg / ml. In one embodiment, The suspending agent is an essential component of the formulation of the present invention.

[0023] The formulation of the present invention may also contain other excipients or carriers. For example, in one embodiment, the present invention The formulation may further contain a wetting agent or a surfactant, and typical examples are listed below. Examples of materials that reduce surface tension include: gelatin, casein, Lecithin, salts of loaded electrophospholipids or their acidic forms (phosphatidylglycerol, phosphatidylglycerol) Tidylinocytes, phosphatidylserine, phosphatidic acid, and alkali metal salts, etc. Those salts, for example, those sodium salts, for example, the trademark name Lipoid® EPG Products available in the area include egg phosphatidylglycerol sodium, gum arabic, etc. Thearic acid, benzalkonium chloride, polyoxyethylene alkyl ether, for example For example, macrogol ether, such as cetomacrogol 1000, polyoxyethylene castor oil Oil derivatives; polyoxyethylene stearate, colloidal silicon dioxide, sodium dodecyl sulfate Thorium, sodium carboxymethylcellulose, bile salts, e.g., sodium taurocholate Lium, sodium deoxytaurocholate, sodium deoxycholate; methyl cellulose Rose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl Pyrmethylcellulose, magnesium aluminate silicate, polyvinyl alcohol ( Ethylene oxides such as PVA, Pluronic (trademark) F68, F108 and F127 Poloxamers and tyroxapoles are block copolymers of side and propylene oxide. Vitamin E-TGPS (α-tocopheryl polyethylene glycol succinate, specifically) Specifically, α-tocopheryl polyethylene glycol 1000 succinate; poloxamine For example, from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine. Tetronic(trademark)908(T90) is a tetrafunctional block copolymer that is derived. 8); Dextran; Lecithin; Dioctyl ester of sodium sulfosuccinate, for example Products marketed under the trademark name Aerosol OT (AOT); sodium lauryl sulfate Thorium (Duponol(trademark) P); Triton(trademark) X-200 is imported under these trademark names. Available alkylaryl polyether sulfonates; polyoxyethylene sorbitan fats Fatty acid esters (Tweens® 20, 40, 60 and 80); sorbitan fatty acids Ester (Span(trademark) 20, 40, 60 and 80 or Arlacel(trademark) 20 , 40, 60 and 80); polyethylene glycol (e.g., Carbowax (trademark)) Products marketed under the trademark names 3550 and 934; sucrose stearate and sucrose. Rose distearate mixture, e.g., Crodesta (trademark) F110 or Crodesta Products available under the trademark name sta(trademark)SL-40; hexyldecyltrimethylammonium Nium chloride (CTAC); polyvinylpyrrolidone (PVP); nonionic surfactants For example, polyethoxylated castor oil (for example, commercially available under the brand name Kolliphor) (If necessary, two or more wetting agents and / or surfactants may be used in combination.)

[0024] In one embodiment, the wetting agent or surfactant is, for example, cellulose, for example, hydroxypropyl Hydroxypropyl methylcellulose (HPC, including various commercially available products) or hydroxypropyl methylcellulose Water-soluble derivatives from cellulose ethers such as (e.g., the commercially available product HPMC2208) It is a polymer. As shown above, the suspending agent may overlap with the wetting agent, and in this regard In one embodiment, the wetting agent (if present) is different from the surfactant. Therefore, the suspending agent And when both the wetting agent and the wetting agent are cellulose ether, in one embodiment, these are different It is a cellulose ether (for example, the suspending agent is microcrystalline cellulose and / or carboxymethylcellulose). The humectant may be sodium xymethylcellulose (and HPMC).

[0025] In one embodiment, a surfactant / wetting agent is present in the formulation of the present invention. The amount of such agent is 0.05 w / v% ~ 10 w / v% or 0.05 w / v% ~ 5 w / v% (for example, 0.05 It can exist in amounts of w / v% to 2 w / v%, for example, about 0.05 w / v% to 1 w / v%, and one substance In application, it exists in amounts of approximately 0.1 w / v% to 0.5 w / v%, for example, about 0.25 w / v%. Therefore, in one embodiment, the surfactant / wetting agent is about 0.5 mg / ml ~ 10 0 mg / ml or 0.5 mg / ml to 50 mg / ml (for example, 0.5 mg / ml to 20 mg / ml) It is present in an amount of mg / ml, and in further embodiments, approximately 0.5 mg / ml to 10 mg / ml. It exists in an amount of approximately 1 mg / ml to 5 mg / ml, for example, approximately 2.5 mg / ml. (One embodiment) Therefore, a wetting agent (or surfactant) is an essential component of the formulation of the present invention.

[0026] In one embodiment, the formulation of the present invention optionally contains one or more buffering agents and / or pH It may contain a adjusting agent. In one aspect of the present invention, the pH of the formulation of the present invention is preferably The pH range is approximately 4 to 8 (for example, 5 to 7), specifically around 6. Therefore, buffers or buffering agents typically consist of two components, such as a weak acid and its conjugate salt. It is a mixture of a group or weak base and its conjugate acid. For example, in connection there may be a loose compound that can be used. Examples of components of the buffering fluid or buffer include salts of weak acids, and in one embodiment, the buffer is Citric acid (citric acid, H2O, etc.; this can be preformed or used to prepare the formulation of the present invention) (which may be formed during the manufacturing process) and sodium hydrogen phosphate (for example, phosphoric acid, respectively) (Disodium hydrogen or sodium dihydrogen phosphate, Na2HPO4 or NaH2PO4) It may contain, and in one embodiment, the pH adjuster is sodium hydroxide (NaOH) and / or salt It may be a strong acid such as an acid (HCl) or a strong base. Therefore, it is used as a buffer (buffer) and pH Examples of the components of the adjusting agent include tartaric acid, maleic acid, glycine, and mixtures thereof. Sodium lactate / lactic acid, ascorbic acid, sodium citrate / citric acid, sodium acetate M / acetic acid, sodium bicarbonate / carbonic acid, sodium succinate / succinic acid, sodium benzoate M / benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate Thorium / sodium carbonate, ammonium hydroxide, benzenesulfonic acid, benzoate Thorium acid, diethanolamine, glucono delta-lactone, hydrochloric acid, hydrogen bromide, lysine methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, glucon Glutamic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA) One or more triethanolamines are mentioned. In one embodiment, the formulation of the present invention is Therefore, a weak acid or preferably an inorganic salt of an acid, such as citric acid and / or phosphate (for example, N Components such as aH2PO4 or preferably sodium hydrogen phosphate (Na2HPO4) Examples of contained buffering agents include citric acid as a component of the buffer / buffering agent. When mentioned together, citric acid hydrate refers to citric acid and water in a 1:1 ratio (citric acid H2O is cited (because citric acid itself is hygroscopic in other cases).

[0027] In one embodiment, the total amount of buffer (or buffering agent) present in the formulation of the present invention is 0.05 w The amount is approximately 0.05 w / v% to 1 w / v%, for example, in one embodiment. It can exist in amounts of approximately 0.1 w / v% to 0.5 w / v%, for example, about 0.2 w / v%. However, in one embodiment, the buffering agent is present in an amount of approximately 0.5 mg / ml to 20 mg / ml. In further embodiments, approximately 0.5 mg / ml to 10 mg / ml, approximately 1 mg / ml to 5 mg / It exists in an amount of ml, for example, about 2 mg / ml (or about 2 mmol / ml to 150 mmol) / ml, for example 5 mmol / ml to 30 mmol / ml, for example approximately 15 mmol / ml It exists in quantity; therefore, when citric acid hydrate and Na2HPO4 are used, the quantity is (These can be approximately 3-4 mmol / ml and 9-11 mmol / ml, respectively). One embodiment Therefore, the buffering agent (or a mixture containing two or more buffering agents) is an essential component of the formulation of the present invention. In one embodiment, this is citric acid (citric acid H2O) and sodium phosphate (e.g. For example, sodium hydrogen phosphate (Na2HPO4) is relatively expressed in mg / ml. It includes ratios of 1:3 to 3:1 (for example, approximately 1:2 to 2:1, for example, approximately 1:1), however However, the ratio is preferably about 1:2 (expressed relative to mg / ml). The conversion to molar ratio can also be determined, for example, relative to mmol / ml. The ratio can be 1:5 to 1:1, for example, approximately 1:4 to 1:2, for example, approximately 1:3. The formulation of the present invention includes acids and bases for pH adjustment, such as the strong acids described herein. and / or may further contain a strong base pH adjuster; for example, a desired pH (e.g., pH 6.0 ± For 0.1), qs of NaOH and / or HCl may be added to the formulation of the present invention. Purified water may also be added for this purpose, and as a pharmaceutically acceptable carrier (or solvent) It also exists and is added in qs based on the w / v ratio provided herein.

[0028] In one embodiment, the formulation of the present invention may optionally contain a sweetener, either natural or artificial. Sweeteners, such as sweeteners or combinations thereof, may be included in the formulations described herein. In one embodiment, the natural sweeteners are raw sugar, granulated sugar, brown sugar, confectionery sugar, and white sugar. Sugar, fructose, honey, fructose, high-fructose corn syrup, corn syrup, man Sugar alcohols such as nitrol, sorbitol, xylitol, and erythritol, hydrogenated Pumps hydrolysate, lactitol or maltitol, osmalt, dextrose, Invert sugar, agave nectar, glucose, lactose, maltose, maple sugar, date sugar, Contains molasses, stevia extract, tagatose, trehalose, or any combination thereof. It is sucrose. In another embodiment, the artificial sweetener is sucralose, aspartame, These are saccharin, neotame, advantame, or acesulfame potassium. In this embodiment, the sweetener is sucralose.

[0029] If a sweetener is present in the formulation of the present invention, the total amount present is 0.01 w / v% ~ 1 w / v%, for example, an amount of approximately 0.05 w / v% to 0.5 w / v%, and in one embodiment, approximately 0. It can exist in amounts ranging from 0.5 w / v% to 0.2 w / v%, for example, about 0.1 w / v%. Therefore In one embodiment, the sweetener is present in an amount of approximately 0.1 mg / ml to 10 mg / ml, and further... In this embodiment, the concentration is approximately 0.5 mg / ml to 5 mg / ml, and approximately 0.5 mg / ml to 2 mg / ml. For example, it exists in an amount of approximately 1 mg / ml.

[0030] The amounts of each component in the formulation of the present invention may be in specific proportions as specified below: Ibrutinib - 70 mg / ml Benzyl alcohol preservative - 10 mg / ml Suspensioning agent - 12 mg / ml Humectant - 2.5 mg / ml Buffer - 2.1mg / ml Sweetener - 1 mg / ml pH adjuster (e.g., NaOH and / or HCl), qs, ad pH 6.0 ± 0. 1 Pharmaceutical carrier - purified water, 1 ml of qsad.

[0031] The formulation of the present invention is a suspension, and therefore in one embodiment is pharmaceutically acceptable purified water. It contains a carrier. The amount of each component in the formulation is relative (w / v) to 1 ml of carrier (purified water). This is shown herein. Therefore, a predetermined volume of the suspension is a specific dose. It can be used to administer [the substance]. In this regard, the suspension is at a lower concentration or Or it may be at a higher concentration. If the suspension is at a lower concentration, the relative amount of the active ingredient (w / v) ) These are divided into two equal parts (for example, 70 mg of ibrutinib or in 2 ml of purified water) This can change to a situation where 35 mg of ibrutinib may be present in 1 ml of purified water. The remaining components may also be adjusted accordingly, but preferably they remain the same. That is, benzyl alcohol, suspending agents, wetting agents, buffers, sweeteners and pH adjusters, etc. With respect to any remaining components (if any), the formulation of the present invention is as follows: These measurements, when taken relative to 1 ml of a carrier (e.g., purified water), as mentioned in the specification, The amount (in mg / ml or w / v) also applies here (for example, per 1 ml of carrier) (For example, 10 mg / ml of benzyl alcohol). 35 mg of API (Eve) per 1 ml. If rutinib is present, and a dose of 70 mg is desired, 2 ml of the suspension is added to the specified volume. The product is obtained (assuming that 35 mg of ibrutinib is present per 1 ml, etc.). The turbidity may be at a higher concentration, in which case the relative amount of API (ibrutinib) is these This can change to twice the amount, for example, 140 mg of ibrutinib in 1 ml of purified water. In this case, for a 70 mg dose, the specified volume is 0.5 ml. A suspension with a higher concentration is... In some cases, the remaining ingredients can also be adjusted accordingly, but preferably these , remain the same, namely benzyl alcohol, suspending agent, wetting agent, buffer, sweetener and Furthermore, with respect to any remaining components (if present) such as pH adjusters, the present invention With respect to the formulations referred to herein, measure relative to 1 ml of a carrier (e.g., purified water) These quantities (in mg / ml or w / v) when determined also apply here. Therefore, the formulation or suspension of the present invention may be at a lower or higher concentration, and thus, The predetermined volume of the mixture / suspension is adjusted accordingly. In this regard, the formulation of the present invention The substance can be adjusted to the existing API (ibrutinib) (7 mg in 1 ml of carrier). The range may be between 700 mg / ml and 700 mg / ml, or other ranges as referred to herein. It could be in the range of 20-200 mg / ml.

