WO2022179490A1 - Compositions pharmaceutiques et leurs procédés de préparation - Google Patents

Compositions pharmaceutiques et leurs procédés de préparation Download PDF

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Publication number
WO2022179490A1
WO2022179490A1 PCT/CN2022/077228 CN2022077228W WO2022179490A1 WO 2022179490 A1 WO2022179490 A1 WO 2022179490A1 CN 2022077228 W CN2022077228 W CN 2022077228W WO 2022179490 A1 WO2022179490 A1 WO 2022179490A1
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Prior art keywords
pharmaceutical composition
aqueous solution
water
amount
solubilizer
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PCT/CN2022/077228
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English (en)
Inventor
Yanqiong LIN
Zhenzhong SHAO
Feng JI
Original Assignee
Ascentage Pharma (Suzhou) Co., Ltd.
Ascentage Pharma Group Corp Limited
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Publication date
Application filed by Ascentage Pharma (Suzhou) Co., Ltd., Ascentage Pharma Group Corp Limited filed Critical Ascentage Pharma (Suzhou) Co., Ltd.
Priority to CN202280013658.9A priority Critical patent/CN116963732A/zh
Publication of WO2022179490A1 publication Critical patent/WO2022179490A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to pharmaceutical compositions and preparation methods thereof.
  • the compound (5S, 5'S, 8S, 8'S, 10aR, 10a'R) -3, 3'- (1, 3-phenyldisulfonyl) bis ⁇ N-diphenylmethyl-5- [ (S) -2- (methylamino) propanamido] -6-oxydecahydropyrrole [1, 2-a] [1, 5] diazacyclicoctene-8-formamide ⁇ (hereafter referred to as compound 1) or its pharmaceutically acceptable salt thereof is an antagonist that can act as a small molecule inhibitor of apoptosis proteins (IAPS) with the following structural formula:
  • Compound 1 or its pharmaceutically acceptable salt which act as small molecule apoptosis inhibitory proteins (IAPS) antagonists, can block the activity and induce apoptosis of IAPs family proteins (XIAP, cIAP-1, cIAP-2 and ML-IAP) , can be used in the treatment of various cancers as well as hepatitis B (HBV) patients.
  • IAPS small molecule apoptosis inhibitory proteins
  • XIAP, cIAP-1, cIAP-2 and ML-IAP IAPs family proteins
  • HBV hepatitis B
  • the injection solution needs to have the following requirements: pH value nearly neutral, less injection volume, lower ionic concentration, suitable osmotic pressure, and so on.
  • the technical problem to be solved by the invention is that preparation of compound 1 or its pharmaceutically acceptable salt with good solubility and stability is not disclosed in the prior art.
  • the present invention provides a pharmaceutical composition and a preparation method thereof.
  • the pharmaceutical composition of the invention can be made into a preparation of compound 1 or its pharmaceutically acceptable salt with good solubility and stability.
  • the compound 1 dissolved poorly in alkaline and nearly neutral solutions, while its solubility improved under acidic conditions, but its solubility failed to meet the requirements when pH value was too low.
  • the hydrochloride salt of the compound 1 is highly soluble in water and acidic buffers, but the pH value of the solution is lower than the recommended pH range for subcutaneous administration and intramuscular administration, which may cause discomfort of patients; and the neutral pH buffer was adopted and the solubility was too low to meet the requirements.
  • the present invention solves the above technical problems by the following technical solutions.
  • the invention provides an aqueous solution comprising
  • the pH value of the aqueous solution is 5.0 ⁇ 8.0, preferably 6.0 ⁇ 7.5;
  • the excipients are bulking agents and/or solubilizers.
  • the pharmaceutically acceptable salt is preferably a hydrochloride salt, more preferably a dihydrochloride salt.
  • the water is one or more of deionized water, purified water and water for injection (e.g., sterile water for injection) .
  • the solubilizer is selected from one or more of cyclodextrin and its analogues, Cremophor EL, Solutol HS-15 and Tween 80, preferably cyclodextrin and its analogues, more preferably one or more of sulfobutylether- ⁇ -cyclodextrin, ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin, most preferably sulfobutylether- ⁇ -cyclodextrin.
  • the bulking agent can be selected from one or more of mannitol, glucan, polyethylene glycol and trehalose, preferably mannitol and/or trehalose.