[0032] In this specification, w / v (generally the weight of the component relative to the volume of the carrier, for example, the volume of purified water) Although the invention described herein is described herein It is also possible to explain the relative weights of each component of the formulation / suspension to each other. It will be understood. In such cases, a pharmaceutically acceptable carrier (e.g., purified water) is the component. It may exist in a range of weight-based volume, for example, 1 per 70 mg of ibrutinib It could be ml (as described herein as a specific embodiment), while for example, 10 Optional, such as 1 ml per mg of ibrutinib and 1 ml per 210 mg of ibrutinib. Other viable dilutions may be (e.g., 1 ml and 1 ml per 35 mg of ibrutinib) (1 ml per 40 mg ibrutinib). In such cases, other formulations / suspensions of the present invention The amounts of all components are also adjusted accordingly. For example, in one embodiment, the formulation of the present invention is provided. The relative amounts (w / w) of the components (relative to each other) and compared to 70 mg of ibrutinib. The following: 5-15 mg of benzyl alcohol preservative; 6-18 mg of suspending agent; Selectively, for example, 1 to 5 mg of a wetting agent; Selectively, for example, 1-3 mg of buffer solution; Selectively, for example, 0.2 to 2 mg of a sweetener; and Optionally, pH adjuster (qs) As stated herein, pharmaceutically acceptable carriers (e.g., purified water) are as described herein. A specified amount (for example, 1 ml to 210 mg of ibrutinib per 10 mg ibrutinib) It is present in 1 ml (for example, about 1 ml per 70 mg of ibrutinib). , suspending agents, wetting agents, buffers, sweeteners and pH adjusters are specified herein in accordance with the present invention. It could be any of the items listed (for example, specific items). In this regard, see below. The formulation is one embodiment of the present invention, and the relative amount of the component compared to 70 mg of ibrutinib ( w / w) is as follows: 8-12 mg of benzyl alcohol preservative; A mixture of 10-14 mg of microcrystalline cellulose and sodium carboxymethylcellulose. A product (for example, Avicel®); Selectively administer 2-3 mg of hydroxypropyl methylcellulose (HPMC); Selectively add 1.5 to 2.5 mg of citrate, H2O and / or sodium hydrogen phosphate. Which phosphate; Selectively 0.5 to 1.5 mg of sucralose; and Optionally, NaOH and / or HCl(qs) to adjust the pH, As stated above, a pharmaceutically acceptable carrier (e.g., purified water) is The specified amount as described herein (for example, 1 ml to 210 ml per 10 mg of ibrutinib) 1 ml per mg of ibrutinib (for example, approximately 1 ml per 70 mg of ibrutinib) To exist.

[0033] As described herein, the formulations of the present invention contain a pharmaceutical carrier such as purified water. Therefore, the dose is administered as a fixed volume of suspension, as described herein. If the dose is 70 mg of ibrutinib, the amount of carrier (e.g., purified water) is 1 ml. Yes. As shown herein, the suspension is either lower in concentration or higher in concentration. However, in any case, the volume of suspension required for a particular dose is predetermined.

[0034] In a further aspect of the present invention, the component of the formulation of the present invention is a pharmaceutical carrier which is 1 ml of purified water. Based on this, the following proportions may be one of the following: Ibrutinib at 20-200 mg / ml; benzyl alcohol at 2.5-25 mg / ml Preservatives; 2-24 mg / ml of suspending agents; optionally, for example, 0.5-10 mg / ml of Wetting agent; optionally, for example, 0.5-10 mg / ml buffer; optionally, for example, 0. Sweeteners in concentrations of 1-5 mg / ml; and optionally, pH adjusters (qs); Ibrutinib at 40-100 mg / ml; benzyl alcohol preservative at 5-15 mg / ml. Agent; 6-18 mg / ml suspending agent; optionally, for example, 1-5 mg / ml wetting agent; Selectively, for example, 1-3 mg / ml buffer solution; optionally, for example, 0.2-2 mg / ml A sweetener; and optionally a pH adjuster (qs); or Ibrutinib at 60-80 mg / ml; benzyl alcohol preservative at 8-12 mg / ml. ; 10-14 mg / ml suspending agent; optionally, for example, 2-3 mg / ml wetting agent; Selectively, for example, a buffer solution of 1.5 to 2.5 mg / ml; optionally, for example, 0.5 to 1. 5 mg / ml of sweetener; and optionally a pH adjuster (qs).

[0035] In certain embodiments, the formulation of the present invention includes specified components (for example, as described above in this specification). Having as described in the embodiments of the present invention, for example, The suspending agent is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose (e.g.) For example, the trademark name Avicel (registered trademark), for instance, Avicel (registered trademark) RC-591 (It is commercially available in [location]; The humectant is hydroxypropyl methylcellulose (HPMC); The buffer solution is citrate, H2O and / or phosphates such as sodium hydrogen phosphate (for example, A mixture of two substances in the ratios described herein; The sweetener is sucralose; and / or The pH adjusters are NaOH and HCl.

[0036] Therefore, in certain embodiments of the present invention, the following formulations of the present invention are included: Ibrutinib at 60-80 mg / ml; 8-12 mg / ml benzyl alcohol preservative; 10-14 mg / ml of microcrystalline cellulose and sodium carboxymethylcellulose A mixture of (e.g., Avicel®); Optionally, 2-3 mg / ml of hydroxypropyl methylcellulose (HPMC); Selectively add 1.5-2.5 mg / ml of citrate, H2O and / or sodium hydrogen phosphate. Phosphates such as um; Selectively administered sucralose at 0.5-1.5 mg / ml; and Optionally, NaOH and / or HCl(qs) to adjust the pH.

[0037] In one embodiment, the formulation of the present invention also contains a wetting agent (e.g., HPMC; e.g., (In the quantities specified in the specification). In one embodiment, the formulation also contains a buffer (for example). For example, citric acid, H2O and / or sodium hydrogen phosphate; in the amounts described herein. In one embodiment, the formulation also contains a sweetener (e.g., sucralose; example). (For example, in the amounts referred to herein). In one embodiment, to adjust the pH, Na OH and / or HCl are added to the formulation of the present invention. pH is appropriate for the shelf life of the formulation. This may be within any suitable range that enables (or maintains), and this is particularly important for the suspension. This is essential, and the main reason why the selection of preservatives is important. Achieving the desired pH. For this purpose, appropriate preparation with NaOH and / or HCl can be attempted. In one embodiment, this The pH of the formulation / suspension is approximately pH 3 to pH 9, but in further embodiments, the pH is , at approximately pH 4 to pH 8 (for example, approximately pH 5 to pH 7, for example, approximately pH 5.5 to pH 6.5) In one embodiment, the pH of the formulation / suspension described herein is adjusted to approximately pH 6. ru.

[0038] An important aspect of the present invention is the presence of benzyl alcohol as a preservative. This is shown in the document. This is as described herein, including examples and tests performed. This was because dilutyl alcohol was the most suitable preservative. For example, API (Ibulcin) Cocrystallization with (B) was exceptionally not observed.

[0039] The formulations / suspensions of the present invention maintain a particle size distribution (PSD) within a specific threshold. The formulation / suspension of the present invention is such that the PSD changes over time and under specific stress conditions (e.g., temperature and other factors). Even considering that it remains within a specific threshold under various storage conditions, it is advantageous compared to others. It is possible.

[0040] In one embodiment, the API (ibrutinib) is carried in a pharmaceutically acceptable carrier (e.g., purified water). To ensure even distribution throughout, suitable stirring is performed as described herein. It is used in the process of preparing turbidity. Even dispersion means, for example, without shaking. Because the suspension may have a gel-like texture, after shaking (or light shaking), the API particles ( ibrutinib particles are dispersed or spread throughout the carrier of the suspension (e.g., water). This means that they are distributed. This results in nearly equal amounts of API (ibrutinib) particles (heavy Any equal portion of a carrier (e.g., water) containing (by quantity) is produced, thereby, the present invention Those concerned should allow ±25%, preferably ±15%, and especially ±10% (or less, for example, ±5%). This means within a deviation of (within). Therefore, 700 mg of ibrutinib in 10 ml of water If dispersed, each portion of 2.5 ml of water (if divided) contains approximately 175 mg of Ibul. It should contain tinib, but within ±25% (i.e., ±43.75 mg), preferably ± A deviation of 15% (i.e., ±26.25 mg) and especially ±10% (i.e., ±17.5 mg) There is a possibility of a difference, and most preferably, the deviation is ±5% (i.e., ±8.75 mg). Therefore, the suspension is physically dispersed throughout the carrier (e.g., aqueous medium) in which it is contained. Substantially uniform or homogeneous (for example, after the time required for dispersion by stirring; see above) (I want to). The larger the volume of water per 1 mg of active ingredient, the smaller the deviation in dispersion. It could potentially become that.

[0041] The formulation of the present invention has a specific particle size and a specific particle size distribution (PSD). It may also contain an active ingredient (API), ibrutinib. For example, d v 50 is a single action form In its current state, it is less than 100 μm, for example, less than 25 μm.

[0042] Furthermore, in relation to the present invention, in a particular embodiment, - d v 10is less than 5 μm (preferably less than 2 μm, for example less than 1.5 μm, for example around 1 .0 or around 1.1 μm (or even less than this), - d v 50 is less than 10 μm (preferably less than 8 μm, for example less than 6 μm, for example 4~ around 5 μm (or even less than this), - d v 90 is less than 20 μm (preferably less than 15 μm, for example less than 10 μm, for example around 8 - 9 μm (or even less than this).

[0043] As used herein, the term d 50 (or d v 50 ) has its customary meaning known to those skilled in the art and can be measured by particle size measurement techniques known in the art, such as sedimentation field-flow fractionation, photon correlation spectroscopy, laser diffraction, or disc centrifugation. The d referred to herein v 50 may be related to the volume distribution of the particles. In that case, "d of 5 μm v 50 " means that at least 50% of the volume of the particles has a particle size less than 5 μm. The same applies to the other particle sizes mentioned, and d v 10 and d v 90 have similar meanings . Usually, the same or approximately the same value is obtained for the average particle size from the volume distribution and the weight distribution .

[0044] In connection with the present invention, the formulations (e.g., suspensions) of the present invention described herein have the advantage that the particle size distribution (PSD) is maintained optimally and thus does not affect the quality of the product .

[0045] A given additive may be classified differently by different practitioners on site, or there may be several different classifications. Because they are often used in common for one of the following functions, they are described herein. There is overlap between the additives (excipients / diluents, etc.) used in the formulation (e.g., suspension). Please be aware of the following. Therefore, the additives mentioned herein are used in the formulations described herein. This should be considered merely an example of the types of additives that may be contained in a substance, and not an exhaustive list. The amount of such additive can be easily determined by someone skilled in the art according to specific desired properties. That is the case.

[0046] In another embodiment, the treatment of a disease is carried out in patients who require such treatment. This includes administering a therapeutically effective amount of the pharmaceutical composition or formulation described herein to the patient. This is one way to do it.

[0047] In another aspect, the treatment of hematological malignancies in patients who require such treatment. A law that administers to a patient a therapeutically effective amount of the pharmaceutical composition or formulation described herein. This method includes the following: In some embodiments, cancer is a B-cell proliferative disorder. In some embodiments, B-cell proliferative disorders include diffuse large B-cell lymphoma, follicular lymphoma, or It is a chronic lymphocytic leukemia. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, cancer is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma ( SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and It is a B-cell malignant tumor selected from multiple myeloma. In some embodiments, the cancer is It is lymphoma or leukemia. In some embodiments, the cancer is diffuse large B-cell lymphoma. Follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia Lymphoid plasma cell lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma Parkinson's disease, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma Lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma It is a tumor, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatous granulomatosis. .

[0048] In another embodiment, a pharmaceutical composition or formulation containing ibrutinib (for example, as described herein) This is a process for preparing (a composition / formulation), and the process involves mixing the components of the composition / formulation with each other. This includes preparing the product. In one embodiment, an essential preservative, benzyl alcohol, is added first. The other components of the composition / compound of the present invention (e.g., carrier, ibrutinib and suspension) are added, followed by other components of the composition / compound of the present invention (e.g., carrier, ibrutinib and suspension). A turbidifier (such as a turbidifying agent) may be added, and in further specific embodiments, the composition / formulation may be as shown in the following examples. It can be prepared as described in [the document].

[0049] In another embodiment, a formulation (e.g., suspension) described herein containing compound 1. A method for treating a patient by administering a drug is provided herein.

[0050] Other purposes, characteristics, and advantages of the methods and compositions / formulations described herein are detailed below. This will become clear from the explanation. However, from this detailed explanation, the purpose of this disclosure and Since the various forms of modification and alteration included in the scope will be apparent to those skilled in the art, a detailed explanation is provided. The specific examples provided illustrate specific embodiments, but are given for illustrative purposes only. Please understand that this is merely a formality. The headings of items used in this specification are for structural purposes only. It is merely a fact and should not be interpreted as limiting the subject matter described. Patents, patent applications Applications, papers, books, manuals and professional publications, including but not limited to those cited in this application, are cited herein. All of the documents or parts thereof referred to in this specification are, for any purpose, by reference in their entirety. It will be explicitly incorporated into the text.

[0051] Embedding by reference All publications and patent applications cited herein are referenced to the extent applicable and relevant. This specification is more fully incorporated here. [Modes for carrying out the invention]

[0052] In some embodiments, the methods described herein are used, for example, for diffuse large B-cell lymphoma. Follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell pre-lymphocytic leukemia Disease, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone Lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell Lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma Examples include peritoneum, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatous granulomatosis. It can be used to treat cancers such as B-cell proliferation disorders, but is not limited to these.

[0053] Hematological malignancies In a particular embodiment, a method for treating hematological malignancies in an individual in need. and a formulation (e.g., suspension) described herein, which contains a certain amount of compound 1. Methods including administration to an individual are disclosed herein.

[0054] In some embodiments, the hematological malignancy is non-Hodgkin lymphoma (NHL). In some embodiments, hematological malignancies include chronic lymphocytic leukemia (CLL), small lymphocytic leukemia, and others. These are lymphomas (SLL), high-risk CLL, or non-CLL / SLL lymphomas. In terms of treatment form, hematological malignancies include follicular lymphoma (FL) and diffuse large B-cell lymphoma (DL). BCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia Multiple myeloma (MM), marginal zone lymphoma, Burkitt lymphoma, non-Burkitt high-grade lymphoma It is a grade B-cell lymphoma or an extranodal marginal zone B-cell lymphoma. In some embodiments, blood Myelodysplastic syndromes include acute or chronic myeloid leukemia and myelodysplastic syndromes. It is acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia. Several implementation forms In some embodiments, hematological malignancies are chronic lymphocytic leukemia (CLL). One example of a hematological malignancy is mantle cell lymphoma (MCL). In some embodiments, Hematological malignancies include diffuse large B-cell lymphoma (DLBCL). Several embodiments So, hematological malignancies are diffuse large B-cell lymphoma (DLBCL) ABC subtypes. In some embodiments, hematological malignancies are diffuse large B-cell lymphoma (DLBCL). It is a GCB subtype. In some embodiments, hematological malignancies are Waldensto. It is Rehm's macroglobulinemia (WM). In some embodiments, hematological malignancies are , multiple myeloma (MM). In some embodiments, hematological malignancies are Burkitt It is a lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL). Yes. In some embodiments, the hematological malignancy is transformed follicular lymphoma. In one embodiment, the hematological malignancy is marginal zone lymphoma.

[0055] In some embodiments, hematological malignancies are relapsed or refractory non-Hodgkin lymphomas ( NHL) In some embodiments, hematological malignancies are recurrent or refractory diffuse Large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL) , relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or Refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstomatitis Rehm macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory Remission marginal zone lymphoma, relapsed or refractory Burkitt lymphoma, relapsed or refractory non- Burkitt's high-grade B-cell lymphoma, relapsed or refractory extranodal marginal zone B-cell lymphoma Yes. In some embodiments, hematological malignancies are recurrent or refractory acute or Chronic myeloid leukemia, relapsed or refractory myelodysplastic syndrome, Relapsed or refractory acute lymphoblastic leukemia or relapsed or refractory precursor B-cell leukemia It is a type of lymphoblastic leukemia. In some embodiments, hematological malignancies are relapsed or refractory. It is a type of chronic lymphocytic leukemia (CLL). In some embodiments, hematological malignancies are It is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, The hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma ( It is an ABC subtype of DLBCL. In some embodiments, hematological malignancies are recurrent It is a GCB subtype of transient or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, hematological malignancies are recurrent or refractory Waldenströmmak It is globulemia (WM). In some embodiments, hematological malignancies are recurrent or This is a refractory multiple myeloma (MM). In some embodiments, hematological malignancies are recurrent It is a primary or refractory Burkitt lymphoma. In some embodiments, hematological malignancies are It is relapsed or refractory follicular lymphoma (FL).

[0056] In some embodiments, hematological malignancies are classified as high-risk hematological malignancies. In some embodiments, the hematological malignancies are high-risk CLL or high-risk SLL. .

[0057] B-cell lymphoproliferative disorders (BCLD) are neoplasms of the blood, particularly non-Hodgkin's B-cell lymphoproliferative disorders. It includes lymphoma, multiple myeloma, and leukemia. BCLD refers to lymphoid tissue (e.g., lymph It may originate from either a tumor or bone marrow (for example, in the case of leukemia and myeloma). These all involve the uncontrolled proliferation of lymphocytes or leukocytes. BCLD includes, for example, Many subtypes such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) There are subtypes. The disease course and treatment of BCLD depend on the subtype of BCLD. However, clinical findings, morphological appearance, and response to treatment are heterogeneous even within each subtype. That is the case.

[0058] Malignant lymphoma is a malignant transformation of cells, primarily found in lymphatic tissue. The two groups of tumors are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Both types of cystoma infiltrate the reticuloendothelial tissue. However, they are new in origin. The presence of living cells, diseased areas, systemic symptoms, and responses to treatment differ (Freedman). et al., “Non-Hodgkin's Lymphomas”Chapter 134,Cancer Medicine,(an approved public ation of the American Cancer Society, B.C. .Decker Inc., Hamilton, Ontario, 2003).

[0059] Non-Hodgkin lymphoma In certain embodiments, treatment for non-Hodgkin lymphoma is performed in individuals who require it. A method comprising a certain amount of compound 1, comprising the formulation described herein (for example, a suspension A method comprising administering a liquid to a solid is disclosed herein.

[0060] In certain embodiments, the treatment of relapsed or refractory non-Hodgkin lymphoma is necessary. A method performed on an individual, wherein the individual contains a therapeutically effective amount of compound 1 as described herein. Methods comprising administering the listed formulations are further disclosed herein. Several implementations Morphologically, non-Hodgkin lymphoma is a relapsed or refractory diffuse large B-cell lymphoma (D LBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory filtration It is cystic lymphoma or relapsed or refractory CLL.

[0061] Non-Hodgkin lymphoma (NHL) is a group of malignant tumors that originate primarily from B cells. NHL can occur in any organ related to the lymphatic system, such as the spleen, lymph nodes, or tonsils. It can occur at any age. NHL often presents with lymph node enlargement and Significant fever and weight loss are present. NHL is classified as either B-cell or T-cell NHL. Lymphomas associated with lymphocyte proliferative disorders after bone marrow or stem cell transplantation are usually B-cell lymphomas. It is a cellular NHL. In the working formulation classification scheme, NHL is its own Based on the history, the tumors were classified into low-grade, intermediate-grade, and high-grade categories. Non-Hodgkin's Lymphoma Pathologic Classi fication Project,”Cancer 49(1982):2112-2 (See page 135). Low-grade lymphoma is slow-growing and has an average survival period of 5-10 years. (Horning and Rosenberg (1984) N.Engl.) (J.Med.311:1471-1475). Chemotherapy leads to remission in the majority of slow chronic lymphomas. While it can trigger a remission, a complete cure is rare, and most patients eventually experience a relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors, but chemotherapy is necessary. The chances of a cure are greater with legal treatment. However, a significant percentage of these patients experience relapses. And further treatment is needed.

[0062] The list of non-exclusive B-cell NHLs includes Burkitt lymphoma (e.g., endemic Burkitt lymphoma). Burkitt lymphoma and sporadic Burkitt lymphoma, cutaneous B-cell lymphoma, marginal zone lymphoma tumor (MZL), diffuse large cell lymphoma (DLBCL), diffuse large and small cell mixed lymphoma Tumor, diffuse small cell lymphoma, diffuse small lymphocyte lymphoma, extranodal marginal zone B cell lymphoma, follicle Lymphoma, follicular cleavage cell (grade 1) lymphoma, follicular cleavage and large cell mixed lymphoma ( Grade 2 lymphoma, follicular large cell lymphoma (grade 3), intravascular large B-cell lymphoma Intravascular lymphoma, large cell immunoblastic lymphoma, large cell lymphoma (LCL), lymphoblasts Lymphoma, MALT lymphoma, Mantle cell lymphoma (MCL), Immunoblastic large cell lymphoma , precursor B lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / Small lymphocyte lymphoma (SLL), extranodal marginal zone B-cell lymphoma - mucosa-associated lymphoid tissue (M) ALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma Lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, waltz This includes Denström macroglobulinemia and primary central nervous system (CNS) lymphoma. Further non-Hodgkin lymphomas are intended to be within the scope of the present invention and will be clear to those skilled in the art. It is gentle.

[0063] DLBCL In certain embodiments, DLCBL is treated in a manner that is necessary for the treatment of the individual. A formulation (e.g., suspension) described herein, containing a certain amount of compound 1, is used. Methods including administration to the body are disclosed herein. In certain embodiments, recurrent or A method for treating refractory DLCBL in individuals who require it, and the treatment is A formulation (e.g., suspension) described herein, containing the effective compound 1, is administered to an individual. Methods including (or administering a therapeutically effective amount of the formulation described herein) are included in this Further disclosures will be made in the specifications.

[0064] As used herein, the term “diffuse large B-cell lymphoma (DLBCL)” is used in this specification. This refers to neoplasms of germinal center B lymphocytes that exhibit a diffuse growth pattern and a high to moderate proliferation index. DLBCL accounts for approximately 30% of all lymphomas, and includes germinal center blast subtypes and immunoblast subtypes. The subtypes include T-cell / histiocyte-rich subtypes, undifferentiated subtypes, and plasmablast subtypes. It can exhibit several morphological variants. DLBCL has various subtypes. Their existence has been shown by genetic testing. These subtypes have various future prospects (predictions) DLBCL appears to have a response to treatment in all age groups. It can affect anyone, but it mainly occurs in the elderly (the average age is in the mid-60s).

[0065] In certain embodiments, the activated B-cell-like subtype (ABC-) of diffuse large B-cell lymphoma is used. A method for treating DLBCL in individuals who require it, comprising 100 mg / The present invention involves administering ibrutinib to an individual in an amount of 1000 mg / day or more. Disclosed in detail: ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) It is thought to arise from postgerminal center B cells that are arrested during cytoplasmic differentiation. DLBCL A The BC subtype (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. It is considered the most difficult to treat among the DLBCL molecular subtypes, and therefore, ABC-D Patients diagnosed with LBCL typically compare to individuals with other types of DLCBL. This shows a significant decrease in survival rate. ABC-DLBCL is a germinal center master regulator. Chromosomal translocations that deregulate BCL6 and transcriptional repressors required for plasma cell differentiation It is most often associated with mutations that inactivate the PRDM1 gene, which codes for Sir.

[0066] Follicular lymphoma In certain embodiments, a method of treating follicular lymphoma in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory follicular lymphoma in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein. As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years. CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein. As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years. CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein.

[0067] As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years. CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein. As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years.

[0068] CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein. As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years. CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein. As used herein, the term "follicular lymphoma" means any of several types of non-Hodgkin lymphoma in which lymphoma cells cluster into nodules or follicles. The term "follicular" is used because the cells tend to grow in a circular or nodular pattern within lymph nodes. The average age of people with this lymphoma is about 60 years. CLL / SLL In certain embodiments, a method of treating CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a certain amount of Compound 1 is disclosed herein. In certain embodiments, a method of treating relapsed or refractory CLL or SLL in an individual who needs it, comprising administering to the individual a formulation (e.g., a suspension) described herein containing a therapeutically effective amount of Compound 1 (or administering a therapeutically effective amount of the formulation described herein) is further disclosed herein.

[0069] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are usually slightly different. These are considered to be the same disease with the same symptoms. Depending on where the cancer cells accumulate, it is called CLL. It is determined whether it is called rheumatoid arthritis or SLL. Cancer cells are mainly found in the lymphatic system (mainly within the body). When it is mainly found in lymph nodes of the small vascular system (lima-shaped structure), it is called SLL. It will be discovered. SLL accounts for approximately 5% to 10% of all lymphomas. Most cancer cells are in the bloodstream and When it is present in the bone marrow, it is called CLL.

[0070] CLL and SLL are both growth-slowing disorders, but CLL is far more common. LL tends to grow more slowly. CLL and SLL are treated in the same way. These conditions are usually not considered curable with standard treatment and depend on the stage and rate of progression of the disease. However, most patients live longer than 10 years. Sometimes, these growths occur over time. Slow-growing lymphomas can transform into more aggressive types of lymphoma.

[0071] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. 100,760 people are living with CLL or are in remission from CLL. It is estimated that the majority of people newly diagnosed with CLL (>75%) are over 50 years old. He is of an age where he is not able to achieve a complete cure for CLL, but rather to control the disease and its symptoms. The focus is on CLL. CLL can be treated with chemotherapy, radiotherapy, biological therapy or bone marrow transplantation. The symptoms are treated with surgery (removal of the enlarged spleen) or radiation therapy (removal of enlarged lymph nodes). It can also be treated with "weight loss." CLL usually progresses gradually, It is generally considered incurable. Certain types of CLL are classified as high-risk. When used in detailed documents, "high-risk CLL" refers to: 1) 17p13-; 2) 11q22- 3) Non-mutant IgVH with ZAP-70+ and / or CD38+; or 4) Triso This refers to a CLL characterized by at least one of the M12.

[0072] The disease has progressed to a point where it can affect the patient's quality of life, which may be indicated by the patient's clinical symptoms or blood If indicated by the number of balls, CLL treatment is typically administered.

[0073] Small lymphocyte leukemia (SLL) is very similar to CLL mentioned above, and it also involves B cells. It is cancer. In SLL, abnormal lymphocytes primarily affect the lymph nodes. However, In CLL, abnormal cells primarily affect the blood and bone marrow. The spleen also affects both aspects of the disease. SLL accounts for approximately 1 / 25 of all cases of non-Hodgkin lymphoma. It can occur at any stage from childhood to old age, but it is rare in those under 50 years of age. SLL is considered a slow chronic lymphoma. That is, the progression of the disease is very slow, and patients They tend to live for many years after diagnosis. However, most patients are diagnosed with a progressive disease. SLL is generally considered to be incurable, although it responds well to various chemotherapy drugs. It is said that some cancers tend to occur more frequently in one sex than the other, but SL Cases and deaths attributable to L are evenly distributed between men and women. The average age at diagnosis is He is 60 years old.