  • the pH regulator can be a conventional pH regulator in the field to be able to adjust the pH value of the aqueous solution to 5.0 ⁇ 8.0 (preferably 6.0 ⁇ 7.5)
  • the pH regulator can be selected from one or more of hydroxide (e.g., sodium or potassium hydroxide) , phosphate (e.g., sodium phosphate, potassium phosphate or calcium phosphate) , dihydric phosphate (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate or calcium dihydrogen phosphate) , citrate (e.g., trisodium citrate dihydrate or potassium citrate) , carbonate (e.g., sodium carbonate or potassium carbonate) , bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate) , acetate (e.g., sodium acetate, potassium acetate or calcium acetate) , trometamol and hydrochloric acid, Preferably trometamol and hydrochloric acid, Preferably tromet
  • the amount of the active ingredient can be 0.1% ⁇ 2.2%of the total mass of the aqueous solution, preferably 0.5% ⁇ 1.2% (e.g., 0.5%or 0.7%) .
  • the solubilizer is preferably cyclodextrin and its analogue, preferably one or more of sulfobutylether- ⁇ -cyclodextrin, ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin, most preferably sulfobutylether- ⁇ -cyclodextrin;
  • the amount of the solubilizer can be 6% ⁇ 16%, preferably 7% ⁇ 10% (e.g., 7%or 8%) of the total mass of the aqueous solution.
  • the bulking agent is preferably mannitol and/or trehalose, and the amount of the bulking agent is 2% ⁇ 10%, preferably 3% ⁇ 5%of the total mass of the aqueous solution.
  • the solubilizer when the excipients are solubilizers and bulking agents, can be one or more of Cremophor EL, solutol HS-15 and Tween 80, and the solubilizer can be mannitol and/or trehalose;
  • the amount of excipient can be 2.1% ⁇ 20%of the total mass of the aqueous solution, preferably 3.5% ⁇ 10%;
  • the amount of the solubilizer can be 0.1% ⁇ 10%of the total mass of the aqueous solution, preferably 0.5% ⁇ 5% (e.g. 0.5%, 1%or 2%) ;
  • the amount of the bulking agent can be 2% ⁇ 10%, preferably 3% ⁇ 5%of the total mass of the aqueous solution of the pharmaceutical composition .
  • the concentration of the pH regulator in the aqueous solution can be 10mmol/L ⁇ 50mmol/L, preferably 10mmol/L ⁇ 25mmol/L.
  • the invention also provides an aqueous solution comprising only the active ingredient, the pH regulators, the excipients, and the water.
  • the aqueous solution comprises 0.7%compound 1, 7.4%sulfobutylether- ⁇ -cyclodextrin, 0.23%Tris-HCl and a residual amount of water, and the percentage is the mass percentage based on the total mass of an aqueous solution.
  • the aqueous solution comprises 0.5%compound 1, 8%sulfobutylether- ⁇ -cyclodextrin, Tris-HCl, and a residual amount of water used to adjust the pH of the aqueous solution to 6.0-7.5.
  • the aqueous solution comprises 0.7%of compound 1, 7%of sulfobutylether- ⁇ -cyclodextrin, Tris-HCl, and a residual amount of water used to adjust the pH of the aqueous solution to 6.0-7.5.
  • the aqueous solution comprises 0.7%of compound 1, 6%of sulfobutylether- ⁇ -cyclodextrin, Tris-HCl, and a residual amount of water used to adjust the pH of the aqueous solution to 6.0-7.5.
  • the invention also provides a preparation method for the aqueous solution comprising the following steps:
  • the pH is adjusted to 5.0 ⁇ 8.0 (preferably 6.0 ⁇ 7.5) , and a filtration step is preferably performed to get the aqueous solution.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Compound 1 of the following structural formula or its pharmaceutically acceptable salt as the active ingredient as the active ingredient, pH regulators, and solubilizers,
  • the pH value of the aqueous solution of the pharmaceutical composition is 5.0 ⁇ 8.0, preferably 6.0 ⁇ 7.5.
  • the pharmaceutically acceptable salt is preferably a hydrochloride salt, preferably a dihydrochloride salt.
  • the solubilizer can be cyclodextrin and its analogues, preferably one or more of sulfobutylether- ⁇ -cyclodextrin, ⁇ -cyclodextrin and 2-hydroxypropyl- ⁇ -cyclodextrin, more preferably sulfobutylether- ⁇ -cyclodextrin.
  • the pH regulator can be a conventional pH regulator in the field to be able to adjust the pH value of an aqueous solution to 5.0 ⁇ 8.0 (preferably 6.0 ⁇ 7.5)
  • the pH regulator can be selected from one or more of hydroxide (e.g., sodium or potassium hydroxide) , phosphate (e.g., sodium phosphate, potassium phosphate or calcium phosphate) , dihydric phosphate (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate or calcium dihydrogen phosphate) , citrate (e.g., trisodium citrate dihydrate or potassium citrate) , carbonate (e.g., sodium carbonate or potassium carbonate) , bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate) , acetate (e.g., sodium acetate, potassium acetate or calcium acetate) , trometamol and hydrochloric acid, preferably trometamol and hydrochloric acid.