[0074] SLL is a slow-onset but persistently progressive disease. The usual pattern of this disease is remission. It has a remission period and shows a high response rate to radiotherapy and / or chemotherapy. This After that, recurrence becomes inevitable after several months or years. A response appears again with retreatment , but the disease recurs again. That is, the short-term prognosis of SLL is extremely good, but as time passes, many patients develop life-threatening complications of the recurrent disease. Considering the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease that minimizes side effects without hindering the quality of life of the patient. The present invention meets this long-standing need in the art .

[0075] Mantle cell lymphoma [[ID=​​​​​​​​​​​​​​​​​​​​​​​​14)(q13;q32). Only about 5% of lymphomas are of this type. They are small to medium in size. In most cases, men are affected. The average age of patients is He is in his early 60s. Lymphoma is usually diagnosed in the lymph nodes, bone marrow, and very often... It has spread extensively, including to the spleen. Mantle cell lymphoma is a type of lymphoma that does not grow very quickly. It is not patellar malformation, but it is difficult to treat.

[0077] Marginal zone B-cell lymphoma In certain embodiments, treatment of marginal zone B-cell lymphoma is performed in individuals who require it. A method for carrying out the process, comprising a formulation described herein (for example, a suspension) containing a certain amount of compound 1. A method comprising administering a turbid solution to an individual is disclosed herein. In certain embodiments, Treatment of relapsed or refractory marginal zone B-cell lymphoma in individuals who require it. A method comprising a therapeutically effective amount of compound 1, comprising the formulation described herein (for example, a suspension Administering the turbid solution to the individual (or administering a therapeutically effective amount of the formulation described herein) Methods including the above are further disclosed herein.

[0078] As used herein, the term “marginal zone B-cell lymphoma” refers to follicular mantle This refers to a group of related B-cell neoplasms that include lymphoid tissue in the marginal zone, which is the patchy area outside the band. Marginal zone lymphoma accounts for approximately 5% to 10% of all lymphomas. The cells of this lymphoma are microscopic. It appears small under a microscope. Marginal zone lymphomas include extranodal marginal zone B-cell lymphoma and nodal marginal zone B There are three main types, including cellular lymphoma and splenic marginal zone lymphoma.

[0079] MALT In certain embodiments, MALT is treated in individuals who require it. This involves using a formulation (e.g., suspension) described herein, which contains a certain amount of compound 1, as a solid. Methods comprising administering to certain persons are disclosed herein. In certain embodiments, recurrent or difficult-to-treat conditions A method for treating therapeutic MALT in individuals in need, and the therapeutically effective dose The formulation (e.g., suspension) described herein, containing compound 1, is administered to an individual. This specification includes a method comprising (or administering a therapeutically effective amount of the formulation described herein). Further details will be revealed in the book.

[0080] As used herein, the term “mucosa-associated lymphoid tissue (MALT) lymphoma” is a marginal term. This refers to extranodal symptoms of marginal zone lymphoma. Most MALT lymphomas are low-grade, however A small number of cases present early as intermediate-grade non-Hodgkin lymphoma (NHL) or It either progresses from a low-grade form. Most MALT lymphomas are located in the stomach. Approximately 70% of gastric MALT lymphomas are caused by Helicobacter pylori. It is associated with ter pylori infection. Several cytogenetic abnormalities have been identified. However, the most common are trisomy 3 or t(11;18). Many cases of MALT lymphoma are also associated with bacterial or viral infections. The average age of patients with peritoneum is approximately 60 years.

[0081] Nodal marginal zone B-cell lymphoma In certain embodiments, treatment for nodal marginal zone B-cell lymphoma is provided to individuals who require it. A method that involves a formulation described herein (for example) containing a certain amount of compound 1. A method comprising administering a suspension to an individual is disclosed herein. In certain embodiments This refers to the treatment of relapsed or refractory nodal marginal zone B-cell lymphoma in individuals who require it. A method of carrying out the process, comprising a therapeutically effective amount of compound 1, and comprising the formulations described herein (e.g.) For example, administering a suspension to an individual (or a therapeutically effective amount of the formulation described herein) Methods including administering are further disclosed herein.

[0082] The term "nodal marginal zone B-cell lymphoma" refers to a type of lymphoma that primarily involves slow B-cell lymphoma found in lymph nodes. This refers to follicular lymphoma. This disease is rare and accounts for 1% of all non-Hodgkin lymphomas (NHL). It accounts for only a small percentage. Most commonly, it is diagnosed in elderly patients, and women are more affected than men. It is easy to develop. This disease is classified as marginal zone lymphoma because the mutation occurs in the marginal zone of B cells. This disease is also classified as nodular because it is limited to the lymph nodes.

[0083] Splenic marginal zone B-cell lymphoma In certain embodiments, the treatment of splenic marginal zone B-cell lymphoma is performed in individuals who require it. A method for carrying out the process, comprising a formulation described herein (for example, a certain amount of compound 1) A method comprising administering a suspension to an individual is disclosed herein. In certain embodiments, , treatment of relapsed or refractory splenic marginal zone B-cell lymphoma in individuals who require it. A method for carrying out this process, comprising a therapeutically effective amount of compound 1, comprising the formulation described herein (for example) Administering a suspension to an individual (or administering a therapeutically effective amount of the formulation described herein) Methods including (doing) are further disclosed herein.

[0084] The term "marginal zone B-cell lymphoma" is a specific term incorporated into the World Health Organization's classification. This refers to low-grade small B-cell lymphoma. Its characteristic features include megasplenia and moderately malignant B-cell lymphoma with villous morphology. Lymphocytosis, involving various organs, especially the bone marrow, with an intrasinusoidal pattern and a relatively slow course. Tumor progression accompanied by increased blast cell morphology and invasive behavior is observed in a small number of patients. Furthermore, cytogenetic studies have shown heterogeneous results, which may indicate a lack of standardized diagnostics. This is because there is a lack of standards.

[0085] Burkitt lymphoma In certain embodiments, treatment for Burkitt lymphoma is performed in individuals who require it. A method comprising a certain amount of compound 1, comprising the formulation described herein (for example, a suspension A method comprising administering a liquid to a solid is disclosed herein. In certain embodiments, A method for treating autosomal or refractory Burkitt lymphoma in individuals who require it. and comprising a therapeutically effective amount of compound 1, the formulation described herein (e.g., suspension) ) to administer to an individual (or to administer a therapeutically effective amount of the formulation described herein) Methods including ) are further disclosed herein.

[0086] The term "Burkitt lymphoma" usually refers to a type of non-Hodgkin lymphoma that typically affects children. This refers to Parkinson's disease (NHL), which begins in the lymph nodes and involves parts of the body other than the lymph nodes. It is a common, highly invasive type of B-cell lymphoma. Despite its rapid growth, Burkitt lymphoma is, in many cases, curable with modern intensive care. Lymphoma can be broadly classified into two types: sporadic and endemic. .

[0087] Epidemic Burkitt lymphoma: This disease is considerably more common in children than in adults. 95% of cases are associated with Epstein-Barr virus (EBV) infection. Burkitt lymphoma accounts for about half of all childhood cancers and primarily occurs in equatorial Africa. A somewhat differential characteristic, rare in spontaneous burkitt disease, is the high likelihood of involvement of the jawbone. Yes. This usually involves the abdomen as well.

[0088] Sporadic Burkitt lymphoma: Affects the rest of the world, including Europe and the Americas. The type of Burkitt lymphoma that affects this is the sporadic type. Here again, this is mainly It is a childhood disease. The association with Epstein-Barr virus (EBV) is limited to endemic cases. Although not very strong, direct evidence of EBV infection is present in 1 out of 5 patients. Lymph nodes The abdomen is also heavily involved, as it significantly affects over 90% of children. The involvement of the bone marrow is... It is more commonly seen than those that develop spontaneously.

[0089] Waldenström macroglobulinemia In certain embodiments, the treatment of Waldenström macroglobulinemia is necessary. A method to be carried out in an individual concerned, comprising a certain amount of compound 1 as described herein. A method comprising administering a formulation (e.g., a suspension) to an individual is disclosed herein. In certain embodiments, relapsed or refractory Waldenström macroglobulinemia A method for administering treatment to an individual in need, comprising a therapeutically effective amount of compound 1. , administering the formulations described herein (e.g., suspensions) to an individual (or having therapeutic effects) A method comprising administering an amount of the formulation described herein is further disclosed herein. ru.

[0090] The term "Waldenström macroglobulinia," also known as lymphoplasmacytic lymphoma. "Lymphocytes" is a type of cancer that involves a subtype of white blood cell called lymphocytes. It is characterized by uncontrolled clonal proliferation of differentiated B lymphocytes. This is due to immunoglobulin M Lymphoma cells are also characterized by producing antibodies called IgM antibodies. The body circulates a large amount of it in the bloodstream, thickening the liquid portion of the blood into a syrup-like consistency. This can lead to reduced blood flow to many organs, potentially causing visual impairment (poor circulation in the blood vessels behind the eye). It causes nerve damage (e.g., headache, dizziness, and confusion) due to poor blood flow in the brain. There is a possibility of rubbing. Other symptoms may include fatigue, weakness, and a tendency to bleed easily. The underlying etiology is not fully understood, but it includes location 6p21.3 on chromosome 6. Several risk factors have been identified, including a personal history of autoimmune diseases caused by autoantibodies. In humans, the risk of developing WM increases 2 to 3 times, and hepatitis, human immunodeficiency virus and The risk is particularly high for those with rickettsial disease.

[0091] Multiple myeloma In certain embodiments, the treatment of myeloma was carried out in an individual in need. Then, a formulation (e.g., suspension) described herein, containing a certain amount of compound 1, is applied to a solid. Methods including administration are disclosed herein. In certain embodiments, relapsed or refractory A method for treating sexual myeloma in individuals in need, comprising the calculation of the effective therapeutic dose. Administering a compound (e.g., suspension) described herein, containing compound 1, to an individual ( A method comprising administering a therapeutically effective amount of the formulation described herein) as described herein Further disclosures will be made.

[0092] MM, myeloma, plasma cell myeloma, or Kahler's disease (named after Otto Kahler) Multiple myeloma, also known as plasma cell cancer, is a cancer of white blood cells, specifically B cells. Plasma cells, which are the primary cells of the immune system, play a crucial role in antibody production in humans and other vertebrates. These are the first important components. They are produced in the bone marrow and transported via the lymphatic system.

[0093] leukemia In certain embodiments, the treatment of leukemia was carried out in individuals who needed it. Then, a formulation (e.g., suspension) described herein, containing a certain amount of compound 1, is applied to a solid. Methods including administration are disclosed herein. In certain embodiments, relapsed or refractory A method for treating sexual leukemia in individuals in need, comprising the calculation of the effective therapeutic dose. Administering a compound (e.g., suspension) described herein, containing compound 1, to an individual ( A method comprising administering a therapeutically effective amount of the formulation described herein) as described herein Further disclosures will be made.

[0094] Leukemia is characterized by an abnormal increase in blood cells, usually white blood cells (white blood cells). It is a cancer of the blood or bone marrow. Leukemia is a broad term encompassing a range of diseases. The first The distinction lies between its acute and chronic forms, (i) acute leukemia is characterized by a rapid increase in immature blood cells Characterized by an increase. When the bone marrow becomes dense in this way, it produces healthy blood cells. It becomes impossible. In acute leukemia, malignant cells grow rapidly and accumulate before overflowing into the bloodstream. Because it spreads to other organs in the body, emergency treatment is required. The acute form of leukemia is common in children. (ii) Chronic leukemia is a relatively mature form of leukemia. It is identified by an excessive accumulation of (still abnormal) white blood cells. Typically, this can last for months or even years. As the disease progresses, cells are produced at a much faster rate than normal cells, resulting in a large amount of cells in the bloodstream. It leads to abnormal white blood cells. Chronic leukemia mainly occurs in the elderly, but theoretically it can occur at any age. It can also occur in groups. In addition, the disease progresses in detail as more and more blood cells are affected. It is divided into lymphoblastic leukemia or lymphocyte leukemia and myeloblastic leukemia. It is divided into (i) immune system cells that deal with infection. Lymphoblastic leukocytes are a type of bone marrow cell that normally continues to form lymphocytes, but undergo cancerous changes in these cells. (ii) blood diseases or lymphocytic leukemia; (ii) red blood cells, some other types of white blood cells and platelets Myeloid leukemia or myeloleukemia is a type of bone marrow cell in which cancerous changes occur in cells that normally continue to form. disease.

[0095] Within these major categories are acute lymphoblastic leukemia (ALL), and B-cell progenitor acute leukemia. Lymphoblastic leukemia (also known as precursor B lymphoblastic leukemia, or precursor B-ALL), acute myelitis This includes AML (mammary leukemia), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL), however There are several subcategories that are not limited to these. Therefore, a particular embodiment So, acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-cell) Progenitor B-ALL (also known as bablastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia Treatment of hair cell leukemia (CML) or hair cell leukemia (HCL) is performed in individuals who require it. A method by which a certain amount of the formulation described herein, containing compound 1, is administered to an individual. Methods including the following are disclosed herein. In some embodiments, leukemia relapses It is a recurrent or refractory leukemia. In some embodiments, the leukemia is recurrent or refractory. Acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia Lymphoblastic leukemia (also known as precursor B-ALL), relapsed or refractory. Acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or This is relapsed or refractory hair cell leukemia (HCL).

[0096] The symptoms, diagnostic tests, and prognostic tests for each of the above-mentioned conditions are publicly known. For example, , Harrison's Principles of Internal Medicine ine(Copyright)” 16th ed.,2004,The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojourn al3(24) and “Revised European American Lymp homa" (REAL) classification system (for example, the Website maintained by the National Cancer Institute Please refer to (see T).

[0097] Compound 1 (or the Specified Several animal models have been used to establish the range of therapeutically effective doses for the formulations described in [the document]. It is for use.

[0098] Compound 1 and its pharmaceutically acceptable salts "Compound 1" or "1-((R)-3-(4-amino-3-(4-phenoxyphen (Nyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)piperidine-1-yl) "Prop-2-en-1-one" or "1-{(3R)-3-[4-amino-3-(4 -phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl]piper "Jin-1-il}prop-2-en-1-on" or "2-propen-1-on,1 -[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidine-1-yl]-1-piperidinyl-" or ibrutinib or Any other suitable name refers to a compound having the following structure: [ka]

[0099] A variety of pharmaceutically acceptable salts are formed from compound 1, including the following: ru: - Compound 1, aliphatic mono and dicarboxylic acids, phenyl-substituted alkanes, hydroxyl Alkanes, alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. Examples include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, and pyruvate. Oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfone Acid addition salts formed by the reaction of acids, such as salicylic acid and other organic acids; - Compound 1, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid Acid addition salts formed by the reaction with inorganic acids, such as phosphorous acid.

[0100] The term "pharmaceutically acceptable salt" referring to compound 1 (ibrutinib) refers to the nutrient being administered to the patient. It does not cause significant irritation in dairy animals and substantially inhibits the biological activity and properties of the compound. This refers to the salt of compound 1 that does not contain the compound 1.

[0101] It is important to understand that references to pharmaceutically acceptable salts include the solvent addition form (solvate). Solvates contain either stoichiometric or nonstoichiometric amounts of a solvent, such as water and ethanol. Nol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether ethyl acetate, isopropyl acetate, isopropyl alcohol (DIPE), ethyl acetate, isopropyl alcohol Al, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone Nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxa pharmaceutically acceptable solvents such as n, heptane, toluene, anisole, and acetonitrile Formed during the process of forming or isolating the product used. In one embodiment, the solvate is limited It is not formed by this process, but by using a Class 3 solvent. The category of solvent is, for example, International Conference on Harmonizat ion of Technical Requirements for Registration ration of Pharmaceuticals for Human Use (ICH),“Impurities:Guidelines for Residua Defined in Solvents, Q3C(R3), (November 2005) Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. It is formed when it is a call. In some embodiments, compound 1 (ibrutinib) For convenience, the solvates or pharmaceutically acceptable salts thereof are prepared during the process described herein. or formed. In some embodiments, the solvate of compound 1 (ibrutinib) is without It is water. In some embodiments, compound 1 (ibrutinib) or its pharmaceutically acceptable The salt exists in a non-solvated form. In some embodiments, compound 1 (ibrutinib) ) or a pharmaceutically acceptable salt thereof exists in a non-solvated form and is anhydrous.

[0102] In yet another embodiment, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is: Examples include amorphous phase, crystalline form, milled form, and nanoparticle form, but are not limited to these. It is prepared in various forms that do not allow it to be used. In some embodiments, compound 1 (ibrutinib) or The pharmaceutically acceptable salt is amorphous. In some embodiments, compound 1 (Eve) Rutinib (or a pharmaceutically acceptable salt thereof) is amorphous and anhydrous. Several implementations In this state, compound 1 (ibrutinib) or its pharmaceutically acceptable salt is crystalline. In some embodiments, compound 1 (ibrutinib) or a pharmaceutically acceptable salt thereof is used in the following way: It is crystalline and anhydrous.

[0103] In some embodiments, compound 1 (ibrutinib) is classified as U.S. 7,514,44 It is prepared as outlined in Specification No. 4.

[0104] Specific terms Unless otherwise defined, all scientific and technical terms used herein are the primary terms of the claims. The title has the same meaning as that generally understood by those skilled in the art in the field to which it pertains. The summary and the following detailed description are illustrative and descriptive only and do not apply to the claims. Please understand that this does not limit the subject matter. In this application, the use of the singular form is not limited to the subject matter. Unless otherwise specified, plural forms are included. The singular forms "one (a)", "one (an)", and "that" are particularly important in context. Unless otherwise specified, it should be noted that plural references are included. In this application, "or The use of "" means "and / or" unless otherwise specified. Furthermore, the term "including" " and "include", "includes", and "included" Other forms of use, such as those mentioned above, are not limited.

[0105] The headings used in this specification are merely for organizational purposes and do not represent the subject matter described. It should not be interpreted as limiting patents, patent applications, papers, books, manuals and This includes, but is not limited to, specialized books, all of the documents or parts thereof cited in this application. Therefore, for all purposes, the entire text is expressly incorporated herein by reference.

[0106] The term "approximately" used before a number means within ±10%, ±5%, or ±1% of the specified value. This indicates the range within which the value can change.

[0107] As used herein, the term "including" means that compositions / formulations and methods, etc., are listed. It is intended to mean that it includes certain elements but does not exclude others. Composition / When used to define formulations and methods, "essentially consisting of" means the intended use Excluding other elements of any essential importance to the combination for use, the composition / This means not excluding elements that do not substantially affect the characteristics of the formulation or method. Let's assume that... "~consists of" means excluding elements that are not specifically listed. The embodiments defined by each of these transitional terms are within the scope of the present invention. be.

[0108] The terms "acceptable" or "pharmaceutically acceptable" in relation to formulations, compositions, or components are as described above. When used in detail, it does not cause any lasting adverse effects on the overall health of the patient being treated, It does not inhibit the biological activity or properties of the compound and is relatively non-toxic. It means that.

[0109] When used herein, administering a specific compound or pharmaceutical composition / compound may be beneficial. "Improvement" of symptoms of a specific disease, disorder, or condition means whether it is permanent, temporary, or sustained. Or, whether transient or not, it may result from or be associated with the administration of the compound or composition / compound. This refers to any possible reduction in severity, delay in onset, slower progression, or shortening of duration.

[0110] "Bioavailability" refers to the rate at which administered compounds are delivered into the systemic circulation of the animal or human being studied. This refers to a percentage of 1. Total exposure (AUC) of the drug during intravenous administration. (0~∞) ) is usually It is defined as 100% bioavailable (F%). "Oral bioavailability" refers to intravenous bioavailability. Compared to internal injection, when a pharmaceutical formulation / composition is taken orally, compound 1 is absorbed into the systemic circulation. This refers to the degree to which it is suitable. In one aspect of the present invention, the formulations / compositions described herein are suitable It is assumed to have bioavailability.

[0111] "Plasma concentration" refers to the concentration of compound 1 in the plasma components of the blood sample being examined. Concentrations may vary between subjects due to potential interactions related to metabolism and / or other therapeutic agents. It is understood that it can change significantly. According to one embodiment disclosed herein, the compound Plasma concentration (C) can vary from subject to subject. Similarly, the maximum plasma concentration (C) can vary. max ), or maximum Time to reach plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC) (0~∞) ) Values ​​such as these may also vary depending on the target. Due to this variation, compound 1 or compound 1 containing The amount required to constitute a “therapeutic effective amount” of any formulation / composition described herein is the amount required to apply to the subject. It may vary from time to time. Furthermore, the formulations / compositions described herein have an absorption process after administration. Due to this, the C content is lower compared to, for example, capsule formulations mentioned above. max It may have. Scientifically acceptable properties and high C max , equivalent C max or sufficient C max Requests such as Preparing an ibrutinib suspension that possesses both PK properties is difficult.

[0112] As used herein, the term "Bruton's tyrosine kinase" means, for example, the United States Patent Office. Homo sapiens as disclosed in Patent No. 6,326,469 This refers to Bruton-type tyrosine kinase derived from piens (GenBank accession number NP_ 000052).

[0113] As used herein, the term "co-administration," etc., refers to a selection of therapeutic agents administered to a single patient. This means including the administration of, and also by the same or different routes of administration, or the same or This is intended to include treatment regimens in which drugs are administered at different times.

[0114] As used herein, the terms “effective dose” or “therapeutic effective dose” mean the disease being treated or The administered agent or compound is sufficient to alleviate one or more of the symptoms of the condition to some extent. It refers to the quantity. The result is a reduction and / or alleviation of the signs, symptoms, or causes of disease or the biological system. It could be any other desired change. For example, the “effective dose” used in treatment is an excessive amount. It is necessary to provide a clinically significant reduction in disease symptoms without adverse side effects. , the amount of the formulation containing the compounds disclosed herein. Appropriate in any individual case The effective dose can be determined using techniques such as dose-increase studies. "Effective dose" includes, for example, a prophylactic effective dose. The "effective dose" of the compounds disclosed herein is, Effective in achieving desired pharmacological effects or therapeutic improvements without excessive harmful side effects. This is the amount. The "effective dose" or "therapeutic effective dose" is determined by the metabolism of compound 1, the age of the subject, their weight, and total Depending on the patient's physical condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician, It is understood that this can vary from case to case. As just one example, the effective therapeutic dose is determined by the dose-increasing clinical trial. This can be determined through everyday experiments, but is not limited to those mentioned above.

[0115] The terms "inhibit," "inhibit," or "inhibitor" of kinases are used in this specification. When used in writing, it refers to the inhibition of enzyme phosphotransferase activity.

[0116] As used herein, the term “irreversible inhibitor” refers to a target protein (e.g., quinine). When it comes into contact with the enzyme, it induces the formation of new covalent bonds with or within proteins. This causes the target protein to revert, regardless of the presence or absence of subsequent irreversible inhibitors. To reduce or eliminate one or more of the biological activities of (e.g., phosphotransferase activity) It means a compound that can be formed.

[0117] As used herein, the term “prophylactic effective dose” means the effective dose of the disease, condition, or disorder being treated. This refers to the amount of a compound applied to a patient that alleviates one or more symptoms to some extent. In terms of application, the amount used may depend on the patient's health condition, weight, etc. Clinical trials for dose increases are being considered. Determining such a prophylactic effective dose through routine experiments, however, is not limited to this, This is considered to be well within the scope of this technical field.

[0118] As used herein, the terms “individual,” “subject,” or “patient” refer to individuals, subjects, or patients in the course of treatment, observation, or practice. It refers to the animal that is the subject of the experiment. This is merely an example and not limited to it, but the subject is... Humans are an example, but it could be any mammal, not limited to humans.

[0119] When used in this specification, IC 50 This refers to the inhibition of Btk in assays that measure reactions. This refers to the amount, concentration, or dosage of a specific test compound that achieves 50% inhibition of the maximum reaction, such as harm. vinegar.

[0120] When used in this specification, EC 50 This refers to induction, elicitation, or enhancement by a specific test compound. A specific test compound elicits a dose-dependent response at 50% of the maximum expression of the specific reaction. This refers to the dosage, concentration, or volume.

[0121] Pharmaceutical composition / formulation When used herein, a pharmaceutical formulation (e.g., suspension) comprises compound 1, a carrier, and a dilute compound. Other chemical components described herein, such as dispersants, suspending agents and / or excipients (applicable) (In some cases) it refers to a mixture with [a specific substance]. Pharmaceutical formulations facilitate the administration of compounds to mammals. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture. .

[0122] The objective of the present invention is to achieve appropriate bioavailability (for example, FDA-approved capsule formulations and The objective is to provide a formulation that has a comparatively advantageous bioavailability. Therefore, one embodiment So, C max The GMR (Geometric Mean Ratio) is in the range of 75% to 95% (for example, 80% to 85%). It can be within the range, AUC last The GMR is 85% to 110% (for example, 85% to 100% or It may be in the range of 85-95%, and / or AUC inf (or AUC) ∞ ) GMR This may be within the range of 80% to 105% (for example, 85% to 95%) as described herein. A formulation (e.g., a suspension) is provided.

[0123] Such exposure-related features are part of any of the embodiments disclosed herein. obtain.

[0124] It is understood that there is considerable overlap among the additives used in the formulations described herein. It should be understood (for example, between a suspending agent and a wetting agent). Therefore, it should not be referred to herein. The additives (or components of the composition / formulation) described herein are included in the compositions or formulations described herein. This is merely an example of possible types of additives, and is not considered to be limiting. The amount of such additive can be easily determined by someone skilled in the art according to the specific desired properties. It is possible.

[0125] Administration and treatment regimens The following administration and treatment regimens refer to the amount of compound 1 and are therefore in relation to the present invention. By appropriately extrapolating the amount, the amount of compound 1 in the formulation (e.g., suspension) described herein It can be applied to quantities.

[0126] In some embodiments, the amount of compound 1 administered to mammals is 300 mg / day or more. The dose is 1000 mg / day or less. In some embodiments, compound 1 is administered to mammals. The amount is between 420 mg / day and 840 mg / day. In some embodiments, infant feeding The amount of compound 1 administered to animals is approximately 420 mg / day, approximately 560 mg / day, or approximately 840 mg / day. The amount is g / day. In some embodiments, the amount of compound 1 administered to mammals is approximately 42 g / day. It is 0 mg / day. In some embodiments, the amount of compound 1 administered to mammals is approximately The daily dose is 560 mg. In some embodiments, the AUC of compound 1 is used. 0~24 It is approximately 15 The AUC ranges from 0 to approximately 3500 ng*h / ml. In some embodiments, the AUC of compound 1 is shown. 0~ 24 The concentration is approximately 500 to 1100 ng*h / ml. In some embodiments, the compound Compound 1 is administered orally. In some embodiments, compound 1 is administered once daily, twice daily, or once daily. It is administered three times a day. In some embodiments, compound 1 is administered daily. In some embodiments, compound 1 is administered once daily. In some embodiments, compound 1 is It is administered every other day. In some embodiments, compound 1 is maintenance therapy.