  • hydroxide
  • the amount of the solubilizer can be 85% ⁇ 95%by weight of the total weight of the pharmaceutical composition, preferably 87% ⁇ 91% (e.g., 89%) .
  • the amount of the active ingredient is 1% ⁇ 10%by weight of the total weight of the pharmaceutical composition, preferably 6.0% ⁇ 10.0%, more preferably 8.3% ⁇ 8.8%.
  • the amount of the pH regulator is 1% ⁇ 5%, preferably 2% ⁇ 3%, more preferably 2.3% ⁇ 2.8%by weight of the total weight of the pharmaceutical composition.
  • the invention also provides a pharmaceutical composition comprising only the pH regulators, the excipients, and the active ingredient.
  • the pharmaceutical compositions comprising 8.3%Compound 1, 88.9% sulfobutylether- ⁇ -cyclodextrin, and 2.8%Tris-HCl, and the percentage is a mass percentage based on the total mass of the pharmaceutical composition.
  • the pharmaceutical composition may also further comprise water to form a pharmaceutical composition comprising water.
  • the water is preferably one or more of deionized water, purified water and water for injection (e.g., sterile water for injection) .
  • the invention also provides a pharmaceutical composition comprising only the pH regulators, the excipients, the active ingredient, and the water.
  • the amount of the active ingredient can be 0.1% ⁇ 2.2%, preferably 0.5% ⁇ 1.2% (e.g., 0.5%or 0.7%) of the total mass of the pharmaceutical composition comprising water.
  • the amount of the solubilizer is 6% ⁇ 16%, preferably 6% ⁇ 10% (e.g., 7% ⁇ 10%) of the total mass of the pharmaceutical compositions containing water.
  • the concentration of the pH regulator in the pharmaceutical composition comprising water can be 10mmol/L ⁇ 50mmol/L, preferably 10mmol/L ⁇ 25mmol/L.
  • the pharmaceutical composition can be lyophilized pharmaceutical composition.
  • the pharmaceutical composition can be a pharmaceutical composition comprising water, a lyophilized pharmaceutical composition or a lyophilized pharmaceutical composition redissolved in water, the water defined as above (pharmaceutical composition comprising water and redissolved pharmaceutical compositions are collectively referred to as aqueous solutions of pharmaceutical composition) .
  • the present invention provides a preparation method for a pharmaceutical composition comprising water comprising the following steps:
  • the pH value is adjusted to 5.0 ⁇ 8.0 (preferably 6.0 ⁇ 7.5) , and a filtration step is preferably performed to get a pharmaceutical composition comprising water.
  • the present invention provides a preparation method for a lyophilized pharmaceutical composition comprising the following steps: the pharmaceutical composition comprising water is freeze-dried to get the lyophilized pharmaceutical composition.
  • the present invention provides a preparation method for a redissolved pharmaceutical composition comprising the following steps: water is added to the lyophilized pharmaceutical composition to get the redissolved pharmaceutical composition.
  • aqueous solution, pharmaceutical compositions comprising water, and redissolved pharmaceutical composition of the present application preferably are administered by injection, and the injection methods include but are not limited to intravenous injection, subcutaneous injection, intramuscular injection, and so on.
  • multiple means two, three, or four.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • the pharmaceutical acceptable acid addition salts refer to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects.
  • the inorganic salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and so on;
  • the organic acids include but are not limited to formate, acetate, 2, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecaprenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate Palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutarate, aspartate, benzoate, methanesulfonate, benzenesulfonate,
  • the pharmaceutical acceptable base addition salts refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of free acids without other side effects.
  • the salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and so on.
  • the inorganic salts preferably are ammonium, sodium, potassium, calcium, and magnesium.
  • organic bases include but are not limited to the following: primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, n-ethylpiperidine, polyamine resins, and so on.
  • organic bases include isopropylamine, diethylamine, ethanolamine, tri
  • pharmaceutical composition means a preparation of the compound of the invention and a medium commonly accepted in the field for the delivery of bioactive compounds to mammals (e.g., humans) .
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the drug delivery of organisms and facilitate the absorption of the active ingredient to exert biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of a compound of the invention and that is relatively non-toxic.
  • the substance can be administered to an individual without causing adverse biological reactions or interacting in an undesirable manner with any of the constituents contained in the composition.
  • the positive improvement effect of the invention is that the invention provides a pharmaceutical composition and a preparation method thereof, and the pharmaceutical composition of the invention can be made into a preparation with good solubility and stability of compound 1 or its pharmaceutically acceptable salt. And some of the preparations in the invention still have good solubility and stability after lyophilization and redissolution. In addition, the aqueous solution of the pharmaceutical composition of the present invention has less discomfort and pain during injection.