[0127] In some embodiments, the compound is administered to a pediatric population (e.g., humans up to 18 years of age). The amount of substance 1 is half of that described herein. For example, each dose is 30-140 mg, 50-100 mg or 60-80 mg, for example, about 70 mg (as specified herein) It may be administered in the form of a 1 ml suspension, and the daily dose for the pediatric population is 15 The dose is between 0 mg / day and 500 mg / day. In some embodiments, it is administered to a pediatric population. The amount of compound 1 administered is between 210 mg / day and 420 mg / day. Several implementations In terms of form, the amount of compound 1 administered to the pediatric population is approximately 210 mg / day, approximately 280 mg / The dosage is approximately 420 mg / day. In some embodiments, the compound administered to mammals is... The amount of 1 is approximately 210 mg / day. In some embodiments, it is administered to mammals. The amount of compound 1 is approximately 280 mg / day. In some embodiments, the AUC0 of compound 1 ~24 The concentration is approximately 150 to 3500 ng*h / ml. In some embodiments, the compound AUC of Item 1 0~24 The concentration is approximately 500 to 1100 ng*h / ml. Several implementations In terms of form, compound 1 is administered orally. In some embodiments, compound 1 is taken once a day. It is administered once, twice or three times a day. In some embodiments, compound 1 is administered daily. In some embodiments, compound 1 is administered once daily. In this configuration, compound 1 is administered every other day. In some embodiments, compound 1 is administered via It is a regular treatment.

[0128] Formulations containing compound 1 may be administered for prophylactic, therapeutic, or maintenance purposes. It is possible. In some embodiments, formulations containing compound 1 are adapted for therapeutic use. It is administered (for example, to subjects diagnosed with hematological malignancies). Several implementations In this state, the formulation containing compound 1 is administered according to the therapeutic purpose (for example, blood cancer). For individuals who are prone to developing blood tumors or are at risk of developing hematological malignancies. (to be administered). In some embodiments, a formulation containing compound 1 is used as maintenance therapy. It is administered to patients in remission.

[0129] In some embodiments, for a pediatric population, the amount of compound 1 is 150 mg / day or more. The amount is 00 mg / day or less. In some embodiments, the amount of compound 1 is 210 mg / day or less. The amount is 420 mg / day or less. In some embodiments, the amount of compound 1 is 200 mg / The amount is between 420 mg / day and 420 mg / day. In some embodiments, the amount of compound 1 is about 180 The amount is mg / day. In some embodiments, the amount of compound 1 is approximately 210 mg / day. In some embodiments, the amount of compound 1 is approximately 280 mg / day. In this state, the amount of compound 1 is approximately 420 mg / day. In some embodiments, pediatrics In the case of the group, the amount of compound 1 is between 2 mg / kg / day and 13 mg / kg / day. In one embodiment, the amount of compound 1 is 2.5 mg / kg / day or more and 8 mg / kg / day or less. In some embodiments, the amount of compound 1 is 2.5 mg / kg / day or more, up to 6 mg / The amount is less than or equal to kg / day. In some embodiments, the amount of compound 1 is 2.5 mg / kg / day The amount is 4 mg / kg / day or less. In some embodiments, the amount of compound 1 is about 2.5 The amount is mg / kg / day. In some embodiments, the amount of compound 1 is approximately 8 mg / kg / day. That is the case.

[0130] As described herein, the formulations of the present invention contain a pharmaceutical carrier such as purified water. Therefore, the dose is administered as a fixed volume of suspension, as described herein. If the dose is 70 mg of ibrutinib, the amount of carrier (e.g., purified water) is 1 ml. Yes. As shown herein, the suspension is either lower in concentration or higher in concentration. However, in any case, the volume of suspension required for a particular dose is predetermined.

[0131] In some embodiments, the pharmaceutical formulations described herein contain about 70 mg of compound 1. Includes. In some embodiments, the suspension is a predetermined volume of suspension (e.g., 1 ml) (Note The required dose is available (available via an injector), and therefore each 1 ml is approximately 70 ml It is prepared to contain compound 1 of g. In some embodiments, 1, 2, 3, 4 or 5 In some embodiments, 2 ml doses of the suspension described herein are administered daily. A 3 or 4 ml dose of the suspension described herein is administered daily. Several implementations In this embodiment, the dose of the suspension described herein is administered once daily. In other embodiments, The suspension doses described herein are administered multiple times a day.

[0132] In some embodiments, the formulations described herein (e.g., suspensions) are administered daily. In some embodiments, the formulations described herein (e.g., suspensions) are 1 It is administered every other day.

[0133] In some embodiments, the formulations described herein (e.g., suspensions) are administered once daily. It is administered. In some embodiments, the formulations described herein (e.g., suspensions) It is administered twice a day. In some embodiments, the formulation described herein (for example) The suspension is administered three times a day. In some embodiments, the formulation described herein The substance (e.g., suspension) is administered four times a day.

[0134] In some embodiments, the formulations described herein (e.g., suspensions) are used to treat diseases It is administered until the individual develops a hatred for it, the toxicity becomes unbearable, or the individual chooses to stop it. In embodiments, the formulations described herein (e.g., suspensions) may exacerbate the disease, It is administered daily until the toxicity becomes unacceptable or the individual selects to do so. Several embodiments Therefore, the formulations described herein (e.g., suspensions) are not intended to exacerbate the disease or be toxic. It is administered every other day until it becomes unacceptable or the individual chooses not to administer it.

[0135] The pharmaceutical compositions or formulations described herein are intended for administering a precise single dose. It may be in a preferred form (for example, as a suspension using a measuring syringe or in a sachet) (As a reconstitution powder containing a pre-prepared dose). Non-limiting examples include vials or ampoules. Aqueous suspension formulations / components packaged in non-resealable containers containing powder and single doses. It is a finished product. Alternatively, a resealable container for multiple doses can be used, in which case this It is common for the formulation / composition to contain a preservative. In some embodiments, each single The dosage form contains 70 mg of compound 1 (or this can be 1 ml or another suitable predetermined dose). (The volume may be a suspension as described herein). In some embodiments, solids (e.g.) For children, the dose is 1 unit per day (for example, 1 ml of the suspension described herein). 70 mg of ibrutinib is administered. In some embodiments, the individual (e.g., small The child should take 2 units per day (for example, 2 × 1 ml of the suspension described herein). 140 mg of ibrutinib is administered. In some embodiments, the individual (e.g., small The child is administered 3 units per day (210 mg of ibrutinib). Several implementations Morphologically, individuals are administered a dose of 4 units (280 mg of ibrutinib) per day.

[0136] The number of variables associated with individual treatment regimes is large and can vary considerably from these recommended values. Since this is not uncommon, the above range is merely a suggestion. Such dosages are used The activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of each individual target, the treatment The severity of the disease or condition being treated and several other variables, not limited to the practitioner's judgment, may vary. It can be changed.

[0137] The toxicity and therapeutic efficacy of such treatment regimens are determined by the LD 50 (50% of the population is deadly Quantity) and ED 50 One possible method is determining the dose that is therapeutically effective in 50% of the population, but this is not limited to this. Toxicity can be determined in cell cultures or experimental animals using standard, undefined pharmaceutical procedures. The dose-to-effect ratio is the therapeutic index, which is the LD 50 and ED 50 Ratio It can be expressed as follows. Compounds exhibiting a high therapeutic index are preferred. Cell culture assay and Data obtained from animal studies can be used to determine dosage ranges for use in humans. Yes. The dosage of such compounds is preferably an ED that minimizes toxicity.50 Circulation including It is within the blood concentration range. The dosage will depend on the form of administration and the route of administration used. It can change within this range.

[0138] Combination therapy In certain embodiments, the treatment of blood cancer was carried out in individuals who needed it. Then, a certain amount of the formulation described herein (e.g., suspension) containing compound 1 is used. Methods including administration to an individual are disclosed herein. In some embodiments, the method This further includes administering a second hematological cancer treatment regimen.

[0139] In some embodiments, the second cancer treatment regimen includes cyclophosphamide, hydroxy It contains daunorubicin, vincristine, and prednisone, and optionally rituximab. nothing.

[0140] In some embodiments, the second cancer treatment regimen includes bendamustine and rituximab Includes.

[0141] In some embodiments, the second cancer treatment regimen includes fludarabine, cyclophosphamide. Includes dol and rituximab.

[0142] In some embodiments, the second cancer treatment regimen includes cyclophosphamide and vincris. The drug contains tin and prednisone, and optionally rituximab.

[0143] In some embodiments, the second cancer treatment regimen includes etoposide, doxorubicin, and bicarbonate. Includes lecithin, cyclophosphamide, prednisolone, and optionally rituximab. .

[0144] In some embodiments, the second cancer treatment regimen includes dexamethasone and lenalidomide Includes.

[0145] Kits / Manufacturing Products Kits or packages containing the formulations described herein are as described herein. It is designed for use in a manner that allows for the optional administration of the formulation. Examples include instructions for use, suitable containers for the formulation, syringes, pipettes, and measuring spoons. The kit may further contain one or more devices, etc., which are not limited to these. The components will be obvious to those skilled in the art, considering the desired delivery instructions and mode.

[0146] For example, if the formulation is a suspension, this requires the use of a suitable adapter and / or sealing device. It can then be packaged in a bottle (for example, a glass bottle) such as an amber-colored glass bottle. One embodiment So, this packaging is for oral administration of suspensions, which may be in the form of pipettes or syringes. The present invention further includes measuring instruments. In one embodiment, the measuring instrument is a pipette (for example, having a tip) (to do so) and plungers (for example, to visually assist in measuring suspensions, even if they are semi-transparent or not) It is not transparent but is colored (for example, it could be blue, and currently it is purple, as required). ()) and in one embodiment, the pipette or syringe is made of polypropylene They are manufactured from suitable polymers such as the pipette, and furthermore, the plunger is also made from the same polymer as the pipette. Or, in one embodiment, a specific polymer such as polyethylene (e.g., high-density polyethylene). It should be manufactured from.

[0147] The kit typically includes a label listing the contents and / or instructions for use, as well as instructions for use. This includes package inserts with attached documents. A complete set of instructions would also typically be included.

[0148] In one embodiment, the label is present on or attached to the container. The letters, numbers, or other symbols forming the label are affixed, molded, or etched onto the container itself. In that case, the label is present on the container and also within the receptacle or carrier that holds the container. In this case, the label is attached to the container (for example, as a package insert). One embodiment Therefore, labels are used to indicate that the contents are intended for a specific therapeutic use. Bell also indicates the use of the contents, for example, the use of the method described herein. [Examples]

[0149] The following examples are intended to illustrate the present invention and do not limit its scope. It should not be interpreted as such.

[0150] Example 1 Examples of the formulations of the present invention can be described as follows.

[0151] [Table 1]

[0152] Here, Avicel RC591 is used, which is a microcrystalline cellulose and cross-crystalline cellulose. A specific mixture with lumellose sodium (carboxymethylcellulose sodium) ru.

[0153] The details of the above formulation are based on the components in 1 ml of purified water. Therefore, 100 ml Starting with purified water, a corresponding large-scale version of the above formulation can be prepared. (By increasing the amount of the ingredient by 100 times).

[0154] Background Examples and Reference Examples Parabens are used as preservatives (e.g., sodium methylparaben and / or methylparaben). Examples of various suspensions of chloroparaben sodium were tested, and these were used in clinical phase 1 studies. Developed without issue to support (International Patent Application, International Publication No. 2016 / 164404) (Please refer to the pamphlet.) Revising the concept of Phase 1 (mainly paraben parsing) A novel multi-stage approach aimed at supporting Phase III clinical trials (by increasing the duration) We obtained the concepts of multiple doses. These concepts are shown in the following table as Composition 1 and Composition 2, respectively. It is being done.

[0155] [Table 2]

[0156] Therefore, with respect to the two suspensions mentioned above, the suspending agent (microcrystalline cellulose and croscarmellose) is important. An increase in the concentration of lumellose sodium and the resulting increase in the amount of citrate (which affects the final target pH) Along with other changes such as (due to), the total amount of parabens increased by 20% (from composition 1 to composition 1). (Item 2).

[0157] As a result of the increased paraben concentration, suspension composition 2 remained stable for several months under various storage conditions. After this state, a crystallization problem was observed. Under a microscope, a large number of fine, novel needle-shaped crystals were found. Observed: Novel needle crystals were found in combination of API and paraben by IR, Raman, and MS analysis. The properties are determined assuming the possibility of crystal formation. This is an inherent result of API-paraben cocrystallization. This is established by the unexpected failures of the PET tests reported in the table below. As a result, the amount of available paraben preservatives was less than expected (e.g., U S Pharmacopoeia <51> and pharmacopoeias such as Ph.Eur.5.1.3 (Antimicrobial efficacy tests conducted and analyzed in accordance with the references.)

[0158] [Table 3]

[0159] The last three entries (except for composition 2 and those with pH adjusted to 5.5 and 6.5) In the same composition, needle-shaped (co)crystals were observed.

[0160] Therefore, compositions / formulations with a paraben level of 120% failed PET. You can see that.

[0161] The above formulations / compositions achieve a more robust preservative system that covers the shelf life of the formulation. It is possible to improve this. Alternative / improved suspensions, for example, in PET tests It does not have defects such as the formation of undesirable crystal (e.g., co-crystal) products. Further research was conducted to provide the product (as outlined below). For example, manufacturing A more robust preservative system that covers the shelf life of the agent and / or, for example, as described herein. It was desired to achieve a suspension with a moderate particle size distribution throughout the entire suspension. It was searched for.

[0162] The above is the motivation for exploring the deformation forms of suspensions and for seeking further preservatives for suspensions. This will provide an overview.

[0163] Study of the solubility of methyl, ethyl, and propylparaben at various temperatures at pH 6 (single (In the body or in the presence of different amounts of propylene glycol) Methyl (in pure or mixed with various percentages of propylene glycol) The thermodynamic solubility of ethyl and propylparaben was evaluated in a buffer solution. As a function of lomerose concentration (0, 2.5 mg / ml, 5 mg / ml, and 10 mg / ml) Furthermore, it was evaluated as a function of temperature (5°C, 20°C, and 40°C). The saturated paraben solution was subjected to a certain amount of heat. The solution was spiked with excess active ingredient (ibrutinib), filtered, and the ibrutinib / para solution was extracted. Ben concentrations were tracked over time (1, 2, 3, and 4 weeks).

[0164] Results / Conclusion The addition of propylene glycol has a slightly positive effect on the solubility of parabens. It is possible. However, the paraben concentration of all formulations (and at all temperatures) is The concentration decreased as a function of time after the addition of brutinib. This is due to the appearance of a viscous substance in the vial. This was accompanied by several physical observation results, and chromatography was performed on all samples at 40°C. Further peaks were observed in the data.

[0165] Therefore, none of these various concepts were suitable for further development. In particular, Methi ethylparaben was not suitable.

[0166] Research on novel concepts: Methyl / ethylparaben vs. other preservatives To test the effectiveness of the preservative, 25 samples were prepared based on the following table, and in each case, 7 Using ibrutinib at 0 mg / ml and a sweetener (sucralose) at 1 mg / ml, p H was prepared using the adjusting agents mentioned herein.

[0167] [Table 4]

[0168] [Table 5]

[0169] [Table 6]

[0170] To avoid any doubt, in the table above, Me Pa refers to methylparaben, and Et P a refers to ethylparaben, Pr Pa refers to propylparaben, and 1Q refers to 1H2 It refers to O.

[0171] Therefore, propylene glycol can be combined with novel excipients or different processes. , a completely novel method using ascorbic acid, benzoic acid or benzyl alcohol and parabens Preservatives were tested. Avicel RC591 was compared to CL611, and HPMC29 10 5 mPas was compared with HPMC2208 3 mPas and HPC, and the quien of the buffer was tested. Acid / Na2HPO4 was compared with buffer Na2HPO4 / NaH2PO4, and the Na salt was determined. Paraben use (in multi-step processes) vs. nonionic paraben use (one-pot process) This was compared to the case in Rothes.

[0172] 25 novel concepts were identified in 6M laboratory stability studies and 1M PET tests ASAP. (Accelerated Stability Assessment Program) Screened in stability studies (5, 40 and 60°C storage (Storage conditions).

[0173] Results from 25 samples Results of a 1-month (1M) ASAP (Accelerated Stability Assessment Program) stability study (5℃, 40 The following general indicators were obtained from (storage conditions of ℃ and 60℃).

[0174] - The results of API assay, purity profile, pH and suspension appearance in all cases were stable and good.

[0175] - Only in terms of preservative stability, some significant differences were observed among different concepts. For parabens, a 1 - 6% reduction was observed in the assay of samples stored at 60℃ for 1 month (1M). The sorbic acid assay was reduced by about 15%, benzoic acid by about 5%, and benzyl alcohol by only 1%.

[0176] Results of 6 - month (6M) laboratory stability Twenty - five new concepts were mainly screened for physical stability under various stress conditions: viscosity, yield point, visual aspects and API (co) crystallization (at various time points).

[0177] The viscosity and yield point of all suspensions over time were acceptable. Only the Avicel structure of the sample containing benzoic acid at pH 4 after 6 months (6M) completely broke down without having a yield point. Avicel is expected to be more stable at 5 < pH < 9.

[0178] The investigation of the visual aspects of the suspension (powder precipitation, water separation, structure destruction, etc.) was carried out by observing the samples stored statically in a glass cylinder for 6M. As a conclusion, in all concepts, the suspension in the cylinder resulted in a high - density form that could not flow even when the cylinder was inverted for 10 seconds. No powder precipitation or water separation was observed. ​​​​​​​​​​The only exception is the concept (Concept 4) which includes Avicel combined with HPC. This was expressed as follows, indicating a separation of approximately 2.5 ml of water at the bottom of the cylinder.

[0179] We are investigating the possibility of novel needle-shaped crystals (typical in co-crystal API-parabens) in various This was determined by microscopic analysis of suspension samples stored / handled according to the specified method.

[0180] - All concepts were stored at 40 and 60°C for 1M: Concepts 22 and 24 only A new type of crystal was discovered.

[0181] - All concepts are based on 6M under periodic conditions (5°C / 12 hours to 40°C / 12 hours). After being stored for 1 million minutes, no new needle-shaped crystals appeared, only 7 concepts (13-20). However, these were observed in all other samples. In acceptable concepts 13-20, periodic patterns After storage for 6M, a novel crystallization was observed only in the concept of containing benzoic acid as an inducer. This was observed. Other samples were stable.

[0182] - All concepts were subjected to physical stress through rolling. All suspension concepts involve placing the suspension at room temperature in a glass vial sealed with a pediatric safety stopper. It was then rolled horizontally at a speed of 25 rpm over a distance of 1 m. After rolling over 1 m, it was coupled. No crystals were found, and no other problems were found in other tests; promising concepts 9, 17, 1 Excess stress is applied by rolling under the same conditions for a total of 3 months on steps 8, 19, and 20. Then, they were left standing at room temperature for 3 months (3M). Between these concepts, concepts 18, 19 and 2 Only 0 was stable. In concept 9, novel crystals were observed, and in concept 17, there was potential. Initial crystallization was observed.

[0183] - Spikes in the sample due to cocrystallization. We attempted to induce rapid cocrystallization by spiking several concepts. Methyl and ethyl compounds The concept of containing parabens is a co-crystalline powder of API / methylparaben and API / Etparaben. The sample was spiked with a small amount of granules at the end. After spiking, the sample was shaken (by hand) to equalize it. The crystals were quantified and evaluated under a microscope (in samples 24 and 25, several crystals were already observed before the spike). (As suspected), it was ultimately stored for 6M under periodic conditions. In conclusion, under periodic conditions, 1 After storage for M to 6M, all samples exhibited novel needle-shaped crystals.

[0184] PET results and analysis (for concepts 17-20) PET tests were performed on all concepts, and the most promising concepts are listed below (see above). The results are shown below.

[0185] [Table 7]

[0186] Based on the results obtained from 25 screened concepts (mainly one of the test conditions) PET results and novel needle (co)crystal formation are available, along with 2M stability data. The first concept selection was made when this was the case. Concepts 17 and 18 (benzoic acid and benzyl benzoate, respectively) Only those containing alcohol as a novel preservative were selected for further investigation (see below). (Please refer to the table.)

[0187] [Table 8]

[0188] Further data on the concepts of benzyl alcohol and benzoic acid To test the stability and preservative effect, benzoic acid and benzyl benzoate were tested based on the following table. Thirteen more samples (concepts 26-38) were prepared using alcohol, and 70 mg / ml of ibrutinib was used as the free base, and 1 mg / ml of a sweetener (sucralose) was used. The pH was adjusted using the adjusting agents mentioned herein.

[0189] [Table 9]

[0190] [Table 10]

[0191] In PET tests and 2M laboratory stability studies, the suspension preservative benzyl alcohol and The concentration of benzoic acid was varied with different Avicel concentrations (12 and 14 mg / ml) and different humectants. (In combination with HPMC2910 and HPMC2208) screens at targeted and limited pH. I did it (see above for details on the method).

[0192] PET results for concepts 26-38 The results of PET scans performed on novel, screened concepts are reported in the table below. However, here we can see that all the concepts passed the test.

[0193] [Table 11]

[0194] [Table 12]

[0195] [Table 13]

[0196]

Table 14

[0197] Conclusions from Concepts 26 to 38 Some suspension concepts containing benzoic acid were physically unstable. At the lower limit pH After 2 months of observation and 6 months of observation at the target pH, the Avicel structure completely disappeared (yield point was not measured). This result was probably related to the very low application pH that is necessary for the antibacterial activity of benzoic acid but causes the instability of Avicel. Avicel is expected to be more stable within the range of 5 < pH < 9.

[0198] In combination with the benzoic acid concept, several new crystallizations were observed after storage at 6 M under periodic conditions and after 3 M rolling rings and 3 M static storage.

[0199] These preliminary results showing a possible co-crystallization of ibrutinib and benzoic acid are also confirmed by the disclosures of International Patent Application Publication No. WO 2016 / 156127 pamphlet and No. WO 2016 / 160604 pamphlet.

[0200] The concept containing benzyl alcohol as a preservative was physically / chemically stable and showed no (co-)crystallization .

[0201] As a conclusion, based on these results, benzoic acid is not further evaluated, while benzyl alcohol was selected as a potential new suspension preservative and for further development research .

[0202] Based on the PET results, the target dose of benzyl alcohol was tentatively selected as 10 mg / ml. At 8 mg / ml, the first positive result was obtained, and with an additional 20% benzyl alcohol... This was taken into consideration as a reason for the process's robustness.

[0203] Concepts using benzyl alcohol Humectant The need for wetting agents such as HPMC was tested: physical stability of the suspension and particle size distribution (PS Test D) showed that the absence of HPMC resulted in a physically unstable suspension after storage at 25°C in 1M. It was found that storage at 25°C for two months resulted in a shift to a larger particle size (PS). It has been revealed. Therefore, the formulation / suspension of the present invention that does not contain HPMC (or another suitable wetting agent) Turbidity is not recommended. Without a wetting agent, particle size is (desired) due to agglomeration. It is possible that it may increase (without exception).

[0204] Regarding hydrophobicity, water solubility, free OH ratio, and surface tension, HPMC2910 and 2208 We compared them and obtained the following results.

[0205] HPMC exhibits certain cloudiness associated with polymer agglomeration due to rising temperatures. It is a thermoreversible polymer with a gelation temperature. The gelation temperature depends on the polymer concentration and hydrophobicity. It is a function of the length of the block and the chemical structure of the polymer. The more hydrophobic the polymer, the better. However, the clouding / gelation temperature is low. HPMC2208 is less hydrophobic than 2910, and The resulting cloud temperature is approximately 20°C higher than that of the HPMC2910.

[0206] HPMC2208 is less hydrophobic and more water-soluble than HPMC2910. As a result, it is easier to use as a humectant for API (ibrutinib). It is expected.

[0207] The surface tension of an HPMC2208 aqueous solution is greater than that of an HPMC2910 aqueous solution of the same concentration. It is also expensive. HPMC2208 is expected to be a better wetting agent for APIs. ru.

[0208] From the NMR test, HPMC2208 with 3 mPas, along with other results found, H It was observed that it contains approximately 18% more free OH groups than PMC2910.

[0209] Conclusion: Therefore, in one embodiment, the HPMC2208 with 3 mPas is mainly based on the above. A novel wetting agent for ibrutinib suspension is expected to be a superior wetting agent. It was selected as an agent.

[0210] Other exams The amount of citrate / H2O required to obtain a target suspension pH = 6.00 ± 0.1 by titration is... The concentration was determined to be 0.7302 mg / ml.

[0211] • The volume determination of the suspension buffer was moderate / good, and the determination of the suspension concentration was 1.021 g / It is ml.

[0212] • PET robustness studies have shown positive results.

[0213] • API / benzyl alcohol / decomposition product assay and pH vs. temperature, oxygen, light and steel DoE sensitivity studies conducted on suspensions to evaluate the sensitivity of quality characteristics showed positive results. The results were shown.

[0214] • To evaluate the manufacturing variability (90-110 wt) of excipients, a DoE robustness study was conducted. The procedure was performed on turbid fluid and yielded positive results (ongoing).

[0215] • A study of pH robustness at the non-conforming boundary was conducted using selected pH boundaries (5.5 and 6.5). I performed the procedure on my mind and obtained a positive result (ongoing).

[0216] Scaling up the process Examples - Pharmaceutical formulations / preparation processes The pharmaceutical formulation / composition of the present invention (the above suspension) is obtained by mixing appropriate components together. It can be prepared or manufactured by the following: Examples of this process include: • To prepare crystalline form A of ibrutinib as described herein (e.g., International Publication No. Refer to pamphlet No. 2013 / 184572; • Mix the remaining components together.

[0217] Large-scale preparation The manufacturing process on a 50L scale is as follows: Add purified water to the mixing container 1. Add a solution of HPMC and benzyl alcohol dissolved in purified water. Add the API and stir the prepared mixture in container 1 until homogeneous. Add Avicel to preparation container 1. Add the solution of sucralose, Na2HPO4, and citrate H2O in purified water to container 1. ru Stir the prepared mixture until it becomes homogeneous. • Measure the pH of the prepared product. • Add purified water to bring the prepared mixture to its final volume. Mix the prepared mixture until it is homogeneous. • Measure the final pH.

[0218] The above process depends on the components contained in the pharmaceutical formulation / composition (for example, used) It may be adapted / modified (based on specific suspending agents, wetting agents, etc.).