  • the lyophilized powders were prepared using the prescription (content per vial) in Table 1 below, with the dosage of 1000 vials of cillin:
  • the specific preparation methods include confecting solution, adjusting solution pH, filtration, filling and freeze-drying, and the process is described as follows:
  • Step (I) the prescribed amount of 10 mmol/L Tris-HCl buffer (pH 7.1) was taken to add with the prescribed amount of compound 1 hydrochloride, and stir until the dissolution was completed.
  • Step (II) the prescribed amount of the sulfobutylether (SBE) - ⁇ -cyclodextrin was added to the above solution, and stir until the dissolution was completed. The pH value was measured. If necessary, the pH was adjusted to 6.0 ⁇ 7.5 with the Tris solution or HCl solution.
  • SBE sulfobutylether
  • the solution was filtered aseptically by a 0.45 ⁇ m filter membrane and a 0.22 ⁇ m filter membrane to get the intermediate-preparation solution.
  • the product was put into a freeze-drying oven for lyophilization.
  • composition 1 The preparation was carried out with the dosage of 1000 vials of cillin.
  • the lyophilized powder constituents obtained in each vial and their dosages are shown in Table 2 below (composition 1) :
  • the properties of the obtained lyophilized powder are as white as loose cake layer.
  • the specific preparation methods include confecting solution, adjusting solution pH, filtration, filling and freeze-drying, and the process was described as follows:
  • Step (I) the prescribed amount of 100 mmol/L HCl solution was taken to add with the prescribed amount of compound 1 and stir until the dissolution was completed.
  • Step (II) the prescribed amount of sulfobutylether (SBE) - ⁇ -cyclodextrin was added to the above solution, and stir until dissolved completely.
  • Step (III) the pH was adjusted to 6.0 ⁇ 7.5 with 1.0 mol/L aqueous solution of trometamol. The water was added to fill and stir well.
  • the solution was filtered aseptically by a filter membrane with a primary pore size of 0.45 ⁇ m and a filter membrane with a secondary pore size of 0.22 ⁇ m.
  • composition 2 The dosage of 1000 vials of cillin were used for preparation.
  • each vial weighs approximately 2 g
  • the properties of the injection product clear colorless transparent solution.
  • the effect experiment consisted of two parts, one was the solubility experiment and the other was the stability experiment.
  • the solution stability was greatly improved by the addition of sulfobutyl ether (SBE ) - ⁇ -cyclodextrin, and the solution stability was investigated by using 25mmol/L Tris-HC buffer system with ideal osmotic pressure and pH value. White substances were precipitated after standing for 3 ⁇ 6 days at high temperature (60°C) . Therefore, the injection has a high risk, so it was proposed to be designed as a lyophilized preparation, and the target concentration of the redissolved solution was 15mg/mL.
  • SBE sulfobutyl ether
  • the invention also investigated the use of different solubilizers, excipients and pH regulaters prescription, and the specific results are as follows.
  • the dosage of solubilizer was up-regulated, and the experimental method: the dosage was prepared in 25 vials of cillin, and the solution was prepared according to the prescription (content in each vial) in table 10. The products were tested after lyophilization.
  • the excipient was changed and the experimental method: the solution was prepared in 25 vials of cillin by prescription (content in each vial) as described in table11. The products were tested after lyophilization.
  • the intermediate-preparation solution prepared according to preparation example 1 was placed at 25°C. Tests were performed at 0, 2, 4, 6 and 24 hours, and the results were shown in Table 14.
  • Table 15 Stability of pharmaceutical compositions containing compound 1 in lyophilized powder form at elevated temperatures (40°C, batch 1)
  • Table 16 Stability of pharmaceutical compositions containing compound 1 in lyophilized powder form at elevated temperatures (40°C, batch 2)
  • Table 17 Stability of pharmaceutical compositions containing compound 1 in injection form at elevated temperatures (40°C)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique et son procédé de préparation. En particulier, l'invention concerne une composition pharmaceutique qui comprend le composé 1 représenté par la formule développée suivante ou son sel pharmaceutiquement acceptable en tant que principe actif, régulateurs de pH et solubilisants. La valeur de pH de la solution aqueuse de la composition pharmaceutique est de 5,0 à 8,0. Les compositions pharmaceutiques permettent aux formulations de présenter une bonne solubilité et une bonne stabilité du composé 1 ou de son sel pharmaceutiquement acceptable.
PCT/CN2022/077228 2021-02-23 2022-02-22 Compositions pharmaceutiques et leurs procédés de préparation WO2022179490A1 (fr)

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CN202280013658.9A CN116963732A (zh) 2021-02-23 2022-02-22 药物组合物及其制备方法

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CN202110223830.0 2021-02-23
CN202110223830 2021-02-23

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