[0219] Biological examples Studies will be conducted to test the safety, tolerability, and / or efficacy of the formulations of the present invention (particularly formulations in the form of suspensions) in subjects (e.g., pediatric populations) having diseases as defined herein (e.g., chronic lymphocytic leukemia, relapsed / refractory mantle cell lymphoma, etc.). Similar studies may also be conducted to test such formulations in combination (as described herein). The present invention includes the following embodiments. [Claim 1] (i) Compound 1 in the presence of an optionally pharmaceutically acceptable carrier (e.g., an aqueous carrier) [ka] ibrutinib or its pharmaceutically acceptable salt / solvate, which is a compound having the structure of , suspending agent and (ii) One or more preservatives, which are benzyl alcohols, Optionally, one or more other pharmaceutically acceptable excipients A stable pharmaceutical formulation containing [the specified ingredient]. [Claim 2] (i) Compound 1 suspended in a pharmaceutically acceptable carrier (e.g., an aqueous carrier) [ka] ibrutinib or a pharmaceutically acceptable salt / solvate thereof, which is a compound having the structure of, (ii) at least one preservative which is benzyl alcohol, Optionally, one or more other pharmaceutically acceptable excipients The pharmaceutical formulation according to claim 1, in the form of a suspension containing the above. [Claim 3] The pharmaceutical formulation according to claim 1 or 2, also containing a preservative selected from one or more of the following: antibacterial agents, antioxidants, free radical scavengers, oxygen absorbers and / or chelating agents, for example, benzoic acid, parabens (methyl or ethylparaben), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercury acetate, thimerosal, sorbic acid, propionic acid, propylene glycol, vitamin E, ascorbic acid palmitate, sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, sodium bisulfite acetone, isoascorbic acid, hydroxypropyl cyclodextrin, sodium citrate, sodium EDTA, malic acid, acetic acid and mixtures thereof. [Claim 4] The preservative comprises more than 50% (by weight) benzyl alcohol, for example more than 90% benzyl alcohol, and for example, the preservative is essentially made of benzyl alcohol, according to claim 1, 2, or (where applicable) 3. [Claim 5] A pharmaceutical formulation according to any one of claims 1 to 4, comprising approximately 0.1 w / v% to 10 w / v% or approximately 1 mg / ml to 50 mg / ml of a preservative. [Claim 6] The pharmaceutical formulation according to claim 5, wherein the preservative is present in an amount of approximately 0.5 w / v% to 2 w / v% or approximately 5 mg / ml to 20 mg / ml. [Claim 7] A pharmaceutical formulation according to any one of claims 1 to 6, comprising a suspending agent selected from alginate, cellulose ether, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, acacia, tragacanth, xanthan gum, bentonite, carbomer, carrageenan, powdered cellulose, and gelatin. [Claim 8] The pharmaceutical formulation according to claim 7, wherein the suspending agent is a cellulose ether such as microcrystalline cellulose (e.g., silicified microcrystalline cellulose SMCC). [Claim 9] A pharmaceutical formulation according to any one of claims 1 to 8, containing a suspending agent in an amount of 0.1 w / v% to 10 w / v% or about 1 mg / ml to 50 mg / ml. [Claim 10] The pharmaceutical formulation according to claim 9, wherein the amount of the suspending agent is approximately 0.5 w / v% to 2 w / v% or approximately 5 mg / ml to 20 mg / ml. [Claim 11] One or more wetting agents (e.g., cellulose ethers such as hydroxypropyl cellulose or hydroxypropyl methylcellulose), one or more buffering agents (e.g., citrate H) 2 A pharmaceutical formulation according to any one of claims 1 to 10, further comprising (containing O and / or sodium hydrogen phosphate), one or more pH adjusters (e.g., sodium hydroxide and / or hydrochloric acid) and / or (e.g., optionally) a sweetener (e.g., sucralose). [Claim 12] A pharmaceutical formulation according to any one of claims 1 to 11, comprising, based on 1 ml of purified water as the pharmaceutical carrier, 20 to 200 mg / ml of ibrutinib; 2.5 to 25 mg / ml of benzyl alcohol preservative; 2 to 24 mg / ml of suspending agent; optionally, for example, 0.5 to 10 mg / ml of wetting agent; optionally, for example, 0.5 to 10 mg / ml of buffer solution; optionally, for example, 0.1 to 5 mg / ml of sweetener; and optionally, a pH adjuster (qs). [Claim 13] The pharmaceutical formulation according to claim 12, comprising, based on 1 ml of purified water as the pharmaceutical carrier, 60-80 mg / ml of ibrutinib; 8-12 mg / ml of benzyl alcohol preservative; 10-14 mg / ml of suspending agent; optionally, for example, 2-3 mg / ml of wetting agent; optionally, for example, 1.5-2.5 mg / ml of buffer solution; optionally, for example, 0.5-1.5 mg / ml of sweetener; and optionally, a pH adjuster (qs). [Claim 14] A pharmaceutically acceptable carrier (e.g., purified water) is present in a predetermined amount, comprising the following relative amounts (w / w) of the aforementioned components (relative to each other) and compared to 70 mg of ibrutinib: 5 to 15 mg of benzyl alcohol preservative; 6 to 18 mg of suspending agent; optionally, for example, 1 to 5 mg of wetting agent; optionally, for example, 1 to 3 mg of buffer; optionally, for example, 0.2 to 2 mg of sweetener; and optionally, a pH adjuster (qs), wherein a pharmaceutically acceptable carrier (e.g., purified water) is present in a predetermined amount, according to any one of claims 1 to 11. [Claim 15] 8-12 mg of benzyl alcohol preservative; 10-14 mg of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose (e.g., Avicel®); optionally 2-3 mg of hydroxypropyl methylcellulose (HPMC); optionally 1.5-2.5 mg of citric acid. 2 The pharmaceutical formulation according to claim 14, comprising: O and / or a phosphate such as sodium hydrogen phosphate; optionally 0.5 to 1.5 mg of sucralose; and optionally NaOH and / or HCl(qs) for adjusting pH, wherein a pharmaceutically acceptable carrier (e.g., purified water) is present in a predetermined amount as described herein (e.g., 1 ml per 10 mg of ibrutinib to 1 ml per 210 mg of ibrutinib, for example, about 1 ml per 70 mg of ibrutinib). [Claim 16] The pharmaceutical formulation according to any one of claims 1 to 15, wherein the ibrutinib is not in the form of a salt or solvate, that is, the ibrutinib is in its free form. [Claim 17] A method for treating a disease in a patient requiring such treatment, comprising administering to the patient a therapeutically effective amount of the pharmaceutical formulation described in any one of claims 1 to 16. [Claim 18] A method for treating a B-cell proliferative disorder, comprising administering a therapeutically effective amount of the pharmaceutical formulation described in any one of claims 1 to 16 to a patient in need. [Claim 19] The method according to claim 18, wherein the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. [Claim 20] The method according to claim 17, wherein the disease is a B-cell malignant tumor. [Claim 21] The method according to claim 20, wherein the disease is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. [Claim 22] The method according to claim 21, wherein the disease is lymphoma or leukemia. [Claim 23] The method according to claim 21, wherein the disease is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis. [Claim 24] A process for preparing a pharmaceutical formulation according to any one of claims 1 to 16, comprising mixing the components with each other.

Claims

1. (i) Compound 1 【Chemistry 1】 ibrutinib, a compound having the structure of [this structure], or a pharmaceutically acceptable salt / solvate thereof, and a suspending agent, (ii) A preservative comprising one or more preservatives, wherein at least one preservative is benzyl alcohol, Optionally, one or more other pharmaceutically acceptable excipients A stable pharmaceutical formulation containing, The aforementioned pharmaceutical formulation contains approximately 0.1 w / v% to 10 w / v% or approximately 1 mg / ml to 50 mg / ml of preservatives. The aforementioned preservative is a pharmaceutical compound containing more than 50% benzyl alcohol by weight.

2. The pharmaceutical formulation according to claim 1, wherein (i) ibrutinib or a pharmaceutically acceptable salt / solvate thereof, and a suspending agent are present in the presence of a pharmaceutically acceptable carrier.

3. (i) Compound 1 suspended in a pharmaceutically acceptable carrier 【Chemistry 2】 ibrutinib, a compound having the structure of, or a pharmaceutically acceptable salt / solvate thereof, (ii) at least one preservative which is benzyl alcohol, Optionally, one or more other pharmaceutically acceptable excipients The pharmaceutical formulation according to claim 1 or 2, in the form of a suspension containing the above.

4. A pharmaceutical formulation according to any one of claims 1 to 3, which also contains a preservative selected from one or more of the following: an antibacterial agent, an antioxidant, a free radical scavenger, an oxygen scavenger, and / or a chelating agent.

5. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the preservative contains more than 70% benzyl alcohol by weight, or the preservative contains more than 99% benzyl alcohol by weight.

6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the preservative is present in an amount of about 0.5 w / v% to 2 w / v% or about 5 mg / ml to 20 mg / ml.

7. A pharmaceutical formulation according to any one of claims 1 to 6, comprising a suspending agent selected from alginate, cellulose ether, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, acacia, tragacanth, xanthan gum, bentonite, carbomer, carrageenan, powdered cellulose, and gelatin.

8. The pharmaceutical formulation according to claim 7, wherein the suspending agent comprises microcrystalline cellulose.

9. A pharmaceutical formulation according to any one of claims 1 to 8, comprising a suspending agent in an amount of 0.1 w / v% to 10 w / v% or about 1 mg / ml to 50 mg / ml.

10. The pharmaceutical formulation according to claim 9, wherein the amount of the suspending agent is about 0.5 w / v% to 2 w / v% or about 5 mg / ml to 20 mg / ml.

11. A pharmaceutical formulation according to any one of claims 1 to 10, further comprising one or more wetting agents, one or more buffering agents, one or more pH adjusters, and / or optionally a sweetener.

12. A pharmaceutical formulation according to any one of claims 1 to 11, comprising, based on 1 ml of purified water as the pharmaceutical carrier, 20 to 200 mg / ml of ibrutinib; 2.5 to 25 mg / ml of benzyl alcohol preservative; 2 to 24 mg / ml of suspending agent; optionally 0.5 to 10 mg / ml of wetting agent; optionally 0.5 to 10 mg / ml of buffer solution; optionally 0.1 to 5 mg / ml of sweetener; and optionally a pH adjuster (q.s.).

13. The pharmaceutical formulation according to claim 12, comprising, based on 1 ml of purified water as the pharmaceutical carrier, 60 to 80 mg / ml of ibrutinib; 8 to 12 mg / ml of benzyl alcohol preservative; 10 to 14 mg / ml of suspending agent; optionally 2 to 3 mg / ml of wetting agent; optionally 1.5 to 2.5 mg / ml of buffer solution; optionally 0.5 to 1.5 mg / ml of sweetener; and optionally a pH adjuster (q.s.).

14. A pharmaceutical formulation according to any one of claims 1 to 11, comprising the following relative amounts (w / w) per 70 mg of ibrutinib: 5 to 15 mg of benzyl alcohol preservative; 6 to 18 mg of suspending agent; optionally 1 to 5 mg of wetting agent; optionally 1 to 3 mg of buffer; optionally 0.2 to 2 mg of sweetener; and optionally a pH adjuster (q.s.).

15. 8-12 mg of benzyl alcohol preservative; 10-14 mg of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose; optionally 2-3 mg of hydroxypropyl methylcellulose (HPMC); optionally 1.5-2.5 mg of citric acid. ２ The pharmaceutical formulation according to claim 14, comprising: O and / or a phosphate such as sodium hydrogen phosphate; optionally 0.5 to 1.5 mg of sucralose; and optionally NaOH and / or HCl (q.s.) for adjusting pH.

16. The pharmaceutical formulation according to any one of claims 1 to 15, wherein the ibrutinib is not in the form of a salt or solvate, that is, the ibrutinib is in its free form.

17. A pharmaceutical formulation according to any one of claims 1 to 16, used in the treatment of a disease.

18. A pharmaceutical formulation according to any one of claims 1 to 16, used in a method for treating B-cell proliferative disorders.

19. The pharmaceutical formulation according to claim 18, wherein the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia.

20. The pharmaceutical formulation according to claim 17, wherein the disease is a B-cell malignant tumor.

21. The pharmaceutical formulation according to claim 20, wherein the disease is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma.

22. The pharmaceutical formulation according to claim 21, wherein the disease is lymphoma or leukemia.

23. The pharmaceutical formulation according to claim 21, wherein the disease is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.

24. The pharmaceutical formulation according to claim 2 or 3, wherein the pharmaceutically acceptable carrier is an aqueous carrier or purified water.

25. The pharmaceutically acceptable carrier is present in an amount of 1 ml per 10 mg of ibrutinib to 1 ml per 210 mg of ibrutinib, or in an amount of about 1 ml per 70 mg of ibrutinib, according to any one of claims 2, 3, and 24.

26. A pharmaceutical formulation according to any one of claims 1 to 25, comprising a preservative selected from the group consisting of benzoic acid, parabens (methyl or ethylparaben), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercury acetate, thimerosal, sorbic acid, propionic acid, propylene glycol, vitamin E, ascorbic acid palmitate, sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, sodium acetone bisulfite, isoascorbic acid, hydroxypropyl cyclodextrin, sodium citrate, sodium EDTA, malic acid, acetic acid, and mixtures thereof.

27. The pharmaceutical formulation according to claim 8, wherein the microcrystalline cellulose is silicified microcrystalline cellulose (SMCC).

28. The humectant comprises a cellulose ether selected from hydroxypropyl cellulose or hydroxypropyl methylcellulose. The buffering agent is citric acid. ２ It contains O and / or sodium hydrogen phosphate, The pH adjusting agent comprises sodium hydroxide and / or hydrochloric acid. The pharmaceutical formulation according to claim 11, wherein the sweetener comprises sucralose.

29. The pharmaceutical formulation according to claim 15, wherein the mixture of microcrystalline cellulose and sodium carboxymethylcellulose is Avicel (registered trademark).

30. A process for preparing a pharmaceutical formulation according to any one of claims 1 to 15, comprising mixing the components of the pharmaceutical formulation with each other.

Images